Anemia of prematurity

Anemia of prematurity means that a baby born early (prematurely) does not have enough red blood cells. Red blood cells carry oxygen to the body. Preterm infants with birth weight <1.0 kg (commonly designated as extremely low birth weight or ELBW, infants) have completed ≤29 weeks of gestation, and nearly all will need red blood cell (RBC) transfusions during the first weeks of life. Every week in the United States, approximately 10,000 infants are born prematurely (ie, <37 weeks of gestation), with 600 (6%) of these preterm infants being extremely low birth weight ¹⁾. Approximately 90% of extremely low birth weight neonates will receive at least one red blood cell transfusion ²⁾.

All babies have some anemia (decrease in hemoglobin concentration) when they are born. In healthy term infants, the nadir hemoglobin value rarely falls below 10 g/dL at an age of 10 to 12 weeks ³⁾. This is normal and is called “physiological anemia of infancy”. For the term infant, a physiologic and usually asymptomatic anemia is observed 8-12 weeks after birth. But in premature babies, the number of red blood cells may decrease faster and go lower than in full-term babies. This may happen because:

• A premature baby may not make enough red blood cells.
• A premature baby may need tests that require blood samples. It may be hard for the baby to produce enough red blood cells to make up for the blood that’s taken out and used in the tests.
• A baby’s red blood cells don’t live as long as an older child’s red blood cells.

Anemia of prematurity is an exaggerated, pathologic response of the preterm infant to this transition. Anemia of prematurity is a normocytic, normochromic, hyporegenerative anemia characterized by a low serum erythropoietin (EPO) level, often despite a remarkably reduced hemoglobin concentration ⁴⁾. Nutritional deficiencies of iron, vitamin E, vitamin B-12, and folate may exaggerate the degree of anemia, as may blood loss and/or a reduced red cell life span.

The anemia of prematurity is caused by untimely birth occurring before placental iron transport and fetal erythropoiesis are complete, by phlebotomy blood losses taken for laboratory testing, by low plasma levels of erythropoietin due to both diminished production and accelerated catabolism, by rapid body growth and need for commensurate increase in red cell volume/mass, and by disorders causing red blood cell losses due to bleeding and/or hemolysis ⁵⁾.

The risk of anemia of prematurity is inversely related to gestational maturity and birthweight ⁶⁾. As many as half of infants of less than 32 weeks gestation develop anemia of prematurity. Anemia of prematurity is not typically a significant issue for infants born beyond 32 weeks’ gestation.

Race and sex have no influence on the incidence of anemia of prematurity.

Testosterone is believed to be at least partially responsible for a slightly higher hemoglobin level in male infants at birth, but this effect is of no significance with regard to risk of anemia of prematurity. The nadir of the hemoglobin level is typically observed 4-10 weeks after birth in the tiniest infants, with hemoglobin levels of 8-10 g/dL if birthweight was 1200-1400 grams, or 6-9 g/dL at birth weights of less than 1200 grams and to approximately 7 g/dL in infants with birth weights <1 kg ⁷⁾.

Anemia of prematurity is usually not serious. Anemia of prematurity spontaneously resolves in many premature infants within 3-6 months of birth ⁸⁾. In others, however, medical intervention is required, because the low oxygen levels in a premature infant can make other problems worse, such as heart and lung problems. Most infants with birth weight <1.0 kg are given multiple red blood cell (RBC) transfusions within the first few weeks of life ⁹⁾.

Red blood cell transfusions are the mainstay of therapy for anemia of prematurity with recombinant human erythropoietin (EPO) largely unused because it fails to substantially diminish red blood cell transfusion needs despite exerting substantial erythropoietic effects on neonatal marrow.

Anemia of prematurity causes

The three basic mechanisms for the development of anemia of prematurity include:

1. Inadequate red blood cell production,
2. Shortened red blood cell life span,
3. Blood loss.

Taken together, the premature infant is at risk for the development of anemia of prematurity because of limited red blood cell synthesis during rapid growth, a diminished red blood cell life span, and an increased loss of red blood cells.

Inadequate red blood cell production

The first mechanism of anemia is inadequate red blood cell production for the growing premature infant. The location of erythropoietin (EPO) and red blood cell production changes during gestation. Erythropoietin (EPO) synthesis initially occurs in the fetal liver but gradually shifts toward the kidney as gestation advances. By the end of gestation, however, the liver remains the major source of erythropoietin (EPO).

Fetal erythrocytes are produced in the yolk sac during the first few weeks of embryogenesis. The fetal liver becomes more important as gestation advances and, by the end of the first trimester, has become the primary site of erythropoiesis. Bone marrow then begins to take on a more active role in producing erythrocytes. By about 32 weeks’ gestation, the burden of erythrocyte production in the fetus is shared evenly by liver and bone marrow. By 40 weeks’ gestation, the marrow is the sole erythroid organ. Premature delivery does not accelerate the ontogeny of these processes.

Although erythropoietin (EPO) is not the only erythropoietic growth factor in the fetus, it is the most important. Erythropoietin (EPO) is synthesized in response to anemia and consequent relative tissue hypoxia. The degree of anemia and hypoxia required to stimulate erythropoietin (EPO) production is far greater for the fetal liver than for the fetal kidney. Erythropoietin (EPO) production may not be stimulated until a hemoglobin concentration of 6-7 g/dL is reached. As a result, new red blood cell production in the extremely premature infant, whose liver remains the major site of erythropoietin (EPO) production, is blunted despite what may be marked anemia. In addition, erythropoietin (EPO), whether endogenously produced or exogenously administered, has a larger volume of distribution and is more rapidly eliminated by neonates, resulting in a curtailed time for bone marrow stimulation.

Erythroid progenitors in premature infants are quite responsive to erythropoietin (EPO), but the response may be blunted if iron or other substrate or co-factor stores are insufficient. Another potential problem is that while the infant may respond appropriately to increased erythropoietin (EPO) concentrations with increased reticulocyte counts, rapid growth may prevent the appropriate increase in hemoglobin concentration.

Shortened red blood cell life span or hemolysis

Also important in the development of anemia of prematurity is that the average life span of a neonatal red blood cell is only one half to two thirds that of an adult red blood cell. Cells of the most immature infants may survive only 35-50 days. The shortened red blood cell life span of the neonate is a result of multiple factors, including diminished levels of intracellular adenosine triphosphate (ATP), carnitine, and enzyme activity; increased susceptibility to lipid peroxidation; and increased susceptibility of the cell membrane to fragmentation.

Blood loss

Finally, blood loss may contribute to the development of anemia of prematurity. If the neonate is held above the placenta for a time after delivery, fetal-placental transfer of blood may occur. Conversely, delayed cord clamping may lessen the degree of anemia of prematurity ¹⁰⁾, although a study by Elimian et al ¹¹⁾ did not find this to be true. More commonly, because of the need to closely monitor the tiny infant, frequent samples of blood are removed for various tests. These losses are often 5-10% of the total blood volume.

Anemia of prematurity differential diagnoses

Conditions to consider in the differential diagnosis of anemia of prematurity are those which diminish red cell production, increase red cell destruction, or cause blood loss.

• Acute Anemia
• Birth Trauma
• Chronic Anemia
• Head Trauma
• Hemolytic Disease of the Newborn
• Parvovirus B19 Infection
• Intraventricular Hemorrhage in the Preterm Infant

Conditions that diminish red blood cell synthesis are as follows:

• Bone marrow infiltration
• Bone marrow depression (eg, pancytopenia, drugs)
• Diamond-Blackfan anemia
• Substrate deficiencies (eg, iron, vitamin E, folic acid)
• Congenital fetal infections (eg, cytomegalovirus, parvovirus, syphilis)

Conditions that cause hemolysis are as follows:

• Congenital fetal infections (eg, cytomegalovirus, parvovirus, syphilis)
• Acute systemic infections (leading to disseminated intravascular coagulation)
• Abnormal red blood cells (spherocytosis, elliptocytosis)
• Nonspherocytic hemolytic anemias (eg, G6PD deficiency, kinase and isomerase deficiencies)
• Hemolytic disease of the newborn (Rh, ABO, other major blood-group incompatibilities between mother and fetus)

Conditions that reduce blood volume are as follows:

• Twin-to-twin transfusion syndrome (donor twin)
• Iatrogenic (eg, excessive blood sampling)
• Hemorrhage (eg, gastrointestinal, central nervous system, subcutaneous tissues)

Anemia of prematurity symptoms

Many clinical findings have been attributed to anemia of prematurity, but they are neither specific nor diagnostic. These symptoms may include the following:

• Poor weight gain despite adequate caloric intake
• Cardiorespiratory symptoms such as tachycardia, tachypnea, and flow murmurs
• Decreased activity, lethargy, and difficulty with oral feeding
• Pallor
• Increase in apneic and bradycardic episodes, and worsened periodic breathing
• Metabolic acidemia – Increased lactic acid secondary to increased cellular anaerobic metabolism in relatively hypoxic tissues

Anemia of prematurity diagnosis

The following are useful laboratory studies:

• Complete blood count (CBC) – White blood cell (WBC) and platelet values are normal in anemia of prematurity. Low hemoglobin values, below 10 g/dL, are found. They may descend to a nadir of 6-7 g/dL. Lowest levels are generally observed in the smallest infants. Red blood cell indices are normal (eg, normochromic, normocytic) for age.
• Reticulocyte count – The reticulocyte count is low when the degree of anemia is considered, as a result of the low levels of erythropoietin (EPO). Conversely, an elevated reticulocyte count is not consistent with the diagnosis of anemia of prematurity.
• Peripheral blood smear – Red blood cell morphology should be normal. Red blood cell precursors may appear to be more prominent.
• Maternal and infant blood typing; direct antibody test (Coombs) – The direct Coombs test result may be coincidentally positive. Despite this, it is important to ensure an immune-mediated hemolytic process related to maternal-fetal blood group incompatibility (hemolytic disease of the newborn) is not present.
• Serum bilirubin – An elevated serum bilirubin level should suggest other possible explanations for the anemia. These would include hemolytic entities, such as G-6-PD deficiency or other kinase/isomerase/enzyme deficiencies, or more common causes such as infection or hemolytic disease of the newborn.
• Lactic acid – Elevated lactic acid levels have been suggested by some to be useful as an aid to determine the need for transfusion.

Anemia of prematurity treatment

Medical treatment options are blood transfusion(s), recombinant erythropoietin (EPO) treatment, and observation.

Observation may be the best course of action for infants who are asymptomatic, not acutely ill, and are receiving adequate nutrition. Adequate amounts of vitamin E, vitamin B-12, folate, and iron are important to blunt the expected decline in hemoglobin levels in the premature infant. Periodic measurements of the hematocrit level in infants with anemia of prematurity are necessary after hospital discharge. Once a steady increase in the hematocrit level has been established, only routine checks are required.

Packed red blood cell transfusions

Packed red blood cell transfusions are the mainstay of therapy for anemia of prematurity. The frequency of blood transfusion varies with gestational age, degree of illness, and, interestingly, the hospital evaluated. Unfortunately, there is considerable disagreement about the indication, timing, and efficacy of packed red blood cell transfusion.

Guidelines for transfusing red blood cells to preterm neonates are controversial, and practices vary greatly ¹²⁾. This lack of a universal approach stems from limited knowledge of the cellular and molecular biology of erythropoiesis during the perinatal period, an incomplete understanding of infant physiological/adaptive responses to anemia, and contrary/controversial transfusion practice guidelines as based on results of randomized clinical trials and expert opinions. Generally, red blood cell transfusions are given to maintain a level of blood hemoglobin or hematocrit believed to be optimal for each neonate’s clinical condition. Guidelines for red blood cell transfusions, judged to be reasonable by most neonatologists to treat the anaemia of prematurity, are listed by Table 1. These guidelines are very general, and it is important that terms such as “severe” and “symptomatic” be defined to fit local transfusion practices/policies. Importantly, guidelines are not mandates for red blood cell transfusions that must be followed; they simply suggest situations when an red blood cell transfusion would be judged to be reasonable/acceptable.

The decision to give a transfusion should not be made lightly, because significant infectious, hematologic, immunologic, and metabolic complications are possible. Late-onset necrotizing enterocolitis has been reported in stable-growing premature infants electively transfused for anemia of prematurity ¹³⁾. Transfusions also transiently decrease erythropoiesis and EPO levels. There is also agreement that the number of transfusions, as well as the number of donor exposures, should be reduced as much as possible.

Clinical trials designed to determine the efficacy of blood transfusions in relieving symptoms ascribed to anemia of prematurity have produced conflicting results ¹⁴⁾. Improved growth has been an inconsistent finding. While some studies have demonstrated a decrease in apneic episodes after blood transfusion, others have found similar results with simple crystalloid volume expansion.

Subjective improvement in activity, decreased lethargy, and improved feeding have been described in some studies. Blood transfusions have been documented to decrease lactic acid levels in otherwise healthy preterm infants who are anemic. Blood transfusions have reduced tachycardia in anemic infants who are transfused.

Some medical professionals have suggested using lactate levels as an aid in determining the need for transfusion.

Table 1. Allogeneic red blood cell transfusions for the anemia of prematurity

Transfuse to maintain the blood hematocrit per each clinical situation:

• > 40% (35 to 45% ^*) for severe cardiopulmonary disease
• > 30% for moderate cardiopulmonary disease
• > 30% for major surgery
• >25% (20 to 25% ^*) for symptomatic anemia
• > 20% for asymptomatic anemia

*Reflects practices that vary among neonatologists. Thus, any value within range is acceptable for local practices.

Reducing the number of transfusions

Studies from individual centers have documented a marked decrease in the administration of packed red blood cell transfusions in the past decades, even before the use of EPO became more frequent. This decrease in transfusions is almost certainly multifactorial in origin. Adoption of standardized transfusion protocols that take various factors into account, including hemoglobin levels, degree of cardiorespiratory disease, and traditional signs and symptoms of pathologic anemia, are acknowledged as an important factor in this reduction. A restricted transfusion protocol may decrease the number of transfusions while also decreasing the hematocrit at discharge ¹⁵⁾.

A 2011 study ¹⁶⁾ evaluated 41 preterm infants with birth weights of 500-1300 g who were enrolled in a clinical trial that compared high and low hematocrit thresholds for transfusion. A rise in systemic oxygen transport and a decrease in lactic acid after transfusion was noted in both groups; however, oxygen consumption did not change significantly in either group. In the low hematocrit group only, cardiac output and fractional oxygen extraction fell after transfusion, which shows that these infants had increased their cardiac output to maintain adequate tissue oxygen delivery in response to anemia. The results demonstrate that infants with low hematocrit thresholds may benefit from transfusion, while transfusion in those with high hematocrit thresholds may provide no acute physiological benefit ¹⁷⁾.

The Premature Infant in Need of Transfusion study ¹⁸⁾ showed that transfusing infants to maintain higher hemoglobin level (8.5-13.5 g/dL) conferred no benefit in terms of mortality, severe morbidity, or apnea intervention compared with infants transfused to maintain a low hemoglobin levels (7.5-11.5 g/dL).

These findings differ from the Iowa study, which found less parenchymal brain hemorrhage, periventricular leukomalacia, and apnea in infants whose transfusion criteria was not restricted and whose hemoglobin level was higher. Clearly, no universally accepted guidelines for transfusion in infants with anemia of prematurity are available at this time, and clinicians must determine their individual standardized transfusion practices.

Anemia of prematurity guidelines

No universally accepted guidelines for transfusion in infants with anemia of prematurity are available at this time, and clinicians must determine their individual standardized transfusion practices.

As an example, note the Children’s Hospital of Wisconsin Transfusion Committee guidelines for consideration:

• An infant with a hemoglobin (Hb) level of less than 8 g/dL may be transfused at the discretion of the attending physician
• A stable infant with a hemoglobin level of 8-10 g/dL without clinical symptoms or other exceptions listed below may be transfused
• An infant with a hemoglobin level of 11-13 g/dL without a supplemental oxygen or continuous positive airway pressure (CPAP) requirement, apnea/bradycardia, significant tachycardia or tachypnea, or other exceptions listed below should not be transfused
• An infant with a hemoglobin level of more than 13 g/dL without an oxygen requirement of more than 40% by hood, CPAP, or ventilator; hypotension that requires pressor medication; major surgery; or other exceptions listed below should not be transfused
• An infant with a hemoglobin level of more than 15 g/dL without cyanotic heart disease, extracorporeal membrane oxygenation (ECMO) therapy, regional oxygen saturations less than 50%, or hypotension that requires pressor medications should not be transfused
• An infant with a history of massive blood loss may be transfused at the discretion of the attending physician

It is of obvious importance to discuss with the family their child’s need for transfusion and to obtain consent before the transfusion. It is also important to discuss with parents the normal course of anemia, the criteria for and risks associated with transfusions, and the advantages and disadvantages of erythropoietin (EPO) administration. Also necessary is consideration of the family’s religious beliefs regarding transfusions.

Reducing the number of donor exposures

Reducing the number of donor exposures is also important. Preservatives and additive systems allow blood to be stored safely for as long as 35-42 days. This can be accomplished by using packed red blood cells stored in preservatives (eg, citrate-phosphate-dextrose-adenine [CPDA-1]) and additive systems (eg, Adsol). Infants may be assigned a specific unit of blood, which may suffice for treatment during their entire hospitalization and thus limit exposure to the single donor of that unit. Concerns that stored blood might increase serum potassium levels are unfounded if the transfused volume is low.

Complications

Potential complications of transfusion include the following:

• Infection (eg, hepatitis, cytomegalovirus [CMV], human immunodeficiency virus [HIV], syphilis)
• Fluid overload and electrolyte imbalances
• Exposure to plasticizers
• Hemolysis
• Posttransfusion graft versus host disease

An important tool in reducing at least one of these transfusion risks is to use all available screening techniques for infection. The risk of cytomegalovirus (CMV) transmission can be dramatically reduced by use of CMV-safe blood. This can be accomplished by using CMV serology–negative cells, along with blood processed through leukocyte-reduction filters or inverted spin technique. These methods also reduce other WBC-associated infectious agents (eg, Epstein-Barr virus, retroviruses, Yersinia enterocolitica) by yielding a leukocyte-poor suspension of packed red blood cells. The American Red Cross now provides exclusively leukocyte-reduced blood to hospitals in the United States.

Recombinant Erythropoietin treatment

Multiple investigations have established that premature infants respond to exogenously administered recombinant human EPO and supplemental iron with a brisk reticulocytosis. Subcutaneous administration of EPO may be preferred, as intravenous administration has increased urinary losses. Although EPO cannot prevent early transfusions, modest decreases in the frequency of late packed red blood cell transfusions have been documented. Additional iron supplementation is necessary during exogenous EPO treatment.

Trials have evaluated the impact of EPO treatment in populations of the most immature neonates. These studies likewise have demonstrated that infants with very low birth weight (VLBW) are capable of responding to EPO with a reticulocytosis.

Studies and a Cochrane Neonatal Systemic review suggest an association between exogenous EPO administration and retinopathy of prematurity ¹⁹⁾.

Yasmeen et al ²⁰⁾ studied 60 preterm low birth weight infants and concluded that short-term recombinant human erythropoietin with iron and folic acid was effective in preventing anemia of prematurity.

EPO with iron does not adversely affect growth or developmental outcomes, but the impact on the number of transfusions a premature infant receives ranges from nonexistent to small.

At this time, no agreement regarding the safety, timing, dosing, route, or duration of therapy has been established. In short, the cost-benefit ratio for EPO has yet to be clearly established, and this medication is not universally accepted as a standard therapy for an infant with anemia of prematurity.

Anemia of prematurity prognosis

Spontaneous recovery of mild anemia of prematurity may occur 3-6 months after birth. In more severe, symptomatic cases, medical intervention may be required.

Chromhidrosis

Chromhidrosis is a rare condition characterized by the secretion of colored sweat ¹⁾. Two glands produce sweat: eccrine and apocrine glands. Eccrine glands secrete a clear, odorless fluid that serves to regulate body temperature. Apocrine glands secrete a thick, milky sweat that, once broken down by bacteria, is the main cause of body odor. Normally, apocrine glands secrete scant amounts of odorless, oily fluid into the hair canal that, upon reaching the skin surface, is degraded by bacteria producing a pheromonal body odor ²⁾.

Chromhidrosis can subdivide into three categories ³⁾:

1. Apocrine chromhidrosis: Apocrine chromhidrosis occurs in the areas where apocrine glands are present and are mostly limited to the anogenital and axillary areas, eyelids, ears, scalp, trunk, and areola. Although apocrine glands are found in the genital, axillary, areolar, and facial skin, chromhidrosis is reported only on the face ⁴⁾, armpis ⁵⁾ and breast areola ⁶⁾. Lipofuscin pigment is responsible for the colored sweat. This pigment is produced in the apocrine gland, and its various oxidative states account for the characteristic yellow, green, blue, or black secretions observed in apocrine chromhidrosis.
2. Eccrine chromhidrosis: Eccrine chromhidrosis is rare and occurs with ingestion of certain dyes or drugs. Eccrine chromhidrosis may occur almost anywhere on the body as eccrine glands are distributed with varying density throughout the skin except for the ear canal, lips, prepuce, glans penis, clitoris, and labia minora. Eccrine glands are smaller than apocrine glands, secrete a dilute salty sweat composed mainly of water and electrolytes directly onto the skin surface, and are innervated by the sympathetic nervous system. They are irregularly spaced on the epidermal ridges of the pads of the digits; however, there are no pores within the furrows. They are involved in thermoregulation, protection of the skin barrier, and excretion of electrolytes ⁷⁾.
3. Pseudochromhidrosis (pseudo-eccrine chromhidrosis): Pseudochromhidrosis results from the interaction of colorless eccrine sweat with extrinsic dyes, paints, or chromogenic bacteria, subsequently producing a colored sweat ⁸⁾.

The yellow, green, and blue apocrine secretions produce a yellow fluorescence under a Wood lamp (UV 360 nm), whereas the dark brown and black apocrine secretions seldom autofluoresce. Substance P is also postulated to be an important neurotransmitter in this process.

Several extrinsic causes of eccrine chromhidrosis and pseudochromhidrosis include chromogenic bacteria, especially Corynebacterium species, fungi, dyes, drugs, and chemical contactants ⁹⁾.

Apocrine chromhidrosis may appear at any age but usually appears after puberty, when the apocrine secretory function begins. The disease is considered chronic, however, may regress with age as apocrine secretion diminishes ¹⁰⁾. Apocrine chromhidrosis displays no occupational or geographical predisposition and is not influenced by climatic or seasonal variation ¹¹⁾. There is no gender predilection, but chromhidrosis has been reported in the literature more commonly in blacks, barring facial chromhidrosis, which has been reported more commonly in whites ¹²⁾. However, there are too few patients reported to draw meaningful conclusions ¹³⁾.

Approximately 10% of people without chromhidrosis have colored sweat that is regarded as acceptable and within the normal range ¹⁴⁾.

Figure 1. Sweat glands

Figure 2. Skin anatomy

Chromhidrosis causes

The increased numbers of lipofuscin pigments in the secretory apocrine cells are presumed to be the cause of apocrine chromhidrosis. Lipofuscin is a yellowish brown pigment that is normally found in the cytoplasm of various organs like the relatively nondividing cells (eg, neurons) and is not specific to apocrine glands ¹⁵⁾. In chromhidrosis, lipofuscins are found in a higher-than-normal concentration or a higher-than-normal state of oxidation in apocrine glands ¹⁶⁾. However, why some glands experience these changes is unclear. This increased level of oxidation results in the green, blue, and even black sweat seen in chromhidrosis.

Apocrine chromhidrosis is considered an intrinsic process ¹⁷⁾. The greater the extent of lipofuscin oxidation, the darker the lipofuscin color, which can range from yellow, green, blue, black, or brown ¹⁸⁾. Apocrine glands are provoked by hot showers and baths, rubbing of the skin, and emotional stimuli such as pain, sexual arousal, or anxiety, which leads to the secretion of colored sweat in the case of apocrine chromhidrosis ¹⁹⁾. Substance P may also play a role in the pathogenesis, which is why capsaicin has shown to be an effective treatment in some patients ²⁰⁾.

