Pallister Killian mosaic syndrome

Pallister-Killian mosaic syndrome also called Pallister-Killian syndrome or PKS, is a rare sporadic developmental disorder caused by mosaic tissue-limited tetrasomy of the short arm of chromosome 12 (12p) that affects many parts of the body ¹⁾. The clinical features are highly variable, ranging from mild to severe. Pallister-Killian mosaic syndrome is characterized by extremely weak muscle tone (hypotonia) in infancy and early childhood, intellectual disability, distinctive facial features, sparse hair, areas of unusual skin coloring (pigmentation), and other birth defects.

Most babies with Pallister-Killian mosaic syndrome are born with significant hypotonia, which can cause difficulty breathing and problems with feeding. Hypotonia also interferes with the normal development of motor skills such as sitting, standing, and walking. About 30 percent of affected individuals are ultimately able to walk without assistance. Additional developmental delays result from intellectual disability, which is usually severe to profound. Speech is often limited or absent in people with this condition.

Pallister-Killian mosaic syndrome is associated with a distinctive facial appearance that is often described as “coarse.” Characteristic facial features include a high, rounded forehead; a broad nasal bridge; a short nose; widely spaced eyes; low-set ears; rounded cheeks; and a wide mouth with a thin upper lip and a large tongue. Some affected children are born with an opening in the roof of the mouth (cleft palate) or a high arched palate.

Most children with Pallister-Killian mosaic syndrome have sparse hair on their heads, particularly around the temples. These areas may fill in as affected children get older. Many affected individuals also have streaks or patches of skin that are darker or lighter than the surrounding skin. These skin changes can occur anywhere on the body, and they may be apparent at birth or occur later in life.

Additional features of Pallister-Killian mosaic syndrome can include hearing loss, vision impairment, seizures, extra nipples, genital abnormalities, and heart defects. Affected individuals may also have skeletal abnormalities such as extra fingers and/or toes, large big toes (halluces), and unusually short arms and legs. About 40 percent of affected infants are born with a congenital diaphragmatic hernia, which is a hole in the muscle that separates the abdomen from the chest cavity (the diaphragm). This potentially serious birth defect allows the stomach and intestines to move into the chest, where they can crowd the developing heart and lungs.

The signs and symptoms of Pallister-Killian mosaic syndrome vary, although most people with this disorder have severe to profound intellectual disability and other serious health problems. The most severe cases involve birth defects that are life-threatening in early infancy. However, several affected people have had milder features, including mild intellectual disability and less noticeable physical abnormalities.

Pallister-Killian mosaic syndrome is usually caused by the presence of an abnormal extra chromosome 12 called isochromosome 12p. An isochromosome is a chromosome with two identical arms. Normal chromosomes have one long (q) arm and one short (p) arm, but isochromosomes have either two q arms or two p arms. Isochromosome 12p is a version of chromosome 12 made up of two p arms. Cells normally have two copies of each chromosome, one inherited from each parent. In people with Pallister-Killian mosaic syndrome, cells have the two usual copies of chromosome 12, but some cells also have the isochromosome 12p. These cells have a total of four copies of all the genes on the p arm of chromosome 12. The extra genetic material from the isochromosome disrupts the normal course of development, causing the characteristic features of Pallister-Killian mosaic syndrome.

Although Pallister-Killian mosaic syndrome is usually caused by an isochromosome 12p, other, more complex chromosomal changes involving chromosome 12 are responsible for the disorder in rare cases.

Treatment depends upon the specific symptoms present in each individual. Treating medical and developmental problems early can help to optimize outcome ²⁾.

Pallister-Killian mosaic syndrome appears to be a rare condition, although its exact prevalence is unknown. This disorder may be underdiagnosed because it can be difficult to detect in people with mild signs and symptoms. As a result, most diagnoses are made in children with more severe features of the disorder. More than 150 people with Pallister-Killian mosaic syndrome have been reported in the medical literature.

Pallister Killian mosaic syndrome causes

Pallister-Killian mosaic syndrome is usually caused by the presence of an abnormal extra chromosome called an isochromosome 12p or i(12p). An isochromosome is a chromosome with two identical arms. Normal chromosomes have one long (q) arm and one short (p) arm, but isochromosomes have either two q arms or two p arms. Isochromosome 12p is a version of chromosome 12 made up of two p arms.

Cells normally have two copies of each chromosome, one inherited from each parent. In people with Pallister-Killian mosaic syndrome, cells have the two usual copies of chromosome 12, but some cells also have the isochromosome 12p. These cells have a total of four copies of all the genes on the p arm of chromosome 12. The extra genetic material from the isochromosome disrupts the normal course of development, causing the characteristic features of this disorder.

Although Pallister-Killian mosaic syndrome is usually caused by the presence of an isochromosome 12p, other, more complex chromosomal changes involving chromosome 12 are responsible for the disorder in rare cases.

