Pseudoachondroplasia

Pseudoachondroplasia is an inherited disorder of bone growth, a type of short-limbed dwarfism. Pseudoachondroplasia was once thought to be related to another disorder of bone growth called achondroplasia, but without that disorder’s characteristic facial features. More research has demonstrated that pseudoachondroplasia is a separate disorder.

All people with pseudoachondroplasia have short stature. The average height of adult males with this condition is 120 centimeters (3 feet, 11 inches), and the average height of adult females is 116 centimeters (3 feet, 9 inches). Individuals with pseudoachondroplasia are not unusually short at birth; by the age of two, their growth rate falls below the standard growth curve.

Other characteristic features of pseudoachondroplasia include short arms and legs; a waddling walk; joint pain in childhood that progresses to a joint disease known as osteoarthritis; an unusually large range of joint movement (hyperextensibility) in the hands, knees, and ankles; and a limited range of motion at the elbows and hips. Some people with pseudoachondroplasia have legs that turn outward or inward (valgus or varus deformity). Sometimes, one leg turns outward and the other inward, which is called windswept deformity. Some affected individuals have a spine that curves to the side (scoliosis) or an abnormally curved lower back (lordosis). People with pseudoachondroplasia have normal facial features, head size, and intelligence.

Common characteristics of pseudoachondroplasia:

• Can affect boys and girls equally
• Diagnosis may not occur until around 2 years of age, when physical characteristics maybe apparent.
• Shortened Limbs
• Short stubby fingers
• Waddling walk
• Joint pain (with age)
• Large range of joint movement (hyperextensibility) in hands, knees and ankles
• Limited range of motion in the elbows, and hips
• Some people have legs that turn outwards (valgus) or inwards (varus). Occasionally have one leg turning in, the other turning out (windswept)
• Sometimes have curved spine (scoliosis)
• ‘Normal’ facial features
• Life expectancy is not affected
• Intelligence is not affected

Pseudoachondroplasia is caused by a mutation in the cartilage oligomeric matrix protein (COMP) gene and is transmitted in an autosomal dominant pattern. Thirty percent of cases are familial with an affected parent transmitting the condition, while 70% occur as a random, new (de novo) mutation in COMP with no previous family history.

The exact birth prevalence pf pseudoachondroplasia is unknown, but estimated to be 1 in 30,000-100,000. Males and females are equally affected.

Treatment for pseudoachondroplasia varies because the condition affects several body systems, and each child’s case is different. Some children will only require careful monitoring. Others will need, non-surgical or surgical treatments to address specific aspects of their condition.

Many children with pseudoachondroplasia are also diagnosed with a variety of orthopaedic conditions including: scoliosis, hip pain, joint stiffness and limb shortening. In most cases, these conditions only become evident – or problematic – as your child grows. Depending on your child’s needs, orthopaedic specialists will treat your child.

Every child’s condition is different, so treatment is determined on a case-by-case basis. For example, if your child has scoliosis, spine specialists will consider the severity of the curve, where it occurs in the spine, and your child’s age and stage of growth, before determining the best course of action. Treatment may include non-surgical options such as bracing and physical therapy, or surgical options such as spinal fusion or implanting growing rods to stabilize your child’s spine as he continues to grow.

For other effects of pseudoachondroplasia, in general, treatment may include:

• Bracing and/or surgery for scoliosis
• Medication or pain relievers for joint pain
• Bracing and/or surgery for knee and lower-leg deformities
• Bracing and/or surgery to treat hip pain
• Physical therapy to help your child remain limber

Pseudoachondroplasia causes

Mutations in the COMP (cartilage oligomeric matrix protein) gene cause pseudoachondroplasia. The COMP gene provides instructions for making a protein that is essential for the normal development of cartilage and for its conversion to bone. Cartilage is a tough, flexible tissue that makes up much of the skeleton during early development. Most cartilage is later converted to bone, except for the cartilage that continues to cover and protect the ends of bones and is present in the nose and external ears.

The COMP protein is normally found in the spaces between cartilage-forming cells called chondrocytes, where it interacts with other proteins. COMP gene mutations result in the production of an abnormal COMP protein that cannot be transported out of the cell. The abnormal protein builds up inside the chondrocyte and ultimately leads to early cell death. Early death of the chondrocytes prevents normal bone growth and causes the short stature and bone abnormalities seen in pseudoachondroplasia.

Pseudoachondroplasia inheritance pattern

Pseudoachondroplasia is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

In some cases, an affected person inherits the mutation from one affected parent. Most cases (70% of cases) result from new mutations in the gene called new (sporadic or de novo) mutation and occur in people with no history of the disorder in their family. In sporadic or de novo mutation case, pseudoachondroplasia is usually not inherited from or “carried” by a unaffected parent. However, once the mutation has occurred, it is transmitted by dominant inheritance from either an affected mother or father to their child. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disorder. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the child.

A few families showed recurrence in what appeared to be autosomal recessive inheritance. Mutational analysis revealed that these cases were the result of parental germline mosaicism for a COMP mutation. As a result, one or more of the parent’s children may inherit the germ cell gene COMP mutation, leading to pseudoachondroplasia, while the parent does not have this disorder because the mutation is not present in sufficient number of body cells. The likelihood of a parent passing on a mosaic germline mutation to a child depends upon the percentage of the parent’s germ cells that have the mutation versus the percentage that do not. There is no test for germline mutation prior to pregnancy. Testing during a pregnancy for familial cases with a known mutation is available and should be discussed with a genetic specialist.

Figure 1. Pseudoachondroplasia autosomal dominant inheritance pattern

People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.

Resources for locating a genetics professional in your community are available online:

• The National Society of Genetic Counselors (https://www.findageneticcounselor.com/) offers a searchable directory of genetic counselors in the United States and Canada. You can search by location, name, area of practice/specialization, and/or ZIP Code.
• The American Board of Genetic Counseling (https://www.abgc.net/about-genetic-counseling/find-a-certified-counselor/) provides a searchable directory of certified genetic counselors worldwide. You can search by practice area, name, organization, or location.
• The Canadian Association of Genetic Counselors (https://www.cagc-accg.ca/index.php?page=225) has a searchable directory of genetic counselors in Canada. You can search by name, distance from an address, province, or services.
• The American College of Medical Genetics and Genomics (http://www.acmg.net/ACMG/Genetic_Services_Directory_Search.aspx) has a searchable database of medical genetics clinic services in the United States.

Pseudoachondroplasia symptoms

Signs of pseudoachondroplasia can vary from child to child, but may include:

• Short arms and legs
• Delay in crawling and walking
• Waddling walk
• Joint pain at an early age
• Limited range of motion at the elbows and hips
• Abnormally large range of joint movement (hyperextendibility) in the hands, knees and ankles
• Knee deformities, such as bow-legs (knees that point outward) or knock-knees (knees that point inward)
• Curvature of the spine, including scoliosis or lordosis, an inward curvature of the cervical (top) and lumbar (middle) portions of the spine
• ‘Normal’ facial features

Pseudoachondroplasia shows variable expression with the severity varying within and between families. Infants with pseudoachondroplasia have normal birth parameters and cannot be distinguished from unaffected newborns since birth length and weight are normal. Generally, the first sign is diminished linear growth starting between 9 to 12 months with length and eventually height falling approximately two years behind the standard growth curve. Disproportionate short stature becomes more apparent with age. Affected children usually begin to walk between 12- 18 months but the gait is abnormal and described as ‘waddling’ reflecting underlying skeletal abnormalities involving the hips. The face is attractive and has been described as angular. Disproportionate shortening of the arms and legs become apparent between 3-5 years of age. The hands and feet are short with the fingers and toes showing dramatic shortening and laxity. All the joints exhibit extreme laxity except the elbows which may have limited extension. The joint laxity at the knees contributes to the lower extremity deformities that include bowing (genu varum) or knock knee (genu valgum) deformities. Sometimes bowing can occur in one leg and a knock knee deformity in the other. Surgical correction is generally required but should be delayed to get maximum sustainable correction.

Spinal abnormalities are common and include: 1) scoliosis or S-shaped spinal curve, 2) exaggerated lumbar lordosis, which is an abnormal inward curvature of the lower portion of the spine and 3) kyphosis, which is abnormal front-to-back (or outward) curvature of the spine so that the spine is abnormally rounded at the top. Underdevelopment (hypoplasia) of the small, tooth-like projection (odontoid) at the top of the spine occurs infrequently. Odontoid hypoplasia causes instability in the neck region (cervical instability), which increases the risk of spinal injury (cervical myelopathy). This complication often requires surgical fusion of the upper spine.

Pain, a common and universal complaint, starts in early childhood and is exacerbated by exercise. Activities that stress the joints should be avoided. This includes all contacts sports and trampoline. Early joint pain may reflect an inflammatory process related to the underlying chondrocyte pathology. Osteoarthritis in early adulthood is a universal finding usually developing into chronic joint pain (arthralgia). The hips, ankles, shoulder, elbows and wrists are particularly affected. Degenerative joint disease is progressive and ultimately may require surgery starting with hip replacement followed by other joint replacements. Symptomatic treatment with anti-inflammatory medications is used for pain management with varying degrees of success.

Final adult height on average is 3’8” (116 cm) in women and 3’9” for men (120 cm) but this can vary as some individuals may attain a height of 4’10”. Intelligence and life expectancy are unaffected and most individuals raise families and lead productive, active and full lives.

Pseudoachondroplasia diagnosis

The diagnosis of pseudoachondroplasia is based upon identification of characteristic clinical and radiographic findings, detailed patient history, and genetic testing. The diagnosis is rarely made at birth because short stature is not present. The distinctive features develop over time, and this sets it apart from other short stature conditions.

Clinical testing and workup

A complete set of x-rays (radiographs) can help to establish a diagnosis by revealing abnormal growth centers (epiphyses) and other characteristic skeletal findings. The diagnosis is made clinically and by reviewing the radiographs. More advanced imaging techniques such as magnetic resonance imaging (MRI) and computed tomography (CT) scans can be used later to assess skeletal health, particular in advance of surgery to correct skeletal malformations. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures.

Genetic counseling helps families understand the genetics and natural history of pseudoachondroplasia as well as providing psychosocial support. Sequencing of the COMP gene confirms the diagnosis and is commercially available. Prenatal diagnosis for pregnancies at increased risk for pseudoachondroplasia is accomplished by chorionic villus sampling or amniocentesis if the COMP gene mutation has been identified in an affected family member.

Pseudoachondroplasia treatment

Treatments are directed toward the specific symptoms as they become apparent and usually require the coordinated efforts of a team of specialists. The team includes geneticist, pediatrician, specialists in treating skeletal disorders (orthopedic surgeons), neurologists, physical and occupational therapists and other healthcare professionals who will systematically and comprehensively plan needed treatments.

Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease severity; the presence or absence of painful symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.

Pain medications may be beneficial in treating pain associated with joint disease. Physical therapy, which can improve joint motion and avoid muscle degeneration (atrophy), is beneficial.

In some patients, surgery may be necessary to achieve better positioning and to increase the range of motion in certain joints. Surgery may be necessary to treat malformation of the hips and, in some individuals, total hip replacement surgery (total hip arthroplasty) may be necessary. Surgical procedures may be recommended to treat abnormalities of the knees and lower legs. Osteotomy, a surgical procedure in which bone is cut to change the alignment, is common in pseudoachondroplasia to treat improper alignment of bones of the lower legs.