Eccrine chromhidrosis is most often caused exogenously by the coloring of clear sweat with the ingestion of water-soluble dyes such as tartrazine, heavy metals such as copper, coloring and flavoring substances in food products, and drugs such as quinines, levodopa, tartrazine-coated bisacodyl, and rifampin ²¹⁾. It is caused endogenously secondarily to hyperbilirubinemia in which patients may present with a greenish hue in a palmoplantar distribution with or without pompholyx-like lesions ²²⁾.

Pseudochromhidrosis is an extrinsic process that occurs when the colorless sweat from eccrine glands subsequently develops color following exposure to exogenous influences like drugs on the surface of the skin that cause changes in the microflora on the skin surface ²³⁾. Chromogenic bacteria such as Serratia marcescens, Bacillus species, and Corynebacterium species are the most common causes. Fungi, including Malassezia furfur, dyes, paints, and chemical agents such as dihydroxyacetone, have also been implicated ²⁴⁾.

Chromhidrosis symptoms

Patients with chromhidrosis will present with colored sweat, with or without staining of their clothing. Some patients may describe warmth or a prickly sensation upon emotional or physical stress preceding the appearance of colored sweat ²⁵⁾.

While there are no complications directly associated with chromhidrosis, there may be implications secondary to psycho-social issues ²⁶⁾.

Chromhidrosis diagnosis

The initial assessment should include a detailed history, including any new medications, started before the onset of chromhidrosis, including vitamins, supplements, and herbal medications ²⁷⁾.

While chromhidrosis is a clinical diagnosis, further studies may be needed to ascertain the type and cause of chromhidrosis if not apparent from the history and physical examination. A Wood’s lamp will fluoresce green, blue, and yellow apocrine gland secretions yellow, while black and dark brown secretions usually do not fluoresce. Skin biopsies can be sent for hematoxylin/eosin staining and fluorescence microscopy to detect and measure lipofuscins within apocrine glands ²⁸⁾.

Cytological examination of secretion smears may aid in detecting lipofuscin pigment within apocrine gland cells. Spectrophotometer analysis of samples from sweat, sebum, urine, skin scrapings, and extraction samples from clothing can help to aid in the diagnosis ²⁹⁾. Bacterial and fungal cultures of the skin may be an option to rule out pseudochromhidrosis ³⁰⁾. Other studies may be necessary to rule out other causes of pigmentation and include complete blood cell counts to rule out a bleeding diathesis and urinary homogentisic acid level to exclude alkaptonuria ³¹⁾.

Chromhidrosis treatment

After a thorough assessment to establish the type of chromhidrosis and causality, therapy may be initiated to target the source. Apocrine chromhidrosis has no fully satisfactory cure or treatment. The treatment of apocrine chromhidrosis aims at either inducing apocrine secretion, thereby emptying the glands resulting in a temporary symptom-free period for up to 3 days, or reducing perspiration. Manual pressure can express apocrine gland contents resulting in an improved appearance for 24 to 72 hours ³²⁾. Capsaicin, applied once or twice daily, depletes the neurons of substance P and can improve the appearance in some patients ³³⁾. Burning sensation at the application site is a common side effect of capsaicin. Topical aluminum chloride and injections of botulinum toxin type A have also reportedly shown benefit in patients ³⁴⁾. The condition usually recurs after cessation of therapy ³⁵⁾.

BOTOX® injections have been attempted in 5 cases of chromhidrosis, with mixed results. BOTOX® is predominantly used to decrease eccrine sweat in persons with hyperhidrosis. However, recent reports demonstrated improvement of facial and axillary chromhidrosis with BOTOX® ³⁶⁾. The mechanism by which BOTOX® suppresses apocrine chromhidrosis is unclear. BOTOX® may suppress apocrine secretion by blocking cholinergic stimulation and substance P release ³⁷⁾.

The treatment of eccrine chromhidrosis revolves around stopping or replacing the causative agent ³⁸⁾.

In cases of pseudochromhidrosis, topical or systemic antimicrobials are often used to eradicate the offending microorganism. Of note, medications may have implications in altering the normal flora, allowing for chromogenic organisms to take their place ³⁹⁾. Discontinuation of these medications should be a consideration in such situations.

Chromhidrosis prognosis

Chromhidrosis is a benign chronic condition that may regress with time. The prognosis for chromhidrosis is good if an extrinsic cause can be identified and addressed appropriately. However, it may lead to significant anxiety, depression, or embarrassment requiring frequent clothing changes during the day ⁴⁰⁾.

Stahl’s ear

Stahl’s ear deformity consists of an extra cartilage fold in the middle (scapha) portion of the ear. This results in a pointy ear shape. Stahl’s ear is a defect that babies are born with.

If Stahl’s ear is treated very early in life (first 8 weeks of life), it can be corrected with the use of a mold that the patient wears for a couple of months. In older children, molding is not as effective. Surgical correction of a Stahl’s ear deformity is then required. This is typically performed when the child is around 7-10 years old.

Figure 1. Stahl’s ear deformity (before and after ear moulding)

Stahl’s ear cause

Stahl’s ear is caused by misshapen cartilage. But the exact reason that this occurs is unclear. Stahl’s ear is characterized by an extra horizontal fold of cartilage (crus). Normally, there are two: superior and inferior. In Stahl’s ear, there is a third horizontal crus. The helix (or upper portion of the ear) may uncurl, giving the ear a pointed shape.

What are the symptoms of Stahl’s ear?

Other than the physical appearance of the ear, there are no other symptoms associated with Stahl’s ear. Affected children usually have normal hearing.

Stahl’s ear treatment

If Stahl’s ear is discovered in the first few weeks to months after birth, ear molding may correct this deformity and avoid the need for surgery. Infants’ ears are still soft and flexible, which makes them responsive to molding. Like many other conditions in which ear molding is useful (such as cryptotia, constricted ears and protruding ears), the earlier the intervention, the shorter the treatment. Early treatment also often leads to better outcomes.

In older children, surgical correction is necessary to correct the deformity. Surgery to correct Stahl’s ear involves reshaping, repositioning and suturing the abnormal cartilage to reverse the pointed shape of the ear. Although a general anesthetic is needed, the operation is done on an outpatient basis and your child will be able to return home the same day.

Sacrococcygeal teratoma

Sacrococcygeal teratoma also called fetal sacrococcygeal teratoma, is a non-cancerous (benign) tumor that develops before birth and grows from a baby’s tailbone (coccyx). Sacrococcygeal teratoma is the most common common congenital germ cell tumor found in newborns, occurring in 1 out of every 35,000 to 40,000 live births ¹⁾. This birth defect is more common in female than in male babies (female to male ratio 3:1-4:1) ²⁾. Although these tumors can grow very large, they are usually not malignant (that is, cancerous), they may grow quite large and once diagnosed, always require surgical removal.

It is likely that all sacrococcygeal teratomas are present at birth (congenital) and most are discovered before birth by a routine prenatal ultrasound examination or an exam indicated for a uterus too large for dates. In rare cases, sacrococcygeal teratomas may be cancerous (malignant) at birth and many will become malignant if surgical resection is not performed. In extremely rare cases, sacrococcygeal tumors may be seen in adults. Most of these represent slow growing tumors that originated prenatally. In the majority of these cases, the tumor is benign, but may cause lower back pain and genitourinary and gastrointestinal symptoms. The cause of sacrococcygeal teratomas is unknown.

Sacrococcygeal teratomas are the most common solid tumor found in newborn babies (neonates). Sacrococcygeal teratomas affecting adults is extremely rare. Adults cases often represent tumors that were present at birth (congenital), but not detected until adulthood.

Sacrococcygeal teratoma tumor is usually covered with skin, but may be covered by a thin, transparent tissue called a membrane. Most tumors have many blood vessels coming through them. They come in many different sizes, and sometimes they may grow outward from the back or toward your child’s stomach.

Sacrococcygeal teratoma is usually discovered either because a blood test performed on the mother at 16 weeks shows a high alpha fetoprotein (AFP) amount, or because a sonogram is performed because the uterus is larger than it should be. The increased size of the uterus is often caused by extra amniotic fluid, called polyhydramnios. The diagnosis of sacrococcygeal teratoma can be made by an ultrasound examination.

When a prenatally diagnosed sacrococcygeal teratoma is associated with fetal hydrops, the tumor can become life-threatening to both mother and baby.

In severe cases, the tumor “steals” blood from fetal circulation, causing the heart to work extra hard and making cardiac failure possible. Cardiac failure exhibits as fetal hydrops, a massive accumulation of fluid in the body of the fetus. In our experience, fetal hydrops associated with sacrococcygeal teratoma is rapidly progressive and nearly always fatal.

For the mother, there is the risk of “maternal mirror syndrome” in which the mom’s condition parallels that of the sick fetus. When fetal hydrops is present, the mother may “mirror” the sick fetus, becoming ill with signs of preeclampsia. Preeclampsia, also called toxemia, is a condition characterized by pregnancy-induced high blood pressure, protein in the urine, and swelling due to fluid retention.

Sacrococcygeal teratoma can usually be cured by surgery after birth, but occasionally cause trouble before birth.

Patients in whom sacrococcygeal teratoma is diagnosed postnatally typically do well after early surgical resection, and the main cause of mortality in these patients (though rare) is attributed to malignancy. However, mortality associated with antenatally diagnosed sacrococcygeal teratoma is in the range of 30-50% ³⁾ and is attributed to tumor morphology and vascularity. Whereas some fetuses are born without complications, others can develop high-output cardiac failure, nonimmune hydrops fetalis and, ultimately, fetal demise.

This wide disease spectrum has prompted several fetal treatment centers to identify ultrasound predictors of survival for fetuses with sacrococcygeal teratoma to help identify high-risk fetuses who may benefit from fetal intervention. The key to optimizing survival in these fetuses is intervention before the development of high-output cardiac failure, hydrops, and maternal mirror syndrome. Identifying fetuses at risk for hydrops and fetal demise isolates those who may be salvaged by reversing the pathophysiology—the premise behind fetal intervention ⁴⁾.

Figure 1. Sacrococcygeal teratoma types

How serious is my baby’s sacrococcygeal teratoma?

In order to determine the severity of your fetus’s condition it is important to gather information from a variety of tests and determine if there are any additional problems. These tests along with expert guidance are important for you to make the best decision about the proper treatment.

This includes:

• The type of defect—distinguishing it from other similar appearing problems.
• The severity of the defect—is your fetus’s defect mild or severe.
• Associated defects—is there another problem or a cluster of problems (syndrome).

The severity of sacrococcygeal teratoma is directly related to the size of the tumor and the amount of blood flow to the tumor. Both the size and the blood flow can now be accurately assessed by sonography and echocardiography. Small or medium-sized tumors without excessive blood flow will not cause a problem for the fetus. These babies should be followed with serial ultrasounds to make sure the tumor does not enlarge or the blood flow does not increase. They can be then delivered vaginally near term, and the tumor removed after birth.

Very large tumors are prone to develop excessive blood flow, which causes heart failure in the fetus. Fortunately, this is easy to detect by ultrasound. These babies need to be closely followed for the development of excess fluid in the abdomen (ascites), in the chest (pleural effusion), around the heart (pericardial effusion), or under the skin (skin edema). It is the extra blood flowing to the tumor that strains the fetal heart enough to cause heart failure (hydrops).

What is maternal mirror syndrome?

In cases with extreme fetal hydrops, the mother may be at risk for maternal mirror syndrome, which is a condition where the mother’s condition mimics that of the sick fetus. Because of a hyperdynamic cardiovascular state, the mother develops symptoms that are similar to pre-eclampsia and may include vomiting, hypertension, peripheral edema (swelling of the hands and feet), proteinuria (protein in the urine), and pulmonary edema (fluid in the lungs). Despite resection of the fetal sacrococcygeal teratoma, maternal mirror syndrome may still occur.

What are my choices during pregnancy?

Most newborns with sacrococcygeal teratoma survive and do well. Malignant tumors are unusual. Fetuses with large cystic sacrococcygeal teratomas rarely develop hydrops and therefore are not usually candidates for fetal intervention/surgery. These cases are best handled with surgical removal of the tumor after delivery. A Cesarean-section (C-section) delivery of the baby may be necessary if the tumor is larger than 10 cm (4 inches).

Because all sacrococcygeal teratomas require complete surgical resection after birth, arrangements should be made for the infant to be born at a specialized hospital with pediatric surgery expertise. Fetuses with large mostly solid tumors need to be monitored frequently between 18 and 28 weeks of gestation for rapid growth of the tumor and the development of excessive blood flow and heart failure (hydrops). A small number of these fetuses with large solid tumors develop hydrops, due to extremely high blood flow through the tumor. These fetuses may be candidates for fetal intervention.

Fetal intervention

Fetal intervention is only offered to women in whom there is evidence of heart failure in the fetus. Women who have fetuses with advanced hydrops, placentomegaly or maternal pre-eclampsia (high blood pressure, protein in the urine) are not candidates for fetal intervention as we have found that these symptoms (the so-called “mirror syndrome”) indicate an irreversible situation.

If hydrops develops after the 32nd week of pregnancy, the fetus may be delivered for intensive management after birth. Before 32 weeks gestation, fetal intervention may be advised to reverse the otherwise fatal heart failure.

Two approaches towards fetal intervention are possible for fetuses with hydrops: minimally invasive surgery and open fetal surgery. Minimally invasive fetal surgery involves inserting a needle through the mother’s abdomen and uterine wall and into the blood vessels that feed the tumor. Radiofrequency waves are used to destroy the blood vessels and, without blood flow, the tumor does not grow and heart failure (hydrops) is reversed. However, damage caused by the probe itself may be difficult to control. Another method of cutting off blood flow to the tumor is injection of drugs (for example, alcohol) that cause blood to clot. None of these methods has so far proven effective in all cases.

Open fetal surgery is an alternative option and has proven successful in a number of cases. In this case, the mother’s uterus is opened under general anesthesia and the fetus’s sacrococcygeal teratoma is surgically removed.

What will happen after birth?

All babies with sacrococcygeal teratoma should be delivered at a specialized hospital with pediatric surgery expertise. Tumors larger than 10 cm in diameter will require C-section delivery. The neonatologist will provide support in the intensive care nursery until the baby is stable enough for surgery. Surgical removal of small tumors is straightforward, but removal of large tumors can be very difficult and dangerous. The baby may require a blood transfusion(s) and intensive support for days or weeks after surgery. Most will get through this difficult period and enjoy a normal life. All babies should have yearly blood tests for elevated alpha feto-protein (AFP), which can signal recurrence of the tumor and possibly a malignancy. If the tumor is quite large and the surgeon performs an extensive complicated removal, there is an increased likelihood of long-term issues. A few babies may have difficulty with urination or stooling.

Sacrococcygeal teratoma types

Sacrococcygeal teratomas are categorized according to the classification developed by the American Academy of Pediatrics, Surgical Section ⁵⁾.

Sacrococcygeal teratoma tumors are categorized according to their location and severity:

• Type 1 sacrococcygeal teratomas are external (outside the body) tumors and are attached to the tailbone.
• Type 2 sacrococcygeal teratomas have both internal (inside the body) and external parts.
• Type 3 sacrococcygeal teratomas can be seen from the outside, but most of the tumor is inside your child’s abdomen.
• Type 4 sacrococcygeal teratomas, the most serious tumors, can’t been seen from the outside. They are inside the body at the tailbone level. Type 4 has the highest rate of malignancy.

Whereas type 1 tumors, being primarily external to the fetus, are easily diagnosed prenatally and are amenable to fetal resection, type 4 tumors can be difficult to diagnose and are not amenable to fetal resection ⁶⁾. The American Academy of Pediatrics, Surgical Section classification describes surgical anatomy and identifies tumors that are amenable to fetal resection, but it does not provide prognostic information, nor does it identify fetuses who would benefit from fetal intervention ⁷⁾.

Sacrococcygeal teratoma cause

The cause of sacrococcygeal teratomas is unknown. Sacrococcygeal teratomas are germ cell tumors. Germ cells are the cells that develop into the embryo and later on become the cells that make up the reproductive system of men and women. Most germ cell tumors occur in the testes or ovaries (gonads) or the lower back. When these tumors occur outside of the gonads, they are known as extragonadal tumors. Researchers do not know how extragonadal germ cell tumors form. One theory suggests that germ cells accidentally migrate during to unusual locations early during the development of the embryo (embryogenesis). Normally, such misplaced germ cells degenerate and die, but in cases of extragonadal teratomas researchers speculate that these cells continue to undergo mitosis, the process where cells divide and multiply, eventually forming a teratoma.

Sacrococcygeal teratomas are thought to arise from an area under the coccyx called the “Henson’s Node”, which is located in the coccyx ⁸⁾. Sacrococcygeal teratoma tumor arises from embryologically multipotent cells from the Hensen node. This is an area where primitive cells persist (germ cells) that can give rise to cells of the three major tissue layers of an embryo: ectoderm, endoderm, and mesoderm. These embryonic layers eventually give rise to the various cells and structures of the body. Sacrococcygeal teratomas can contain mature tissue that looks like any tissue in the body, or immature tissue resembling embryonic tissues.

Sacrococcygeal teratoma pathophysiology

The vascular supply to an sacrococcygeal teratoma commonly arises from the middle sacral artery, which can enlarge to the size of the common iliac artery and cause a vascular steal syndrome ⁹⁾. These large vascular tumors can lead to high-output cardiac failure as a consequence of arteriovenous shunting through the tumor, resulting in placentomegaly, hydrops, and, ultimately, fetal demise ¹⁰⁾.

Polyhydramnios is commonly seen because of increased fetal cardiac output, which often leads to preterm labor and premature rupture of membranes. Conversely, oligohydramnios can also occur if an intrapelvic portion of the tumor causes significant urinary obstruction ¹¹⁾.

In severe cases, maternal mirror syndrome, in which the mother develops symptoms that mimic those of the hydropic fetus, may develop. Mothers develop symptoms similar to those of severe preeclampsia, such as hypertension, emesis, peripheral edema, pulmonary edema, and proteinuria ¹²⁾.

Fetal surgery is contraindicated after maternal mirror syndrome has developed; accordingly, prognostic indicators have been characterized so as to identify patients before terminal progression of this disease. Mothers who potentially have maternal mirror syndrome need to be very closely monitored and may require delivery or pregnancy termination for maternal safety.

Sacrococcygeal teratoma symptoms

The signs and symptoms of sacrococcygeal teratoma depend largely on the size and specific location of the tumor. Small tumors often do not cause any symptoms (asymptomatic) and can usually be removed surgically after birth without difficulty. However, larger sacrococcygeal tumors can cause a variety of complications before and after birth. Some tumors can be diagnosed by ultrasound before your child is born. An abnormally sized uterus is typically the first sign that your baby may have a tumor. The size discrepancy can be due to a massive tumor or to polyhydramnios (excess amniotic fluid). Less common presentations include maternal preeclampsia. Fetal sacrococcygeal teratoma may be cystic, solid or mixed in its sonographic appearance. The heterogeneous appearance of the mass may be due to mixed areas of tumor necrosis, cystic degeneration, hemorrhage or calcification.

Sacrococcygeal teratomas can grow rapidly in the fetus and require very high blood flow resulting in fetal heart failure, a condition known as hydrops. This is manifest as dilation of the heart, and the collection of fluid in tissues of the body, including the skin and body cavities such as around the lungs (pleural effusion), around the heart (pericardial effusion), and/or in the abdominal cavity (ascites). If neglected, hydrops can also be dangerous for the mother resulting in similar symptoms of swelling, hypertension, and fluid on the lungs with shortness of breath. In addition to hydrops, which can occur in approximately 15% of very large fetal sacrococcygeal teratomas, these tumors can cause polyhydramnios (too much amniotic fluid), fetal urinary obstruction (hydronephrosis), bleeding into the tumor or rupture of the tumor with bleeding into the amniotic space, or dystocia (a condition where the fetus cannot be delivered due to the size of the tumor. It is very important to have very close monitoring during pregnancy to recognize these symptoms as early as possible.

In adults, sacrococcygeal teratomas may not cause symptoms (asymptomatic). In some cases, they may cause progressive lower back pain, weakness, and abnormalities due to obstruction of the genitourinary and gastrointestinal tracts. Such symptoms include constipation and increased frequency of stools or urinary tract infections. In rare cases, sacrococcygeal tumors cause partial paralysis (paresis) of the legs and tingling or numbness (paresthesia).

Sacrococcygeal teratoma diagnosis

Most sacrococcygeal teratomas are now diagnosed antenatally because of the widespread use of routine obstetric ultrasonography ¹³⁾.

If your baby is prenatally diagnosed with fetal sacrococcygeal teratoma, your doctor will continue to monitor your pregnancy to watch for any growth of the tumor or changes in your baby’s condition that may require intervention. Your baby may need fetal surgery to remove the sacrococcygeal teratoma if the size and severity of the tumor cause complications such as fetal hydrops that put you or your baby at risk.

Other tumors may not be visible until after your baby is born. After delivery, your child may have symptoms that indicate a possible sacrococcygeal teratoma, such as being unable to urinate or have a bowel movement because the tumor is pressing on their bladder or rectum. Some children have no symptoms at all.

 

 

In most cases, sacrococcygeal teratomas are diagnosed at birth when a large tumor is detected protruding from the sacral region. Many sacrococcygeal teratomas are found incidentally on routine prenatal ultrasounds or they may be detected on an ultrasound that is obtained because the uterus is too large for the stage of pregnancy due to the bulk of the tumor, or accumulation of amniotic fluid. During an ultrasound, reflected sound waves create an image of the developing fetus. Even small sacrococcygeal teratomas may be visible on an ultrasound picture.

In some cases, a sample of the amniotic fluid or maternal serum may be taken and studied to determine the levels of alpha-fetoprotein (AFP). AFP is a normal fetal plasma protein that when elevated may indicate the presence of certain conditions such as a sacrococcygeal teratoma.

If a sacrococcygeal teratoma is diagnosed prenatally a careful examination is usually done to rule out other anomalies. In some institutions a fetal MRI scan is also performed to better delineate the anatomy of the tumor and displaced structures. For large sacrococcygeal teratomas, very frequent ultrasounds and echocardiograms (to measure the size of the cardiac chambers and blood flows) are required to monitor for signs of evolving hydrops. During an echocardiogram, reflected sound waves are used to take pictures of the heart. It is extremely important that a medical team experienced with large fetal sacrococcygeal teratoma follows the pregnancy. All fetuses with large sacrococcygeal teratomas need delivery by a “classical” cesarean section (large incision in the uterus) to avoid tumor rupture and hemorrhage at the time of delivery. Most fetuses with large tumors are born premature and need expert perinatal care from a multidisciplinary team.

In adults, a diagnosis of sacrococcygeal teratoma may be suspected during a routine pelvic or rectal examination that detects the presence of a mass or tumor. A diagnosis of sacrococcygeal teratoma may be confirmed by surgical removal and microscopic examination of affected tissue (biopsy). One procedure is known as fine needle aspiration, in which a thin, hollow needle is passed though the skin and inserted into the nodule or mass to withdraw small samples of tissue for study.

In addition to an ultrasound, other specialized imaging techniques may be used to diagnose a tumor as well as evaluate the size, placement, and extension of the tumor and to serve as an aid for future surgical procedures. After birth, such imaging techniques may include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. In cases of malignant sacrococcygeal teratomas, laboratory tests and specialized imaging tests may also be conducted to determine possible infiltration of regional lymph nodes and the presence of distant metastases.

Sacrococcygeal teratoma staging

When an individual is diagnosed with a sacrococcygeal teratoma, assessment is also required to determine the extent or “stage” of the disease. Staging is important to help characterize the potential disease course and determine appropriate treatment approaches. Certain of the same diagnostic tests described above may be used in staging.