Pallister-Killian mosaic syndrome inheritance pattern

Pallister-Killian mosaic syndrome is not inherited. The chromosomal change responsible for the disorder typically occurs as a random event during the formation of reproductive cells (eggs or sperm) in a parent of the affected individual, usually the mother. Affected individuals have no history of the disorder in their families.

An error in cell division called nondisjunction likely results in a reproductive cell containing an isochromosome 12p. If this atypical reproductive cell contributes to the genetic makeup of a child, the child will have two normal copies of chromosome 12 along with an isochromosome 12p.

As cells divide during early development, some cells lose the isochromosome 12p, while other cells retain the abnormal chromosome. This situation is called mosaicism. Almost all cases of Pallister-Killian mosaic syndrome are caused by mosaicism for an isochromosome 12p. If all of the body’s cells contained the isochromosome, the resulting syndrome would probably not be compatible with life.

Pallister Killian mosaic syndrome symptoms

Pallister-Killian mosaic syndrome has the following characteristics:

• Low muscle tone or floppiness (hypotonia)
• Facial features that are common to the syndrome-high forehead, broad nasal bridge, wide space between the eyes
• Sparse scalp hair at birth
• High arched palate
• Hypopigmentation
• Extra nipples
• Cognitive and developmental delays (cognitive and motor skills). Althought most Pallister-Killian mosaic syndrome children have these delays, many children are only mildly handicapped.
• Delayed speech development or no speech
• Repetitive behaviors (stereotypy)
• Difficulties with walking
• Feeding difficulties
• Impaired vision
• Hearing loss
• Seizures
• Diaphragmatic hernias

Common facial features of Pallister-Killian mosaic syndrome:

• Macroglossia (an enlarged tongue that may protrude from the mouth)
• Wide-set eyes (hypertelorism)
• Wide mouth with thin upper lip
• Highly arched or cleft palate
• High, rounded forehead
• Broad nasal bridge
• Downslanting eyes
• Low-set ears
• Short neck

Individuals with Pallister-Killian mosaic syndrome typically have low muscle tone at birth (hypotonia), sparse scalp hair, a high forehead, a coarse face, an abnormally wide space between the eyes, a broad nasal bridge, a highly arched palate, a fold of the skin over the inner corner of the eyes, and large ears with lobes that are thick and protrude outward.

Infants that are born with significant hypotonia can experience problems with feeding, breathing, walking and standing. About seventy percent of affected individuals are unable to walk without assistance.

Additional features frequently found in affected individuals may include streaks of skin in which there is no color (hypopigmentation); extra nipples; seizures; droopy upper eyelids, crossed eyes (strabismus); joints that will not move (contractures); and delays in perceiving, recognizing, judging, sensing, reasoning or imagining (cognitive delays). Intellectual disability and difficulties with speech development often occur as well. In rare cases, affected children may experience hearing loss.

Congenital heart defects, hernias of the diaphragm, a narrowing of the external auditory canal (stenosis) and an abnormal opening in the anus have also been associated with Pallister-Killian mosaic syndrome. Some affected individuals may have an underdeveloped (hypoplastic) lung, abnormalities of the genitourinary system, and skeletal malformations. Symptoms may vary according to which tissue has the additional chromosomal material, and may also affect each side of the body unevenly.

Heart

Approximately 25% of children with Pallister-Killian mosaic syndrome will have a congenital heart difference. Sometimes these can be detected by simply listening to the heart to see if there is a murmur (note: while a murmur may indicate a congenital heart difference many murmurs can be normal or “benign”), but some heart differences (such as atrial septal defects (ASDs) which are not uncommon in Pallister-Killian mosaic syndrome) do not cause a murmur and can cause significant problems to the child. For this reason experts recommend that all children with Pallister-Killian mosaic syndrome be evaluated by a cardiologist as early as possible and have an echocardiogram performed whether there is a murmur or not. If the heart is normal then the child is cleared, as a congenital heart defect will be present at birth and not develop later on.

Experts recommend periodic cardiac evaluations for all children with Pallister-Killian mosaic syndrome (once every year or two, or as recommended by their cardiologist) even for those who do not have a congenital heart difference, as changes in the heart muscle called hypertrophic cardiomyopathy have been reported. This is rare but should be checked for at regular intervals.