In some children, spinal abnormalities may require surgical intervention. Abnormal curvature of the spine, e.g. scoliosis, usually does not require surgery, but in severe cases, surgery has been effective. More serious spinal problems such as cervical instability may require spinal fusion.

Follow-up care

Your child with pseudoachondroplasia should be monitored by an orthopaedic physician throughout his development, into adulthood.

Doctors will watch for degenerative joint disease and neurological problems (such as weakness in an arm or leg), and assess lower-limb alignment and joint pain. It is not uncommon for children with pseudoachondroplasia to have legs that are slightly different lengths, which can affect the way the child walks (gait) in the short-term, and can affect hip function in adulthood.

If your child had spine, hip or leg surgery, he or she will need to see the orthopaedic surgeon about one to two weeks after surgery, then again at three and six months post-surgery. After that, annual monitoring by trained clinicians is strongly encouraged to ensure any problems are spotted and treated as soon as possible.

Additionally, physicians may recommend your child see several specialists because other body systems may be affected by pseudoachondroplasia.

For example, your child may see:

• An orthopaedist for any bone-, muscle- and joint-related issues
• Physical therapists and occupational therapists to expand your child’s physical dexterity and skill
• A neurologist or neuromuscular specialist to address any nerve or muscle weakness
• A psychologist or social worker to address any body-image and related mental health issues

During follow-up visits, X-rays and other diagnostic testing may be done. The goal of continued monitoring is to help spot any irregularities in growth or development and to address health issues as they develop.

Pseudoachondroplasia prognosis

Children with pseudochondroplasia can lead relatively normal lives. They have normal intelligence and an average life span.

Ongoing medical monitoring is important for people with pseudoachondroplasia. About half will eventually require hip replacement, and some may develop arthritis or further spine problems.

If you have questions about how your child’s condition and any related health issues may affect your child’s prognosis or long-term goals, talk to your child’s healthcare provider.

Couvade syndrome

Couvade syndrome also called sympathetic pregnancy, refers to the various physical symptoms of varying intensity and severity experienced in expectant fathers ¹⁾, for which there is no explanation during the period of the transition to parenthood ²⁾. Couvade syndrome is the common but poorly understood phenomenon whereby the expectant father experiences somatic symptoms during the pregnancy for which there is no recognized physiological basis ³⁾. Couvade syndrome symptoms commonly include indigestion, increased or decreased appetite, weight gain, diarrhea or constipation, headache, and toothache. Onset is usually during the third gestational month with a secondary rise in the late third trimester. Symptoms generally resolve with childbirth. Couvade syndrome has been seen as an expression of somatized anxiety, pseudo-sibling rivalry, identification with the fetus, ambivalence about fatherhood, a statement of paternity, or parturition envy. It is likely that the dynamics of couvade may vary between individuals and may be multidetermined ⁴⁾.

Couvade syndrome is not listed as a diagnostic category in the American Diagnostic and Statistical Manual of Mental Disorders or the World Health Organization’s (WHO) International Classification of Diseases. In addition, Couvade syndrome is not described or discussed in many medical textbooks, although a few handbooks in family practice mention it as a condition of unknown cause.

Couvade syndrome is best examined from the anthropological perspective. The term “couvade” (from the French “couver,” meaning to brood, to hatch) was first used by the anthropologist Edward Burnett Tylor in 1865 to describe the child expectancy habits that he had observed among smaller scale communities ⁵⁾. Couvade syndrome is used to describe a man’s empathic responses to his wife’s pregnancy ⁶⁾.

Based on the data analysis, the prevalence of Couvade syndrome among the participants in a study was very high compared to elsewhere. For example, the prevalence of Couvade syndrome in the UK has been estimated between 11% and 50%, although it should be noted that all the data are some decades old ⁷⁾. In Australia, the proportion of expectant fathers presenting symptoms of Couvade syndrome is 31%, in the United States it is between 25 and 52%, and in Sweden it is 20% ⁸⁾, while in Thailand an estimated 61% of expectant fathers are reported to have Couvade syndrome ⁹⁾. In Poland, 72% of expectant fathers experience at least one of the signs of Couvade syndrome during their wife’s pregnancy ¹⁰⁾. However, in some international studies ¹¹⁾, the presence of only two symptoms is deemed sufficient to denote the presence of Couvade syndrome.

Most diagnoses are made by the exclusion of physical causes and the condition is self-limiting because it tends to resolve after childbirth ¹²⁾. In a study published in 1983, it was concluded that men’s symptoms are a reflection of their level of attachment to the unborn child and involvement in the pregnancy ¹³⁾. Men who have prepared for their parental role, for example by making antenatal visits, report a higher susceptibility to being afflicted by Couvade syndrome ¹⁴⁾. According to attachment theory, the man’s closeness to the fetus gives rise to the Couvade syndrome ¹⁵⁾.

Couvade syndrome causes

Couvade syndrome cause is unknown. Couvade syndrome (sympathetic pregnancy) is an involuntary disorder whereby an expectant father experiences physiological and/or psychological symptoms for which there is no explanation during the period of the transition to parenthood ¹⁶⁾. Couvade syndrome is distinguished from other syndromes by its time course, commencing in the first trimester, temporarily disappears in the second trimester, and emerges again with greater severity in the third trimester and the fact that it is not caused by illness or injury ¹⁷⁾. In a study published in 1983, it was concluded that men’s symptoms are a reflection of their level of attachment to the unborn child and involvement in the pregnancy ¹⁸⁾. Men who have prepared for their parental role, for example by making antenatal visits, report a higher susceptibility to being afflicted by Couvade syndrome ¹⁹⁾. According to attachment theory, the man’s closeness to the fetus gives rise to the Couvade syndrome ²⁰⁾.

Several investigators have reported that the Couvade syndrome is related to various psychosocial factors such as anxiety in expectant fathers; empathy to total identification with the expectant mother as a somatic expression of anxiety; ambivalence about fatherhood and symbolic representation of deeper conflicts; the view of the fetus as a rival for the mother’s attention and a regressive manifestation of the narcissistic injury of losing his position as a “favorite;” paternity issues; roots of fatherliness that develops secondarily to motherliness from the biological dependence on the mother to the biological sexuality as sources of fatherhood; sexuality and gender identity issues as an activation of a passive femininity; parturition envy as the male’s envy of the female’s ability to bear and give birth to children; defense against aggressive impulses as a self-inflicted punishment for his feelings of aggression toward the unborn child; all mostly psychodynamic in nature ²¹⁾.

There is evidence suggesting that these shifts in behavior in males are mediated by physiological changes similar to those seen in pregnant females that induce parental care. Increases of prolactin and decreases of testosterone are associated with paternal behavior. Also, estradiol levels in men peak in the late prenatal period while cortisol levels increase immediately before birth in both men and women with up to a 75% increase from baseline ²²⁾.

Couvade syndrome symptoms are most likely the result of men’s desire to participate, to be more a part of the pregnancy, which will, after all, transform their life ²³⁾. While their wife is pregnant, they are preparing for their new role as a father. Overall, research findings could be explained by both the emotional contagion within couples and the general eagerness of fathers to have children as soon as they get married. Although expectant fathers are expected to be actively involved in their wife’s pregnancy, they receive little guidance on how to do so. In a previous study, Mrayan et al. ²⁴⁾ reported that the major goal behind getting married is to have children and create a family. Some decades ago, Weaver and Cranley ²⁵⁾ found a positive association between paternal–fetal attachment and the incidence of physical symptoms resembling pregnancy in the expectant father.

Couvade syndrome symptoms

Couvade syndrome fathers complained of leg cramps (55.8%), increased appetite (55.8%), stomach distention (49.2%), nausea and abdominal pain, weight gain (45.2%), loss of concentration (44.2%) and lack of motivation (42.7%). The least experienced signs, but which were still significant, were sleeping less than usual (35.2%), feeling frustrated (28.7%), and for some sleeping more than usual (23.1%). It has been suggested that these symptoms mimic the pregnant woman’s nocturnal restlessness as pregnancy progresses ²⁶⁾. Usually, couples share a bedroom and a bed, which also may explain men’s vulnerability to sharing their wife’s sleep disturbances during pregnancy. All these reported signs are also very common and considered normal physiological changes in pregnancy ²⁷⁾. These findings are consistent with those reported by Ganapathy ²⁸⁾ who investigated the frequency of Couvade syndrome symptoms among first-time expectant fathers in India. His results revealed that the most commonly reported physical symptoms are related to gastrointestinal disturbances such as changes in appetite, constipation, flatulence, indigestion, nausea, diarrhea, and abdominal pain ²⁹⁾. Another notable result from a study was that toothache was one of the symptoms commonly experienced by the men during their wife’s pregnancy (43%). Steel ³⁰⁾ states that if a patient presents with unexplained toothache and has a pregnant partner, particularly if other unexplained symptoms are also present, perhaps the possibility of Couvade syndrome should be considered. Many years ago, Trethowan ³¹⁾ identified that more toothache is recorded among expectant fathers compared to a matched control.

Table 1. Frequency of physical symptoms of Couvade syndrome among married males

Table 2. Frequency of psychological symptoms of Couvade syndrome among married males.

Couvade syndrome treatment

Couvade syndrome is normal for the expectant fathers to experience some discomforts during their wife’s pregnancy and it is not considered an illness. Expectant fathers need to know that Couvade syndrome is not a rare or unusual occurrence. In addition, health-care providers need to start monitoring the health status of expectant fathers, and armed with a better understanding of the variety of responses normally experienced by expectant fathers during their wife’s pregnancy, health-care providers will be better able to provide them with the necessary support and education to help them through this transitional period.

What is Morquio syndrome

Morquio syndrome also called mucopolysaccharidosis type IV (MPS IV), is a rare genetic metabolic condition in which the body is unable to break down long chains of sugar molecules called glycosaminoglycans (GAG) ¹⁾. Glycosaminoglycans (GAG) are long chains of sugar molecules used in the building of bones, cartilage, skin, tendons and many other tissues in the body. These sugar chains are submicroscopic and cannot be seen with the eye, but can be studied using special scientific instruments and analytical methods. Toxic levels of glycosaminoglycans (GAG) sugars accumulate in cell structures called lysosomes, leading to the various signs and symptoms associated with the condition. These glycosaminoglycans sugars accumulate in cells, blood, tendons and ligaments, causing damage over time. There is also evidence that GAG are bioactive. This means that their accumulation can cause activation of other chemical reactions in the body (i.e. they may trigger inflammation in joints). Babies may show little sign of the disease, but as more and more glycosaminoglycans (GAG) accumulates, symptoms start to appear. Sugar or foods normally eaten will not affect whether there is more or less buildup of glycosaminoglycans (GAG). Affected children generally develop features of Morquio syndrome (MPS IV) between the ages of 1 and 3. These signs and symptoms may include abnormalities of the skeleton, eyes, heart and respiratory system.

Affected children have a characteristic facial appearance that may include an enlarged head, broad mouth, prominent cheekbones, an unusually small nose, widely spaced and thinly enameled teeth, and widely separated eyes with subtle corneal clouding. The liver and spleen may be mildly enlarged. Children with Morquio syndrome (MPS IV) show marked growth retardation with short trunks and normal limbs from early in life. The elbows, wrists, hips, knees and other large joints are abnormally flexible, causing overall instability. Affected individuals exhibit a waddling gait with frequent falls. Early development and intelligence are typically normal, unlike other MPS storage disorders. High frequency hearing impairment is common.