Sacrococcygeal teratomas are classified according to the American Academy of Pediatrics Surgical Section ¹⁴⁾:

• Type 1 – the tumor is predominantly external with a very minimal internal component. Type I is rarely associated with malignancy.
• Type 2 – the tumor is predominantly external but has some internal extension into the presacral space.
• Type 3 – the tumor is visible externally, but is predominantly located in the pelvic area with some extension into the abdomen.
• Type 4 – the tumor is not visible externally and is located in the presacral space. Type 4 has the highest rate of malignancy.

Sacrococcygeal teratoma treatment

The initial management of a fetus with a sacrococcygeal teratoma requires the coordinated efforts of a perinatal team of medical professionals such as maternal fetal medicine physicians to deliver the infant, and pediatric surgeons and neonatologists to resect the tumor and manage the medical issues of the infant who can sometimes be critically ill. All prenatally diagnosed sacrococcygeal teratomas require surgery to remove the tumor during the neonatal period and if the tumor is large, as quickly as possible to avoid rupture of the sacrococcygeal teratoma. Resection always involves resection of the tumor along with the coccyx. Failure to resect the coccyx is associated with a 30% local recurrence rate of the sacrococcygeal teratoma tumor. This can usually be done from the back of the neonate but for some tumors with extensive extension into the pelvis and abdomen, an abdominal incision must also be performed. Most children that undergo early resection of sacrococcygeal teratomas ultimately do well with a very low incidence of malignant or benign tumor recurrance, and normal urogenital, bowel, and lower extremity neurologic function. These children are usually followed by the pediatric surgeon by rectal examinations and interval serum AFP levels to monitor for recurrence for 3 years before they are considered cured with no possibility of tumor recurrence.

In rare instances where malignancy is diagnosed by the pathologist after resection a team of medical professionals who specialize in the diagnosis and treatment of cancer (medical oncologists) will need to be consulted. Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as primary tumor location and corresponding complications; extent of the primary tumor (stage); whether it has spread to lymph nodes or distant sites; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular interventions should be made by physicians and other members of the health care team in careful consultation with the patient or parents, based upon the specifics of the case; a thorough discussion of the potential benefits and risks; and other appropriate factors.

In rare cases, complications resulting from a sacrococcygeal teratoma may necessitate intervention before birth (prenatally). Interventions such as tapping the amniotic fluid (amniocentesis) to reduce the volume and delay the onset of preterm labor may be required. If the tumor has hemorrhaged and the fetus is anemic, a fetal blood transfusion may be helpful. Occasionally, an obstructed fetal urinary tract will need to be treated by a vesicoamniotic shunt (a catheter between the bladder and amniotic fluid) to relieve the obstruction and prevent damage to the kidneys. In rare cases when the fetus is documented to be in the early stages of hydrops, open fetal surgery may be required (surgery on the fetus in the womb) to “debulk” the tumor and reduce the demand for blood flow. After removal of the bulk of the tumor, the fetus is returned to the womb so that the hydrops can improve prior to birth. Although this has been successful about 50% of the time, it is a major undertaking and extensive consideration of the risks to the mother is appropriate. Although radio frequency ablation (a technique where a needle is inserted into the tumor and radiofrequency energy is applied to the tumor to destroy blood flow) has been reported, all survivors have had complications of damage to the genitourinary system so this approach is considered highly experimental.

In adults, surgical removal of the entire tumor and the tailbone (coccyx) is the main treatment option. Removal of the coccyx lowers the chance of recurrence. For benign tumors surgical removal of the tumor is usually sufficient. However, for malignant tumors, affected individuals should receive additional treatment with chemotherapy and radiation therapy.

Because malignant sacrococcygeal teratomas are extremely rare, especially in adults, no standard chemotherapeutic regimen or radiation therapy has been established.

Monitoring and delivery

If your baby’s condition is stable with no high output cardiac failure (fetal hydrops), your pregnancy will be followed with regular ultrasound monitoring. If the sacrococcygeal teratoma is small, a vaginal delivery at term may be planned.

If the sacrococcygeal teratoma is large or if there is an excess of amniotic fluid (polyhydramnios), an early cesarean section is planned to avoid tumor rupture as well as the risks of preterm labor and premature delivery.

If fetal hydrops develops, you may be a candidate for fetal surgery.

Sacrococcygeal teratoma surgery

Fetuses with sacrococcygeal teratoma are considered for fetal surgery to remove the tumor or fetal intervention only in extreme cases on an individual basis. Depending on the diagnosis and severity of your child’s sacrococcygeal teratoma, they may undergo fetal surgery to remove the sacrococcygeal teratoma before birth, or they may have tumor resection surgery after they’re born.

Fetal surgery is only indicated when fetal hydrops is present, putting your child’s life at risk.

Small tumors without significant vascularity are unlikely to affect the fetus significantly ¹⁵⁾. These fetuses are unlikely to develop high-output cardiac failure or hydrops and can be monitored throughout gestation with serial ultrasound. Those with signs of placentomegaly and hydrops after lung maturity (usually after 32 weeks’ gestation) are delivered on an emergency basis. Only fetuses of less than 32 weeks’ gestation with signs of impending hydrops that have tumors amenable to surgical resection are considered for fetal intervention ¹⁶⁾.

As with all invasive procedures, the risks and benefits of fetal intervention must be considered for each patient. However, consideration for the risk to and safety of the pregnant mother are unique to fetal surgery. Before fetal intervention is considered, a multidisciplinary team should counsel and evaluate each family. The evaluation should include the following ¹⁷⁾:

• Detailed ultrasound to confirm the diagnosis and to detect any other anatomic abnormalities
• Fetal magnetic resonance imaging (MRI) for additional anatomic information
• Fetal echocardiography to rule out congenital heart disease and to assess fetal cardiac function
• Amniocentesis for fetal karyotyping

In 2009, Wilson et al ¹⁸⁾ proposed the following criteria for surgical resection of sacrococcygeal teratoma:

• No maternal contraindications to fetal surgery (medical or surgical issues, body mass index [BMI] < 36, anesthesia risks)
• Fetal gestational age of 20-30 weeks
• A favorable American Academy of Pediatrics Surgical Section stage and no additional anomalies
• Impending hydrops (evidence of ascites, pleural effusion, and subcutaneous edema)
• Normal fetal karyotype
• Fetal cardiac output greater than 600-900 mL/kg/min (adjusted for gestational age)

Contraindications

Contraindications for fetal intervention for sacrococcygeal teratoma include the following ¹⁹⁾:

• Significant placentomegaly (placental thickness at cord insertion >35-45 mm with a gestational age < 30 weeks)
• Maternal mirror syndrome
• Multiple gestation
• Chromosomal abnormality
• Other fetal anatomic abnormalities

Ex-Utero Intrapartum Treatment (EXIT) Procedure

In some cases, early delivery of the fetus without sacrococcygeal teratoma resection has led to adverse events between delivery and neonatal resection (eg, tumor hemorrhage and fetal exsanguination). In cases where delivery and tumor resection may lead to hemodynamic instability, the ex-utero intrapartum treatment (EXIT) procedure may be considered. EXIT to resection of fetal sacrococcygeal teratoma may be considered for a fetus of 27-32 weeks’ gestation with a large vascular type 1 or 2 tumor requiring early delivery but in the absence of maternal contraindications ²⁰⁾.

The EXIT procedure, originally developed to establish an airway in a fetus with airway compromise while the fetus was still connected to placental circulation for oxygenation, has been adapted to resuscitate fetuses with other anomalies who may experience instability during birth ²¹⁾. For fetuses with sacrococcygeal teratoma, the EXIT procedure allows tumor debulking to interrupt the vascular steal phenomenon, which minimizes preoperative manipulation and trauma to the tumor ²²⁾. The infant can be stabilized before definitive oncologic resection.

The EXIT procedure is performed with the mother under general anesthesia ²³⁾ to maximize uterine relaxation and uteroplacental blood flow. The hysterotomy, fetal monitoring, and IV access are performed as described for open fetal surgery.

After debulking of the tumor, the fetus is intubated and given surfactant before the umbilical cord is clamped. The hysterotomy, fascial, and skin closure are performed in the same fashion as the open fetal sacrococcygeal teratoma resection.

Roybal et al ²⁴⁾ reported one survivor using this technique, with neurologic complications due to tumor invasion into the spinal canal. Surgeons at the University of California San Francisco ²⁵⁾, have treated two fetuses with EXIT to sacrococcygeal teratoma resection, with a survival of 50%; one patient died of necrotizing enterocolitis and sepsis.

Open fetal surgery

Fetal exposure for sacrococcygeal teratoma resection is similar to what has been reported for other open fetal surgical procedures ²⁶⁾.

The uterus is exposed through a Pfannenstiel incision. If the placenta is located posteriorly, the superior and anterior skin and subcutaneous tissue flaps are created, and a midline fascial incision is then created to expose the uterus.

An anterior hysterotomy is performed while the uterus remains in the abdomen. However, if the placenta is located anteriorly, the rectus muscles will have to be divided in order to prevent uterine vascular compromise as the uterus is lifted out of the abdomen to perform a posterior hysterotomy.

A large ring retractor is used to maintain exposure ²⁷⁾.

Intraoperative sterile ultrasonography is used to delineate the position of the fetus and the placenta, and continuous echocardiography is used to monitor fetal well-being throughout the operative procedure.

If the pregnancy is complicated by polyhydramnios and placentomegaly, the true edge of the placenta is not always appreciated on ultrasonography, and the hysterotomy should be planned even farther away from this edge.

Stay sutures are placed on the uterus, and a small hysterotomy is made, which is then extended with a stapler designed especially to be used on the uterus ²⁸⁾. This hemostatic stapler is used to secure the membranes to the uterine wall to prevent separation of membranes. The fetus is positioned so that the tumor is exposed through the hysterotomy.

A ”fetal cocktail,” which consists of a paralytic agent (either pancuronium or rocuronium) and fentanyl, is administered to the fetus with an intramuscular injection. A pulse oximeter is placed on the fetus to monitor fetal well-being (see the first image below). Intravenous (IV) access is obtained for administration of fluids, blood, or medication. Use of this strategy of fetal monitoring during open fetal surgery allows administration of fluids in response to changes in preload during the resection and may improve fetal survival ²⁹⁾.

The fetus is kept buoyant and warm in the uterus with continuous infusion of warmed lactated Ringer solution into the uterus.

After the sacrococcygeal teratoma is resected, a two-layer uterine closure is performed. However, before the uterus is completely closed, lactated Ringer solution is instilled into the uterus until ultrasound shows that normal amniotic fluid volume has been restored.

An omental flap can be secured over the hysterotomy, and the fascia, subcutaneous tissue, and skin are closed.

Radiofrequency ablation

Several centers have described salvage of hydropic fetuses with sacrococcygeal teratoma with open fetal resection. However, preterm labor remains the Achilles heel of fetal surgery. To circumvent preterm labor and to decrease maternal morbidity associated with fetal intervention for sacrococcygeal teratoma, minimally invasive techniques, such as radiofrequency ablation (RFA), have been described ³⁰⁾.

This technique employs US guidance to target the vessels feeding the sacrococcygeal teratoma to reduce tumor vascularity. An eight-prong LeVeen radiofrequency probe is deployed through a 15-gauge needle into an umbrellalike configuration to a diameter of 20-35 mm ³¹⁾. It delivers energy in a spherical volume to cause tissue and tumor necrosis.

Radiofrequency ablation for sacrococcygeal teratoma has been controversial. The potential risks of this procedure include gas embolization due to microbubbles, hyperkalemia caused by tissue necrosis, perineal damage, and hemorrhage.

In a report of four fetuses with sacrococcygeal teratoma, radiofrequency ablation successfully reduced tumor vascularity in all cases ³²⁾. However, intrauterine fetal demise due to hemorrhage into the tumor occurred in one case, and another fetus underwent termination after postoperative MRI showed fetal brain damage. The two remaining fetuses survived but had evidence of perineal damage at birth.

Lam et al reported using radiofrequency ablation to treat sacrococcygeal teratoma in an 18-week-old fetus, but the fetus died 2 days postoperatively ³³⁾. Ibrahim et al ³⁴⁾ reported a fetus born with sciatic nerve injury and malformation of the acetabulum and femoral head after radiofrequency ablation for sacrococcygeal teratoma. A study from Korea ³⁵⁾ reported six cases of fetal sacrococcygeal teratoma treated with radiofrequency ablation; five of the six patients survived, and one patient had left-leg palsy and fecal and urinary incontinence.

In summary, although radiofrequency ablation has been used as salvage therapy in fetuses who would have otherwise died, many of these patients were born with complications. The keys to successful treatment with radiofrequency ablation may be (1) limiting the extent of coagulation in any single attempt to prevent massive hemorrhage or perineal necrosis and (2) performing a series of limited ablations ³⁶⁾. Radiofrequency ablation as a treatment modality for fetal sacrococcygeal teratoma remains limited and problematic, and more studies are necessary to determine whether and how this technique should be used.

Laser ablation

Laser ablation for sacrococcygeal teratoma was first described in 1996 at 20 weeks’ gestation ³⁷⁾. The pregnancy was complicated by polyhydramnios but not by placentomegaly or hydrops. Two unsuccessful attempts were made at 20 weeks’ and 26 weeks’ gestation to ablate the main vessels feeding the sacrococcygeal teratoma, but the infant survived.

In this technique, local anesthesia is infiltrated into the skin and subcutaneous tissues ³⁸⁾. Cordocentesis is performed to deliver fetal anesthesia with fentanyl (15 µg/kg) and pancuronium (2 mg/kg) ³⁹⁾. This can also be delivered intramuscularly to the fetus. Under US guidance, a 1.9-mm 60° fetoscope is introduced into the amniotic cavity percutaneously through a sheath, and a 0.4-mm neodymium-doped yttrium-aluminum-garnet (Nd:YAG) laser fiber is used to coagulate the vessels ⁴⁰⁾.

In a retrospective study of 12 patients undergoing fetal intervention for sacrococcygeal teratoma, four patients underwent laser ablation, but only one patient survived ⁴¹⁾. In a case report, a 24-week-old hydropic fetus underwent percutaneous laser ablation for sacrococcygeal teratoma but died 2 days after fetal intervention ⁴²⁾. In another study, a 22-week-old fetus underwent percutaneous laser ablation of tumor vessels and survived.

An additional retrospective multicenter study identified five fetuses that underwent minimally invasive fetal intervetion for hydrops or cardiac insufficiency as a result of sacrococcygeal teratoma ⁴³⁾. Four of these five fetuses underwent laser ablation, and three of them were targeted vascular ablations. Survival for the fetuses that underwent fetal intervention was 40%, but many patients required multiple procedures because of the recurrence of hydrops, cardiac insufficiency, or both.

Laser ablation for sacrococcygeal teratoma, like radiofrequency ablation for sacrococcygeal teratoma, represents the movement in fetal surgery toward minimally invasive techniques. However, the outcomes vary, and current experience is too limited to determine whether laser ablation will be effective in reducing mortality in fetuses with sacrococcygeal teratoma.

Sacrococcygeal teratoma prognosis

Most fetal sacrococcygeal teratomas are generally not malignant and the prognosis tends to be good after resection. Several institutions have reported outcomes with and without fetal intervention for antenatally diagnosed sacrococcygeal teratoma ⁴⁴⁾. Among patients with antenatally diagnosed sacrococcygeal teratoma, 36-41% require fetal intervention ⁴⁵⁾.

Most fetuses with sacrococcygeal teratoma do well with surgical treatment after birth. Babies with small tumors that can be removed along with the coccyx bone after birth can be expected to live normal lives. They will need to be born in a hospital with pediatric surgeons and a specialized nursery. After hospital discharge, it is our practice to follow children who have had an sacrococcygeal teratoma resection closely. Experts recommend follow-up with a pediatric surgeon and pediatric oncologist with blood testing of alpha-fetoprotein (AFP) throughout childhood.

Fetuses with larger tumors or tumors that go up inside the baby’s abdomen will require more complex surgery after birth, but in general do well. Again, they will have to be followed by an oncology service with blood tests for several years. Fetuses with very large tumors, which can reach the size of the fetus itself, can pose a difficult problem both before and after birth.

Experts have found that those sacrococcygeal teratomas that are largely cystic (fluid-filled) generally do not cause a problem for the fetus before birth. However, when the sacrococcygeal teratoma is made up of mostly solid tissue, with a lot of blood flow, the fetus can suffer adverse effects. This is because the fetus’s heart has to pump not only to circulate blood to its body, but also to all the blood vessels of the tumor, which can be as big as the fetus. In essence, the heart is performing twice its normal amount of work. The amount of work the heart is doing can be measured by fetal echocardiography. This sensitive test can determine how hard the heart is working when the fetus is approaching hydrops, or heart failure. If hydrops does develop, usually in rapidly growing solid tumors, the fetus usually will not survive without immediate intervention before birth. These fetuses must be followed very closely, and may benefit from fetal surgery.

If hydrops does not develop, these babies may require Cesarean-section delivery and an extensive operation after birth. Most babies will do well once the tumor is completely removed. Long-term consequences include the recurrence of the tumor or difficulty with bowel and/or bladder control as a consequence of the surgical procedure. Your child should be followed by an oncologist and pediatric surgeon throughout childhood.

Mortality due to sacrococcygeal teratoma is mainly attributed to tumor morphology; small cystic sacrococcygeal teratomas rarely cause problems in utero. Rapid growth of large vascular tumors can rupture and hemorrhage during delivery, and this is usually fatal ⁴⁶⁾.

The overall survival rate of antenatally diagnosed sacrococcygeal teratoma is 47-83% ⁴⁷⁾, but the survival rate after fetal surgery is 50-75% ⁴⁸⁾. It is important to note that survival after fetal intervention should be compared with survival for the subgroup of patients with hydrops and no intervention, in whom the survival rate approaches 0% ⁴⁹⁾.

About 40-50% of survivors with antenatally diagnosed sacrococcygeal teratoma have long-term morbidity, which may include obstructive uropathy, bowel and bladder incontinence caused by damage to the sacral nerves due to the tumor or damage during sacrococcygeal teratoma resection, and dissatisfaction with cosmetic outcomes ⁵⁰⁾.

Prognostic indicators

Placentomegaly and hydrops are harbingers of fetal demise in sacrococcygeal teratoma ⁵¹⁾.

A retrospective review of 17 fetuses with antenatally diagnosed sacrococcygeal teratoma treated at the University of California, San Francisco ⁵²⁾, between 1986 and 1998 evaluated the factors associated with hydrops. There was a significant difference in tumor morphology (solid vs cystic) and vascularity in fetuses who developed hydrops compared with those without hydrops. In addition, fetuses who developed hydrops were diagnosed at an earlier gestational age (19 vs 25 weeks) and were delivered at an earlier gestational age (28 vs 38 weeks).

In this series, 12 fetuses developed hydrops, four of whom survived ⁵³⁾. Of the four survivors, three underwent fetal intervention because they developed hydrops before viability, and one patient developed hydrops at 32 weeks’ gestation and was delivered immediately. All fetuses who did not develop hydrops survived.

This study showed that fetuses with predominantly solid and highly vascular tumors were at high risk for developing hydrops. These patients should undergo close follow-up throughout gestation with serial US and echocardiography and may be considered for fetal intervention upon signs of impending hydrops.

A retrospective review of 23 patients evaluated at the Children’s Hospital of Philadelphia ⁵⁴⁾ between 2003 and 2006 with antenatally diagnosed sacrococcygeal teratoma showed that sacrococcygeal teratomas with a growth rate exceeding 150 cm³/week are associated with increased perinatal mortality.

In a study from University of California San Francisco that retrospectively reviewed 28 fetuses with antenatally diagnosed sacrococcygeal teratoma between 1991 and 2005, solid tumor volume–to–head volume ratio (STV/HV) on ultrasound was identified as a predictor of poor outcomes ⁵⁵⁾. All patients with an solid tumor volume–to–head volume ratio (STV/HV) lower than 1 survived, whereas 61% of fetuses with an solid tumor volume–to–head volume ratio (STV/HV) higher than 1 died.

In addition, the study determined that 97.3% of fetuses with an solid tumor volume–to–head volume ratio (STV/HV) higher than 1 were associated with one or more abnormal US findings, such as polyhydramnios, hepatomegaly, placentomegaly, cardiomegaly, ascites, pericardial effusion, or integumentary edema ⁵⁶⁾. With serial ultrasound , increases in the STV/HV ratio can guide management in fetal sacrococcygeal teratoma so that fetal intervention or early delivery can be performed before hydrops develops ⁵⁷⁾.

In a study from the Fetal Center at Texas Children’s Hospital ⁵⁸⁾, tumor volume–to–fetal weight ratio (TFR) was a marker of poor outcome in 12 fetuses with sacrococcygeal teratoma between 2004 and 2009. With MRI or US, tumor volume was determined by the prolate ellipsoid formula and fetal weight by the Hadlock formula. A tumor volume–to–fetal weight ratio (TFR) higher than 0.12 before 24 weeks’ gestation predicted poor outcomes (fetal hydrops, demise, or neonatal death) with 100% sensitivity, 83% specificity, a negative predictive value of 100%, and a positive predictive value of 80%.

Of the 12 fetuses with sacrococcygeal teratoma in this series, 33% (4/12) developed hydrops ⁵⁹⁾. All fetuses who developed hydrops had a tumor volume–to–fetal weight ratio (TFR) higher than 0.12 by 24 weeks’ gestation, and three fetuses died. One patient underwent fetal intervention after hydrops developed and survived. Thus, tumor volume–to–fetal weight ratio (TFR) may be used to identify fetuses with sacrococcygeal teratoma who are at risk for poor outcomes before 24 weeks’ gestation and who may benefit from fetal intervention.

Tumor volume–to–fetal weight ratio (TFR) higher than 0.12 in combination with tumor morphology was further validated as a sonographic predictor of poor prognosis in a subsequent retrospective study from University of California San Francisco ⁶⁰⁾.

In a review of 79 fetuses with antenatally diagnosed sacrococcygeal teratoma at three fetal centers from 1986 to 2011, receiver operating characteristic (ROC) analysis revealed that a tumor volume–to–fetal weight ratio (TFR) higher than 0.12 before 24 weeks’ gestation was predictive of a poor prognosis, as was solid tumor morphology and the presence of hydrops ⁶¹⁾. However, none of these factors were found to be independent predictors of a poor prognosis on multivariate analysis.

In a retrospective review ⁶²⁾ of 28 pathology-confirmed isolated sacrococcygeal teratoma patients evaluated with at least two documented ultrasound scans and followed through hospital discharge between 2005 and 2012, a faster sacrococcygeal teratoma growth rate—calculated as the difference between tumor volumes on a late-gestation sonogram and an early-gestation sonogram divided by the difference in time—was associated with adverse outcomes (death, high-output cardiac failure, hydrops, and preterm delivery).

Sacrococcygeal teratoma can create a low-resistance large arteriovenous shunt, which can progressively increase preload and afterload on the fetal heart, leading to volume overload, ventricular dilation, ventricular hypertrophy, and high-output cardiac failure ⁶³⁾. A 10-year retrospective review ⁶⁴⁾ of seven fetuses showed that the most important prognostic criteria for maternal and fetal complications due to antenatally diagnosed sacrococcygeal teratoma included cardiomegaly, hydrops, and increased preload indexes of the fetal venous system.

Studies on fetuses with sacrococcygeal teratoma show that combined cardiac output increases dramatically before the development of hydrops ⁶⁵⁾. Fetuses with combined cardiac output that exceeded 700-800 mL/kg/min died in utero ⁶⁶⁾. Rychik et al ⁶⁷⁾ analyzed the acute cardiovascular effects of fetal surgery in four patients with sacrococcygeal teratoma and saw a significant decrease in combined cardiac output (690 ± 181 mL/kg/min vs 252 ± 82 mL/kg/min) after fetal resection of sacrococcygeal teratoma.