Stomach and intestines

Individuals with Pallister-Killian mosaic syndrome may have both functional and structural differences of their gastrointestinal (GI) system. The most common functional difference is gastroesophageal reflux disease (GERD). GERD usually manifests as “spitting up” but sometimes the refluxing stomach contents are not actually “spit up” but do cause discomfort in the esophagus (the tube between the mouth and the stomach) which may result in arching of the back or irritability. Some reflux may even be “silent” (without any clinical signs in your child). This should be evaluated for in all newborns and young children with Pallister-Killian mosaic syndrome and may involve studies called a milk scan or pH probe. This is an important evaluation because if left untreated this can result in damage to the esophagus due to the acid from the stomach, which if left untreated for many years can result in cancer. Depending on the severity of the reflux some children may need surgical correction of the connection between the stomach and the esophagus, while others will do fine on anti-reflux medicines.

All kids with Pallister-Killian mosaic syndrome should also be evaluated in the newborn period for structural differences in the gastrointestinal tract. The most concerning is intestinal malrotation, where the small intestines are looped in the abdomen in a reverse manner. Children with this finding are at increased risk for the intestine to become twisted (“volvulus”) and if left untreated can rupture, which can be a life-threatening event. This is especially important to identify early as many kids with Pallister-Killian mosaic syndrome are unable to vocalize where their pain and discomfort lies and may make diagnosis of a volvulus difficult in an emergent situation with physicians that are unfamiliar with Pallister-Killian mosaic syndrome. A simple test called an “upper GI with small bowel follow-through” which is basically a series of X-rays following the passage of a liquid that can be visualized on the x-rays that the child drinks or has placed in the feeding tube, can easily rule a malrotation in or out. This is a one time test as a malrotation is either present at birth or not.

Other gastrointestinal issues that should be evaluated for in the newborn period include diaphragmatic, umbilical and inguinal hernias, and differences in the anus like narrowing of the opening (anal stenosis) or complete closure of the opening (anal atresia or imperforate anus).

Your gastroeneterologists and nutritionists are also excellent resources for feeding issues and concerns about growth and weight gain.

Bones and joints

While some orthopedic problems are readily apparent at birth, such as extra fingers or toes, there are a few potential problems that will need the targeted attention of an orthopedist. Because of their low muscle tone and lax joints, all children with Pallister-Killian mosaic syndrome should be evaluated for congenital hip dislocations. This can usually be easily done with an ultrasound of the hips. Early diagnosis and correction is important and will save later complications and difficulties for ambulation. Another fairly common issue, again likely related to the low muscle tone in Pallister-Killian mosaic syndrome, is kyphoscoliosis (curvature of the spine). This usually develops as a later complication but kids with Pallister-Killian mosaic syndrome should be monitored regularly for this both by physical exam and radiologic studies if indicated.

Eyes

While children with Pallister-Killian mosaic syndrome can have the same ophthalmologic differences as children without Pallister-Killian mosaic syndrome, identifying any visual differences early and treating it will help in optimizing learning and should be undertaken early and on a regular basis. In addition to general visual issues, kids with Pallister-Killian mosaic syndrome may be at increased risk for ptosis (droopy eyelids) that may need to be surgically corrected in order to be sure that the child’s visual fields aren’t obstructed.

Ears, nose, and throat

A good ENT evaluation is warranted as there are increased rates of various differences involving the mouth and palate that should be evaluated. Children with Pallister-Killian mosaic syndrome have a higher rate of cleft palate (incomplete closure of the roof of the mouth), which may be easily seen on exam or be very subtle and only involve the muscle that can’t be easily visualized (called velopharyngeal incompetence). Untreated clefts can result in feeding difficulties, infections and delays in development of speech. Individuals with Pallister-Killian mosaic syndrome may also be at increased risk of enlargement of the tonsils and adenoid glands as well as enlargement of the tongue that may result in obstruction of the airway.

There may be structural differences of the ear as well as hearing loss, which may need to be managed by an ENT.

Although the exact prevalence of hearing loss in Pallister-Killian mosaic syndrome is not known (as high as 90% of kids has been reported), it is a significant issue and it is recommended that all newborns with Pallister-Killian mosaic syndrome have a thorough audiologic evaluation. This should be retested at regular intervals depending on the presence and severity of hearing loss in the child, and should be done by an audiologist and not simply in the pediatrician’s office. Early recognition of a hearing loss and appropriate interventions will help to optimize developmental outcomes.

Kidney, bladder and genitalia

Children wit Pallister-Killian mosaic syndrome can have a variety of kidney and bladder differences. All newborns with Pallister-Killian mosaic syndrome should have a renal (another word for kidney) and bladder ultrasound to rule out any structural differences. Any child with Pallister-Killian mosaic syndrome who has had a urinary tract infection should have a functional study called a
vesicoureterogram (VCUG) to rule out reflux between the bladder and the ureters (the tubes that drain the urine from the kidney into the bladder).

Boys with Pallister-Killian mosaic syndrome are at increased risk of having genital differences such as undescended testes, hypospadias (where the opening in the penis (urethra) is not at the tip of the penis) and other differences. These often need surgical correction and should be evaluated by the urologist early in the newborn period.