Individuals with Morquio syndrome (MPS IV) are missing one of two specific enzymes which are essential in the breakdown of certain GAG called keratan sulfate (KS) and chondroitin-6-sulfate (CS).

There are two forms of Morquio syndrome (MPS IV):

1. MPS IVA (MPS IV type A) is caused by changes (mutations) in the GALNS gene. MPS IVA is caused by a defect in the GALNS gene that instructs the body to make the enzyme N-acetyl- galactosamine-6-sulfate sulfatase (GALNS), which is also called galactosamine-6-sulfatase.
2. MPS IVB (MPS IV type B) is caused by mutations in the GLB1 gene. MPS IVB is caused by a defect in the GLB1 gene that instructs the body to make the enzyme beta-galactosidase (GLB1). Because of this gene defect, cells either produce the enzymes in low amounts or not at all, and incompletely broken down glycosaminoglycans (GAG) remains stored inside cells in the body and begins to build up, causing progressive damage.

Both forms are inherited in an autosomal recessive manner. Treatment is based on the signs and symptoms present in each person ²⁾.

The exact prevalence of Morquio syndrome (MPS IV) is unknown, although it is estimated to occur in 1 in 200,000 to 300,000 individuals. MPS IVA (95% of individuals affected by MPS IV) occurs more often than MPS IVB (5% of affected individuals).

What causes Morquio syndrome

Mutations in the GALNS and GLB1 genes cause Morquio syndrome (MPS IV). These genes provide instructions for producing enzymes involved in the breakdown of large sugar molecules called glycosaminoglycans (GAGs). GAGs were originally called mucopolysaccharides, which is where this condition gets its name. When Morquio syndrome (MPS IV) is caused by mutations in the GALNS gene it is called Morquio A syndrome (MPS IV type A or MPS IVA), and when it is caused by mutations in the GLB1 gene it is called Morquio B syndrome (MPS IV type B or MPS IVB). In general, the two types of Morquio syndrome (MPS IV) cannot be distinguished by their signs and symptoms.

Mutations in the GALNS and GLB1 genes reduce or completely eliminate the activity of the enzymes produced from these genes. Without these enzymes, GAGs accumulate within cells, specifically inside the lysosomes. Lysosomes are compartments in the cell that break down and recycle different types of molecules. Conditions such as Morquio syndrome (MPS IV) that cause molecules to build up inside the lysosomes are called lysosomal storage disorders. In Morquio syndrome (MPS IV), GAGs accumulate to toxic levels in many tissues and organs, particularly in the bones. The accumulation of GAGs causes the bone deformities in this disorder. Researchers believe that the buildup of GAGs may also cause the features of Morquio syndrome (MPS IV) by interfering with the functions of other proteins inside lysosomes and disrupting the movement of molecules inside the cell.

Morquio syndrome inheritance pattern

Morquio syndrome is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

It is rare to see any history of autosomal recessive conditions within a family because if someone is a carrier for one of these conditions, they would have to have a child with someone who is also a carrier for the same condition. Autosomal recessive conditions are individually pretty rare, so the chance that you and your partner are carriers for the same recessive genetic condition are likely low. Even if both partners are a carrier for the same condition, there is only a 25% chance that they will both pass down the non-working copy of the gene to the baby, thus causing a genetic condition. This chance is the same with each pregnancy, no matter how many children they have with or without the condition.

• If both partners are carriers of the same abnormal gene, they may pass on either their normal gene or their abnormal gene to their child. This occurs randomly.
• Each child of parents who both carry the same abnormal gene therefore has a 25% (1 in 4) chance of inheriting a abnormal gene from both parents and being affected by the condition.
• This also means that there is a 75% ( 3 in 4) chance that a child will not be affected by the condition. This chance remains the same in every pregnancy and is the same for boys or girls.
• There is also a 50% (2 in 4) chance that the child will inherit just one copy of the abnormal gene from a parent. If this happens, then they will be healthy carriers like their parents.
• Lastly, there is a 25% (1 in 4) chance that the child will inherit both normal copies of the gene. In this case the child will not have the condition, and will not be a carrier.

These possible outcomes occur randomly. The chance remains the same in every pregnancy and is the same for boys and girls.

Figure 1 illustrates autosomal recessive inheritance. The example below shows what happens when both dad and mum is a carrier of the abnormal gene, there is only a 25% chance that they will both pass down the abnormal gene to the baby, thus causing a genetic condition.

Figure 1. Morquio syndrome autosomal recessive inheritance pattern

People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.

Resources for locating a genetics professional in your community are available online:

• The National Society of Genetic Counselors (https://www.findageneticcounselor.com/) offers a searchable directory of genetic counselors in the United States and Canada. You can search by location, name, area of practice/specialization, and/or ZIP Code.
• The American Board of Genetic Counseling (https://www.abgc.net/about-genetic-counseling/find-a-certified-counselor/) provides a searchable directory of certified genetic counselors worldwide. You can search by practice area, name, organization, or location.
• The Canadian Association of Genetic Counselors (https://www.cagc-accg.ca/index.php?page=225) has a searchable directory of genetic counselors in Canada. You can search by name, distance from an address, province, or services.
• The American College of Medical Genetics and Genomics (http://www.acmg.net/ACMG/Genetic_Services_Directory_Search.aspx) has a searchable database of medical genetics clinic services in the United States.

Morquio syndrome symptoms

People affected by Morquio syndrome (mucopolysaccharidosis type IV or MPS IV) often develop signs and symptoms of the condition in early childhood between ages 1 and 3. Morquio syndrome is considered progressive; however, the rate at which symptoms worsen varies significantly among affected people. All people affected by Morquio syndrome develop skeletal problems such as scoliosis, knock-knees, short stature, pectus carinatum and variety of other abnormalities of the ribs, chest, spine, hips, and wrists ³⁾. Another common feature of Morquio syndrome (MPS IV) is an underdeveloped odontoid process (a peg-like bone in the neck that helps stabilize the cervical vertebrae). This can misalign, compress and damage the spinal cord, leading to paralysis or even death ⁴⁾.

Other signs and symptoms of Morquio syndrome include ⁵⁾:

• Scoliosis or kyphosis
• Knock knees
• Heart and vision problems
• An enlarged liver (mild hepatomegaly)
• Short height
• Coarse facial features
• Hypermobile joints
• Corneal clouding and vision loss
• Heart valve abnormalities
• Respiratory complications, including airway obstruction, sleep apnea and restrictive lung disease
• Widely-spaced, discolored teeth with thin enamel
• Mild to moderate hearing loss

Skeletal X-rays typically show marked flattening of the vertebra. The long bones of the arms and legs are characteristically shorter and thicker than normal. The skull is large for the rest of the body. The connection between the first and second vertebrae in the neck is poorly developed and this abnormality can be life threatening. A trivial injury may cause the two vertebrae to slip on each other and compress the spinal cord. Surgery to stabilize the upper cervical spine, usually by spinal fusion, can be lifesaving but life expectancy is decreased somewhat despite surgery. The deformity of the chest causes a strain on the heart and lungs, which may eventually cause respiratory failure.

Figure 2. Morquio syndrome ulnar deviation of both wrists and joint enlargement in a male age 15 years with MPS IVA

Figure 3. Morquio syndrome with shortened forearm and ulnar deviation of the wrist in a male age 15 years with MPS IVA

Figure 4. Morquio syndrome with pectus anomaly and short neck in a male age 15 years with MPS IVA

Figure 5. Morquio syndrome with severe genu valgum (knock-knee) in a male age 15 years with MPS IVA

Morquio syndrome diagnosis

Diagnosis of Morquio syndrome starts with a thorough medical history and physical exam.

Physical examination. In severe MPS IVA the following findings are usually observed between ages one and three years; in slowly progressive MPS IVA the following findings may not become evident until as late as the second decade of life:

• Marked disproportionate short stature with short trunk and normal limbs (arm span exceeds height)
• Ulnar deviation of the wrists (see Figures 2 and Figure 3)
• Pectus carinatum and flaring of the lower rib cage (Figure 4)
• Gibbus (short-segment structural thoracolumbar kyphosis resulting in sharp angulation of the back), kyphosis, and scoliosis
• Genu valgum (knock-knee) (Figure 5)
• Hypermobile joints
• Waddling gait with frequent falls

Your child’s doctor might order:

• Genetic testing
• X-ray images to produce images of your child’s bones
• MRI scans to produce images of organs and other structures
• Echocardiogram to examine the heart and its functioning
• Laboratory tests e.g., urine glycosaminoglycans (GAG) analysis. Excessive amounts of keratan sulfate will usually be present in the urine.

Diagnosis of MPS IVA is confirmed by low N-acetylgalactosamine-6-sulfate sulfatase (GALNS) enzyme activity in cultured blood or skin cells and/or molecular genetic testing to identify GALNS gene mutations.

MPS IVB diagnosis is confirmed by the finding of a beta-galactosidase deficiency in blood or skin cells and/or molecular genetic testing to identify GLB1 gene mutations.

Morquio syndrome treatment

The goals of managing Morquio syndrome (MPS IV) are to improve quality of life, to slow down the progression of the disease, and to prevent permanent tissue and organ damage. Currently there is no cure for Morquio syndrome (MPS IV); however, early intervention may help prevent irreversible damage. Treatment options for Morquio syndrome (MPS IV) include those aimed at disease management and supportive or palliative care (care that makes a person with a disease that cannot be cured more comfortable).

In 2014, the FDA approved a recombinant human N-acetylgalactosamine-6-sulfate sulfatase (GALNS) intravenous enzyme replacement therapy (elosulfase alfa, or Vimizim) for the treatment of MPS IVA (Morquio A syndrome). Vimizim is manufactured by BioMarin Pharmaceutical Inc. Vimizim (elosulfase alfa) is administered weekly via intravenous infusion.

There is no treatment for MPS IVB (Morquio B syndrome).

Other treatment of MPS IV is symptomatic and supportive. Surgery to decompress and fuse the bones of the upper neck to the base of the skull can prevent destabilization of the cervical vertebrae and potential damage to the spinal cord.

Management of affected individuals with MPS IV is best undertaken by multiple specialists, including: a physical therapist for physical rehabilitation, a psychiatrist for psychological support, educational professionals for learning optimization, and home care professionals for affected individuals with medical equipment dependence.

Surgeons may also play a crucial role in treating affected individuals. The placement of a bioprosthetic or prosthetic valve may be required for affected individual with ventricular hypertrophy (overgrowth). Enlarged tonsils and adenoids may need to be removed in order to relieve upper-airway obstruction and sleep apnea. Additionally, ventilation tubes and hearing aids may be needed for individuals with hearing loss. Penetrating keratoplasty (corneal replacement) may be needed to treat corneal opacification (scarring or clouding of the cornea), which causes impaired vision.

Since children with MPS IVA are of normal intelligence, they usually attend regular classes, but they made need to sit close to the front of the classroom if they have difficulties hearing or seeing. They may also need to use a wheelchair around school grounds.

Genetic counseling is recommended for affected individuals and their families.

Morquio syndrome life expectancy

Disease severity varies significantly for individuals with Morquio syndrome (MPS IV), and it is not possible to predict the expected life span for a given individual. Those on the more slowly progressing end of the disease spectrum may have a reasonably normal lifespan. However, the availability of new and ever-improving treatments as well as other surgical procedures provides hope for better future outcomes for individuals affected by Morquio syndrome (MPS IV).