In a retrospective review ⁶⁸⁾ of 11 fetuses with sacrococcygeal teratoma, those with poor outcomes (ie hydrops, fetal demise, neonatal death) had a cardiothoracic ratio higher than 0.5, a combined ventricular output exceeding 550 mL/kg/min, tricuspid or mitral valve regurgitation, or a mitral valve Z-score higher than 2. Identifying these cardiovascular indicators of poor outcome helps identify patients at high risk for fetal demise and can prompt fetal surgical intervention before the development of hydrops.

Pulmonary hypoplasia

Pulmonary hypoplasia also called lung hypoplasia refers to deficient or incomplete development of parts of the lung, which can be unilateral or bilateral ¹⁾. Pulmonary hypoplasia is characterized by small, underdeveloped lungs that can affect not only breathing but also heart function, ability to feed, hearing and overall development. Some children with pulmonary hypoplasia develop a related condition known as pulmonary hypertension, which causes high blood pressure in the arteries of the lungs (the pulmonary arteries). Over time, this pressure causes the pulmonary arteries to narrow, making the right side of the heart work harder as it forces blood through the narrowed arteries.

The true prevalence of pulmonary hypoplasia is unknown. The reported incidence is between 9 to 11 per 100,00 live birth which is an underestimation, as infants with lesser degrees of hypoplasia likely survive in the neonatal period ²⁾. Incidence also varies by cause. In cases of premature rupture of membranes at 15-28 weeks gestation, the reported prevalence of pulmonary hypoplasia ranges from 9 to 28% ³⁾. Most cases are secondary to congenital anomalies (such as congenital diaphragmatic hernia and cystic adenomatous malformations) or complications related to pregnancy that inhibit lung development. These include, but are not limited to, renal and urinary tract anomalies, amniotic fluid aberrations, diaphragmatic hernia, hydrops fetalis, skeletal and neuromuscular disease and conditions like pleural effusions, chylothorax and intrathoracic masses that cause compression of the fetal thorax ⁴⁾.

Pulmonary hypoplasia may be primary or secondary. Primary pulmonary hypoplasia is extremely rare and routinely lethal. The severity of the lesion in secondary pulmonary hypoplasia depends on the timing of the insult in relation to the stage of lung development. This typically occurs prior to or after the pseudoglandular stage at 6-16 weeks of gestation ⁵⁾. In pulmonary hypoplasia, the lung consists of incompletely developed lung parenchyma connected to underdeveloped bronchi. Besides disturbances of the bronchopulmonary vasculature, there is a high incidence, approximately 50-85%, of associated congenital anomalies such as cardiac, gastrointestinal, genitourinary, and skeletal malformations. The diagnosis can result in a spectrum of respiratory complications ranging from transient respiratory distress, chronic respiratory failure, bronchopulmonary dysplasia to neonatal death in very severe cases. Strict diagnostic criteria are not established for pulmonary hypoplasia; various parameters such as lung weight, lung weight to body weight ratio, total lung volume, mean radial alveolar count and lung DNA assessment have been used to classify pulmonary hypoplasia ⁶⁾.

Your child should be followed by a pediatric pulmonologist after birth so that appropriate diagnostic tests can be performed and routinely followed. Your child’s care and pulmonary hypoplasia treatment plan is based on their specific needs, taking into account each unique diagnosis and treatment your child has received. If early surgery is not performed during infancy, close follow-up of your child is needed. As some cystic lung abnormalities can spontaneously resolve over months to years. Newborns who have been referred for a cystic lesion observed by fetal ultrasonography may have complete resolution on postnatal chest CT. Also, the occurrence of pneumonia or repeated respiratory infections may suggest surgical intervention is needed in a patient who has been conservatively managed.

Various aerosolized medications such as bronchodilators and corticosteroids should be considered if symptoms suggest reactive airway disease or obstructive airway disease.

Persistent pulmonary arterial hypertension can be treated with various pulmonary vasodilators such as inhaled nitric oxide and sildenafil, and endothelin receptor inhibitors such as bosentan.

Pulmonary hypoplasia causes

Pulmonary hypoplasia occurs secondary to a variety of conditions that limit lung development. There are several key factors required for the adequate development of the lung. These are:

• sufficient amniotic fluid volumes
• adequate volume of the thoracic cavity
• normal breathing movement
• normal fluid within the lung

A deficiency in any of these could lead to pulmonary hypoplasia.

For lung development to proceed normally, physical space in the fetal thorax (chest cavity) must be adequate, and amniotic fluid must be brought into the lung by fetal breathing movements, leading to distension of the developing lung. Several studies have demonstrated that gestation age at rupture of membranes (15-28 weeks gestation), latency period (duration between rupture of membranes and birth) and the amniotic fluid index (AFI of less than 1 cm or 5 cm) can influence the development of pulmonary hypoplasia ⁷⁾.

Most cases of pulmonary hypoplasia are secondary to other congenital anomalies or pregnancy complications. Some cases however can occur as a primary event ⁸⁾.

With secondary causes, it can result from factors directly or indirectly compromising the thoracic space available for lung growth.

Intrathoracic causes include:

• Congenital diaphragmatic hernia: most common intrathoracic cause
• Congenital cystic adenomatoid malformation (CCAM) or congenital pulmonary airway malformation (CPAM)
• Extralobar sequestration / pulmonary sequestration
• Agenesis of the diaphragm
• Mediastinal mass(es)/tumor(s)
  • Mediastinal teratoma
  • Thoracic neuroblastomas
• Congenital heart diseases with poor pulmonary (arterial) blood flow
  • Tetralogy of Fallot
  • Hypoplastic right heart
  • Pulmonary artery hypoplasia or unilateral absence of the pulmonary artery
  • Scimitar syndrome causing a unilateral right-sided pulmonary hypoplasia
  • Trisomies 18 and 21
• Pleural effusions with fetal hydrops, hydrothorax

Extra-thoracic causes include:

• Oligohydramnios and its causes
  • Potter sequence: fetal renal anomalies
  • Fetal renal agenesis
  • Urinary tract obstruction
  • Bilateral renal dysplasia
  • Bilateral cystic kidneys
  • Prolonged rupture of membranes (PROM)
  • Preterm premature rupture of membranes (PPROM)
• Skeletal dysplasias, especially those causing a narrow fetal thorax
  • Jeune syndrome (asphyxiating thoracic dystrophy)
  • Thanatophoric dysplasia
  • Achondroplasia
  • Achondrogenesis
  • Osteogenesis imperfecta
  • Short rib polydactyly syndrome
  • Campomelic dysplasia
• Large intra-abdominal mass compressing the thorax
• Neuromuscular conditions interfering with fetal breathing movements
  
  • Central nervous system (CNS) lesions
  • Lesions of the spinal cord, brain stem, and phrenic nerve
  • Neuromuscular diseases (eg, myotonic dystrophy, spinal muscular atrophy)
  • Arthrogryposis multiplex congenital secondary to fetal akinesia
  • Maternal depressant drugs

Other associations include:

• Fryns syndrome
• Meckel Gruber syndrome
• Neu-Laxova syndrome
• Pena-Shokeir syndrome

Fetal lung fluid and oligohydramnios

Maintenance of fetal lung volume plays a major role in normal lung development. Normal transpulmonary pressure of about 2.5 mm Hg allows the fetal lung to actively secrete fluid into the lumen ⁹⁾. The effect of stretch of the lung parenchyma induces and promotes lung development. Studies in sheep have demonstrated that tracheal ligation and therefore increased lung distension, accelerates lung growth whereas chronic tracheal fluid drainage has the opposite effect ¹⁰⁾. Cohen and colleagues ¹¹⁾ have found that in-utero overexpression of the cystic fibrosis transmembrane conductance regulator (CFTR) increased liquid secretion into the lung, accelerating lung growth in a rat model.

Oligohydramnios is considered to be an independent risk factor for the development of pulmonary hypoplasia. This is likely due to reduced distending forces on the lung. Studies have demonstrated that severe oligohydramnios decreased lung cell size, alters cell shape and may also negatively affect Type 1 cell differentiation which ultimately induces pulmonary hypoplasia.

It has been postulated that the Rho-ROCK pathway can affect the growth of the lung epithelium. Embryonic mouse models have demonstrated that ROCK protein inhibitor decreases the number of terminal lung buds. There are currently several groups studying the role of the Rho/ROCK pathway which has potential therapeutic implications in the reversal of lung hypoplasia ¹²⁾.

Role of growth factors

Several growth factors such as fibroblast growth factor (FGF), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF), promote cell proliferation and differentiation. Transforming growth factor family proteins like TGFß1 can oppose these effects.

Embryologically, lungs arise from the foregut. Thyroid transcription factor 1 (TTF-1) is thought to be the earliest embryologic marker associated with cells committed to pulmonary development. FGF signaling is thought to be essential in the formation of TTF-1 expressing cells and this is thought to occur even before the pseudoglandular stage of lung development. Sonic hedgehog (SHH) signaling is further responsible for branching morphogenesis and mesenchymal proliferation. Disruption of any of these pathway may result in primary pulmonary hypoplasia ¹³⁾.

FGF7 and FGF10 promote epithelial proliferation and formation of the bronchial tree. Overexpression of FGF10 can also stimulate the formation of cysts in the rat lung ¹⁴⁾. EGF promotes lung branching and Type II alveolar cell proliferation. PDGF plays a crucial role in alveolarization. VEGF promotes angiogenesis and the differentiation of embryonic mesenchymal cells into endothelial cells. Bone morphogenetic protein was thought to oppose lung growth; however recent data suggests that in the presence of mesenchymal cells, BMP4 is a potent inducer of tracheal branching ¹⁵⁾. Aberrant expression of these growth factor proteins in the amniotic fluid during pregnancy have been implicated in abnormal lung development. Interestingly, higher concentrations of VEGF are seen in the amniotic fluid in the second and third trimester and may be a molecular marker for hypoxia which requires further investigation ¹⁶⁾.

Congenital diaphragmatic hernia

The pathogenesis of pulmonary hypoplasia associated with congenital diaphragmatic hernia remains unclear. Several mechanisms have been suggested. The nitrofen model of congenital diaphragmatic hernia is widely accepted. Nitrofen is a human carcinogen and the retinoid acid signaling pathway is essential for the normal development of the diaphragm. Perturbation of this pathway with compounds such as nitrofen, can induce congenital diaphragmatic hernia and pulmonary hypoplasia. Esumi and colleagues demonstrated that that administration of insulin-like growth factor 2 (IGF2) to nitrofen-induced hypoplastic lungs lead to alveolar maturation ¹⁷⁾. Furthermore, recent data suggests that prenatal treatment with retinoic acid results in increased levels of placental IGF2 and promotes both placental and fetal lung growth in nitrofen induced congenital diaphragmatic hernia ¹⁸⁾.

Interestingly, erythropoietin (EPO) is a direct target of retinoic acid. A recent study has demonstrated decreased levels of erythropoietin mRNA in the liver and kidney of rats which may explain modifications in the pulmonary vasculature in congenital diaphragmatic hernia ¹⁹⁾.

A recent study has also suggested a possible role of interleukin 6 (IL-6) in inducing catch-up growth particularly in nitrofen pre-treated explant fetal rat lungs ²⁰⁾.

In cases of congenital diaphragmatic hernia (congenital diaphragmatic hernia) associated with pulmonary hypoplasia, hypertrophy of the contralateral lung has been demonstrated, with associated pulmonary artery hypertension. The hypoxemia in pulmonary hypoplasia stems from hypoventilation and right-to-left extrapulmonary shunting.

Pulmonary hypoplasia symptoms

There is wide variation in the clinical presentation of pulmonary hypoplasia, depending on the extent of hypoplasia and other associated anomalies ²¹⁾.

The history may include poor fetal movement or amniotic fluid leakage and oligohydramnios. The neonate may be asymptomatic or may present with severe respiratory distress or apnea that requires extensive ventilatory support. In older children, dyspnea and cyanosis may be present upon exertion, or a history of repeated respiratory infections may be noted.

The external chest may appear normal or may be small and bell shaped, with or without scoliosis. A mediastinal shift is observed toward the involved side, and dullness upon percussion is heard over the displaced heart. In right-sided hypoplasia, the heart is displaced to the right, which may lead to a mistaken diagnosis of dextrocardia. Breath sounds may be decreased or absent on the side of hypoplasia, especially over the bases and axilla.

Some infants may present with otherwise asymptomatic tachypnea, and other may have severe respiratory distress at birth requiring ventilatory support. Pneumothorax, either spontaneous or associated with mechanical ventilation, may occur.

Infants with secondary pulmonary hypoplasia may have associated congenital anomalies or features suggestive of neuromuscular diseases. Such patients may have myopathic facies, with a V-shaped mouth, muscle weakness, and growth restriction. Multiple genetic syndromes associated with primary pulmonary hypoplasia are reported in the literature such as Scimitar Syndrome, Trisomy 21, and Pena-Shokeir Syndrome (fetal akinesia) ²²⁾.

Compression deformities due to prolonged oligohydramnios, contractures, and arthrogryposis may be present. The Potter facies (hypertelorism, epicanthus, retrognathia, depressed nasal bridge, low set ears) suggest the possibility of lung hypoplasia caused by the associated renal defects.

Abdominal masses, such as cystic renal diseases and an enlarged bladder, must be sought. Associated anomalies of the cardiovascular, gastrointestinal (eg, tracheoesophageal fistula, imperforate anus, communicating bronchopulmonary foregut malformation), and genitourinary systems, as well as skeletal anomalies of the vertebrae, thoracic cage, and upper limbs, may be found upon examination ²³⁾.

Pulmonary hypoplasia complications

Complications in pediatric pulmonary hypoplasia are as follows:

• Mortality due to acute respiratory failure in the neonatal period
• Chronic respiratory failure or insufficiency
• Pneumothorax, either spontaneous or as a result of ventilatory support
• Persistent pulmonary hypertension caused by a reduced pulmonary vascular bed and worsened by hypoxia or a coexisting left-to-right intracardiac shunt
• Chronic lung disease of infancy caused by prolonged ventilatory support
• Airway abnormalities, including tracheobronchial compression and tracheomalacia caused by the displaced aorta and enlarged left pulmonary artery
• Restrictive lung disease due to reduced total lung capacity
• Recurrent respiratory infections
• Recurrent wheezing episodes
• Reduced exercise tolerance
• Scoliosis in adolescent years due to abnormal thoracic cage development
• Nutritional, musculoskeletal, neurological, and gastrointestinal comorbidities
• Delayed growth and development

Pulmonary hypoplasia diagnosis

If the cause of the pulmonary hypoplasia is renal pathology, serum creatinine, blood urea, and electrolytes levels should be measured to assess renal function.

Radiographs

Chest radiographic findings vary. The ribs may appear crowded with a low thoracic-to-abdominal ratio, and the chest wall is classically bell-shaped; however, lung fields are clear unless there is also coexisting respiratory distress syndrome. Pneumothorax or other forms of air leak are frequently present. Films may also show features of the neonate’s underlying condition. In severe cases, there may be mediastinal shift with a homogenous density on the involved hypoplastic side and compensatory herniation of the contralateral lung across the mediastinum. Rib deformities may be observed. See the images below.

2D and 3D ultrasonography

Thoracic circumference (TC), thoracic circumference to abdominal circumference (TC:AC) ratio and lung area (LA) are frequently used measurements to assess prenatal risk for pulmonary hypoplasia ²⁴⁾. Thoracic circumference (TC) and lung area (LA) are gestational-age dependent whereas TC:AC ratio is not affected by gestational age. All of these measurements have a high specificity (between 40-100%) but none have a high enough sensitivity to be used reliably in clinical practice. However, in fetuses with congenital diaphragmatic hernia, the observed to expected lung-to-head ratio (LHR) measured by two-dimensional ultrasound remains the best predictor of pulmonary hypoplasia ²⁵⁾.

Three-dimensional ultrasound techniques, which include pulmonary volume measurement, appears to have a high sensitivity 92% and specific 84% and appears to be a reliable technique to predict pulmonary hypoplasia ²⁶⁾. Barros and Colleagues ²⁷⁾ found that lung volumes measurements using 3D ultrasound has a high sensitivity (83.3%) and specificity (100%) for predicting lethal pulmonary hypoplasia in infant with skeletal anomalies.

Targeted fetal ultrasonography may demonstrate renal malformations, oligohydramnios, and decreased fetal movements in fetal neuromuscular diseases. While this is readily available at most centers, diagnosing disease requires expertise and can be limited by the presence of maternal obesity, low amniotic fluid index (AFI) and fetal malposition ²⁸⁾.

Autopsy studies have shown that pulmonary hypoplasia is associated with a reduction in a number of pulmonary vessels and with increased arterial smooth muscle thickness, which may lead to increased pulmonary vascular resistance and decreased pulmonary arterial compliance. Pulmonary vasculature remodeling and pulmonary hypertension is particularly common in congenital diaphragmatic hernia and results in high mortality ²⁹⁾. Given abnormalities in the vasculature, Doppler ultrasonography has been studied as way to predict pulmonary hypoplasia. Determination of pulmonary artery blood velocity waveforms is one tool used to diagnose pulmonary hypoplasia, however as a single test is unreliable. Pulsatile index of the ductus arteriosus for predicting pulmonary hypoplasia had a sensitivity of only 37% and specificity of 2% which is again, not clinically reliable ³⁰⁾.

Other imaging studies

Echocardiography may be used to identify associated cardiac anomalies. The frequency of cardiovascular malformations associated with isolated congenital diaphragmatic hernia is 11-15% ³¹⁾. The most common anomalies include atrial and ventricular septal defects, conotruncal defects, and left ventricular outflow tract obstructive defects.

Angiography is indicated to confirm the diagnosis of any aberrant pulmonary vessels, to rule out scimitar syndrome, and to confirm reduced pulmonary vascular bed.

MRI or magnetic resonance angiography (MRA) may also be used to identify the smaller pulmonary arterial supply to the affected lung and the presence of other abnormal vascular anatomy.

Both MRI and ultrasonography appear to be useful in determining the degree of pulmonary hypoplasia ³²⁾. Particularly in congenital diaphragmatic hernia, MRI based total fetal lung volume (FLV) and fetal body volume (FBV) measurements are useful in predicting post-natal survival. Recent studies are also demonstrating that MRI based FLV:FBV ratio measurements are not only able to predict neonatal mortality but also able to predict extracorporeal membrane oxygenation (ECMO) requirement with high accuracy ³³⁾.

Lung scintigraphy has been used to evaluate the degree of pulmonary hypoplasia in infants with congenital diaphragmatic hernia. One study suggested that lung scintigraphy is useful to predict long-term pulmonary morbidity and poor nutritional status in survivors of congenital diaphragmatic hernia ³⁴⁾.

Other tests

Obtaining an ECG and/or echocardiogram is important to distinguish between dextrocardia and dextroposition caused by pulmonary hypoplasia. In dextrocardia, ECG findings include an inverted P wave and T in lead 1, with negative QRS deflection and a reverse pattern between aVR and aVL. A mirror image progression is observed from V1 to a right-sided V6 lead. A tall R in lead V1 or an RS ratio equal to or greater than 1 also suggests dextrocardia.

The frequency of cardiovascular malformations associated with isolated congenital diaphragmatic hernia is 11-15% ³⁵⁾. The most anomalies include atrial and ventricular septal defects, conotruncal defects, and left ventricular outflow tract obstructive defects.

Bronchoscopy or bronchography is indicated because the reduced size of a bronchus and its branches confirms the diagnosis.

Pulmonary function testing is difficult to obtain in the young age, however it may a useful tool in monitoring the course of the disease to assess lung maturation and development. A recent study has demonstrated that lung function remains abnormal in the first three years of life in children with congenital diaphragmatic hernia. This study revealed normalization of total lung capacity, however with increasing residual volumes likely due to pulmonary overinflation. They hypothesized that the pulmonary hyperinflation was not due to normal alveolarization that occurs in the first three years of life, but is likely due to overdistended, simplified air spaces that was functionally different from those seen in normally grown lungs ³⁶⁾. Another study reported normalization of all lung function parameters after surgery by age 24 months ³⁷⁾. As expected, lung function significantly correlated with increase in age, height, and, especially, weight.

Histologic findings

On autopsy, in pulmonary hypoplasia, the overall lung size is reduced, cell numbers are decreased, branches of airways may be narrower and fewer, alveolar differentiation may be reduced, and a surfactant deficiency may be present.

Histopathologic descriptions of pulmonary hypoplasia may have limited value since some may appear similar to normal lung. However, in other cases there may be a reduction in a number of pulmonary vessels (and smaller pulmonary arterioles) and increased arterial smooth muscle thickness, indicating the presence of pulmonary hypertension.

The diagnosis of pulmonary hypoplasia is made if the lung weight–to–body weight ratio is less than 0.015 in infants born before 28 weeks of gestation and less than 0.012 in infants born after 28 weeks of gestation, in conjunction with a mean radial alveolar count (RAC) of less than 4%. The radial alveolar count (RAC) provides a simple objective measurement of the “relative paucity of alveoli” or “crowding of bronchial structures, which is unaffected by the state of expansion of the lungs.

In addition, in infants with severe risk factors (renal anomalies, diaphragmatic hernia), lung hypoplasia may be diagnosed by a lung volume–to–body weight ratio less than the 10th percentile when assessed on age-specific reference values ³⁸⁾.

Pulmonary hypoplasia treatment

In fetuses with pulmonary hypoplasia, interventions can be done prenatally and treatment goals should be established for postnatal care. Prenatal interventions are performed with the goal of delaying preterm labor and allowing for lungs to mature.

Preterm rupture of membranes without signs of fetal distress or intrauterine infection is treated conservatively with or without tocolytics, antibiotics, and steroids in various combinations. Antenatal corticosteroids enhance fetal lung maturation in pregnancies less than 34 weeks of gestation. If gestational age is uncertain, lung maturity can be determined by aspiration of amniotic fluid from the vaginal vault. The lamellar body counts are a direct measurement of surfactant production by type II pneumocytes. If this initial screen shows neither clearly mature nor immature fetal lung, then the lecithin/sphingomyelin (L/S) ratio can be determined from amniotic fluid. The risk of respiratory distress is very low when the L/S ratio is greater than 2.0.

Amnioinfusions and amniopatch techniques have shown promising results in the treatments of preterm labor. Amnioinfusion consists of instilling isotonic fluid into the amniotic cavity. Amniopatch consists of intraamniotic injection of platelets and cryoprecipitate with the goal of sealing amniotic fluid leak. Small cases series have reported that both techniques reduce perinatal complications and prolong pregnancy particularly in severe oligohydramnios ³⁹⁾.

After delivery, the infant needs respiratory support, which can range from supplying supplemental oxygen to mechanical ventilation, including high-frequency ventilation and extracorporeal membrane oxygenation (ECMO). Ventilatory strategies that have veered toward the use of gentle volume recruitment, permissive hypercapnia, especially in cases of congenital diaphragmatic hernia (congenital diaphragmatic hernia), have led to increased survival and improved outcomes ⁴⁰⁾. Fetal MRI based lung volume assessment may be useful in predicting the severity of pulmonary hypoplasia and may also predict the need for ECMO. Weidner and colleagues demonstrated lower FLV:FBV ratios in infants who required ECMO ⁴¹⁾. While the timing of congenital diaphragmatic hernia repair for infant on ECMO remains controversial, there are studies that show that surgical repair of congenital diaphragmatic hernia while on ECMO, can be done safely and is associated with good survival and there may be increased mortality associated with delayed repair ⁴²⁾. Pulmonary hypertension contributes to significant mortality in patient with congenital diaphragmatic hernia and this particular subset of patients may have additional benefit from early ECMO support.

