What is the diagnosis?

Our proband suffers from Pallister-Killian syndrome (PKS). PKS is characterised by craniofacial dysmorphism, hypotonia in infancy and early childhood, developmental delay, intellectual disability and other birth defects.

Patients with PKS have distinctive facial features described as "coarse". It includes features such as prominent or tall forehead, sparse eyebrows/lashes, hypertelorism, epicanthal folds, broad nasal bridge, short nose, anteverted nares, large mouth with thin upper lip and/or thick lower lip, high arched or cleft palate, micrognathia, low-set and/or posteriorly rotated ears and short neck. Most of them have sparse hair and areas of alopecia, particularly in the temples, which may be filled up as the child grows up.

Severity of the disease and additional features are highly variable. Some patients are noted to have vision and/or hearing loss, seizures, congenital diaphragmatic hernia, polydactyly, genital abnormalities, and heart defects. Hyper/ Hypo-pigmentation of the skin and accessory nipples can also be observed.

What is the molecular genetics behind PKS?

PKS is caused by mosaic tetrasomy 12p, extra choromosomal materials are detected. Four copies of the 'p' arms of chromosome 12 are present instead of two, therefore it is described as "tetrasomy 12p". Usually, the two extra 12p form a mirror image known as isochromosome (as shown in Figure 2). Also, this chromosomal abnormality only presents in some of the cells but not every cell of the patient thus it is referred as 'mosaic'.

Tetrasomy 12p is associated with tissue-limited mosaicism, meaning that the chromosomal changes could only be detected in specific tissues. Often, children with PKS appeared to have normal chromosomes in lymphocytes, only by examining buccal mucosa or skin cells would be able to make a diagnosis.^1,2

Figure 2 Photo taken from "Pallister-Killian syndrome" (Rare Chromosome Disorder Support Group, 2016).3

Very interestingly, for our proband, the chromosomal imbalance was identified in the blood sample of but not in the CVS. Also, this is a very special case that the initial diagnosis was not made using conventional cytogenetic method. In fact, the extra chromosome 12 materials were first identified in a retrospective analysis of the exome sequencing data (Figure 3); which is not the perfect/usual tool we use for detecting copy number variants/chromosomal changes. The finding was confirmed after repeated aCGH. This highlights the diagnostic journey of PKS can be complicated.

(a)

(b)

Figure 3 (a) Gain of genetic material is observed in chromosome 12 (indicated by the arrow). (b) The gain of genetic material is localised in p arm of chromosome 12, and the intensity is twice as the reference, indicating a tetrasomy 12p.

What is the management?

The management and treatment of a child with PKS depends on the severity and the symptoms presented. It requires a multidisciplinary team consisting of developmental paediatrician, rehabilitation team, geneticist, ophthalmologist, otolaryngologists, neurologist, and orthopaedic surgeon. These children may need resuscitation at birth and special care for the management of hypotonia. There is an increase in the incidence of diaphragmatic hernias and fetal hydrops in PKS. These children may benefit from early intervention program and special education. Regular screening for visual and/or hearing problems and aggressive management of seizure, contractures and scoliosis are required.

What is the risk of recurrence?

All PKS cases occur sporadically. The extra isochromosome 12p typically results from nondisjunction of the reproductive cells. During early development of the embryo, some cells lose the isochromosome while others retain it, leading to mosaicism of tetrasomy 12p.⁴ Parents are very unlikely to be the carriers; hence the recurrent risk is low.

Conclusion/Learning point

In view of the unique genetic aetiology, the genetic diagnosis of PKS can sometimes be difficult. Since the individual has tissues with normal chromosomal material and abnormal chromosomal material at different distribution, sampling can be challenging and false negative test result may lead to a further delay in genetic diagnosis. Recognising features of PKS becomes very important and special diagnostic tests may be required to end the diagnostic odyssey. A diagnosis of PKS should be considered in a child with coarse facies, profound intellectual disability and localised alopecia especially around the temporal region.

Acknowledgments

We would like to express our gratitude to the patient and his family for their contribution. Informed consent was obtained for publication.

References

1. Peltomäki P, Knuutila S, Ritvanen A, Kaitila I, Chapelle A. Pallister-Killian syndrome: cytogenetic and molecular studies. Clin Genet 1987;31:399-405.

2. Warburton D, Anyane-Yeboa K, Francke U, Reynolds JF. Mosaic tetrasomy 12p: Four new cases, and confirmation of the chromosomal origin of the supernumerary chromosome in one of the original Pallister-Mosaic syndrome cases. Am J Med Genet 1987;27:275-83.

3. Rare Chromosome Disorder Support Group. Pallister-Killian Syndrome. Rarechromo.org [https://www.rarechromo.org/media/information/Chromosome%2012/Pallister-Killian%20syndrome%20FTNW.pdf]

4. Gajecka M. Unrevealed mosaicism in the next-generation sequencing era. Mol Genet Genomics 2016;291:513-30.