Morquio syndrome (MPS IV) has a highly variable phenotype. This means that some children may have many of the symptoms described below and may be severely affected while others may not experience all of the symptoms and have a milder presentation. There is currently no reliable way of telling from biochemical diagnostic tests how severe the disease will be. Detailed studies have shown that in individuals with attenuated, or slowly progressing, Morquio syndrome (MPS IV), a very small amount of active enzyme is working. This small amount of enzyme will digest some of the accumulating GAG, resulting in the disease being less severe than in an individual who has almost no enzyme activity.

DNA tests do not always correctly determine the severity of Morquio syndrome (MPS IV). Many different kinds of mutations(permanent changes) in the gene that produces the enzyme deficiency have been identified. The gene has been studied extensively to see if there is any relationship between specific genetic mutations and the symptoms of the disease. There are some common mutations of the gene that result in absolutely no enzyme being produced. If both copies of the defective gene inherited by an individual are of this kind, evidence suggests that the individual’s condition is likely to be at the severe end of the spectrum. Other common mutations of the gene cause very small amounts of defective enzyme to be produced, and still other mutations are not common at all and may only occur in a single known family. In these cases, it is virtually impossible to predict severity of disease using DNA analysis.

There is therefore no perfectly reliable way to determine the exact course of disease for individuals with Morquio syndrome (MPS IV). Even with the same small amount of enzyme activity, and even within the same family, there can be variations in severity that cannot be explained by the enzyme level or DNA mutation. It is important to remember that whatever name is given to your child’s condition, Morquio syndrome (MPS IV) is a spectrum with a variety of symptoms, and is extremely varied in its effects. This booklet addresses a wide range of possible symptoms that individuals with Morquio syndrome (MPS IV) may encounter; however, parents should be aware that their child(ren) may not experience them all or to the degree described.

Early diagnosis of Morquio syndrome (MPS IV) is critical. The earlier Morquio syndrome (MPS IV) is diagnosed, the sooner potential treatment options can be explored and supportive care may be started to help you or your loved one, and potentially prevent some of the permanent damage that may be caused by the disease.

Hemihyperplasia

Hemihyperplasia also called hemihypertrophy, is a condition in which there is excessive (hyper) growth (trophy) of only one side (hemi) of one or more body parts ¹⁾. The overgrowth may be limited to a portion of the body, such as a leg or arm, or it may involve several different areas of the body, including the arms, face (causing asymmetry of the nose, eyes or cheeks), tongue, jaw, teeth and ears. There may be associated asymmetric hypertrophy of internal organs. All tissue types can be affected, including the bones, skin, muscle, fat and nerves that are connected to the area of overgrowth. Hemihyperplasia may not be apparent at birth, but becomes most noticeable as the child grows.

Hemihyperplasia can be an isolated hemihyperplasia (occur by itself) or be part of well-defined genetic syndromes such as in the case of Beckwith-Wiedemann syndrome, Proteus syndrome, Russell-Silver syndrome, Klippel-Trenaunay-Weber syndrome, McCune-Albright syndrome and Sotos syndrome ²⁾. Isolated hemihyperplasia is usually sporadic, but a number of familial occurrences have been described. In most cases, the cause of isolated hemihypertrophy is unknown. In cases where hemihyperplasia is part of a genetic syndrome, the cause depends on the specific syndrome.

The reported incidence of hemihyperplasia is thought to occur in around one in 86,000 live births, but this number may change as there is more agreement on a definition and more people looking for it.

Rowe ³⁾ proposed a classification system for hemihyperplasia, based on anatomic site of involvement. According to this classification, complex hemihyperplasia is defined as involvement of half of the body (at least one arm and one leg), simple hemihyperplasia is the involvement of a single limb and hemifacial hyperplasia is the involvement of one side of the face. The degree of asymmetry is variable, and mild cases are easily overlooked ⁴⁾. The prevalence of isolated hemihyperplasia is difficult to establish accurately because many cases may be so mild as not to come to medical attention. The prevalence for hemihyperplasia was reported as approximately 1 in 86,000 ⁵⁾.

Hemihyperplasia can be diagnosed at birth or appear later in childhood, and can follow an irregular growth pattern. At times new growth may be excessive, while at other times it may be modest.

Hemihyperplasia treatment may include surgery to correct the differences in the affected body part(s) ⁶⁾.

The risk of tumor development in isolated hemihyperplasia is approximately one in 20, or around 5%. Because most of the cancers occur in the abdomen, the recommendation has been made (by the participants of the First International Conference on Molecular and Clinical Genetics of Childhood Renal Tumors–among others) that children with hemihypertrophy receive a screening abdominal ultrasound every 3 months until age 7 and, at minimum, a careful physical examination every 6 months until growth is completed. There is currently inadequate indication to screen children above 6 years of age ⁷⁾.

Figure 1. Isolated hemihyperplasia

Footnote: Enlargement of the left hand and forearm (arrows) and enlargement of the left foot, leg, and thigh (arrows).

Hemihyperplasia causes

Hemihyperplasia can be an isolated hemihyperplasia (occur by itself) or be part of well-defined genetic syndromes such as in the case of Beckwith-Wiedemann syndrome, Proteus syndrome, Russell-Silver syndrome, and Sotos syndrome ⁹⁾. Isolated hemihyperplasia is usually sporadic, but a number of familial occurrences have been described. In most cases, the cause of isolated hemihypertrophy is unknown. In cases where hemihyperplasia is part of a genetic syndrome, the cause depends on the specific syndrome.

Hemihyperplasia symptoms

Children with hemihyperplasia may not show any symptoms other than a subtle difference between the two sides of the face. As overgrowth progresses, a greater difference may be seen and the overgrowth may lead to difficulty with eating, chewing seeing and breathing. Appearance-related concerns may arise as the disease progresses.

Hemihypertrophy is often linked with mild mental retardation, genito-urinary anomalies, and an oncogenic potential (Wilms’ tumor) ¹⁰⁾. Wilms’ tumor accounts for most renal neoplasms in childhood, and occurs with roughly equal incidence in both genders and all races, with a yearly incidence of 7.8 per million children younger than 15 years ¹¹⁾. An imperative feature of Wilms’ tumor is the association with congenital anomalies, the most common being genitourinary anomalies (4.4%), and hemihypertrophy (29%) ¹²⁾. The risk of tumor development in isolated hemihyperplasia is approximately one in 20, or around 5%. The best follow-up plan is to follow the patients until the age of 7 years; these children should have abdominal ultrasound scans at 3 monthly intervals. With daily caretaker abdominal examination at the discretion of the doctor or parent. There is currently inadequate indication to screen children above 7 years of age ¹³⁾.

Hemihyperplasia diagnosis

Hemihyperplasia is diagnosed with clinical examination and supplemented with radiologic studies such as a CT scan or MRI.

Hemihyperplasia treatment

Treatment of hemihyperplasia addresses both functional and appearance-related purposes. Procedures performed include suction-assisted lipectomy, excision of excessive skin and subcutaneous tissue, and contouring or reducing facial bones.

The goal of surgery is to preserve as much nerve and muscle function as possible. Surgery can occur on an outpatient basis, or if it is more extensive it will require hospitalization for a one to two day period.

Incisions can vary around the face depending on the area that is hyperplastic but, in general, are hidden in creases, folds, or intraorally. A moderate amount of soft tissue swelling can occur following surgery and eating may be compromised short term following discharge. Swelling will improve over time and any numbness or the like as a consequence of the surgery will generally improve.

Fat pad atrophy

Fat pad atrophy is the gradual loss of the fat pad in the ball or heel of your foot. Fat pad atrophy of the foot are more common in aging population affecting 30% of patients over the age of 60 as you lose the fat layer under your skin and your body produces less collagen and usually presents with severe foot pain during walking ¹⁾. Fat pad atrophy is the thinning of the pad that exposes the delicate connective tissue elements to strain and pressure creating inflammation and micro-injury. As a result, your heels may begin to hurt as the day wears on. In poorly managed cases, patients present with severe pain and discomfort.

The heel contains specialized fat pads which protect the foot from harsh repetitive stress generated during the gait cycle. The fat pad is the the thick pad of connective tissue that runs under the ball and heel of the foot and forms the lower aspect of foot. The purpose of the fat pad is:

• To provide cushioning to minimize the effect of friction, pressure and gravitational forces on the foot musculature; and,
• To serve as a mechanical anchor that helps in shifting the body weight without overwhelming connective tissue elements.

These fat pads are divided into a thin, superficial microchamber and a thicker, deeper macrochamber ²⁾. Fat pad atrophy of the deeper macrochamber causes pain with ambulation and can cause substantial disability.

The risk profile and prevalence of fat pad atrophy is fairly comparable in males and females. However, some experts believe that females are relatively more vulnerable to develop this condition because of:

• High heels which do not support the bottom of the foot; and,
• Ill-fitting or very tight footwear which aggravates the risk of injuries such as callus formation. If left untreated, such injuries can lead to various degenerative foot changes.

Fat pad atrophy is best managed conservatively with the use of heel cups, soft insoles, gel pads and soft-soled footwear for comfort. The heel cup helps to centralize and increase the bulk of the soft tissue under the calcaneus.

Fat pad atrophy causes

The causes are not totally clear. Some people just seem to develop this and others do not. Fat pad atrophy can occur in a number of rheumatological problems and runners due to the years of pounding on the heel may be at a greater risk for this. Those with a higher arch foot (pes cavus) also get a displacement of the fat pad which can give a similar problem to fat pad atrophy.

Certain factors that may aggravate the risk of developing fat pad atrophy such as:

• Age: The relationship between aging and fat pad atrophy has been studied. The risk of developing degenerative foot conditions increases with progressing age. With increasing age new cartilage and fat tissue formation decreases which makes the bones weaker and more prone to damage. However, it has not been possible to demonstrate whether fat pad atrophy is a normal part of the aging process or whether it indicates pathology ³⁾. Molines-Barroso et al ⁴⁾ have not found differences between age groups.
• Collapsed bone: Degeneration or damage to the long bones of the foot can exert significant pressure over the fat pad leading to increased wear and tear damage..
• Footwear: Use of high-heeled shoes can cause as well as aggravate the risk of foot pad atrophy.
• High arch: Certain anatomical characteristics, such as high pedal arches can also cause changes in the foot pad by applying direct pressure on the connective tissue architecture.
• Injury: Injuries caused by significant trauma such as an accident, or other forms of trauma which leads to multiple fractures or surgeries can also increase the risk of developing fat pad atrophy
• Family history: Family history or genetics plays a very important role in development of atrophic and degenerative conditions.
• Arthritis: Inflammation of joints especially in the setting of rheumatoid arthritis aggravates the risk of fat pad atrophy as the bones becomes more vulnerable to damage as a result of ongoing inflammation
• Diabetes: Individuals with persistently high blood sugar levels are vulnerable to develop neuropathy (which leads to numbness and loss of sensation in the foot) ⁵⁾. The chances of developing pressure-induced atrophic changes increases resulting in fat pad atrophy.
• Steroid injections: Steroid injections in the foot, especially if done too frequently can cause fat pad atrophy.
• Medications: Chronic use of steroids is also known to cause fat pad atrophy in adults.