There is conflicting data regarding the efficacy of inhaled nitric oxide (iNO) to manage pulmonary hypertension secondary to congenital diaphragmatic hernia. Randomized controlled trials of inhaled nitric oxide (iNO) treatment for infants with congenital diaphragmatic hernia have shown marginal, if any, efficacy. Poor left ventricular function and/or left ventricular hypoplasia may account for some of the poor response to iNO. Infants with severe respiratory failure secondary to pulmonary hypoplasia and documented persistent pulmonary hypertension of the newborn may benefit from iNO, but the data are limited ⁴³⁾. Aggressive ventilation in these infants causes overexpansion of lungs with compresses intra-alveolar capillaries which further aggravates pulmonary hypertension. If this is the case, hemodynamics should be optimized prior to initiating nitric oxide. More recently there are smaller population studies that show that nitric oxide may be beneficial as adjunct therapy in combination with Sildenafil and dopamine infusions to improve survival, but larger studies are needed ⁴⁴⁾.

Low lung compliance associated with congenital diaphragmatic hernia is thought to be secondary to surfactant deficiency, although there is very limited and conflicting data regarding this theory. One study shows that infants with congenital diaphragmatic hernia had lower rates of synthesis of surfactant protein B (SP-B) and less SP-B in tracheal aspirates compared with age-matched controls without lung disease ⁴⁵⁾. While surfactant is not contraindicated, it does not seem to provide additional survival benefit in infants with congenital diaphragmatic hernia.

Of note, overexpansion of hypoplastic lungs compresses intra-alveolar capillaries and aggravates pulmonary hypertension. Partial liquid ventilation has also been used; however, data are lacking to support or refute the use of partial liquid ventilation in children with acute lung injury or acute respiratory distress syndrome ⁴⁶⁾.

Dialysis for support of renal function is provided in some cases, but it should be started only after careful consideration. Patients with severe chronic renal impairment with pulmonary hypoplasia have a poor prognosis; the ultimate outcome is difficult to improve, even with optimal renal and respiratory support.

Some studies suggest that strict infection control may improve the outcome of neonates with congenital diaphragmatic hernia without the need for extracorporeal membrane oxygenation (ECMO) ⁴⁷⁾.

Medical management of cystic adenomatoid malformations (CCAM) and prognosis is dependent on the size of the lesion. Microcysts 58</ref> Spontaneous improvement and possible resolution may occur over months to years in many of these lesions ⁴⁸⁾. Their management must be individualized, with very large lesions resulting in lung hypoplasia or fetal hydrops required possible fetal surgery ⁴⁹⁾. In most cases of fetal lung lesions, continued observation with possible postnatal therapy occurs if respiratory distress or failure to thrive develops ⁵⁰⁾.

Multiple studies have proven the importance of the retinoic acid signaling pathway in lung development as mentioned above. In keeping with this, the role of retinoic acid supplementation and antioxidants in pulmonary hypoplasia has been extensively studied. There is some promising human data that demonstrated decrease in incidence of bronchopulmonary dysplasia in extremely low birth infants who received vitamin A supplementation ⁵¹⁾. There are also several animal models that show an increase in VEGF expression and increased lung alveolarization in response to vitamin A supplementation. Despite encouraging in vitro work, supplementation with vitamin A failed to reverse oligohydramnios-induced pulmonary hypoplasia in fetal rats.

Surgical treatment

A multidisciplinary team with expertise in fetal surgery should be involved, when feasible, in all cases of severe pulmonary hypoplasia. A major indication for fetal surgery is the presence of hydrops and a gestation of less than 32 weeks. In general cases that require surgical intervention are large cystic lung malformations and congenital diaphragmatic hernias.

Cystic lung malformations

Thoracocentesis or thoracoamniotic shunts can allow for drainage of fluid from the congenital cystic adenomatoid malformation (CCAM), but the fluid usually rapidly re-accumulates. Thoracoamniotic shunts may be offered in pregnancies complicated by hydrops secondary to the presence of a large or multiple communicating macrocysts or severe pleural effusions. Shunt placement has been reported to decrease congenital cystic adenomatoid malformation (CCAM) mass volumes by an average of 50%, and as much as 80% in some cases ⁵²⁾.

In cases of significant mass effect due to congenital congenital cystic adenomatoid malformations (CCAMs) (or other solid lung mases) recommendations for delivery can range from an ex utero intrapartum treatment (EXIT) procedure with tumor resection while still on placental bypass, to elective cesarean delivery and immediate pediatric surgical evaluation and resection, to delivery with on-site pediatric surgical services. In cases in which masses plateau earlier in their growth phase, and presents a nonsignificant risk of pulmonary hypoplasia or hemodynamic compromise, surgery can be planned as an outpatient at age 4-6 week ⁵³⁾. Therefore, the management of the congenital cystic lung abnormalities needs to consider the spontaneous improvement and possible resolution that occurs over months to years in many of these lesions ⁵⁴⁾. Up to 15% of prenatally diagnosed congenital cystic adenomatoid malformations (CCAMs) regress and may sonographically “disappear” by becoming isoechoic within the surrounding normal lung tissue. However, these lesions can still be identified on postnatal CT scan with contrast.

The risks of subsequent malignant degeneration of congenital cystic adenomatoid malformations (CCAMs) are poorly understood. After removal by lobectomy, the remaining normal ipsilateral lung demonstrates compensatory lung growth, and in general these children have no residual respiratory problems ⁵⁵⁾.

Thoracocentesis or thoracoamniotic shunts can allow for drainage of fluid from the congenital cystic adenomatoid malformation (CCAM), but the fluid usually rapidly reaccumulates. Thoracoamniotic shunts may be offered in pregnancies complicated by hydrops secondary to the presence of a large or multiple communicating macrocysts or severe pleural effusions. Shunt placement has been reported to decrease congenital cystic adenomatoid malformation (CCAM) mass volumes by an average of 50%, and as much as 80% in some cases ⁵⁶⁾.

Intrauterine vesicoamniotic shunts and endoscopic ablation of posterior urethral valves are other techniques that are currently used in fetuses with urinary tract obstruction and pulmonary hypoplasia. With careful case selection, pulmonary hypoplasia is prevented, and postnatal renal and respiratory function is improved ⁵⁷⁾.

Congenital diaphragmatic hernia

In experimental animals, percutaneous fetal endoluminal tracheal occlusion (FETO) induces lung growth and morphologic maturation. Fetal endoluminal tracheal occlusion (FETO) with a clip may lead to accelerated lung growth and prevent pulmonary hypoplasia. Fetal endoluminal tracheal occlusion (FETO) is currently being studied at some centers across Europe, as a way to improve survival in cases of pulmonary hypoplasia associated with severe congenital diaphragmatic hernia ⁵⁸⁾. There are variations in the technique but most centers prefer the non-invasive technique, where a balloon, inserted into the tracheal lumen at 22-28 weeks’ gestation ⁵⁹⁾. Balloon occlusion creates a transpulmonic pressures, prevent fluid egress of fluid from the fetal lung which stimulate lung growth. It has been suggested that later insertion of the balloon beyond 29 weeks does not results in significant lung growth ⁶⁰⁾. A recent study from Texas has reported improved postnatal outcomes in infants with severe congenital diaphragmatic hernia ⁶¹⁾. This procedure was found to be minimally invasive, may reverse pulmonary hypoplasia changes, and may improve survival rate in these highly selected cases. In addition, the airways can be restored before birth.

The optimal time of surgery for congenital diaphragmatic hernia repair varies from center to center. Surgical repair typically involves primary or patch closure of the diaphragm through an open abdominal approach. Successes have been reported with an endoscopic approach; however, it is associated with an increased incidence of hernia recurrence ⁶²⁾. The decision is made based on the severity of the lesion, hemodynamics of the patient and the center’s preferences. Intraoperative considerations include the length of operative time, as thoracoscopic repair is associated with substantially longer operative times, leading to concerns for intraoperative instability, carbon dioxide retention, and pulmonary vasospasm for patients with moderate-to-severe pulmonary hypertension ⁶³⁾. There are some studies that suggest that early intervention in patients on ECMO, reduced the total duration of ECMO, reduced surgical complications and increased survival. However, this data may be skewed toward patients who may have been too sick to be weaned off ECMO prior to surgery and further studies are needed ⁶⁴⁾.

Follow up care

Since chronic lung disease is common in survivors of pulmonary hypoplasia, these infants and children have an increased risk of fatality and serious morbidity from upper respiratory tract infections (URTIs) and lower respiratory tract infections (LRTIs). Antiviral and antibiotics should be administered based on clinical symptoms and signs.

Children may be given bronchodilators and/or inhaled corticosteroids for the treatment of wheezing episodes and/or reactive airway disease.

Respiratory syncytial virus (RSV) prophylaxis should be considered during RSV season in infants younger than two years who have been treated with oxygen or medication for chronic lung disease within 6 months of the start of RSV season. Palivizumab is a humanized monoclonal antibody (IgG) directed against the fusion protein of RSV and has been shown to reduce the risk of hospitalization from RSV infection in high-risk pediatric patients by 55%. RSV season in most parts of the United States is from October to March. The dose is 15 mg/kg via intramuscular injection monthly throughout RSV season.

Children with pulmonary hypoplasia should receive the influenza vaccine at the start of every influenza season, which in the United States, while varying from season to season, begins as early as October. The influenza season peaks in January or February and continues as late as May.

Children with chronic lung disease are considered at high risk for invasive pneumococcal disease. If younger than two years, they should be administered the 13-valent pneumococcal conjugate vaccine (PCV13) 4-dose series at ages two, four, and six months, with a booster dose at 12-15 months. If aged 24 months to five years, they should receive 1 or 2 doses of PCV13 if they have not already completed the 4-dose series. Anyone over the age of two, with chronic lung disease, should also receive 1 dose of PCV23.

Pulmonary hypoplasia prognosis

Mortality has traditionally been very high. In a retrospective study of 76 premature infants less than 35 weeks’ gestation, 20 had prolonged rupture of membrane of more than 5 days and were clinically diagnosed with pulmonary hypoplasia. Of those 20 infants with pulmonary hypoplasia, 18 died. In another retrospective study of 117 infants of less than 37 weeks’ gestation who had prolonged rupture of membrane of more than 99 hours, 11 died and were considered to have pulmonary hypoplasia. The median age of death was 20 hours (range, 12-48 hours), mostly commonly from respiratory failure.

In different studies, mortality rates associated with pulmonary hypoplasia are reported to be as high as 71-95% in the perinatal period ⁶⁵⁾.

The following conditions increase the risk of mortality ⁶⁶⁾:

• Earlier gestational age at rupture of membranes, particularly at less than 25 weeks of gestation
• Severe oligohydramnios (amniotic fluid index < 4) for more than 2 weeks
• Earlier delivery (decreased latency period)
• Right-sided lesion
• Presence of genetic anomalies

To avoid mortality from severe lung hypoplasia in association with congenital diaphragmatic hernia or congenital cystic adenomatoid malformation (CCAM), fetal surgical intervention has been attempted. Most studies report a mortality rate of 25-30% in neonates with congenital diaphragmatic hernia andcongenital cystic adenomatoid malformation (CCAM) at high volume centers; mortality can be as high as 45% at peripheral care centers. However, in other cystic lung lesions, most are clinically asymptomatic and may not need aggressive management ⁶⁷⁾.

Risk factors for a poor outcome include the presence of hydrops fetalis, with a mortality rate as high as 80-90%. Other indicators include the type of congenital cystic adenomatoid malformation (CCAM) and its size. All of these factors reflect the degree of pulmonary compromise with lesions that result in varying degrees of pulmonary hypoplasia.

There is a recent retrospective study from Barcelona that studied 60 cases of pulmonary hypoplasia between 1995 to 2014, that found a mortality rate of 47% in the first 60 days of life and up to 75% in the first day of life ⁶⁸⁾.

While antepartum amnioinfusions for treatment of oligohydramnios have significantly reduced the risk of pulmonary hypoplasia, longitudinal follow-up studies are lacking on the long-term outcomes of these children.

Of children with pulmonary hypoplasia secondary to congenital diaphragmatic hernia, the postnatal survival rate of congenital diaphragmatic hernia at tertiary centers has improved, with reported rates of 70-92% ⁶⁹⁾. However, the survival rates do not account for the cases of congenital diaphragmatic hernia that are stillborn, died outside a tertiary center, or died as a result of spontaneous or therapeutic abortion.

Congenital diaphragmatic hernia survivors have a high incidence of respiratory, nutritional, musculoskeletal, neurological, and gastrointestinal morbidities ⁷⁰⁾. In a prospective study of 41 congenital diaphragmatic hernia survivors, abnormal muscle tone was found in 90% at age 6 months and 51% at age 24 months. While almost half (49%) had normal scores for neurocognitive and language skills, 17% had mildly delayed and 15% had severe delayed scores. Likewise, in psychomotor testing, while 46% had normal scores, 23% and 31% scored as mildly delayed and severely delayed, respectively. Autism was present in 7%. Studies of brain maturation using MRI show delayed structural brain development and other abnormalities that may lead to long-term neurologic complications ⁷¹⁾.

In a retrospective follow-up study of 55 children survivors with scimitar syndrome followed at one center, a high rate of respiratory complications was observed. All (100%) of the children had right lung hypoplasia of varying degrees of severity. The median duration of follow-up was 7.2 years. Pulmonary infections were reported in 38%, and 43% of children reported wheezing episodes during the last 12 months of follow-up. A restrictive pattern of lung function was observed in the majority of patients, likely related to right-sided lung hypoplasia. Lower total lung capacity values were seen in children with the infantile form of scimitar syndrome, possibly reflective of the severity of pulmonary hypoplasia in these children ⁷²⁾.

Right-sided hypoplasia, typically secondary to right sided congenital diaphragmatic hernia, seems to carry a higher mortality. This is likely due to higher risk of recurrent herniation, increased risk of pulmonary complications, requiring pulmonary vasodilator therapy and tracheostomy. However, no differences in neurodevelopmental outcomes was found ⁷³⁾.

A minimum lung volume of 45% compared with age-matched control subjects has been shown to be a predictor of survival in neonates with diaphragmatic hernia treated with extracorporeal membrane oxygenation (ECMO). Similarly, a functional residual capacity of 12.3 mL/kg, about one half the normal capacity, has been thought to be a predictor of survival in pulmonary hypoplasia with congenital diaphragmatic hernia.

Hyperparathyroidism in children

Hyperparathyroidism is caused by overactive parathyroid glands. Parathyroid glands are tiny glands located near the thyroid. Hyperparathyroidism is quite rare in children and usually presents with bone disease or kidney stones ¹⁾. Overactive parathyroid glands produce high levels of parathyroid hormone (PTH), which, in turn, results in increased levels of calcium in the bloodstream ²⁾. The excess calcium released by the bones can lead to osteoporosis and osteomalacia (both bone-weakening diseases). Another result of hyperparathyroidism is kidney stones, because of high levels of calcium excreted into the urine by the kidneys.

The parathyroid glands are 4 tiny glands that lie in your neck, just behind the butterfly shaped thyroid gland. Sometimes the parathyroid glands may also be found elsewhere in the body.

The parathyroid glands are not related to the thyroid except by name ( ‘para’ comes from the Greek for ‘near’) and they have a completely different function from the thyroid.

Most people have four tiny yellow glands which are about the size of a grain of rice. The job of the parathyroid glands is to continually adjust your calcium levels to keep them stable. Parathyroid hormone (PTH) is secreted by parathyroid glands and plays a role in calcium and skeletal metabolism ³⁾. Parathyroid hormone (PTH) helps manage levels of calcium in your bloodstream. High levels of the parathyroid hormone (PTH) lead to high levels of calcium. This occurs because the hormone causes bones to start breaking down. Minerals from the bone are released into the blood. This causes high levels of calcium in the blood (hypercalcemia). The calcium is then processed by the kidneys. This process can cause thinning bones (osteoporosis) and kidney stones. Kidney stones are hard mineral crystals that get stuck in the urinary system. On the other hand, the secretion of parathyroid hormone (PTH) is reduced by 1,25 (OH)(2) vitamin D(3) ⁴⁾.

Figure 1. Parathyroid glands

What do the parathyroid glands do?

The parathyroid glands’ only purpose is to make parathyroid hormone (PTH), which helps maintain the right balance of calcium in your body. Parathyroid hormone (PTH) raises blood calcium levels by:

• causing bone, where most of your body’s calcium is stored, to release calcium into the blood
• helping your intestines absorb calcium from food
• helping your kidneys hold on to calcium and return it to your blood instead of flushing it out in urine

When the level of calcium in your blood falls too low, the parathyroid glands release just enough parathyroid hormone (PTH) to bring your blood calcium levels back to normal.

You need calcium for good health. This mineral helps build bones and teeth and keep them strong. Calcium also helps your heart, muscles, and nerves work normally.

Although their names are similar, the parathyroid glands and the thyroid gland are not related.

Pediatric hyperparathyroidism causes

Causes of hyperparathyroidism include benign (noncancerous) tumors on the parathyroid glands or enlargement of the parathyroid glands.

Primary hyperparathyroidism

“Primary” means this disorder begins in the parathyroid glands, rather than resulting from another health problem such as kidney failure. In primary hyperparathyroidism, one or more of the parathyroid glands is overactive. As a result, the gland makes too much parathyroid hormone (PTH).

In primary hyperparathyroidism too much parathyroid hormone (PTH) is produced by one or more of the parathyroid glands because they have become enlarged or overactive. This in turn causes the body to release calcium from the bones into the blood and results in high calcium levels (hypercalcaemia).

Primary hyperparathyroidism causes ⁵⁾:

• Single adenoma
• Multigland disease
  • Familial causes of hyperparathyroidism
  • Multiple endocrine neoplasia type 1 (MEN 1)
  • Multiple endocrine neoplasia type 2A (MEN 2A)
  • Familial hyperparathyroidism
  • Hyperparathyroidism-jaw tumor syndrome
• Parathyroid carcinoma

In about 8 out of 10 people the most common cause of primary hyperparathyroidism is a parathyroid gland becoming enlarged due to the development of a benign (non-cancerous) tumor called an adenoma ⁶⁾. The tumor causes the gland to become overactive. This is more commonly diagnosed in women, particularly postmenopausal women, but can affect both men and women and all ages, including, less commonly, children.

In most other cases, extra PTH comes from two or more adenomas or from hyperplasia, a condition in which all four parathyroid glands are enlarged. People with rare inherited conditions that affect the parathyroid glands, such as multiple endocrine neoplasia type 1 or familial hypocalciuric hypercalcemia are more likely to have more than one gland affected.

Sometimes all four parathyroid glands may become enlarged – this is called parathyroid hyperplasia. This may occur sporadically (without a family history) or as part of three familial (inherited) syndromes: multiple endocrine neoplasia type 1 (MEN 1) and multiple endocrine neoplasia type 2A (MEN 2A), and isolated familial hyperparathyroidism. In MEN 1, the problems in the parathyroid glands are associated with other tumors in the pituitary and the pancreas. In MEN 2A, overactivity of the parathyroid glands is associated with tumors in the adrenal gland or thyroid.

Radiotherapy treatment to your head or neck may increase the risk of developing a parathyroid adenoma or carcinoma (cancer). Only in extremely rare cases will the tumor be due to parathyroid cancer (parathyroid carcinoma).

How common is primary hyperparathyroidism?

In the United States, about 100,000 people develop primary hyperparathyroidism each year ⁷⁾. Primary hyperparathyroidism is one of the most common hormonal disorders.

Who is more likely to develop primary hyperparathyroidism?

Primary hyperparathyroidism most often affects people between age 50 and 60. Women are affected 3 to 4 times more often than men ⁸⁾. The disorder was more common in African Americans, followed by Caucasians, in one large study performed in North America ⁹⁾.

Pediatric hyperparathyroidism symptoms

Most people with primary hyperparathyroidism have no symptoms. When symptoms appear, they’re often mild and similar to those of many other disorders.

The following are the most common symptoms of hyperparathyroidism in children. However, each child may experience symptoms differently. Symptoms may include:

• Kidney pain (due to the presence of kidney stones)
• Diminished bone density that causes bone pain
• Joint aches and pains
• Abdominal pain
• Nausea
• Vomiting
• Fatigue
• Excessive urination
• Confusion
• Muscle weakness
• Fractures
• Weight loss
• Diarrhea
• Depression
• Headache

Figure 2. Primary hyperparathyroidism symptoms

If left untreated, symptoms can become much worse.

In severe cases, extremely high levels of calcium (hypercalcemia) can cause:

• vomiting
• drowsiness
• dehydration
• confusion – difficulty thinking and speaking clearly
• agitation
• muscle spasms, tremors.
• bone fractures
• irregular heart beat
• high blood pressure
• loss of consciousness
• coma and, very rarely, if not treated, death

Hypercalcemia can be a life threatening condition if it is not treated.

Compared to adults, children more commonly have symptoms and involvement of other parts of the bodies, such as kidney, pancreas, and bones, at diagnosis. Additionally, hyperparathyroidism in children is more commonly part of a syndrome, such as multiple endocrine neoplasia (MEN).

The symptoms of hyperparathyroidism may resemble other conditions or medical problems. Always consult your child’s doctor for a diagnosis.

Long term effects

If primary hyperparathyroidism goes undiagnosed, further complications, can develop. Primary hyperparathyroidism most often affects the bones and kidneys, although it also may play a part in other health problems.

High blood calcium levels might play a part in other problems, such as heart disease, high blood pressure, and trouble concentrating. However, more research is needed to better understand how primary hyperparathyroidism affects the heart, blood vessels, and brain.

These are common complications of primary hyperparathyroidism:

Kidney stones

The small intestine may absorb more calcium from food, adding to high levels of calcium in your blood. Extra calcium that isn’t used by your bones and muscles goes to your kidneys and is flushed out in urine. The kidneys play an important role in regulating the blood calcium levels and operate to restore the correct levels by removing excess calcium from the blood. Over a prolonged period of time excess calcium can accumulate and form kidney stones. Small stones may be passed in the urine without you noticing but larger stones may get stuck. These can cause pain in your loin area that radiates to your groin. You may also notice blood in your urine. Kidney stones can be very painful. Continual high levels of calcium in your blood can damage your kidneys and eventually can cause kidney failure.

Weakened bones

Increased parathyroid hormone (PTH) in your blood causes too much calcium to be released from your bones, which can lead to weakness and bone pain. This can eventually cause osteopenia and osteoporosis. It also makes the bones more susceptible to fractures. If bones break after a low impact fall it may be indicative of primary hyperparathyroidism.

Left untreated, many patients with primary hyperparathyroidism have progressive loss of cortical bone while successful surgery leads to a substantial increase in bone mineral density, an effect that can persist for up to 15 years ¹⁰⁾.

Eyes

Calcium can be collect in the cornea of your eye (corneal calcifications) but this doesn’t usually cause any symptoms.

Pancreas

Although it is rare, high calcium can cause inflammation of your pancreas and this causes upper abdominal pain (pancreatitis).

Stomach

High calcium levels can stimulate the production of excess acid in your stomach and lead to peptic stomach ulceration.

Brain

Calcium plays an important role in the normal working of the brain and spinal cord. Patients whose primary hyperparathyroidism goes undiagnosed for a long time and who therefore suffer from hypercalcemia over a long period of time, may develop some of the following symptoms: fits, uncoordinated muscles (affecting walking, talking and eating), changes in personality and/or hallucinations.

Pediatric hyperparathyroidism diagnosis

The subtle nature of the symptoms of hyperparathyroidism can result in the condition going undiagnosed for some time, although the diagnosis of hyperparathyroidism is generally clear once appropriate tests are done.

The key to diagnosis is to check the level of calcium in the blood and at the same time to measure the levels of parathyroid hormone (PTH) and vitamin D. These three elements interact with each other and it is the relationship between them that is important in reaching a diagnosis.

Blood tests

• total calcium
• parathyroid hormone (PTH)
• vitamin D (25 OH cholecalciferol)

In a straightforward case, blood tests will show a high level of calcium, a high level of parathyroid hormone (PTH) and often (though not always) a low level of vitamin D in your blood. Phosphate levels may also be low. Elevated PTH is the only source in primary hyperparathyroidism.

