Pallister-Killian Syndrome: Clinical and Genetic Insights

Pallister-Killian syndrome (PKS) is a rare sporadic disorder characterised by tissue-limited mosaic tetrasomy of the short arm of chromosome 12. Clinically, affected individuals present with a distinctive craniofacial appearance, global developmental delay, hypotonia, intellectual disability and pigmentary skin anomalies. A broad phenotypic spectrum encompasses seizures, diaphragmatic hernia, congenital heart defects and hearing loss. The mosaic distribution of the isochromosome 12p across tissues underlies variable severity and can complicate diagnosis, as standard karyotyping of peripheral blood may miss low-level mosaicism. Advances in molecular cytogenetic techniques—particularly array comparative genomic hybridisation (aCGH) and interphase fluorescence in situ hybridisation (FISH)—have improved detection of supernumerary 12p cell lines in lymphocytes, buccal cells and fibroblasts without the need for invasive skin biopsy. Neuroimaging studies increasingly reveal structural brain abnormalities such as corpus callosum hypoplasia, cerebral atrophy and perisylvian polymicrogyria, which contribute to seizures and neurodevelopmental delay. At the molecular level, overexpression of dosage-sensitive genes on 12p disrupts developmental pathways, with emerging data pinpointing critical regions associated with specific malformations. Early and accurate diagnosis of PKS is essential for genetic counselling, tailored supportive therapies and anticipatory management of complications. Ongoing research seeks to refine genotype–phenotype correlations, elucidate the neurogenetic basis of cognitive impairment and explore novel interventions to ameliorate the clinical course.

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Pallister-Killian Syndrome: Clinical and Genetic Insights publication trend

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Technical terms

Mosaicism: Presence of two or more genetically distinct cell lines in one individual, here referring to variable proportions of cells with an extra 12p.

Tetrasomy 12p: Four copies of the short arm of chromosome 12, typically arranged as an isochromosome in mosaic form.

Isochromosome: A structurally abnormal chromosome with two identical arms, in PKS comprising two copies of 12p joined at the centromere.

Polymicrogyria: A malformation characterised by an excessive number of small, irregular gyri, often affecting perisylvian regions in PKS.

Array comparative genomic hybridisation (aCGH): A high-resolution technique to detect copy number variations across the genome, enabling identification of low-level mosaic cell lines.

Fluorescence in situ hybridisation (FISH): A molecular cytogenetic method that uses fluorescent probes to visualise specific DNA sequences on chromosomes, useful for detecting extra copies of 12p in interphase cells.

References

1. Structural brain abnormalities in Pallister-Killian syndrome: a neuroimaging study of 31 children. Orphanet Journal of Rare Diseases (2024).
2. Case Report: A Case Study on the Neurodevelopmental Profile of a Child With Pallister–Killian Syndrome and His Unaffected Twin. Frontiers in Pediatrics (2022).
3. Pallister–Killian Syndrome versus Trisomy 12p—A Clinical Study of 5 New Cases and a Literature Review. Genes (2021).
4. A review of structural brain abnormalities in Pallister‐Killian syndrome. Molecular Genetics & Genomic Medicine (2017).
5. Postnatal clinical phenotype of five patients with Pallister–Killian Syndrome (tetrasomy 12p): Interest of array CGH for diagnosis and review of the literature. Molecular Genetics & Genomic Medicine (2019).
6. Genome-Wide Expression Analysis in Fibroblast Cell Lines from Probands with Pallister Killian Syndrome. PLOS ONE (2014).