Teeth

Although tooth eruption may be delayed, most of the dental issues faced by kids with Pallister-Killian mosaic syndrome are the same as other children. Sometimes treatment can be complicated by developmental delays and it may be necessary to do exams and procedures under general anesthesia. For this reason it is best to develop a relationship with a pediatric dentist who has experience with special needs children and to try and be seen by 1 year of age.

Developmental delay

One of the major, and most challenging, issues that parents have to deal with is that of cognitive delays in their child. While there are no specific treatments targeted at kids with Pallister-Killian mosaic syndrome for these issues, having annual visits with a pediatric developmental specialist has many benefits. These evaluations will help identify those areas that may need more, or less, focused therapies and help develop an individualized therapy plan for your child. The developmental pediatrician is also a valuable advocate for implementing appropriate programs in your child’s
school.

Neurological

Most families with a child with Pallister-Killian mosaic syndrome end up seeing a neurologist at some point, often early on due to the low muscle tone (hypotonia). Low muscle tone is almost universally present in children with Pallister-Killian mosaic syndrome but may evolve as they get older into increased muscle tome (hypertonia). This can result in contractures (tightening of joints) that may need surgical treatment if left to advance. The neurologist can monitor this and recommend targeted physical therapy to help keep these joint loose.

Seizures are another major concern for families with a child with Pallister-Killian mosaic syndrome. Up to 80% of children with Pallister-Killian mosaic syndrome will develop seizures at some point. These can be severe and if undiagnosed or untreated can have a devastating impact on the child’s growth and development. Early diagnosis and management is critical, although some children’s seizures are quite refractory to treatment. An early and close relationship with a good pediatric neurologist is essential.

Pallister Killian mosaic syndrome diagnosis

Pallister Killian mosaic syndrome diagnosis is usually made from a chromosome study of skin cells (fibroblasts) that reveals 47 chromosomes including an extra small chromosome that has two short (p) arms and no long (q) arm (isochromosome). Chromosomal microarray, the first tier analyses in malformation syndromes, can also reveal Pallister Killian syndrome, if the right tissue is selected. Blood chromosome analyses usually shows normal number of chromosomes, but some affected persons have some blood cells (lymphocytes) with an isochromosome 12p. Cells with high cell turnover such as blood may lose the additional chromosomal material over time, and thereby give a false negative result on blood. Therefore, a normal blood chromosomal analysis does not completely rule out Pallister-Killian mosaic syndrome.

Two individuals with Pallister-Killian mosaic syndrome have been reported with five copies (hexasomy) for chromosome 12p.

Pallister-Killian mosaic syndrome can be diagnosed before birth (prenatally) by removing a small amount of fluid that is in the womb during pregnancy (amniocentesis) or by removing a small number of cells from outside the sac where the fetus develops (chorionic villous sampling). Cell cultures may yield a false negative however, and a normal chromosomal analysis does not completely rule out the condition.

Pallister Killian mosaic syndrome treatment

There is no specific therapy for individuals with Pallister-Killian mosaic syndrome. Affected children may benefit from early intervention programs and special education. Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.

Pallister Killian mosaic syndrome life span

Life expectancy in Pallister-Killian mosaic syndrome has not been formally looked at but what experts do know is this: there seems to be two or three main time points to consider. For the very severely affected newborn with a diaphragmatic hernia or severe congenital heart defect or other severe structural or functional anomaly this will have the most significant effect on morbidity and mortality and many newborns succumb early form these congenital differences.

The most concerning issues that impact life expectancy are undiagnosed or untreated medical conditions, such as reflux, malrotation of the intestine or seizures. Experts advocate for aggressive clinical evaluation’s for these issues and if present for aggressive treatment as this will not only improve health and life expectancy but also optimize learning and happiness for the children (any parent should understand the impact that untreated gastroesophageal reflux, for example, can have on a child resulting in constant/recurrent pain and discomfort, risk for aspiration and damage to the esophagus).

For the child with Pallister-Killian mosaic syndrome who has overcome these neonatal issues and is being managed effectively for the commonly associated medical issues, lifespan should be long or close to normal. For any individual with chronic medical issues like seizures or cognitive impairment there is an overall impact on life expectancy but not a large one. Experts know of some individuals with Pallister-Killian mosaic syndrome in their 40s and 50s, and it is likely that there are many older individuals out there who have never been diagnosed since the type of testing
available in the past decade or so is primarily used in the pediatric setting.

It would be great for parents to report the ages of their kids as well as for parents who have lost a child with Pallister-Killian mosaic syndrome to report how old their child was were when they passed away and what the cause of death was. This could form the initial database that can eventually be used to better answer this question as well as to help identify causes of death in individuals with Pallister-Killian mosaic syndrome so that experts can better identify those problems early and avoid bad outcomes.