Once doctors diagnose hyperparathyroidism, a 24-hour urine collection can help find the cause. This test measures certain chemicals, such as calcium and creatinine, a waste product that healthy kidneys remove. You will collect your urine over a 24-hour period and your health care professional will send it to a lab for analysis. Results of the test may help tell primary hyperparathyroidism from hyperparathyroidism caused by a kidney disorder. The test can also rule out familial hypocalciuric hypercalcemia, a rare genetic disorder, as a cause.

However, sometimes diagnosis is more difficult. Your tests may be normal (within the reference range) or levels not especially high, but you may still be experiencing symptoms. This can lead to a doctor determining you to be a ‘mild case’ and deciding to monitor you for a while – the practice of ‘watch and wait’ that some doctors adopt can lead to much distress.

In addition to a complete medical history and physical examination, diagnostic procedures for hyperparathyroidism may include:

• Bone X-rays. A diagnostic test that uses invisible electromagnetic energy beams to produce images of internal tissues, bones, and organs onto film.
• Laboratory tests. The tests will measure calcium, phosphorus, magnesium, and hormone levels.
• Ultrasonography. A procedure that evaluates the structure of the parathyroid gland using sound waves recorded on an electronic sensor.
• Nuclear medicine tests. These include Sestamibi and other scans that use small amounts of radioactive materials to evaluate how a parathyroid gland is functioning and to help diagnose problems.
• Computed tomography scan (also called a CT or CAT scan). A diagnostic imaging procedure that uses a combination of X-rays and computer technology to produce horizontal, or axial, images (often called slices) of the body. A CT scan shows detailed images of any part of the body, including the bones, muscles, fat, and organs. CT scans are more detailed than general X-rays.
• Magnetic resonance imaging (MRI). A diagnostic procedure that uses a combination of large magnets, radiofrequencies, and a computer to produce detailed images of organs and structures within the body.

Pediatric hyperparathyroidism treatment

Specific treatment for hyperparathyroidism will be determined by your child’s doctor in consultation with you.

Considerations include:

• Your child’s current health status and past health history
• Severity of the condition
• Your child’s ability to take medications and tolerate medical procedures
• Expectations for the course of the disease
• Your beliefs and concerns

Treatment often includes surgery to remove the parathyroid tissue, but sometimes your child may be monitored or offered medical treatment, depending on your child’s circumstances. Medical treatment with bisphosphonates or cinacalcet can be useful in selected patients ¹¹⁾. The decision whether to recommend surgery is based on age, the degree of hypercalcemia, and the presence or absence of complications due to hyperparathyroidism.

Some patients who are not surgical candidates may benefit from medical management of primary hyperparathyroidism.

• Bisphosphonates can increase bone mineral density in those with osteoporosis or osteopenia.
• Agonists to the calcium-sensing receptor, such as cinacalcet will lower PTH and calcium levels. Cinacalcet is a medicine that decreases the amount of PTH the parathyroid glands make and lowers calcium levels in the blood. Doctors may prescribe cinacalcet to treat very high calcium levels in people with primary hyperparathyroidism who can’t have surgery. However, they do not increase bone density ¹²⁾. If you have bone loss, your doctor may prescribe alendronate or other medications to help increase bone density.

For patients where observation is the selected course of action, periodic monitoring with measurement of serum and urine calcium, renal function, and bone densitometry is required. If there is worsening hypercalcemia or development of complications, then surgery should be recommended ¹³⁾.

Surgery

Surgery is the treatment of choice for those with recurrent kidney stones.

The only cure for primary hyperparathyroidism is surgery to remove the affected parathyroid gland(s) and usually brings about a permanent cure. This operation is called a parathyroidectomy. In the hands of an experienced surgeon the success rates are high, particularly if the affected gland(s) can be located by preoperative scans. However, very often scans are negative or inconclusive. A skilled surgeon will not necessarily regard this as an obstacle to going ahead with surgery.

The current guidelines state that surgery should be recommended for asymptomatic primary hyperparathyroidism when ¹⁴⁾:

• Serum calcium is more than 1 mg/dL greater than the upper limit of normal
• Age younger than 50 years
• Osteoporosis
• GFR less than 60 mL/min
• Urine calcium greater than 400 mg/24 hours
• Evidence of renal calcification or stones

Most commonly one, or at most two, parathyroid adenomas are removed. However, all abnormal parathyroid glands may need to be removed if all four parathyroid glands are overactive, as in the rarer condition of parathyroid hyperplasia. In this case it may be possible to leave half a parathyroid gland in situ to avoid developing hypoparathyroidism, a lifelong condition, but this is not always possible. It is essential to discuss your treatment plan with your surgeon.

Parathyroid surgery is normally a straightforward procedure most often requiring an overnight hospital stay for recovery. For removal of a single adenoma, most surgeons are able to perform minimally invasive surgery via a small incision which, after healing, leaves a barely visible scar.

Surgeons often use imaging tests before surgery to locate the overactive gland or glands to be removed. The tests used most often are sestamibi, ultrasound, and CT scans. In a sestamibi scan, you will get an injection, or shot, of a small amount of radioactive dye in your vein. The overactive parathyroid gland or glands then absorb the dye. The surgeon can see where the dye has been absorbed by using a special camera.

Surgeons use two main types of operations to remove the overactive parathyroid gland or glands:

1. Minimally invasive parathyroidectomy. Also called focused parathyroidectomy, surgeons use this type of surgery when they think only one of the parathyroid glands is overactive. Guided by a tumor-imaging test, your surgeon will make a small incision, or cut, in your neck to remove the gland. The small incision means you will probably have less pain and a faster recovery than people who have more invasive surgery. You can go home the same day. Your doctor may use regional or general anesthesia during the surgery.
2. Bilateral neck exploration. This type of surgery uses a larger incision that lets the surgeon find and look at all four parathyroid glands and remove the overactive ones. If you have bilateral neck exploration, you will probably have general anesthesia and may need to stay in the hospital overnight.

Parathyroid surgery is safe. Rarely, problems can occur after surgery. In about 1 out of every 100 people, the nerves controlling the vocal cords are damaged during surgery, which most often results in hoarseness ¹⁵⁾. This condition usually gets better on its own.

Low calcium levels in the blood may occur after surgery but usually return to normal in a few days or weeks. On rare occasions, not enough parathyroid tissue is left to make PTH, which can result in hypoparathyroidism.

Should I change my diet if I have primary hyperparathyroidism?

You don’t need to change your diet or limit the amount of calcium you get from food and beverages. You will need to take a vitamin D supplement if your vitamin D levels are low. Talk with your health care professional about how much vitamin D you should take.

If you lose all your healthy parathyroid tissue and develop lasting low-calcium levels, you’ll need to take both calcium and vitamin D for life.

Monitoring

Some people who have mild primary hyperparathyroidism may not need surgery right away, or even any surgery, and can be safely monitored.

You may want to talk with your doctor about long-term monitoring if you

• don’t have symptoms
• have only slightly high blood calcium levels
• have normal kidneys and bone density

Long-term monitoring should include regular doctor visits, a yearly blood test to measure calcium levels and check your kidney function, and a bone density test every 1 to 2 years.

If you and your doctor choose long-term monitoring, you should

• drink plenty of water so you don’t get dehydrated
• get regular physical activity to help keep your bones strong
• avoid certain diuretics, such as thiazides

Childhood glaucoma

Childhood glaucoma also called congenital glaucoma, pediatric glaucoma or infantile glaucoma, is glaucoma that occurs in babies and young children. Childhood glaucoma is usually diagnosed within the first year of life. Glaucoma is a condition in which the normal fluid pressure inside the eyes (intraocular pressure or IOP) slowly rises as a result of the fluid aqueous humor – which normally flows in and out of the eye – not being able to drain properly from the anterior chamber of the eye resulting in increased pressure within the eye. Instead, the fluid collects and causes pressure damage to the optic nerve (a bundle of more than 1 million nerve fibers that connects the retina with the brain) and loss of vision.

Glaucoma is classified according to the age of onset. Glaucoma that begins before the child is 3 years old is called infantile or congenital (present at birth) glaucoma. Glaucoma that occurs in a child is called childhood glaucoma. Infantile glaucoma develops between the ages of 1-24 months. Glaucoma with onset after age 3 years is called juvenile glaucoma. Another way to classify glaucoma is to describe the structural abnormality or systemic condition which underlies the glaucoma.

Childhood glaucoma is a rare condition that may be inherited, caused by incorrect development of the eye’s drainage system before birth. This leads to increased intraocular pressure (IOP), which in turn damages the optic nerve. It is estimated that 1 in 5,000 to 10,000 children under 2 years of age will develop primary congenital/ primary infantile glaucoma. However, if a child has cataract surgery or one of the other conditions listed above, the incidence of glaucoma will be much higher. For example, 50% of patients with aniridia will develop glaucoma during their lifetime.

Symptoms of childhood glaucoma include enlarged eyes, cloudiness of the cornea, and photosensitivity (sensitivity to light). Your child needs to be assessed by an ophthalmologist. Ideally the child should be referred to an ophthalmologist with experience in managing childhood glaucoma. The nature of assessment undertaken varies with the age of the child. In children over 7 years the tests used are very similar to those used for adults, i.e. pressure measurement, visual field assessment and examination of the optic disc after dilatation of the pupil.

Both medication and surgery are required in some cases. In an uncomplicated case, surgery can often correct such structural defects.

The treatment for glaucoma in older children is generally medical (eye drops) initially and if these fail, surgery is considered. This is similar to the situation with older adults with glaucoma.

Medical treatments may involve the use of topical eye drops and oral medications. These treatments help to either increase the exit of fluid from the eye or decrease the production of fluid inside the eye. Each results in lower eye pressure.

There are two main types of surgical treatments: filtering surgery and laser surgery. Filtering surgery (also known as micro surgery) involves the use of small surgical tools to create a drainage canal in the eye. In contrast, laser surgery uses a small but powerful beam of light to make a small opening in the eye tissue. Most glaucoma surgery in children can be done safely as a day case without the need for overnight admission. If surgery is required within the first four to five weeks of life the infant may remain in overnight for monitoring after the anesthetic.

Operations such as trabeculectomy or drainage tubes are used. These procedures aim to create a controlled leak or “fistula” by which the aqueous can bypass the trabecular meshwork and escape to drain via the external blood system of the eye.As with adults anti-inflammatory and antibiotic drops are used post operatively. When trabeculectomy is performed in children an anti-metabolite such as 5-fluorouacil (5-FU for short) is very often used as children heal much more rapidly than adults.Laser trabeculoplasty is rarely used in the treatment of glaucoma in children of any age. A cyclo-destructive procedure, such as diode laser treatment of the ciliary body, is sometimes used in the treatment of aphakic glaucoma in children.

Despite timely and aggressive treatment, childhood glaucoma can still cause significant and permanent vision loss. Early diagnosis and treatment, as well as close monitoring are crucial for obtaining a long-term successful outcome.

Figure 1. Eye anatomy

Figure 2. Normal aqueous outflow

How would a parent know if a child is suffering from glaucoma?

In keeping with the rest of an infant the immature eye is floppy and somewhat elastic. Thus early in life (that is before the second birthday) raised intraocular pressure will stretch the eye and actually cause it to increase in size (it expands in all directions/ rather like a balloon being inflated). Early medical writers termed this buphthalmos (ox eye) as this increase in size of the eye was thought to make the infant’s eye look like an ox’s eye.

The stretching of the eye has a number of harmful effects on the eye. As the eye enlarges the cornea increases in size. One of the many layers of the cornea, Descemet’s membrane, does not have much give and rather than stretch it will split as the eye enlarges. This splitting results in the cornea losing some of its clarity and becoming cloudy. This cloudiness of the cornea is the result of fluid entering the cornea from the anterior chamber via the splits in Descemet’s membrane and is known as corneal edema. Corneal edema causes discomfort and sensitivity to light and increased tear production.

Thus the cardinal features of infantile glaucoma that may be identified by a parent are photophobia (sensitivity to light), increased tearing with an enlarged and cloudy cornea.

What happens when glaucoma is suspected in a young child?

The child needs to be assessed by an ophthalmologist (eye specialist). Ideally the child should be referred to an ophthalmologist with experience in managing childhood glaucoma. Often an examination under anesthetic is required to adequately examine the child and confirm the diagnosis of glaucoma. The diagnosis is confirmed by the presence of typical corneal changes (enlargement, clouding and splits in Descemet’s membrane), raised intraocular pressure and optic disc cupping.

Will my child’s vision be impaired?

Severe loss of vision due to infantile glaucoma is fortunately rare. However, if glaucoma is not appropriately treated there is a risk of progressive visual impairment. Rarely does childhood glaucoma result in severe visual impairment but life-long follow-up is needed for all children after a diagnosis of glaucoma is made. Vision impairment is particularly seen if the onset of the glaucoma is at or before birth. Glasses are commonly required for myopia (short sightedness). This is due to the overall length of the eyeball being increased by the raised intraocular pressure. Photophobia may be a persistent problem if the splits in Descemet’s membrane are severe.

Therefore prompt recognition and timely treatment will improve the chance of a good vision outcome.

Will my child’s lifestyle need to alter in any way?

Most children with infantile glaucoma lead normal lives. Glasses may be required for focusing errors or photophobia. Adolescents often have difficulty accepting the need for long-term medication and regular medical review. Ensuring compliance with regular use of eye drops may be especially difficult. The small number of children with more severe visual impairment will require some degree of help at school.

Is childhood glaucoma hereditary?

Some types of childhood glaucoma are hereditary. About 10% of primary congenital/infantile glaucoma cases are inherited. Recent research has identified some specific gene mutations linked to this disease; for which genetic testing and counseling for affected families is may be available.

Other conditions that cause secondary glaucoma can be inherited. For example, neurofibromatosis and aniridia are dominantly inherited and are passed on to the children of affected individuals approximately 50% of the time. The incidence of glaucoma that occurs in association with these conditions, however, is less predictable.

What are the chances of another baby of mine developing glaucoma?

The risk is not zero but it is quite low. Primary open angle glaucoma in adolescents may show a familial tendency just as in adult open angle glaucoma. Inherited juvenile open angle glaucoma is well recognized but very rare. This form of glaucoma is generally not detectable till the twenties rather than during later childhood.

Childhood glaucoma causes

Glaucoma occurs when the fluid drainage from the eye is blocked by abnormal development or injury to the drainage tissues, thus, resulting in an increase in the intraocular pressure, damage to the optic nerve, and loss of vision.

There are many causes of childhood glaucoma. It can be hereditary or it can be associated with other eye disorders. If glaucoma cannot be attributed to any other cause, it is classified as primary glaucoma. If glaucoma is a result of another eye disorder, eye injury, or other disease, it is classified as secondary glaucoma.

Approximately 20% of children with primary congenital glaucoma have a mutation in the CYP1B1 gene. If one child in a family has primary congenital glaucoma then the risk for a subsequent child to be affected is about5% and if there are two affected children in one family the risk for subsequent children is 25%. Data suggests that the risk for a parent with a diagnosis of primary congenital glaucoma of having an affected child is 2%.

Most primary congenital glaucoma cases are sporadic (with no family history), however, about 10-40% are familial, with an autosomal recessive inheritance pattern and penetrance varying from 40-100% ¹⁾. Autosomal dominant inheritance has also been reported ²⁾. Five loci have been identified by linkage analyses: GLC3A (located on choromosome 2p22-p21), GLC3B (1p36.2-p36.1), GLC3C (14q24.3), GLC3D (14q24.2-q24.3, not overlapping with GLC3C), and GLC3E (9p21) ³⁾.

Thus far, a gene associated with primary congenital glaucoma has been identified in three of these five loci. Further details are below.

The GLC3A loci contains the cyctochrome P4501B1 (CYP1B1) gene, which was the first reported primary congenital glaucoma-causing gene. It codes for an enzyme that metabolizes compounds vital for the developing eye, and is expressed in fetal and adult neuroepithelium and ciliary body ⁴⁾. Severe trabecular meshwork atrophy is seen in mouse models deficient of CYP1B1 ⁵⁾. In zebrafish, CYP1B1 has been found to indirectly affect neural crest migration to the anterior segment and angle by playing a role in ocular fissure closure ⁶⁾. While the exact mechanism by which CYP1B1 mutations causes primary congenital glaucoma is unknown, scientists know that CYP1B1 mutations are associated with 15-20% of primary congenital glaucoma cases in Japan and the United States, and all cases in Slovakia Roma ⁷⁾.

The GLC3D locus contains latent transforming growth factor beta binding protein 2 (LTBP2). LTBP2 is expressed in trabecular meshwork and ciliary processes however its role in the eye is unknown ⁸⁾. In nonocular tissues, it is involved in tissue repair and cell adhesion ⁹⁾. LTBP2 null mutations have been reported in consanguineous Iranian and Pakistani families, and Slovakian Roma with primary congenital glaucoma. Homozygosity for a variant of an LTBP2 mutation was associated with worse outcomes even while undergoing more surgical interventions ¹⁰⁾.

GLC3E contains the tunica interna endothelial cell kinase (TEK, also known as TIE2) gene. The angiopoietin/TEK (ANGPT/TEK) signaling pathway is required in Schlemm canal development, and includes 3 ligands (ANGPT1, ANGPT2, and ANGPT4) and 2 receptors (TEK and TIE). TEK-knockout mice can have no Schlemm canal and TEK-hemizygous mice have a severely underdeveloped Schlemm canal ¹¹⁾. Additionally, ANGPT1 mutations have been identified in a few primary congenital glaucoma patients who do not have other known primary congenital glaucoma-causing genes, revealing another member of the ANGPT/TEK signaling pathway that may be a cause of primary congenital glaucoma ¹²⁾.

Lastly, though not associated with the above loci, but originally associated with juvenile open angle glaucoma and primary open angle glaucoma, the myocilin/trabecular meshwork-induced glucocorticoid response protein (MYOC) gene on chromosome 1q24 may also explain a small proportion of primary congenital glaucoma cases, up to 5.5% ¹³⁾.

Primary congenital glaucoma patients may have one or more genes affected, and the previously discussed genes may regulate or interact with each other ¹⁴⁾. CYP1B1 may play a role as a modifier gene for MYOC expression ¹⁵⁾ and a digenic mode of inheritance has been considered for CYP1B1 and MYOC ¹⁶⁾ and CYP1B1 and TEK ¹⁷⁾.

Currently, the chance of identifying a genetic cause is 40% when genetic testing is done ¹⁸⁾.

Infantile and childhood glaucoma may be associated with other abnormalities in the eye. The most common of these is a history of having had cataract surgery as an infant, this is called “aphakic glaucoma”. Other eye abnormalities that can be associated with glaucoma are the anterior segment dysgenesis group of disorders which includes Axenfeld-Reiger syndrome. Glaucoma can occur in association with other systemic abnormalities such as the Sturge-Weber syndrome and rubella (German measles) embryopathy. Juvenile arthritis may cause inflammation in the eye (uveitis) that may be complicated by the development of glaucoma. Primary open angle glaucoma does occur rarely in older children and adolescents.

Childhood glaucoma symptoms

Glaucoma is rare in children, as compared to the adult. However, when it does occur, the symptoms may not be as obvious in children. Many children are diagnosed before they are 6 months old. Glaucoma can affect one eye or both.

The most common symptoms of congenital/infantile glaucoma are excessive tearing, light sensitivity and a large, cloudy cornea (the normally clear front surface of the eye) which can cause the iris (colored part of the eye) to appear dull. Excessive tearing accompanied by mattering/discharge in a child is usually not caused by glaucoma but instead is the result of congenital nasolacrimal duct obstruction (blocked tear duct).

Juvenile glaucoma tends to develop without any obvious symptoms, similar to adult glaucoma. Patients with juvenile glaucoma often have a positive family history. On exam the eye pressure will typically be elevated and there may be signs of optic nerve cupping (enlargement of the center “cup” portion of the optic nerve).

The following are the most common symptoms of childhood glaucoma. However, each child may experience symptoms differently. Symptoms may include:

• excessive tearing
• light sensitivity (photophobia)
• closure of one or both eyes in the light
• cloudy, enlarged cornea (large eye)
• one eye may be larger than the other
• vision loss

If the eye pressure increases rapidly, there may be pain and discomfort. Parents may notice that the child becomes irritable, fussy, and develops a poor appetite. Early detection and diagnosis is very important to prevent loss of vision. The symptoms of glaucoma may resemble other eye problems or medical conditions. Always consult your child’s physician for a diagnosis.

Childhood glaucoma diagnosis

In addition to a complete medical history and eye examination of your child, diagnostic procedures for childhood glaucoma may include:

• visual acuity test – the common eye chart test (with letters and images), which measures vision ability at various distances.
• pupil dilation – the pupil is widened with eyedrops to allow a close-up examination of the eye’s retina and optic nerve.
• visual field – a test to measure a child’s side (peripheral) vision. Lost peripheral vision may be an indication of glaucoma.
• tonometry – a standard test to determine the fluid pressure inside the eye.

Younger children may be examined with hand-held instruments, whereas older children are often examined with standard equipment that is used with adults. An eye examination can be difficult for a child. It is important that parents encourage cooperation. At times, the child may have to be examined under anesthesia, especially young children, in order to examine the eye and the fluid drainage system, and to determine the appropriate treatment.

Childhood glaucoma treatment

Specific treatment for glaucoma will be determined by your child’s opthalmologist (eye specialist) based on:

• your child’s age, overall health, and medical history
• extent of the disease
• your child’s tolerance for specific medications, procedures, or therapies
• expectations for the course of the disease
• your opinion or preference

It is important for treatment of childhood glaucoma to start as early as possible. Childhood glaucoma is treated by lowering the intraocular pressure (IOP) via medical and/or surgical means. Treatment may include:

• Medications: Some medications cause the eye to produce less fluid, while others lower pressure by helping fluid drain from the eye.
• Conventional surgery: The purpose of conventional surgery is to create a new opening for fluid to leave the eye. Surgical procedures are performed by using microsurgery or lasers. The purpose of surgery is to create an opening for fluid to leave the eye. Surgical procedures used to treat glaucoma in children include the following:
  • Trabeculotomy and goniotomy: A surgical opening is made into the drainage area of the eye (known as the trabecular meshwork drainage system), therefore establishing a more normal anterior chamber angle that allows the fluid to drain more freely, lowering the intraocular pressure (IOP). A goniotomy is an internal trabeculotomy procedure that is used in congenital glaucoma.
  • Trabeculectomy: A surgical procedure that involves the removal of part of the trabecular meshwork drainage system, allowing the fluid to drain from the eye.
• Iridotomy: In this procedure, a small hole is made through the iris – the colored part of the eye – to allow fluid to flow more freely in the eye. The surgeon may use a laser to create this hole (laser iridotomy).
• Cyclophotocoagulation: A procedure that uses a laser beam to freeze selected areas of the ciliary body – the part of the eye that produces aqueous humor – to reduce the production of fluid. This type of surgery may be performed with severe cases of childhood glaucoma.

Both medications and surgery have been successfully used to treat childhood glaucoma. Most cases of primary childhood glaucoma are treated with surgery.

Initial treatment may be eye drops or medication by mouth to lower the pressure in the eye. Over the long-term medications have a significant risk of complication in young children and compliance with medical therapy is an even greater problem with young patients than it is with older ones. Surgery is usually required and has a very high success rate.

Childhood glaucoma is the result of blockage of aqueous (fluid) drainage at the trabecular meshwork of the anterior chamber angle. Operations aim to restore the more normal drainage of aqueous. The two most common operations are goniotomy and trabeculotomy. Both involve opening up the tissue in the angle to enable the aqueous to escape more easily from the eye and thus lower the pressure. All surgery for childhood glaucoma is done under a general anesthetic. It is not uncommon for more than one operation to be needed to completely control the raised pressure of infantile glaucoma.

In some instances operations more often used with adult glaucoma such as trabeculectomy or Molteno tubes are used. These procedures aim to create a controlled leak or “fistula” by which the aqueous can bypass the trabecular meshwork and escape from the eye. As with adults anti-inflammatory and antibiotic drops are used post operatively. When trabeculectomy is performed in children an antimetabolite such as 5-fluorouacil (5-FU for short) is very often used as children heal much more rapidly than adults.