Fat pad atrophy symptoms

Some characteristic symptoms of fat pad atrophy include:

• Pan in the foot (metatarsalgia) which becomes worse when wearing high heels or walking over a hard flat surface.
• Pain in the foot when a person is in standing position for extended periods of time. (62% of diagnosed sufferers report excessive foot pain after a long walk or long period of standing.)
• Feeling of the development of a mass or swelling in the foot/ heel.
• The ball of foot may become excessively thick due to callus formation.

Fat pad atrophy diagnosis

Currently, fat pad atrophy is a diagnosis of exclusion, and there are no tissue thickness parameters to define the condition.

Fat pad atrophy treatment

Fat pad atrophy is best managed conservatively with the use of heel cups, soft insoles, and soft-soled footwear. The heel cup helps to centralize and increase the bulk of the soft tissue under the calcaneus.

Additional management for fat pad atrophy includes:

• Avoiding activities which puts too much pressure on your foot such as walking on hard, flat or uneven surfaces.
• Avoiding wearing high heel and switch to comfortable footwear.
• Opting instead for low impact weight bearing exercises to optimize healing and regeneration processes.
• Use paddings or insoles to allow even distribution of weight to minimize the direct impact of pressure.
• Chose footwear that supports the foot (especially the heel and arches) to provide cushioning and shock absorbing.

When conventional methods fail, healthcare providers may recommend surgical treatment as a last resort. Existing small clinical trial suggests that fat grafting can restore foot function in patients with heel fat pad atrophy by preserving shock absorbing soft tissue and reducing pain ⁶⁾. However, these findings will need to be corroborated in a larger sample and longer follow up clinical trials. The fat cells were harvested from patient’s abdomen by manual liposuction, processed and injected by Coleman technique, and introduced into the macrochamber fat compartment ⁷⁾. Although the fat grafting could increase the tissue thickness under the metatarsal for a prolonged period, data demonstrate that by 6 months, and even more at 12 months, the fat had resorbed under the metatarsal or shifted in position ⁸⁾. Despite decreasing tissue thickness over time, fat grafting for forefoot fat pad atrophy significantly improves pain and disability outcomes, decreases foot pressures and forces, and prevents against worsening foot pressures and forces. Pedal fat grafting is a safe, minimally invasive approach to treat fat pad atrophy.

There are minimal data describing the use of augmentation of the fat pad with internal techniques. In 1994, a subjective study was performed by Chairman ⁹⁾. Fifty patients were subjectively interviewed over 9 to 28 months postoperatively after fat grafting in combination with bone surgery. All but two patients had subjective improvement in pain, but no objective data were recorded. Fat was harvested from the calf, with no explanation of how the fat was processed.

Rocchio ¹⁰⁾ published a case series of 25 patients treated with acellular dermal graft to treat fat pad atrophy. GRAFTJACKET matrix (Wright Medical, Memphis, Tenn.) was surgically inserted using a “parachute technique” and a tie-over bolster. Patients were non–weight-bearing for 2 weeks and half underwent concomitant bony or soft-tissue operations. Most patients were satisfied with the treatments. Ultrasound thickness demonstrated significant increases over the course of the study, but only nine patients made it to the 6-month ultrasound and only two made it to 12 months, reducing the significance of the long-term conclusions of the study. Objective pain assessments and foot pressure/forces were not measured. A disadvantage of this technique is that incision and dissection of the plantar surface of the foot requires disruption of the natural fibrous septa, potentially leading to neurovascular damage or aberrant scar formation. There remains scant evidence-based research to date on acellular dermis for fat pad augmentation in the foot.

More data have been published about injectable materials, such as silicone ¹¹⁾. Injected liquid silicone increases plantar tissue thickness, decreases plantar pressure, and stimulates proliferation of surrounding collagen fibers. However, after 2 years, the cushioning ability of silicone diminished, resulting in increased plantar pressure ¹²⁾. Another adverse event of silicone is the potential to migrate and not remain in the allocated fat pad position ¹³⁾. Although migration appears to be asymptomatic, microscopic droplets can be identified in the groin lymph nodes. In diabetic patients, silicone may be at risk for infection as a foreign body. Other fillers commonly used for facial augmentation have been used off-label by podiatrists and foot and ankle specialists as an off-the-shelf solution to this problem, with no evidence in the literature. The use of 1 to 2 mL of filler per metatarsal head may result in a very expensive temporary solution. Some fillers that require reconstitution with saline may have a dispersion of the product with ambulation that can lead to unpredictable results and likely require multiple treatments with no guarantee of success.

Encephalitis in children

Encephalitis is a term used to describe inflammation of the brain. The inflammation causes the brain to swell, which leads to changes in the child’s neurological condition, including mental confusion and seizures. Encephalitis can be life threatening and requires urgent treatment in hospital.

It’s not always clear what causes encephalitis, but it can be caused by:

• viral infections – several common viruses can spread to the brain and cause encephalitis in rare cases, including the herpes simplex virus (which causes cold sores and genital herpes) and the chickenpox virus
• a problem with the immune system, the body’s defence against infection – sometimes something goes wrong with the immune system and it mistakenly attacks the brain, causing it to become inflamed
• bacterial or fungal infections – these are much rarer causes of encephalitis than viral infections

Some types of encephalitis are spread by mosquitoes (such as Japanese encephalitis), ticks (such as tick-borne encephalitis) and mammals (such as rabies).

You cannot catch encephalitis from someone else.

Encephalitis often causes only mild flu-like signs and symptoms such as a fever or headache or no symptoms at all. Sometimes the flu-like symptoms are more severe. Encephalitis can also cause confused thinking, seizures, or problems with movement or with senses such as sight or hearing.

In some cases, encephalitis can be life-threatening. Timely diagnosis and treatment are important because it’s difficult to predict how encephalitis will affect each individual.

Encephalitis needs to be treated in a hospital. The earlier treatment is started, the more successful it’s likely to be.

Specific treatment for encephalitis will be determined by your child’s doctor based on:

• Your child’s age, overall health, and medical history
• The extent of the condition
• Your child’s tolerance for specific medications, procedures, or therapies
• Expectations for the course of the condition
• Your opinion or preference

The key to treating encephalitis is early detection and treatment. A child with encephalitis requires immediate hospitalization and close monitoring. Sometimes, depending on what doctors think the specific cause of the encephalitis is, certain medications can be used to fight infections that may cause it.

The goal of treatment is to reduce the swelling in the head and to prevent other related complications. Medications to control the infection, seizures, fever, or other conditions may be used.

The extent of the problem is dependent on the severity of the encephalitis and the presence of other organ system problems that could affect the child. In severe cases, a breathing machine may be required to help the child breathe easier.

Treatment depends on the underlying cause, but may include:

• antiviral medicines
• steroid injections
• treatments to help control the immune system
• antibiotics or antifungal medicines
• painkillers to reduce discomfort or a high temperature
• medicine to control seizures or fits
• support with breathing, such as oxygen through a face mask or a breathing machine (ventilator)

As the child recovers, physical, occupational, or speech therapy may be necessary to help the child regain muscle strength and/or speech skills.

How long someone with encephalitis needs to stay in hospital can range from a few days to several weeks or even months.

Your health care team will educate you and your family after hospitalization on how to best care for your child at home and outlines specific clinical problems that require immediate medical attention by his or her doctor. A child with encephalitis requires frequent medical evaluations following hospitalization.

Is encephalitis contagious?

Brain inflammation itself is not contagious. But the viruses that cause encephalitis can be. Of course, getting a virus does not mean that someone will develop encephalitis.

Encephalitis in children causes

There are more than 100 different recognized causes that can lead to encephalitis in children and many of these differ with respect to the season, the area of the country, and the exposure of the child. According to a new review of medical records ¹⁾, viral, bacterial and autoimmune causes account for most cases of encephalitis in children, but more than four in 10 have no recognized cause.

Viruses are the leading cause of encephalitis. Although vaccines for many viruses, including measles, mumps, rubella, and chickenpox have greatly lowered the rate of encephalitis from these diseases, other viruses can cause encephalitis. These include herpes simplex virus (HSV), human herpesvirus 6 (HHV-6), West Nile virus (carried by mosquitoes), varicella zoster virus and rabies (carried by a number of different animals).

Encephalitis can also occur following a bacterial infection, such as Bartonella henselae (the cause of cat scratch fever), Lyme disease (carried by ticks), Streptococcus pneumoniae, Rickettsia rickettsii (the cause of Rocky Mountain spotted fever), tuberculosis and syphilis, and by parasites, such as toxoplasmosis (carried by cats).

Autoimmune and immune-mediated causes of encephalitis represented 45% of all patients with an identified etiology. The most frequently identified single cause in this group was anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis ²⁾. Second most common was acute disseminated encephalomyelitis (ADEM) ³⁾.

Male patients were more likely to present with infectious causes, whereas female patients were more likely to have autoimmune causes. The proportion of autoimmune cases relative to infectious cases increased with increasing age.

Compared with autoimmune encephalitis, infectious encephalitis was more likely to occur in immunocompromised patients and to be associated with abnormal brain MRI findings.

Common viral causes

The viruses that can cause encephalitis include:

• Herpes simplex virus (HSV). Both HSV type 1 — associated with cold sores and fever blisters around your mouth — and HSV type 2 — associated with genital herpes — can cause encephalitis. Encephalitis caused by HSV type 1 is rare but can result in significant brain damage or death.
• Other herpes viruses. These include the Epstein-Barr virus, which commonly causes infectious mononucleosis, and the varicella-zoster virus, which commonly causes chickenpox and shingles.
• Enteroviruses. These viruses include the poliovirus and the coxsackievirus, which usually cause an illness with flu-like symptoms, eye inflammation and abdominal pain.
• Mosquito-borne viruses. These viruses can cause infections such as West Nile, La Crosse, St. Louis, western equine and eastern equine encephalitis. Symptoms of an infection might appear within a few days to a couple of weeks after exposure to a mosquito-borne virus.
• Tick-borne viruses. The Powassan virus is carried by ticks and causes encephalitis in the Midwestern United States. Symptoms usually appear about a week after a bite from an infected tick.
• Rabies virus. Infection with the rabies virus, which is usually transmitted by a bite from an infected animal, causes a rapid progression to encephalitis once symptoms begin. Rabies is a rare cause of encephalitis in the United States.
• Childhood infections. Common childhood infections — such as measles (rubeola), mumps and German measles (rubella) — used to be fairly common causes of secondary encephalitis. These causes are now rare in the United States due to the availability of vaccinations for these diseases.

Encephalitis in children prevention

It’s not always possible to prevent encephalitis, but some of the infections that cause it can be prevented with vaccinations. Keep your own and your children’s vaccinations current. Before traveling, talk to your doctor about recommended vaccinations for different destinations.

Vaccinations include the:

• measles, mumps and rubella (MMR) vaccine – a routine vaccination offered to all children in England
• Japanese encephalitis vaccine – recommended for travelers to at-risk areas, such as parts of Asia
• tick-borne encephalitis vaccine – recommended for travelers to certain parts of Europe (but not the UK) and Asia
• rabies vaccination – recommended for travelers to at-risk areas where access to medical care is likely to be limited

Speak to a doctor if you’re not sure whether your vaccinations are up to date, or you’re planning to travel abroad and do not know if you need any vaccinations.

The best way to prevent viral encephalitis is to take precautions to avoid exposure to viruses that can cause the disease.

