Pallister-Killian syndrome (PKS)

What is Pallister-Killian syndrome (PKS)?

Pallister-Killian syndrome is a very rare genetic condition with just 150 recorded cases to date. Although this figure may actually be higher as individuals with mild symptoms may go undiagnosed.

This rare disease is a multi-system disorder. Its defining features include low muscle tone (hypotonia) in infancy and early childhood, intellectual disability, unique facial features and other features which are usually present at birth.

Syndrome Synonyms:
Isochromosome 12p Syndrome Pallister-Killian syndrome Tetrasomy 12p syndrome Tetrasomy 12p, Mosaic

What gene changes cause Pallister-Killian syndrome (PKS)?

The syndrome is caused by the presence of an extra abnormal chromosome, known as isochromosome 12p, meaning a cell may have up to four copies of the small arm of chromosome 12.

The syndrome is not inherited and occurs due to mutations during reproductive cell production in the parents which leads to mosaicism, some cells may have the abnormality, some may not. Most occur due to mutations in the mother’s cells.

Mosaic inheritance occurs very early in the development of a fetus. Essentially it is an error in cell division. The human body is made up of 46 chromosomes, in 23 pairs. Mosaicism occurs when an individual has cells in their body with more or less chromosomes than the usual 46. This can trigger issues that affect different systems and parts of the body.

What are the main symptoms of Pallister-Killian syndrome (PKS)?

Facial and physical characteristics include sparse hair, a high forehead, broad nasal bridge, widely spaced eyes, low set ears, rounded cheeks, a cleft or high arched palate.

Extra fingers or toes, a large big toe and short arms and legs also characterize the syndrome.

Infants with the syndrome are often born with birth defects, as well as unusual skin coloring in patches of the skin. 30% of individuals will also suffer from serious mobility issues and be unable to walk unassisted.

One of the most serious syndromes associated with the syndrome is extremely low muscle tone, as this can cause breathing and feeding difficulties in infants. 40% of individuals are born with a congenital diaphragm hernia that can cause serious medical complications concerning the internal organs.

Individuals with the syndrome may also experience hearing and vision loss and generally present with limited or zero speech.

Possible clinical traits/features:
Short neck, Stenosis of the external auditory canal, Renal cyst, Renal dysplasia, Webbed neck, Thin vermilion border, Single transverse palmar crease, Sparse eyelashes, Seizure, Postaxial hand polydactyly, Postaxial foot polydactyly, Obesity, Omphalocele, Patent ductus arteriosus, Inguinal hernia, Intellectual disability, profound, Intestinal malrotation, Short nose, Anteverted nares, Muscular hypotonia, Rhizomelia, Long philtrum, Macroglossia, Micrognathia, Mesomelia, Joint hypermobility, Macrotia, Kyphoscoliosis, Cryptorchidism, Decreased body weight, Postnatal microcephaly, Flexion contracture, Coarse facial features, Clinodactyly of the 5th finger, Congenital hip dislocation, Congenital diaphragmatic hernia, Coarctation of aorta, Delayed eruption of teeth, Delayed skeletal maturation, Epicanthus, Everted lower lip vermilion, Downturned corners of mouth, Cognitive impairment, Hearing impairment, Short phalanx of finger, Hypospadias, Hypohidrosis, Hypopigmented streaks, Hypoplastic labia majora, Short toe,

How does someone get tested for Pallister-Killian syndrome (PKS)?

The initial testing for Pallister-Killian syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow. 

Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.   

Medical information on Pallister-Killian syndrome

Pallister-Killian syndrome is characterized by distinctive facial features (broad forehead, hypertelorism, wide mouth), sparse hair, areas of unusual skin pigmentation, congenital birth defects, and intellectual disability. Patients with this condition are tetrasomic for the short arm of chromosome 12, and affected individuals have mosaicism from an isochromosome consisting of the short arms of chromosome 12. The facial features are distinct. They tend to be coarse, with a broad forehead, normal OFC, apparent hypertelorism, sagging cheeks, and a droopy mouth. The facial coarsening becomes progressively more severe with age (Horneff et al., 1993). Hair seems sparse, especially over the temporal areas. Hypopigmented macules and even a swirly hyperpigmentation, reminiscent of incontinentia pigmenti, can be found. Supernumerary nipples are commonly found. Birth weight is often normal. Zakowski et al., (1992) reported a case with aplasia cutis of the axilla and lateral neck.

As the condition can only be diagnosed by looking at skin chromosomes, and this is not routinely done when the blood karyotype is normal, it is necessary to recognize this condition clinically. Manasse et al., (2000) reported reliable diagnosis by FISH on buccal mucosal cells.

Mild cases can be difficult to diagnose (see Bielanska et al., 1996, for example). Schaefer et al., (1997) also emphasize the variability of the phenotype, including cases with mild developmental delay and hypomelanosis of Ito but without characteristic facial abnormalities.

Cormier-Daire et al., (1997) presented data in one case suggesting the origin of the isochromosome was prezygotic. Struthers et al., (1999) presented a case where the extra marker chromosome was shown to be of maternal origin. On reviewing the literature, they suggested that a premeoitic mitotic error may be the most likely mechanism.

Paladini et al., (2000) report a characteristic facial profile that can be detected by ultrasound in the second trimester of pregnancy.

Intellectual disability can be severe but can also be mild (Stalker et al., 2006).
Mauceri et al., (2000) reported a case with a pineal tumor.

Pachygyria and polymicrogyria (parieto-temporal lobes) were reported by Adachi et al., (2003).

Cases with trisomy 12p show somewhat similar features (Allen et al., 1996; Rauch et al., 1996). West syndrome has been reported to be associated (Yamamoto et al., 2007). Some cases have been reported that were initially diagnosed as Fryns syndrome (McPherson et al., 1993; Stratton et al., 1994; Corning et al., 2000). This is an important differential diagnosis. Rodriguez et al., (1994) reported three further cases that emphasize this point.

Three patients were reported by Jamuar et al. (2012) with skeletal features that might be diagnostically useful. They were delayed ossification of vertebral bodies and pubic bones, flared anterior ribs, and broad metaphyses of the long bones, especially the femurs.

There is an excellent review by Blyth et al., (2015).

* This information is courtesy of the L M D.
If you find a mistake or would like to contribute additional information, please email us at: [email protected]

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