Many children with pediatric glaucoma develop myopia (nearsightedness) and require glasses. Also, amblyopia (“lazy eye”) and strabismus (misalignment of the eyes) occur more frequently and may require treatment with patching or surgery.

Follow up

Regular and life long follow up will be required. When the child is quite young it may be necessary for periodic examinations under anaesthetic. As well as monitoring for raised intraocular pressure the follow up will involve monitoring of the development of vision, determine the need for glasses and when older assess any damage to peripheral visual field.

Protruding ears

Protruding ears also called prominent ears, are ears that stick out more than 2 cm from the side of the head. Protruding ears don’t cause any functional problems such as hearing loss.

In most people, protruding or prominent ears are caused by an underdeveloped antihelical fold. When the antihelical fold does not form correctly, it causes the helix (the outer rim of the ear) to stick out.

Most people with protruding ears also have a deep concha, the bowl-shaped space just outside the opening of the ear canal, which pushes the entire ear away from the side of the head.

Figure 1. Ear anatomy

Normal external ear anatomy

The ear is shaped like the letter C, formed by the helix and the earlobe. Inside the C is the letter Y, formed by the antihelix and the superior and inferior crura. The central part of the ear is shaped like a conch sea shell, and is called the concha. There is a small bump in front of the ear canal called the tragus. On the other side of the concha is another bump called the antitragus.

The ear is made primarily of cartilage covered by skin. The earlobe has no cartilage and is made of skin and fat. Although there are some muscles attached to the ear, most people cannot control them, which is why only a small percentage of people can wiggle their ears. The external ear is supplied by four different sensory nerves.

Protruding ears treatment

There are both non-surgical and surgical options for treating protruding ears.

Non-surgical ear molding

If a protruding ear is discovered in the first few weeks after birth, ear molding may correct this deformity and avoid the need for surgery. Ear molding works best in the first few weeks of life when infant ears are soft and pliable. Infant ears have very high levels of maternal estrogen (estrogen which crossed from mother to baby while in the womb and during the birthing process). Because of the increased estrogen levels, infant ears are very moldable, soft and responsive to external molding during the first few weeks and months after birth.

By 6 weeks of age, these levels of maternal estrogen fall to normal, and the ears become more rigid and less pliable. This is why early intervention is so important. If neonatal ear deformities are recognized early enough, they can often be successfully treated by non-surgical molding, preventing the need for surgery later in life.

Because some ear deformities will self-correct over time, your child should be monitored closely for the first 7 to 10 days of life. If the shape or deformity of the ear doesn’t improve in the first week or two, non-surgical infant ear molding may be recommended as the most appropriate treatment approach.

Ear molding uses a combination of commercially available ear molding devices and orthodontic molding materials to reshape the ear.

First, your child will be fit with a non-surgical molding appliance. For the best results, the device should be applied within the first one to two weeks of life. The device is worn continuously for two weeks.

After two weeks, your child’s doctor will examine your child’s ear. If the deformity has not been corrected yet, a new device will be reapplied. This process is repeated every two weeks until acceptable improvement or correction is seen.

Most ears, if treated early, respond to ear molding to improve the shape of the ear. In general, the younger your child is when treatment for prominent ears is started, the shorter the duration of therapy. However, children a few months of age have been treated successfully with non-surgical ear molding.

Protruding ears surgery

Surgery to correct protruding ears is called a setback otoplasty. It can be performed as early as 5 to 6 years of age when ears are almost fully grown.

The procedure to correct protruding ears is usually performed through an incision behind the ears. The cartilage is reshaped to create an antihelical fold. This will support the ear in its new position closer to the head. Sometimes, additional sutures are placed on the back of the conchal to bring the entire ear closer to the side of the head. A postoperative dressing is used to help keep the ears in their new positions. This dressing will typically stay in place for 1 to 2 weeks. Although a general anesthetic is needed, the operation is done on an outpatient basis and your child will be able to return home the same day.

Insurance companies often consider otoplasty to be a cosmetic operation, and therefore they may not cover the cost of this procedure. Before cosmetic ear surgery, discuss the procedure with your insurance carrier to determine what coverage, if any, you can expect.

Ear plastic surgery

To correct prominent ears that lack folds, an ENT (ear, nose, and throat) specialist, or otolaryngologist, places permanent stitches in the upper ear cartilage and ties them in a way that creates a fold to prop up the ear. Scar tissue will form later, holding the fold in place. Corrective surgery, called otoplasty, may be considered on ears that stick out more than 4/5ths of an inch (2 cm) from the back of the head. It can be performed at any age after the ears have reached full size, usually at five- or six-years-old. Having the surgery at a young age has two benefits: (1) the cartilage is more pliable, making it easier to reshape, and (2) the child will experience the psychological benefits of the cosmetic improvement.

An ENT specialist begins the surgery with an incision behind the ear where the ear joins the head. In addition, ears may also be reshaped, reduced in size, or made more symmetrical. The reshaped ear is then secured in position while healing occurs. Typically, otoplasty surgery takes about two hours. The soft dressings over the ears will be used for a few weeks as protection, and the patient usually experiences only mild discomfort. Headbands are sometimes recommended beyond that for a month following surgery.

Myringoplasty

Myringoplasty also called tympanoplasty is microsurgical technique to reconstruct a ruptured or perforated eardrum (tympanic membrane) with the placement of a graft, either medial or lateral to the tympanic membrane annulus, often using the patient’s own tissues. The goal of this surgical procedure is not only to close the perforation but also to improve hearing. The success of the operation depends on the ability to eradicate disease from the middle ear (eg, inflamed granulation tissue and cholesteatoma). Various techniques have been developed and refined, and a number of grafting materials are available. Both the lateral and medial grafting techniques are detailed below.

Myringoplasty can be used for small perforations, such as nonhealing tympanic membranes after pressure-equalizing tube extrusion or traumatic perforations. The technique involves freshening the edges of the perforation to promote healing and placing a carefully trimmed graft lateral to the defect ¹⁾. Grafting materials for myringoplasty include fat, Gelfilm, Gelfoam, AlloDerm, and cigarette paper. Gelfoam can also be placed as packing in the middle ear to support the graft.

Myringoplasty is a safe and effective outpatient procedure used to both eradicate disease from the middle ear and restore hearing and middle ear function ²⁾. Your child will need to stay in the hospital overnight. A number of surgical approaches and grafting techniques are available for use by the surgeon. Paramount to success are the preoperative assessment, good hemostasis intraoperatively, and thoughtful surgical planning with careful placement of the graft.

When planning myringoplasty, the surgeon must consider the location of the perforation (marginal versus central), and size (total versus subtotal). Areas of myringosclerosis and tympanosclerosis should be noted. Important comorbidities worth noting include craniofacial disorders and underlying environmental allergies or chronic allergic rhinitis. Critical factors that make myringoplasty less successful include adhesive otitis media, severe eustachian tube dysfunction with either perforation of the contralateral ear or ongoing intermittent otorrhea, cholesteatoma, and previous surgical repair ³⁾.

Myringoplasty key points

• A myringoplasty is an operation to fix a hole in the eardrum.
• The operation usually takes about two to three hours.
• Your child will sleep and feel no pain during the operation.
• After the operation, your child will have to stay overnight in the hospital.
• While your child gets better at home, there are some things your child should not do.

Tympanic membrane anatomy

The eardrum also called tympanic membrane is a thin layer of tissue that vibrates in response to sound. An understanding of the tympanic membrane anatomy is critical to successful repair. Myringoplasty (tympanoplasty) procedure mandates an understanding of the layers. The tympanic membrane typically consists of the following 3 layers:

1. Lateral epithelial layer
2. Middle fibrous layer
3. Medial mucosal layer

The outer epithelial layer is composed of stratified squamous epithelium, which is continuous with the skin of the external auditory canal. This is significant because in-growth of this outer epithelial portion through the perforation can result in an epithelial cyst called an acquired cholesteatoma. Untreated, this cyst then releases destructive enzymes that can enlarge the size of the perforation and ultimately cause ossicular erosion. The lateral grafting technique that is discussed later in this text requires that this entire epithelial layer be stripped from the drum remnant prior to placement of the graft so as to avoid iatrogenic cholesteatoma formation.

The middle fibrous layer is composed of connective tissue consisting of outer radial fibers and inner circular fibers. It provides strength to the drum. A healed perforation is also commonly deficient of this middle fibrous layer. The epithelial and endothelial layers regenerate creating a “dimeric” membrane. This miscalculation can be corrected when carefully examined under binocular microscopy. Because this middle layer is absent in the pars flaccida superiorly, the posterior-superior aspect of the drum can be drawn inward toward the middle ear as a retraction pocket.

The inner layer of the tympanic membrane consists of simple cuboidal and columnar epithelium cells. This layer is identical to the mucosal lining of the rest of the middle ear mucosal tissue and is considered to be critical to ensure healing of tympanic membrane perforations, and the surgeon often abrades or rasps the undersurface of the tympanic membrane remnant to stimulate regrowth.

Annulus

The peripheral edge of the tympanic membrane is rimmed by a dense fibrous layer called the annulus, which is essentially a thickening of the pars tensa. Successful elevation of the annulus is critical for medial grafting technique. The annulus is deficient superiorly at the “12 o’clock” location. This area is the notch of Rivinus and can guide the surgeon to a natural plane to elevate the annulus.

Ear canal

The ear canal has bone in the medial component (inner one-third). The lateral portion, which extends into the pinna, is composed of cartilage. The boney/cartilaginous interface is located at the medial two-thirds junction. Most incisions that are made to raise a tympanomeatal flap or perform either an endaural or transcanal approaches are made at this location as well. The superiorly placed vascular strip is another critical area within the ear canal. This region is demarcated by the tympanosquamous suture line superiorly and the tympanomastoid junction line inferiorly. Canal incisions are often made along these junctions.

Middle ear

The middle ear is an air-filled space bordered by the bony labyrinth of the inner ear medially, the tympanic membrane laterally, and the cranium superiorly. This space contains the ossicles, nerves (facial nerve, chorda tympani, Jacobsen nerve), small muscles (stapedius and tensor tympani), ligaments, and blood vessels. The petrous portion of the internal carotid artery and the internal jugular vein, which are both in proximity to the middle ear space, can be dehiscent and should be noted on any preoperative imaging. Rarely, middle ear pathology can involve these structures.

In order for successful grafting of the tympanic membrane to improve hearing, an intact ossicular chain must be present. The malleus transmits energy from the tympanic membrane to the incus, which itself is connected to the stapes superstructure resting on the oval window. Diarthrodial joints connect the 3 ossicles and allow the transmission of acoustic energy from the tympanic membrane to the inner ear. The incudostapedial joint is the most fragile and, hence, has the highest likelihood to require repair.

Mastoid

The middle ear communicates with the mastoid air cells via the mastoid antrum. The temporal bone air cells are usually pneumatized by 3 years of age. However, the air cells can remain underdeveloped and sclerotic in patients with persistent eustachian tube dysfunction. A poorly pneumatized or fluid-filled mastoid bone predisposes a patient to require a more extensive tympanomastoidectomy to improve the chances of successful graft placement.

Eustachian tube

The eustachian tube connects the middle ear with the nasopharynx and allows pressure equilibration in the middle ear. Enlarged adenoids or biofilms within this lymphoid tissue are hypothesized to predispose a patient to persistent middle ear disease. This bony-cartilaginous tube is approximately 45° from the horizontal in adults but only 10° from horizontal in infants. In addition, the infant eustachian tube is about 50% of the adult length.

Inner ear

The inner ear is composed of the cochlea, which is the end-organ for hearing, and the vestibular organs. The vestibular organs include the utricle, saccule, and the 3 semicircular canals and are involved in balance.

Figure 1. Ear anatomy

Figure 2. Tympanic membrane anatomy (right ear)

Myringoplasty surgery

Myringoplasty (tympanoplasty) is an outpatient procedure for adults and for most children. The operation takes about two to three hours. Your child will need to stay in the hospital overnight.

Your child will sleep and feel no pain during the operation. Just before your child has the operation, they will be given a sleep medicine. This is called a general anesthetic. This means that your child will sleep and feel no pain during the operation.

The ear nose and throat (ENT) doctor will take a tiny piece of tissue from an area around the ear. This is done by making a cut behind your child’s ear. The piece of ear tissue is then used to fix the hole in your child’s eardrum. Your child will have dissolvable stitches behind the ear and gauze packing in the ear to absorb any fluid.

Various techniques and grafting materials can be used. Which approach is used depends on the size and location of the perforation, the presence or absence of cholesteatoma or granulation tissue, the status of the ossicles and mastoid, other anatomical considerations (eg, narrow external auditory canals), as well as the surgeon’s preference and expertise ⁴⁾.

Examining the middle ear and ossicles and removing any elements of adhesions or cholesteatoma is critical. The chosen approach should provide optimal visualization of the perforation and tympanic membrane. One should be careful not to disrupt an intact and mobile ossicular chain if the hearing loss is only low-frequency conductive, as is often the case with hearing loss secondary to a perforation ⁵⁾.

Before the operation

Evaluation of the patient for myringoplasty involves a detailed history and physical examination. Important aspects of the history include the duration of the perforation, severity of otalgia, otorrhea, hearing loss, vertigo, previous attempts at repair, otitis media, and otitis externa. The number and frequency of infections (including time of most recent infection) provide insight into the severity of disease. Past otologic surgical history is critical and should include any history of tympanostomy tubes (also called myringotomy tubes, ventilation tubes, or pressure equalization (PE) tubes) and details of any prior tympanoplasties (including approaches, grafts used, outcomes).

Prior to considering surgery in any patient, acute and chronic infections should be controlled using ototopical, oral, and/or intravenous antibiotics or antifungals, if indicated. Ototopical drops with steroids may also be needed if granulation tissue or aural polyps are visualized to improve inflammation. Ideally, an ear should be “dry” for 3-4 months before surgery is performed to enhance the chance of success. Individuals who undergo surgery must keep the operated ear dry for a period of several weeks or until the graft has healed. Operating on an actively infected ear is contraindicated.

Physical examination

The physical examination should focus on pneumatic otoscopy and otomicroscopy. In the office, tuning forks can give an important assessment of hearing; in older patients, tuning forks can be used to confirm audiometric findings. Additional assessments include documentation of facial nerve functionality and inspection for previous incisions. Although a small amount of cerumen is tolerated in the routine otoscopic examination, obstructive cerumen should be removed when evaluating a patient for myringoplasty in order to provide an unimpeded view of the entire tympanic membrane.

Monomeric (or more accurately, dimeric) areas may appear as perforations until inspected more closely under microscopy. Retraction pockets should be closely inspected for accumulation of squamous debris. Considering the status of the contralateral ear when considering repair of a tympanic membrane perforation is essential. The ear with more significant hearing loss is usually operated on first if bilateral perforations exist.

Audiometric testing

Audiometry should be performed preoperatively in all surgical candidates. Tympanometry can add useful information in younger children who are difficult to properly examine. The primary reason for audiometric analysis is to establish the degree of conductive hearing loss. Perforations usually cause low-frequency conductive loss ⁶⁾. If underlying ossicular discontinuity exists and is not addressed during surgery, then postoperative hearing can be worse despite an intact neo-tympanum. One should consider ossicular involvement if the conductive hearing loss is flat across all frequencies or greater than 35 db. Finally, the presence and degree of any sensorineural hearing loss should be documented preoperatively.

Radiographic testing

Computed tomography (CT) and magnetic resonance imaging (MRI) is not essential but may be indicated in patients in whom a concern for cochlear, labyrinthine, or intracranial pathology exists. Other patients who might be considered for preoperative imaging include patients with a history of facial palsy, children with craniofacial abnormalities, and revision cases in which the anatomy may be distorted.

Pre-operative imaging assists the surgeon in preoperatively identifying pathology and planning surgery. CT scan should be ordered when concern exists for cholesteatoma and in patients with previous mastoid surgery, otalgia, or vertigo. MRI is beneficial for delineating the integrity of the dura as well as detecting small retrocochlear lesions such as acoustic neuromas.

Grafting materials

Various materials exist for use for tympanic membrane grafting. True temporalis fascia is the most common graft because of its ease of harvest and its abundant availability, even in revision cases. Some surgeons prefers loose areolar fascia (also known as “fool’s fascia”) and prefer to save the true fascia for revision cases. Also, the “fool’s fascia” is considered by some to be more pliable, have less donor site morbidity, and to be more transparent after healing. It is available via the same postauricular incision that can be used for tympanoplasty, or a separate incision can be made in or beyond the postauricular hairline if a transcanal or endaural technique is used. A mild amount of donor site morbidity occurs, with postoperative pain over the temporalis muscle being the most common symptom.

• The postauricular incision is marked and injected with lidocaine with epinephrine.
• Dissection is carried down onto the fascia (loose areolar /true temporalis).
• The graft is harvested.
• Muscle is removed from the fascia graft, and the graft is then set on the back table for later use.

Cartilage is available to be harvested easily from either the tragus or the conchal bowl, if a post-auricular approach is being used. Tragal cartilage is harvested with perichondrium attached via a small incision on the internal surface of the tragus ⁷⁾. This graft is an appropriate size and carries very little donor site morbidity. In addition, the perichondrium can be reflected to stabilize the graft. Conchal cartilage also carries no additional significant morbidity. Other grafting materials include lobular fat, periosteum, perichondrium, vein, and AlloDerm.

Myringoplasty procedure

Transcanal approach

The transcanal approach is especially good for small posterior perforations, but can be used for medium-sized perforations if the anterior tympanic membrane is easily visualized. This technique can be challenging for significant anterior perforations, narrow/stenotic ear canals, or individuals with a significant anterior canal bulge. Inspecting the perforation prior to preparing the patient and determining that at least a 5-mm speculum can be placed is important. Canalplasty can be used to improve visualization if slightly limited.

Medial graft

When performing a transcanal medial tympanoplasty procedure, the following steps are followed:

1. The ear canal is suctioned and surgical Betadine used during the surgical prep is removed.
2. The external auditory canal is cleaned and injected with 1% lidocaine with 1:100,000 epinephrine or 0.5% lidocaine with 1:200,000 epinephrine, primarily for vasoconstriction to optimize visualization during the procedure.
3. The edge of the perforation is dissected and removed using a sharp pick and cup forceps; this “postage-stamping” and “freshening” of the perforation is critical to ensure that the graft incorporates into the native tympanic membrane remnant.
4. Next, a tympanomeatal flap is created. It is customized based on the location of the perforation and surgeon’s preference. The flap design should be such that it can be easily and atraumatically raised and the undersurface of tympanic membrane perforation can be readily accessed. A medially-based tympanomeatal flap is usually created with radial incisions at 12 o’clock and 6 o’clock (ie, superiorly and inferiorly) that either connect directly or via a semilunar incision in the posterior canal just medial to the bony-cartilaginous junction.
5. The tympanomeatal flap is raised medially with a round knife. To avoid traumatic tearing, take great care not to suction on the flap.
6. When the annulus is reached, the tympanotomy is made such that the instrument of choice (eg, round knife, gimmick, sickle knife, pick) lifts the annulus while hugging the bony groove from which the fibrous annulus can be dissected. The fibrous annulus is then dissected circumferentially with care not to injure the ossicles, the chorda tympani nerve, or residual drum. The flap is then positioned, usually anteriorly, such that the perforation is exposed.
7. A canalplasty of the posterior or anterior external auditory canal can be performed to optimize visualization. Take care not to injure the facial nerve or temporomandibular joint.
8. If indicated, the middle ear and ossicles are inspected and palpated to confirm ossicular continuity. Middle ear disease (granulation tissue, tympanosclerosis, adhesions, cholesteatoma) is completely removed. Removing hypertrophic middle ear mucosa with either a McCabe dissector or Duckbill elevator, particularly mucosa abutting the fibrous annulus in anterior tympanic membrane perforations, is important.
9. Ossicular reconstruction can be performed if necessary, followed by grafting of the perforation. Elevating the tympanic membrane remnant off the long process of the malleus with a sickle knife may be necessary. This allows both closer inspection of the ossicles and better placement of the graft.
10. The middle ear must be carefully packed with the surgeon’s preferred material – either Gelfilm, Gelfoam, or Surgicel. This is often soaked in either oxymetazoline, antibiotic ear drops, or diluted epinephrine (1:10,000). Packing the mesotympanum and hypotympanum is important, although excess packing should be avoided near the ossicles so as to prevent adhesions.
11. The graft is trimmed on the back table. The graft should adequately cover the entire defect. Hemostasis is critical to intraoperative visualization and successful placement of the graft. The graft should be well supported so as to avoid shifting or displacement.
12. Some surgeons advocate that nitrous oxide anesthetic be switched off at this point because this particular agent has a tendency to accumulate in spaces such as the middle ear and can potentially dislodge the graft.
13. The tympanomeatal flap is laid back down over the graft, and the posterior canal skin edges are laid flat. Pieces of Gelfoam, Surgicel, or antibiotic ointment are placed along the tympanic membrane and graft and layered laterally to cover the canal incisions.
14. Antibiotic ointment is placed in the lateral canal, and either Vaseline-coated or antibiotic-coated sculpted cotton ball is placed in the external auditory meatus.
15. An optional Glasscock or mastoid pressure dressing is placed at the end of the case, particularly if a mastoidectomy has been performed.

Endaural approach

The endaural technique is useful with many perforations, especially when a small atticotomy is anticipated (when improved access to and visualization of the epitympanum is needed). Many of the steps involved in the transcanal technique are similarly performed in the endaural tympanoplasty as well. When performing an endaural medial tympanoplasty procedure, the following steps are followed:

1. The canal is prepared as detailed above, but the injection may continue laterally to the lateral external auditory canal and tragus.
2. An incision is made at 12 o’clock and extended superolaterally between the tragus and helical root.
3. A medially-based tympanomeatal flap is raised, and the middle ear is entered with the same care as described previously. The tympanic membrane is freed superiorly and inferiorly.
4. Middle ear work is carried out as indicated. Atticotomy can be performed using a small curette or drill if access into the epitympanum is needed.
5. Grafting is performed and the tympanomeatal flap is laid back down. Gelfoam is placed along the tympanic membrane and fills the canal. Antibiotic ointment and a cotton ball are used laterally.

Postauricular approach

The postauricular technique is the most commonly performed approach for either revision tympanoplasties or those in which a mastoidectomy is anticipated. This technique offers the best visualization of the anterior tympanic membrane and is preferred for large anterior perforations. In addition, it can be combined with mastoidectomy if disease is found in the mastoid that requires the surgeon’s attention. A basic outline of the procedure follows:

1. The canal is prepared in a similar fashion to the transcanal technique.
2. Radial and horizontal canal incisions are made as described previously, and the canal is packed with cotton soaked in oxymetazoline or epinephrine.
3. A postauricular incision is marked 5 mm posterior to the auricular crease in a curvilinear fashion, extending form the mastoid tip to the temporal line. The incision is injected with 1% lidocaine with either 1:100,000 epinephrine or 0.5% lidocaine with 1:200,000 epinephrine. The incision is carried down through the skin and subcutaneous tissue with care not to enter the ear canal. When the temporalis fascia is reached, a graft can be harvested using a Freer elevator and scissors. If multiple previous grafts have been harvested, either tissue from the contralateral ear or AlloDerm can be used as well.
4. A periosteal incision is made in a “T” or “7” fashion, and the periosteum is raised into the lateral ear canal until the previously-made canal incisions are reached. The cotton in the ear canal is removed.
5. A rubber Penrose drain can be inserted to retract the lateral canal and auricle anteriorly. Self-retaining retractors such as Weitlaner or Perkins retractors are used to provide further exposure. The perforation is visualized and prepared.
6. The tympanomeatal flap is raised medially and the middle ear is entered as described previously. Do not suction on the flap.
7. Canalplasty can be performed and middle ear work is carried out as indicated, including ossicular reconstruction. The perforation is grafted, and the tympanomeatal flap is laid back down with Gelfoam layered lateral to the tympanic membrane.
8. The auricle and lateral ear canal are relaxed and the postauricular incision is closed in a layered fashion. The remainder of the ear canal is packed with Gelfoam and antibiotic ointment. A pressure dressing is applied to prevent a postauricular hematoma.