• Practice good hygiene. Wash hands frequently and thoroughly with soap and water, particularly after using the toilet and before and after meals.
• Don’t share utensils. Don’t share tableware and beverages.
• Teach your children good habits. Make sure they practice good hygiene and avoid sharing utensils at home and school.

Protection against mosquitoes and ticks

To minimize your exposure to mosquitoes and ticks:

• Dress to protect yourself. Wear long-sleeved shirts and long pants if you’re outside between dusk and dawn when mosquitoes are most active, and when you’re in a wooded area with tall grasses and shrubs where ticks are more common.
• Apply mosquito repellent. Chemicals such as DEET can be applied to both the skin and clothes. To apply repellent to your face, spray it on your hands and then wipe it on your face. If you’re using both sunscreen and a repellent, apply sunscreen first.
• Use insecticide. The Environmental Protection Agency recommends the use of products containing permethrin, which repels and kills ticks and mosquitoes. These products can be sprayed on clothing, tents and other outdoor gear. Permethrin shouldn’t be applied to the skin.
• Avoid mosquitoes. Refrain from unnecessary activity in places where mosquitoes are most common. If possible, avoid being outdoors from dusk till dawn, when mosquitoes are most active. Repair broken windows and screens.
• Get rid of water sources outside your home. Eliminate standing water in your yard, where mosquitoes can lay their eggs. Common problems include flowerpots or other gardening containers, flat roofs, old tires and clogged gutters.
• Look for outdoor signs of viral disease. If you notice sick or dying birds or animals, report your observations to your local health department.

Protection for young children

Insect repellents aren’t recommended for use on infants younger than 2 months of age. Instead, cover an infant carrier or stroller with mosquito netting.

For older infants and children, repellents with 10% to 30% DEET are considered safe. Products containing both DEET and sunscreen aren’t recommended for children because reapplication — which might be necessary for the sunscreen component — will expose the child to too much DEET.

Tips for using mosquito repellent with children include:

• Always assist children with the use of mosquito repellent.
• Spray on clothing and exposed skin.
• Apply the repellent when outdoors to lessen the risk of inhaling the repellent.
• Spray repellent on your hands and then apply it to your child’s face. Take care around the eyes and ears.
• Don’t use repellent on the hands of young children who may put their hands in their mouths.
• Wash treated skin with soap and water when you come indoors.

Encephalitis in children symptoms

Encephalitis sometimes starts off with flu-like symptoms, such as a high temperature and headache.

Encephalitis often is preceded by a viral illness, such as an upper respiratory infection, or a gastrointestinal problem, such as diarrhea, nausea, or vomiting. The following are the most common symptoms of encephalitis. However, each child may experience symptoms differently. Symptoms may include:

• Fever
• Headache (or bulging of the fontanelles, the soft spots on a baby’s head)
• Sensitivity to light
• Neck stiffness
• Sleepiness or lethargy
• Increased irritability
• Seizures or fits
• Skin rashes
• Difficulty talking and speech changes
• Changes in alertness, confusion, or hallucinations
• Confusion or disorientation
• Changes in personality and behavior
• Weakness or loss of movement in some parts of the body
• Loss of energy
• Loss of appetite
• Unsteady gait
• Nausea and vomiting
• Loss of consciousness

The symptoms of encephalitis may resemble other problems or medical conditions. Call for an ambulance immediately if you or someone else has these symptoms.

Symptoms of encephalitis may be mild to begin with, but can become more serious over hours or days.

Occasionally the symptoms may develop gradually over several weeks or even months.

Early symptoms

The first symptoms of encephalitis can be similar to flu, such as:

• a high temperature
• a headache
• feeling and being sick
• aching muscles and joints

Some people may also have a spotty or blistery rash on their skin.

But these early symptoms do not always appear and sometimes the first signs of encephalitis may be more serious symptoms.

Serious symptoms

More severe symptoms develop when the brain is affected, such as:

• confusion or disorientation
• drowsiness
• seizures or fits
• changes in personality and behavior, such as feeling very agitated
• difficulty speaking
• weakness or loss of movement in some parts of the body
• seeing and hearing things that are not there (hallucinations)
• loss of feeling in certain parts of the body
• uncontrollable eye movements, such as side-to-side eye movement
• eyesight problems
• loss of consciousness

There may also be symptoms of meningitis, such as a severe headache, sensitivity to bright lights, a stiff neck and a spotty rash that does not fade when a glass is pressed against it.

Call your local emergency services number immediately to request an ambulance if you or someone else has serious symptoms of encephalitis.

It’s a medical emergency that needs to be seen in hospital as soon as possible.

Pediatric encephalitis common complications

Encephalitis can damage the brain and cause long-term problems including:

• memory problems
• personality and behavioral changes
• speech and language problems
• swallowing problems
• repeated seizures or fits – known as epilepsy
• emotional and psychological problems, such as anxiety, depression and mood swings
• problems with attention, concentrating, planning and problem solving
• problems with balance, co-ordination and movement
• persistent tiredness

These problems can have a significant impact on the life of the affected person, as well as their family, friends and carers.

Inflammation can injure the brain, possibly resulting in a coma or death.

Encephalitis in children diagnosis

The diagnosis of encephalitis is made after the sudden or gradual onset of specific symptoms and after diagnostic testing. During the examination, your child’s doctor obtains a complete medical history of your child, including his or her immunization history. Your child’s doctor may also ask if your child has recently had a cold or other respiratory illness, or a gastrointestinal illness, and if the child has recently had a tick bite, has been around pets or other animals, or has traveled to certain areas of the country.

Diagnostic tests that may be performed to confirm the diagnosis of encephalitis may include the following:

• X-ray. A diagnostic test that uses invisible electromagnetic energy beams to produce images of internal tissues, bones, and organs onto film.
• 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.
• 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.
• Blood tests
• Urine and stool tests
• Sputum culture. A diagnostic test performed on the material that is coughed up from the lungs and into the mouth. A sputum culture is often performed to determine if an infection is present.
• Electroencephalogram (EEG). A procedure that records the brain’s continuous, electrical activity by means of electrodes attached to the scalp.
• Lumbar puncture (spinal tap). A special needle is placed into the lower back, into the spinal canal. This is the area around the spinal cord. The pressure in the spinal canal and brain can then be measured. A small amount of cerebral spinal fluid (CSF) can be removed and sent for testing to determine if there is an infection or other problems. CSF is the fluid that bathes your child’s brain and spinal cord.
• Brain biopsy. In rare cases, a biopsy of affected brain tissue may be removed for diagnosis.

Encephalitis in children treatment

Encephalitis needs to be treated urgently. Treatment involves tackling the underlying cause, relieving symptoms and supporting bodily functions.

It’s treated in hospital – usually in an intensive care unit (ICU), which is for children who are very ill and need extra care.

How long someone with encephalitis needs to stay in hospital can range from a few days to several weeks or even months.

Treating the cause

If a cause of encephalitis is found, treatment will start straight away.

Possible treatments include:

• antiviral medicine – used if encephalitis is caused by the herpes simplex or chickenpox viruses; it’s usually given into a vein three times a day for 2 to 3 weeks.
  • Antiviral medications commonly used to treat encephalitis include:
    • Acyclovir (Zovirax)
    • Ganciclovir (Cytovene)
    • Foscarnet (Foscavir)
  • Some viruses, such as insect-borne viruses, don’t respond to these treatments. But because the specific virus may not be identified immediately or at all, doctors often recommend immediate treatment with acyclovir. Acyclovir can be effective against HSV, which can result in significant complications when not treated promptly.
  • Antiviral medications are generally well tolerated. Rarely, side effects can include kidney damage.
• steroid injections – used if encephalitis is caused by a problem with the immune system and sometimes in cases linked to the chickenpox virus; treatment is usually for a few days
• immunoglobulin therapy – medicine that helps control the immune system
• plasmapheresis – a procedure which removes the substances that are attacking the brain from the blood
• surgery to remove abnormal growths (tumors) – if encephalitis was triggered by a tumor somewhere in the body
• antibiotics or antifungal medicine – used if encephalitis is caused by a bacterial or fungal infection

If there’s no treatment for the underlying cause, treatment is given to support the body, relieve symptoms, and allow the best chance of recovery.

Supportive care

Encephalitis puts a lot of strain on the body and can cause a range of unpleasant symptoms.

Most children need treatment to relieve these symptoms and to support certain bodily functions until they’re feeling better.

This may involve:

• fluids given into a vein to prevent dehydration
• painkillers to reduce discomfort or a high temperature
• medicine to control seizures or fits
• medicine to help the person relax if they’re very agitated
• oxygen given through a face mask to support the lungs – sometimes a machine called a ventilator may be used to control breathing
• medicine to prevent a build-up of pressure inside the skull

Occasionally, surgery to remove a small piece of the skull may be needed if the pressure inside increases and medicine is not helping.

Follow-up therapy

If you experience complications of encephalitis, you might need additional therapy, such as:

• Physical therapy to improve strength, flexibility, balance, motor coordination and mobility
• Occupational therapy to develop everyday skills and to use adaptive products that help with everyday activities
• Speech therapy to relearn muscle control and coordination to produce speech
• Psychotherapy to learn coping strategies and new behavioral skills to improve mood disorders or address personality changes

Encephalitis in children prognosis

Encephalitis is a serious condition and, although some children will make a good recovery, it can cause persistent problems and can be fatal.

For example, encephalitis due to the herpes simplex virus (the most common type of encephalitis) is fatal in 1 in 5 cases even if treated, and causes persistent problems in around half the children who have it.

The chances of successful treatment are much better if encephalitis is diagnosed and treated quickly.

Some children eventually make a full recovery from encephalitis, although this can be a long and frustrating process.

Some children never make a full recovery and are left with long-term problems caused by damage to their brain.

Common complications include:

• memory loss
• frequent seizures or fits
• personality and behavioral changes
• problems with attention, concentration, planning and problem solving
• persistent tiredness

These problems can have a significant impact on the life of the affected person, as well as their family and friends.

But help and support is available.

Support and rehabilitation

Recovering from encephalitis can be a long, slow and difficult process. Many children will never make a full recovery.

Specialized services are available to aid recovery and help the person adapt to any persistent problems – this is known as rehabilitation.

This may involve support from:

• a neuropsychologist – a specialist in brain injuries and rehabilitation
• an occupational therapist – who can identify problem areas in the person’s everyday life and work out practical solutions
• a physiotherapist – who can help with movement problems
• a speech and language therapist – who can help with communication

Before leaving hospital, the health and care needs of the affected person will be assessed and an individual care plan drawn up to meet those needs.

This should involve a discussion with the affected person and anyone likely to be involved in their care, such as close family members.

Diastrophic dysplasia

Diastrophic dysplasia also called diastrophic dwarfism, is a type of short limb skeletal dysplasia (micromelic dwarfism) that is present at birth (congenital). The word “dysplasia” refers to abnormal growth. Diastrophic dysplasia is a disorder of cartilage and bone development that leads to an onset of joint pain and deformity. Diastrophic dysplasia is a rare genetic condition that causes short stature and unusually short arms and legs (short-limbed dwarfism), where a child’s legs and arms do not grow and develop to the typical adult length. Adult patients have a stature between 100 and 140 cm. Other characteristics of diastrophic dysplasia are abnormal development of bones (skeletal dysplasia) and joints (joint dysplasia) in many areas of the body; progressive abnormal curvature of the spine (scoliosis and/or kyphosis); abnormal tissue changes of the outer, visible portions of the ears (pinnae); and/or, in some cases, malformations of the head and facial (craniofacial) area. Typically there is limb shortening, hitchhiker thumbs, spinal deformity, and large joint contractures with associated deformities and premature degenerative disease. Other classic findings include ulnar deviation of the fingers, a large sandal gap (space between first and second pedal digits), and clubfoot. However, the range and severity of associated symptoms and physical findings may vary greatly from case to case.

Diastrophic dysplasia is characterized by limb shortening, normal-sized skull, hitchhiker thumbs, spinal deformities (scoliosis, exaggerated lumbar lordosis, cervical kyphosis), and contractures of the large joints with deformities and early-onset osteoarthritis. Joint contractures and spinal deformity tend to worsen with age ¹⁾. Other typical findings are ulnar deviation of the fingers, gap between the first and second toes, and clubfoot ²⁾. On occasion diastrophic dysplasia can be lethal at birth, but most affected individuals survive the neonatal period and develop physical limitations with normal intelligence ³⁾. Occasionally, children with diastrophic dysplasia die in infancy due to respiratory complications such as pneumonia.

At birth, babies with diastrophic dysplasia tend to be shorter, usually about 16.5 inches long. On average, most newborns are between 19 and 21 inches long.

In most infants with diastrophic dysplasia, the first bone within the body of each hand (first metacarpals) may be unusually small and “oval shaped,” causing the thumbs to deviate away (abduction) from the body (“hitchhiker thumbs”). Other fingers may also be abnormally short (brachydactyly) and joints between certain bones of the fingers (proximal interphalangeal joints) may become fused (symphalangism), causing limited flexion and restricted movement of the finger joints. Affected infants also typically have severe foot deformities (talipes or “clubfeet”) due to abnormal deviation and fusion of certain bones within the body of each foot (metatarsals). In addition, many children with the disorder experience limited extension, partial (subluxation) or complete dislocation, and/or permanent flexion and immobilization (contractures) of certain joints.

In most infants with diastrophic dysplasia, there is also incomplete closure of bones of the spinal column (spina bifida occulta) within the neck area and the upper portion of the back (lower cervical and upper thoracic vertebrae). In addition, during the first year of life, some affected children may begin to develop progressive abnormal sideways curvature of the spine (scoliosis). During adolescence, individuals with the disorder may also develop abnormal front-to-back curvature of the spine (kyphosis), particularly affecting vertebrae within the neck area (cervical vertebrae). In severe cases, progressive kyphosis may lead to difficulties breathing (respiratory distress). Some individuals may also be prone to experiencing partial dislocation (subluxation) of joints between the central areas (bodies) of cervical vertebrae, potentially resulting in spinal cord injury. Such injury may cause muscle weakness (paresis) or paralysis and/or life-threatening complications.

In addition, most newborns with diastrophic dysplasia have or develop abnormal fluid-filled sacs (cysts) within the outer, visible portions of the ears (pinnae). Within the first weeks of life, the pinnae become swollen and inflamed and unusually firm, thick, and abnormal in shape. Over time, the abnormal areas of tissue (lesions) may accumulate deposits of calcium salts (calcification) and eventually develop into bone (ossification). Some affected infants may also have abnormalities of the head and facial (craniofacial) area including incomplete closure of the roof of the mouth (cleft palate) and/or abnormal smallness of the jaws (micrognathia). In addition, in some affected infants, abnormalities of supportive connective tissue (cartilage) within the windpipe (trachea), voice box (larynx), and certain air passages in the lungs (bronchi) may result in collapse of these airways, causing life-threatening complications such as respiratory obstruction and difficulties breathing. In some individuals with the disorder, additional symptoms and physical findings may also be present.

Children with diastrophic dysplasia have characteristic craniofacial features (Figure 1).

Children born with diastrophic dysplasia may do physical things — like rolling over, sitting up and walking — later than other children.

Diastrophic dysplasia is caused by mutations in the SLC26A2 gene and is inherited in an autosomal recessive manner ⁴⁾. Diastrophic dysplasia occurs equally in males and females and most often in whites. Although the exact prevalence of diastrophic dysplasia is unknown, researchers estimate that it affects about 1 in 500,000 newborns in the United States. Diastrophic dysplasia is more common in Finland, where it affects about 1 in 33,000 newborns ⁵⁾.

Management of diastrophic dysplasia consists of maintaining joint position and mobility through physical therapy and casting. Surgical correction of clubfoot may be necessary. Arthroplasty of the hips and knees to decrease pain and increase motility may also be indicated. Indications for surgical correction of scoliosis have not yet been established ⁶⁾.

Figure 1. Diastrophic dysplasia

Footnote: The clinical appearances of children with diastrophic dysplasia showing the characteristic craniofacial features (A–C). Figure 1A shows a 10‐year‐old boy with severe short stature, thickened ear lobes and multiple contractures (elbows, pelvis, and knees). Figure 1B shows a 2‐year‐old girl with severe short stature, thickened ear lobes and swellings of the pinnae associated with narrow external auditory canals. Figure 1C shows a 6‐month‐old boy with micromelic dwarfism, a characteristic craniofacial contour and contractures of the elbows and knees. Figure 1D shows a 12‐year‐old girl whose knees had been operated on to relieve the contractures; however, the contractures had recurred.

Diastrophic dysplasia causes

Diastrophic dysplasia is one of several skeletal disorders caused by mutations in the SLC26A2 gene also called DTDST gene (diastrophic dysplasia sulfate transporter gene) that has been located on the long arm (q) of chromosome 5 (5q32-q33.1). The SLC26A2 gene or DTDST gene provides instructions for making a protein that transports charged molecules (ions), particularly sulfate ions, across cell membranes. This protein appears to be active in many of the body’s tissues, including developing cartilage. Cartilage is a tough, flexible tissue that makes up much of the skeleton during early development. Most cartilage is later converted to bone, except for the cartilage that continues to cover and protect the ends of bones and is present in the nose and external ears.

Cartilage cells use sulfate ions transported by the SLC26A2 protein to build molecules called proteoglycans. These molecules, which each consist of several sugars attached to a protein, help give cartilage its rubbery, gel-like structure. Because sulfate ions are required to make proteoglycans, the transport activity of the SLC26A2 protein is essential for normal cartilage formation.

Mutations in the SLC26A2 gene or DTDST gene impede cellular incorporation of sulfate and result in production of undersulfated cartilage proteoglycans, disrupting the assembly of cartilage matrix, preventing bones from forming properly and resulting in the skeletal problems characteristic of diastrophic dysplasia ⁸⁾.

Diastrophic dysplasia inheritance pattern

Diastrophic dysplasia is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

It is rare to see any history of autosomal recessive conditions within a family because if someone is a carrier for one of these conditions, they would have to have a child with someone who is also a carrier for the same condition. Autosomal recessive conditions are individually pretty rare, so the chance that you and your partner are carriers for the same recessive genetic condition are likely low. Even if both partners are a carrier for the same condition, there is only a 25% chance that they will both pass down the non-working copy of the gene to the baby, thus causing a genetic condition. This chance is the same with each pregnancy, no matter how many children they have with or without the condition.

• If both partners are carriers of the same abnormal gene, they may pass on either their normal gene or their abnormal gene to their child. This occurs randomly.
• Each child of parents who both carry the same abnormal gene therefore has a 25% (1 in 4) chance of inheriting a abnormal gene from both parents and being affected by the condition.
• This also means that there is a 75% ( 3 in 4) chance that a child will not be affected by the condition. This chance remains the same in every pregnancy and is the same for boys or girls.
• There is also a 50% (2 in 4) chance that the child will inherit just one copy of the abnormal gene from a parent. If this happens, then they will be healthy carriers like their parents.
• Lastly, there is a 25% (1 in 4) chance that the child will inherit both normal copies of the gene. In this case the child will not have the condition, and will not be a carrier.

These possible outcomes occur randomly. The chance remains the same in every pregnancy and is the same for boys and girls.

Figure 3 illustrates autosomal recessive inheritance. The example below shows what happens when both dad and mum is a carrier of the abnormal gene, there is only a 25% chance that they will both pass down the abnormal gene to the baby, thus causing a genetic condition.

Figure 2. Diastrophic dysplasia autosomal recessive inheritance pattern

People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.

Resources for locating a genetics professional in your community are available online:

• The National Society of Genetic Counselors (https://www.findageneticcounselor.com/) offers a searchable directory of genetic counselors in the United States and Canada. You can search by location, name, area of practice/specialization, and/or ZIP Code.
• The American Board of Genetic Counseling (https://www.abgc.net/about-genetic-counseling/find-a-certified-counselor/) provides a searchable directory of certified genetic counselors worldwide. You can search by practice area, name, organization, or location.
• The Canadian Association of Genetic Counselors (https://www.cagc-accg.ca/index.php?page=225) has a searchable directory of genetic counselors in Canada. You can search by name, distance from an address, province, or services.
• The American College of Medical Genetics and Genomics (http://www.acmg.net/ACMG/Genetic_Services_Directory_Search.aspx) has a searchable database of medical genetics clinic services in the United States.

Diastrophic dysplasia symptoms

The symptoms and physical findings associated with diastrophic dysplasia may be extremely variable, differing in range and severity even among affected family members (kindreds). However, in all individuals with the disorder, there is abnormal development of bones and joints of the body (skeletal and joint dysplasia).

Symptoms of diastrophic dysplasia can include:

• Shortening of the limbs
• Scoliosis and increased lumbar lordosis with a prominent abdomen
• Hip dysplasia, in which the two hip joints are misaligned or crooked
• Deformities of the joints
• Foot deformities
• Hernia
• Cauliflower ear, a deformity of the cartilage of the ear
• Cleft palate, an opening or gap in the roof of the mouth
• Hitchhiker’s thumb, where the thumb sticks out at a right angle to the hand, looking like the child is trying to hitch a ride
• Brachydactyly, in which one or more of the fingers is abnormally short

During normal development before birth (embryonic and fetal development) as well as development during early childhood, cartilage in many areas of the body is gradually replaced by bone (ossification). In addition, a layer of cartilage (epiphyseal cartilage [growth plate]) separates the shafts (diaphyses) of long bones (e.g., bones of the arms and legs) from their ends (epiphyses), allowing long bones to grow until the cartilage is no longer present. In those affected by diastrophic dysplasia, however, there is delayed growth before and after birth (prenatal and postnatal growth retardation), the development of the ends of the long bones (epiphyses) is irregular, and the ossification of the epiphyses is delayed. Thus, affected newborns and children typically have markedly short, bowed arms and legs and short stature (short-limbed dwarfism). In addition, in such cases, growth failure is typically progressive, in part due to absence of the “growth spurt” that usually occurs during puberty. The severity of such growth failure may vary greatly from case to case, including among affected siblings.

Due to abnormalities of skeletal development, infants and children with diastrophic dysplasia also have additional distinctive malformations of bones of the hands, feet, and other areas of the body. For example, the first bone within the body of each hand (first metacarpals) may be unusually small, short, and “oval shaped.” As a result, the thumbs deviate away (abduction) from the body (“hitchhiker thumbs”). In addition, other fingers may be abnormally short (brachydactyly) and joints between particular bones of the fingers (proximal interphalangeal joints) may become fused (symphalangism), causing limited flexion and restricted movement (reduced mobility) of the finger joints. In some cases, bones of the wrists may also be malformed due to premature ossification.