Grafting technique

Although variations exist, 2 primary grafting techniques exist: medial grafting (or underlay) and lateral grafting (or overlay). These terms refer to the position of the graft in relation to the fibrous annulus, not to the malleus or tympanic remnant.

The medial grafting technique is performed as described previously. The primary advantage of the medial graft technique is that it is quicker and easier to perform than lateral grafting. It also carries a high success rate (approximately 90% in experienced hands). The biggest disadvantage is its limited exposure and poor utility for larger perforations and its difficulty with repair of near-total perforations.

Advantages of the lateral graft technique include wide exposure and versatility for larger perforations and for any needed ossicular reconstruction. Disadvantages include the requirement of a higher technical skill level, a longer operative time, slower healing rate, and the risk of blunting and lateralization of the graft. The lateral graft technique is championed by the some doctors as a technique more suited for total drum replacement. The basic steps involved in lateral grafting are described as follows:

1. Lateral (overlay) tympanoplasty is performed through the previously-described postauricular incision. Important differences exist in the canal incisions. In this procedure, a vascular strip is created by making radial incisions at about 2 o’clock and 5 o’clock. These incisions are connected medially just lateral to the annulus on the posterior canal wall and laterally just medial to the bony-cartilaginous junction along the anterior canal wall.
2. The skin of the anterior external auditory canal is raised medially. When the annulus is reached, squamous epithelium is raised off of the tympanic remnant, and the canal skin is removed in continuity with the remnant skin and stored in saline solution. This maneuver is done with a cupped forceps.
3. Bony canalplasty can be performed anteriorly to ensure visualization of the entire annulus. Protecting the flap with a portion of trimmed Silastic as a shield is helpful. Care must be taken not to enter the glenoid fossa, which risks injuring the temporomandibular joint (TMJ) and causing prolapse into the ear canal.
4. Antibiotic-soaked Gelfoam is packed into the middle ear to support the tympanic remnant. The fascia graft is placed medial to the malleus and draped onto the posterior canal wall for stabilization. If possible, the graft should not extend onto the anterior canal wall in an effort to prevent blunting of the graft.
5. The canal skin/tympanic remnant is returned and placed lateral to the graft and carefully positioned. Gelfoam is then packed tightly into the anterior aspect of the medial canal to prevent blunting, and the vascular strip is laid back down, covering the lateral extension of the fascia graft to improve its blood supply. Antibiotic-soaked Gelfoam is then packed into the rest of the external auditory canal.
6. The postauricular incision is closed in layers, and antibiotic ointment is placed on the incision and in the lateral canal. A cotton ball is placed in the external auditory meatus, and a mastoid pressure dressing is applied.

Myringoplasty recovery

After the operation, your child’s surgical team will take your child to the recovery room, also called the Post Anesthetic Care Unit (PACU). This is where your child will wake up. Your child will stay in PACU for about one hour. Your child’s surgical team will then move your child to a room on the nursing unit.

Your child’s surgical team will give your child fluids through a tube in their arm, called an IV, until they are able to drink easily. Your child will have a gauze bandage around their head, which will be taken off the day after the operation.

Postoperative hearing should be immediately assessed in the recovery room with a tuning fork. If a pressure dressing is applied, it should be removed on the first or second postoperative day depending on surgeon preference.

Although the ear must be kept otherwise dry, patients are allowed to wash their hair, while keeping a cotton ball with Vaseline in the canal for dry ear measures. Pain is usually managed with acetaminophen and/or ibuprofen. Narcotics such as hydrocodone (Vicodin or Norco) are usually prescribed when a post-auricular approach is used. Oral antibiotics are the surgeon’s preference and can be given for 5-7 days. A cotton ball is replaced in the external auditory meatus as needed for bleeding or drainage. Ototopical drops are typically administered postoperatively for 7-21 days after surgery and continued until the first postoperative visit.

At the first postoperative visit (3-4 weeks after surgery), the ear is examined under the microscope, and any canal packing or residual antibiotic is removed. At this time, a good assessment can be made as to the healing and neovascularization of the graft. Granulation tissue at the tympanomeatal flap is addressed. Ototopical drops are continued as the graft continues to heal. Postoperative audiometric testing is delayed until healing is complete (typically 6-12 weeks). Follow-up visits are scheduled to ensure complete proper healing and restoration of hearing.

Medications that may be prescribed after surgery

• Pain control: Acetaminophen (Tylenol) liquid solution may be given. Some children will requireprescription pain medication. Pain may be worse during evening; some children should be given medication at night.
• NO ibuprofen (Motrin or Advil) or aspirin for twoweeks after surgeryunless otherwiseinstructed by physician.
• Antibiotic eardrops may be prescribed twoweeks after surgery. Give drops at room temperature.
• Antibiotics may be prescribed for 7 to 10 days.

Special precautions after ear surgery

1. No nose blowing for two weeks. Sneeze with an open mouth.
2. Water precautions: Keep ear canal dry for the first twoweeks;place cotton ball coated with Vaseline in the ear(s) when bathing. Hair may be washed twodays after surgery. The sutures may get wet but the ear canal should stay dry. No swimming for usually 4 to 6 weeks. The physician will advise you when the ear can get wet.
3. Wound and suture line care: A large dressing is usually applied after surgery and should be left in place for one-twodays. After the dressing is removed (at your appointment or at home as instructed by your doctor), clean the incisionwith hydrogen peroxide and apply bacitracin ointment. Use Q-tips or cotton balls to clean the incision. Wash your hands before and after cleaning the incision. Apply a cotton ball to the outside of the ear canal if drainage is present.
4. Keep the incision protected from the sun for 6 to 12 months, keep covered or apply sunscreen.

Taking care of your child at home

Please follow these steps at home to help your child get better:

• Your child may have a small gauze bandage over their ear. Please keep this bandage on for one or two days after going home.
• Do not let the cut behind your child’s ear get wet. Do not get any water in the ear. Your child can have a bath, but take care not to pull on the ear or get it wet if you need to wash their hair.
• Do not let your child play contact sports like hockey or soccer until the ENT doctor says it is OK.
• Do not let your child go swimming until the ENT doctor says it is OK.
• Do not let your child play a musical instrument that you blow in until the ENT doctor says it is OK.
• Do not let your child blow their nose. Have them cough or sneeze with their mouth open.
• Your child may return to school or day care when your ENT doctor says it is OK. Usually, this will be one week after the operation.

Pain management at home

Follow these instructions when your child goes home after the procedure.

You may give your child medicine for pain.

You may receive a prescription for pain medication before you leave the hospital. Follow the dosage instructions given to you by the pharmacist. Although these prescription pain medications can be beneficial, they are also potentially very dangerous if not used properly.

When using these medications, if you notice any changes in either breathing or level of drowsiness that concern you, stop the medication and seek medical attention. If your child is unresponsive, call your local emergency services number immediately.

Do not give your child over-the-counter medicine that may have a sedative effect (makes people sleepy) while giving the prescription for pain medicine. Examples of these medicines are decongestants and antihistamines. Discuss these medications with your pharmacist.

You may give your child acetaminophen if they have pain. Give the dose printed on the bottle for your child’s age. Do not give your child ibuprofen or acetylsalicylic acid for two weeks after the surgery. These medications could increase your child’s risk of bleeding after the operation. Check with the nurse or doctor first before giving these medicines to your child.

Myringoplasty recovery time

Routine activities may be resumed in 2-5 days. Most children return to school in 3 to 5 days if eating and sleeping well and pain-free. Vigorous exercise, heavy lifting and physical activities should be avoided for 2 weeks. No swimming until advised by your doctor, typically in 4-6 weeks.

Follow-up care

A follow-up appointment with the ENT doctor

The ENT unit will make a follow-up appointment with the doctor for your child. If everything is normal during the appointment, the doctor will:

• Check your child’s ear to see how it is healing.
• Take out the packing from your child’s ear.
• Tell you when your child can start to play sports again.

Myringoplasty complications

Common complaints after surgery:

• Nausea and vomiting may occur for the first 24 to 48 hours.
• Pain: Mild to moderate ear pain and/or pain at theincision site for 3 to 5 daysis expected.
• Fever: A low-grade fever may be observed several days.
• Ear drainage after surgery. Packing material is placed in the ear canal; sometimes there is clear, pink, or bloody drainage from the ear for 3-5 days. This may also occurwhen ear drops are started.
• Dizziness or unsteadiness: Dizziness is common for several days.
• Decreased hearing in the operated ear for several weeks.

Complications of the surgery include recurrence of the perforation, tympanic membrane retraction, otorrhea, cholesteatoma development, persistence or worsening of any conductive hearing loss, sensorineural hearing loss (rare), and taste disturbances. Post-auricular incisions are at risk for hematoma, and a mastoid pressure dressing is recommended for the first postoperative night. Outcomes can be optimized by a proper and detailed preoperative assessment and the careful construction of an effective surgical plan.

The graft can fail because of infection, failure to pack the graft securely in place, technical error, failure to clear mastoid and middle ear disease, and because of a concurrent undetected cholesteatoma. Excising all tympanosclerosis at the edge of the perforation so as to allow vascularized perimeters to incorporate the graft is critical.

Myringoplasty outcomes

The indications and outcomes vary depending on the specific clinical problem. Success rates of tympanic membrane closure vary greatly in the literature (35-98%) but are usually greater than 80% and depend largely on the size and location of the perforation, surgical technique, and overall health of the middle ear ⁸⁾.

Linear scleroderma

Linear scleroderma represents a unique form of localized scleroderma that primarily affects children, with 67% of patients diagnosed before 18 years of age ¹⁾. Linear scleroderma manifests as thickened and hardened skin bands, which are most often on the face or extremities. Linear scleroderma is the most common form of scleroderma in children. Women are affected about four times more than men.

When linear scleroderma occurs on the scalp or face, it is referred to as linear scleroderma “en coup de sabre” (a French expression meaning “cut from a sword”), given the resemblance of the skin lesions to the stroke of a sabre. The sclerotic band is generally located on the forehead but can extend to the scalp (causing scarring alopecia), and to the nose as well as the upper lip. The skin is hypo or hyperpigmented, atrophic and adheres to the underlying bone. This form of scleroderma can sometimes be associated with ipsilateral hemiatrophy of the face and is therefore hardly individualizable from Parry-Romberg syndrome.

Linear scleroderma of the limbs is called “monomelic” and often begins in childhood. Sclero-atrophic bands appear gradually and then extend to the muscles and tendons; this may lead to an extreme aspect of pansclerotic morphea with joint and bone deformities sometimes associated with a stop or growth retardation of the limb.

Localized scleroderma typically only affects the skin, although in some cases the underlying muscle and tissue may be involved (subcutaneous morphea). Localized scleroderma is not a fatal disease, but quality of life is often adversely affected because of changes in the appearance of the skin, the occurrence of joint contractures that affect movement, and, rarely, serious deformities of the face and extremities.

Linear scleroderma treatments may include medications, which may include nonsteroidal anti-inflammatories (NSAIDs) or corticosteroids, penicillamine and/or immunosuppressive drugs and therapies to protect the skin, physiotherapy and exercise, and/or surgery as indicated.

Figure 1. Linear morphea scleroderma

Figure 2. Localized scleroderma face (en coup de sabre)

Figure 3. Linear scleroderma forehead (en coup de sabre)

What is scleroderma?

Scleroderma means “hard skin”, which is a rare autoimmune connective tissue disorder of unknown cause in which an overproduction of abnormal collagen causes normal tissues to be replaced with thick, dense scar tissue that can affect underlying bones and muscles if left untreated ²⁾.

• Although any age can be affected, the peak incidence is 20-40 years of age, and 15% of cases occur before the age of 10 years
• The female to male ratio is 3:1
• Scleroderma is less common in black people
• The onset of scleroderma is generally insidious, and although asymptomatic, affected skin often ceases to sweat
• The severity and outcome of scleroderma are variable ³⁾.

There are two forms of scleroderma:

1. Localized scleroderma primarily affects the skin and may have an impact on the muscles and bones. Localized scleroderma is the most common form found in children.
2. Systemic sclerosis a chronic, degenerative disease rarely seen in children. In systemic scleroderma, there is an involvement of the internal organs, such as the digestive tract, heart, lungs, and kidneys, among others.

It is important to understand that localized scleroderma is different from the form of scleroderma which affects internal organs, called systemic sclerosis, often incorrectly stated, as systemic scleroderma.

Scleroderma has been associated with:

• Drugs eg bleomycin, carbidopa, penicillamine
• Chemicals eg polyvinyl chloride, solvents used in dry cleaning, pesticides
• Graft-versus-host disease following bone marrow transplantation

What is localized scleroderma?

Localized scleroderma is a type of scleroderma that typically only affects the skin, although in some cases the underlying muscle and tissue may be involved (subcutaneous morphea).

Localized scleroderma is characterized by inflammation and thickening of the skin from excessive collagen deposition. Collagen is a protein normally present in our skin. It provides structural support. However, when too much collagen is made, the skin becomes stiff and hard. Some patients with localized scleroderma, an estimated 10 to 20 percent, develop joint pain.

Localized scleroderma is not infectious and cannot be spread by touch or contact with the patient. Localized scleroderma is not hereditary; however, in rare instances similar problems may be present in relatives. Localized scleroderma is thought to be an autoimmune disease but, other than the presence of blood autoantibodies (confusingly similar to those with some internal diseases), patients have no other known or profound defect in the immune system.

Localized scleroderma types

Names and terminology are widely varied and cause a great deal of confusion in localized scleroderma. Patients are often told they have “scleroderma,” which may frighten them. A newly diagnosed patient may think they have systemic sclerosis and will develop internal organ involvement. This is not true.

There are four main types of localized scleroderma. Each type is characterized by the shape and amount of affected skin.

The four types are:

1. Morphea – This is the most common type of localized scleroderma. It presents as one or a few (3-4) patches of skin thickening with different degrees of pigment changes. Some areas are dark while others are lighter than the surrounding normal skin. Often, the skin lesion is not quite hard to the touch. It is generally painless, but pruritus (itching) may be present. A violet-colored border may be seen when the lesions are still very active and extending. Sometimes, doctors will classify morphea further into other sub-types, according to the shape or depth of the lesions. For example, “guttate” morphea refers to “drop-like” shaped areas of skin involvement, whereas “subcutaneous” morphea indicates a substantial involvement of deeper tissues with relative sparing of the overlying skin. The subcutaneous type may extend deep into muscle tissues in very rare instances, but this does not indicate internal organ involvement.
2. Generalized morphea – Generalized morphea involves larger skin patches than morphea, often including more of the body surface. Rarely, most of the body may be involved. Some patients with generalized morphea also have a band of thickening on an arm or leg as seen in linear scleroderma, another type of localized scleroderma. Moreover, individual patches of morphea are common in linear scleroderma. Therefore, although one type of localized scleroderma usually predominates, patients may have a combination of different types of skin involvement. Patients with generalized morphea, because of the extensive surface area involved, may encounter considerable cosmetic disability resulting from the appearance of the problem (many dark and light areas of skin). Also, because of skin thickening over the joints, patients may have limited joint function.
3. Linear scleroderma as the name implies, shows a band or line of skin thickening. It may extend deep into the skin and even involve the underlying muscle. The band of skin thickening is more common on the legs and arms and, when crossing the joints, may prevent proper joint motion. On rare occasions linear scleroderma can be a serious problem in children, especially when it extends deep into the skin. Sometimes, for reasons we do not yet understand, linear scleroderma delays growth of the underlying bones in children who are still in an active growth phase.
4. En coup de sabre – An unusual form of linear scleroderma on the face or scalp may appear as a white line referred to as “en coup de sabre.” This is a French term meaning “cut from a sword,” because of the way it looks. Some people think it may be completely different from linear scleroderma. En coup de sabre can be very destructive, as when it results in atrophy (loss of tissue) of the face in children; this process may involve the tongue and mouth. Rarely, the condition is associated with abnormalities in the growth of facial bones, which can potentially lead to considerable deformities. There may be some overlap between en coup de sabre and a rare atrophy in the face, known as Parry-Romberg syndrome.

Does localized scleroderma go away?

As a general rule, localized scleroderma is a self-limiting problem, at least in terms of activity of the process; the color changes are likely to remain. Sometimes, new lesions may appear for a few years, but eventually, the process of developing new areas of involvement will subside. The one possible exception to this statement is en coup de sabre, which may run an unpredictable course and become active again, even many years or decades after it first appeared.

Linear scleroderma causes

Scleroderma occurs as a result of the overproduction of collagen by the body. Why exactly this occurs, however, is unknown. There is some evidence that genetic and environmental factors play a role in the genesis of scleroderma. Silica and certain organic solvents are recognized as risk factors of occurrence of systemic scleroderma. The result is an activation of the immune system, causing blood vessel damage and injury to tissues that result in scar tissue formation and the accumulation of excess collagen.

Genetic factors play at least a limited role. According to three US cohorts, the prevalence of the disease was 13 times higher in first-degree relatives of scleroderma patients than in the general population. OX40L gene polymorphism correlates with systemic scleroderma. IRF5 gene was found to correlate with systemic scleroderma as well as with the occurrence of interstitial lung disease during scleroderma ⁴⁾.

Scleroderma has been associated with:

• Drugs eg bleomycin, carbidopa, penicillamine
• Chemicals eg polyvinyl chloride, solvents used in dry cleaning, pesticides
• Graft-versus-host disease following bone marrow transplantation

Linear scleroderma symptoms

Linear scleroderma is a progressive loss of subcutaneous fat with pigment changes in the skin. Linear scleroderma is a type of localized scleroderma in which the area of skin affected appears in a band. It typically first appears in young children on one side of the body. A shiny, thickened streak of tough darker (or lighter) looking skin that may involve a leg or arm and may spread along a line to feet or hand (sometimes on head, face, scalp, and forehead). This often affects deeper layers of skin, spreads over joints and may limit the movement of the joint, or if extensive may not allow the limb to grow normally.

Symptoms of localized scleroderma may include:

• Shiny, thickened patches of skin
• Discolored (lighter or darker) skin
• Joint tightness

Up to 30% of patients with more severe types of linear scleroderma or generalized scleroderma can have extracutaneous non-specific inflammatory symptoms. These include:

• Fatigue, lethargy
• Non-specific joint pain and/or inflammation (arthralgia, arthritis)
• Muscle pain
• Reflux/heartburn
• Raynaud phenomenon (cold hands with red/white/blue colour changes)
• Eye dryness, irritation or blurred vision due to ocular involvement (most commonly episcleritis, anterior uveitis, keratitis) – related or unrelated to the site of morphoea

These extracutaneous manifestations imply that localized scleroderma is a systemic inflammatory condition. In contrast, systemic sclerosis results in direct damage and fibrosis of the lungs, heart, kidneys and/or gastrointestinal tract — which do not occur in localized scleroderma.

Scleroderma can result in cosmetic problems, scarring, growth abnormalities and limited motion if joints are affected. Symptoms may resemble other medical conditions, so always consult your child’s physician to confirm her diagnosis before pursuing treatment.

Linear scleroderma complications

Linear scleroderma of the limbs may cause functional disabilities, particularly if the disease affects the underlying bone. Linear scleroderma “en coup de sabre” may induce esthetic and/or functional concerns.

Linear scleroderma diagnosis

Doctors who are familiar with scleroderma, or who are experts at examining the skin, can arrive at the diagnosis without much difficulty after a careful examination. In some cases, further tests may be needed to confirm the diagnosis. These tests may include taking a small sample of the skin (a biopsy) and some blood samples. It’s important that the entire skin surface be examined, so that a complete record is made of what is present at first (baseline record). Photographic documentation is also valuable.

Diagnosis of linear scleroderma is usually based on the changes in the skin and internal organs. Because linear scleroderma is often associated with a positive antinuclear antibody, an antibody test may help distinguish the type of scleroderma present.

In addition to a complete medical history and physical examination, your child may undergo additional diagnostic testing, including an echocardiogram, electrocardiogram (EKG or ECG) or X-ray. An EKG can detect abnormal heart rhythms which may be caused by changes in the heart muscle tissue due to scleroderma. X-rays may detect changes in bone and soft tissues, the gastrointestinal tract, and the lungs caused by scleroderma

Linear scleroderma is sometimes confused with Parry-Romberg syndrome because both conditions are characterized by the same progressive loss of subcutaneous fat. Like Parry-Romberg disease, the onset of linear scleroderma occurs is in childhood and may involve the facial region. Unlike Parry-Romberg disease, there is no optic nerve dysfunction, burnout phase and generally no muscle or bone atrophy.

Medical professionals who are experienced in diagnosing and treating children with linear scleroderma and Parry-Romberg syndrome will be able to distinguish between the two and provide an accurate diagnosis.

Linear scleroderma treatment

Treatment for scleroderma depends on your child’s overall health and the severity of the condition. Treatment may include:

• Medication — Your child’s medical team may recommend medications such as nonsteroidal anti-inflammatory medications (NSAIDs) or corticosteroids to relieve pain; penicillamine to slow the thickening process and delay damage to internal organs; or immunosuppressive medications. Linear scleroderma of the face or limbs generally requires the combination of systemic corticosteroids and methotrexate to avoid functional and/or esthetic disabilities ⁵⁾.
• Skin protection — Sunblock or protective padding can be used to protect the affected area.
• Physical therapy — Physical therapy and exercise can be used to maintain muscle strength.
• Surgery — Surgical treatment may involve fat transferred by injection or excision of isolated patches of abnormal tissue. In the fat transfer technique, fat is aspirated from elsewhere in the body, cleaned, and reinjected into the tissue under the skin to add volume, contour and shape. This is a minimally invasive procedure and usually can be done on an outpatient basis.

If large areas of discolored, irregular skin are involved, the preferred treatment option may be direct excision of the abnormal tissue with closure of the adjacent normal skin. While this procedure may leave a scar, the scar is typically less noticeable than the existing deformity. This procedure is also typically done on an outpatient basis, and your child can return home the same day.

In severe atrophy, large amounts of tissue may be transferred to the affected area using microsurgical techniques. This transferred tissue often comes from the trunk or legs. The tissue may be placed deeply to add volume, closer to the surface of the skin to replace damaged skin, or both.

Linear scleroderma prognosis

In localized scleroderma, the hardening of the skin generally ceases in the two years after the onset of the disease, and the lesions do not extend to other parts from the body ⁶⁾. However, the disease can sometimes last several years, and some plaques may become more marked even after the end of inflammation.

Linear scleroderma has the potential to cause serious complications. The linear areas of the skin thickening may extend to the underlying tissue and muscle in children, which may impair growth in the affected leg or arm.

Extensive lesions of linear scleroderma, when cross joint lines, can impair motion of that particular joint. Unless continued efforts are made to maintain a full range of motion to the affected joint with physical therapy, this complication may be permanent and result in the affected area (for example, the elbow, arm, finger, etc.) being in a fixed position (contracture). Many patients with linear scleroderma, especially if older at the age of onset of the disease, will have only minor skin changes and minimal skin thickening. Linear scleroderma remains active for two to five years, but can last longer in some cases. Sometimes patients develop recurrences after a period of what was thought to be inactive disease. This “recurrence” is more frequent in patients with “en coup de sabre.”

En coup de sabre is potentially the most disfiguring form of localized scleroderma, because it affects the face and scalp. It can be mild, with only slight atrophy of the skin. However, depending on its locations on the face, it can lead to considerable problems, especially in children. It is possible that it is an entity by itself, and not truly a type of linear scleroderma. If located on the scalp, it can cause varied degrees of hair loss. When involving the face, it can lead to indentations or depressions of the skin surface, especially on the forehead. The process can extend to the underlying bone. Recurrences can occur, even when it seems the disease has gone into remission.