Infants with the disorder also typically have severe foot deformities (talipes or “clubfeet”) due to abnormal fusion and deviation of bones within the body of each foot (metatarsals). In most cases, the heels turn outward (talipes valgus) while the fore part of each foot deviates inward (metatarsus adductus). In other infants, the soles of the feet may be flexed (talipes equinus) and, in some cases, the heels may also turn inward (talipes equinovarus). The great toes, like the thumbs, may also deviate away (abduction) from the body.

In addition to having limited flexion of finger joints, many affected infants and children also experience partial dislocation (subluxation) and/or complete dislocation of particular joints of the body. For example, in many cases, dislocations of the knees and hips occur upon weightbearing. Affected individuals may also have abnormally loose and/or stiff joints; experience limited extension of joints at the elbows and/or knees; and/or develop permanent flexion and immobilization (contracture) of certain joints (e.g., knees). Due to joint and bone abnormalities such as those affecting the feet, many individuals with diastrophic dysplasia have a tendency to walk on tiptoe. In addition, affected individuals may be predisposed to degenerative changes (osteoarthrosis) of particular joints (e.g. of the hips), resulting in pain with use of the joint, tenderness, stiffness, and, in some cases, deformity.

Many infants with diastrophic dysplasia also have abnormalities of bones within the spinal column (vertebrae). For example, in most affected infants, there may be incomplete closure of vertebrae (spina bifida occulta) within the neck area and the upper portion of the back (lower cervical and upper thoracic vertebrae) and/or abnormal narrowing of portions of the vertebrae of the lower back (interpedicular narrowing in lumbar vertebrae). During the first year of life, some infants may begin to develop progressive abnormal sideways curvature of the spine (scoliosis). In addition, during adolescence, individuals with diastrophic dysplasia may also develop abnormal front-to-back curvature of the spine (kyphosis), particularly affecting vertebrae of the neck region (cervical vertebrae). In severe cases, progressive kyphosis may result in difficulties breathing (respiratory distress). Some individuals with the disorder may also be prone to experiencing partial dislocation of joints between the central areas (bodies) of cervical vertebrae (cervical subluxation), potentially resulting in compression of the spinal cord. (This cylindrical structure of nerve tissue extends from the lower portion of the brain and is located inside the central canal within the spinal column [spinal cavity].) Such spinal cord injury may result in muscle weakness (paresis) or paralysis and/or life-threatening complications.

Most newborns with diastrophic dysplasia also have or develop fluid-filled sacs (cysts) within the outer, visible portions of the ears (pinnae). Within approximately two to five weeks after birth, the pinnae become swollen and inflamed. When such swelling and inflammation subside, the pinnae remain unusually thick, hard, and abnormal in shape. The abnormal areas of tissue (lesions) may gradually accumulate deposits of calcium salts (calcification) and eventually be replaced by bone (ossification). Although affected infants may experience associated abnormal narrowing (stenosis) of the external ear canal (external auditory canal), hearing is usually normal. However, according to reports in the literature, other affected infants and children may experience hearing impairment due to such auditory canal stenosis or abnormal fusion or absence of the three tiny bones (auditory ossicles) in the middle ear that conduct sound to the inner ear.

Some infants with diastrophic dysplasia also have characteristic malformations of the head and facial (craniofacial) area, such as an unusually high, prominent forehead; abnormal smallness of the jaws (micrognathia); and/or a broad, highly arched roof of the mouth (palate) or incomplete closure of the palate (cleft palate). Cleft palate has been reported to occur in anywhere from 25 to 60% of affected infants, and may cause difficulties with feeding and/or breathing. In addition, in some infants with diastrophic dysplasia, abnormalities of supportive connective tissue (cartilage) within the windpipe (trachea), voice box (larynx), and air passages in the lungs (bronchi) may cause abnormal narrowing (e.g., laryngotracheal stenosis) and collapse of such airways. In such cases, life-threatening complications such as respiratory obstruction and difficulties breathing (respiratory distress) may result. However, in many cases nasal speech (hyponasality) occurs as a result of the abnormally shaped vocal tract.

Approximately one third of infants and children with diastrophic dysplasia also have dental abnormalities, such as abnormally small teeth and dental crowding. In addition, in some cases, affected infants may have benign, reddish purple growths in the midportion of the face (midline frontal hemangioma) due to an abnormal distribution of tiny blood vessels (capillaries). Some individuals with the disorder may also have additional symptoms and physical findings.

Diastrophic dysplasia diagnosis

In some families with a previous history of diastrophic dysplasia, it is possible that the disorder may be detected before birth (prenatally) during early pregnancy (e.g., first trimester) based upon the results of specialized genetic (i.e., DNA marker) testing. In addition, in some cases, the disorder may be detected during mid pregnancy (e.g., second trimester) through fetal ultrasonography, a specialized imaging technique in which sound waves are used to create an image of the developing fetus. In such cases, diagnosis is most easily established when a clear family history is present. During fetal ultrasonography, a diagnosis of diastrophic dysplasia may be considered due to detection of certain characteristic findings, such as marked shortening of bones of the fingers (phalanges), arms, and legs; abnormal deviation (abduction) of the thumbs (“hitchhiker thumbs”) and great toes; severe deformities of both feet (talipes or “clubfeet”); and/or other findings.

In most cases, diastrophic dysplasia is diagnosed and/or confirmed at birth based upon a thorough clinical evaluation, identification of characteristic physical findings, and a variety of specializing tests, such as advanced imaging techniques.

The diagnosis of diastrophic dysplasia rests on a combination of clinical, radiologic, and histopathologic features. Diagnostic evaluation for diastrophic dysplasia begins with a thorough medical history and physical examination of your child. The diagnosis is confirmed by molecular genetic testing of SLC26A2, the only gene in which pathogenic variants are known to cause diastrophic dysplasia ⁹⁾. Biochemical studies of fibroblasts and/or chondrocytes may be used in the rare instances in which molecular genetic testing fails to identify SLC26A2 pathogenic variants.

Doctors use a variety of diagnostic tests to diagnose diastrophic dysplasia and possible complications, including:

• X-rays, which produce images of bones.
• Magnetic resonance imaging (MRI), which uses a combination of large magnets, radiofrequencies and a computer to produce detailed images of organs and structures within the body.
• Computed tomography (CT) scan, which uses a combination of X-rays and computer technology to produce cross-sectional images (“slices”) of the body.
• EOS imaging, an imaging technology which creates 3-dimensional models from two planar images. Unlike a CT scan, EOS images are taken while the child is in an upright or standing position, enabling improved diagnosis due to weight-bearing positioning.
• Blood tests, which can help determine drug usage and effectiveness, biochemical diseases and organ function.
• Genetic testing, in which a sample of your child’s saliva is used to identify your child’s DNA.
• Radioisotope bone scan, which can help locate areas of abnormal growth.
• Arthrography, which uses colored dye injected into a joint — most commonly the shoulder, hip, knee, elbow or wrist — and X-ray images are taken to identify any problems.

Diastrophic dysplasia treatment

Every child’s condition is different, so treatment is determined on a case-by-case basis. The treatment of diastrophic dysplasia is directed toward the specific symptoms that are apparent in each individual. Treatment for diastrophic dysplasia is multi-pronged because the condition affects several body systems. Treatment may require the coordinated efforts of a team of specialists who may need to work together to systematically and comprehensively plan an affected child’s treatment. Such specialists may include pediatricians; physicians who diagnose and treat abnormalities of the skeleton, joints, muscles, and related tissues (orthopedists); surgeons; physical therapists; dental specialists (orthodontists); specialists who assess and treat hearing problems (audiologists); and/or other health care professionals.

In some cases, careful monitoring may be all that is required. Physicians may carefully monitor affected infants to ensure prompt detection and appropriate preventive or corrective treatment of respiratory obstruction and distress that may result due to certain abnormalities potentially associated with the disorder (e.g., laryngotracheal stenosis). In addition, special supportive measures may be used to help ensure an appropriate intake of nutrients in infants who experience feeding difficulties due to cleft palate. In some cases, surgical procedures may be performed to correct malformations resulting in breathing and/or feeding difficulties. The specific procedures performed will depend upon the location, severity, and combination of such anatomical abnormalities.

In other cases, nonsurgical or surgical treatments may be needed to address specific aspects of the condition.

For example, if your child has scoliosis, a team of orthopaedic surgeons will consider the severity of the curve, where it occurs in the spine, and your child’s age and stage of growth, before determining the best course of action. Treatment may include nonsurgical options such as bracing and physical therapy, or surgical options such as spinal fusion or implanting growing rods to stabilize your child’s spine as she continues to grow.

In affected children with dental abnormalities, braces (orthodontics), dental surgery, and/or other corrective procedures may be undertaken to correct such malformations. Steroid injections and/or other measures may also be used to help decrease the ear deformity that often affects infants with the disorder.

Many children with diastrophic dysplasia are also diagnosed with a variety of orthopaedic conditions including: hip dysplasia, and hand and foot anomalies. In some cases, these conditions are present at birth and can be treated when the child is young.

For example, a child with hitchhiker’s thumb will likely need hand surgery; while a child with a bowed leg may only need a long-leg cast.

In other cases the complication from diastrophic dysplasia may only become evident — or problematic — as your child grows. This is often true for spinal deformities such as scoliosis and hip conditions.

In some cases, physical therapy in combination with surgical and supportive measures may be helpful in improving an affected individual’s ability to walk and perform other movements (mobility). According to the medical literature, although the foot deformities (i.e., talipes or clubfeet) associated with the disorder may be resistant to treatment, early, persistent therapy may be helpful in achieving beneficial results. In addition, because particular skeletal changes associated with diastrophic dysplasia are progressive (e.g., kyphosis) and, in some cases, may lead to severe complications (e.g., respiratory distress, compression of the spine, potential paresis or paralysis), physicians may perform ongoing monitoring to ensure prompt detection of and appropriate preventive and/or corrective measures for such abnormalities.

Genetic counseling will be of benefit for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.

Follow-up care

Your child with diastrophic dysplasia should continue to be monitored by an orthopaedic physician into adulthood. Annual visits to follow the development of the spine and hips is appropriate.

If your child had spine surgery, he or she will need to see the orthopaedic surgeon about one to two weeks after surgery, then again at three and six months post-surgery. After that, annual monitoring by trained clinicians is strongly encouraged to ensure any problems are spotted and treated as soon as possible.

Additionally, physicians may recommend your child see several different specialists because so many body systems are involved in a diagnosis of diastrophic dysplasia.

For example, your child may see:

• An otolaryngologist or plastic surgeon for cleft palate
• A geneticist for individual or family counseling
• An orthopaedist for any bone- and muscle-related issues
• A pulmonologist for any breathing issues
• Physical therapists and occupational therapists to expand your child’s physical dexterity and skill
• Nutritionists to improve your child’s dietary health

During follow-up visits, X-rays and other diagnostic testing may be done. The goal of continued monitoring is to help spot any irregularities in growth or development and to address health issues as they develop.

Diastrophic dysplasia life expectancy

Children with diastrophic dysplasia can lead normal lives. They can hold good jobs, get married, have children and more.

If you have questions about how your child’s condition and any related health issues may affect your child’s prognosis or long-term goals, talk to your child’s healthcare provider.