Postnatal clinical phenotype of five patients with Pallister-Killian Syndrome (tetrasomy 12p): Interest of array CGH for diagnosis and review of the literature.

Marie Noelle Bonnet Dupeyron,Audrey Labalme,Amerh Salem Alqahtani,Hélène Tevissen,Patrick Edery,Marianne Till,Gaetan Lesca,Damien Sanlaville,Laurence Lion‐Francois,Maryline Carneiro,Caroline Schluth Bolard,Audrey Putoux,Massimiliano Rossi

doi:10.1002/mgg3.939

Abstract

BackgroundPallister–Killian syndrome (PKS) is a rare sporadic disorder caused by tetrasomy of the short arm of chromosome 12. The main clinical manifestations are global developmental delay, intellectual disability, epilepsy, dysmorphic features, hypopigmented and/or hyperpigmented lesions, and multiple congenital anomalies. PKS is associated with tissue mosaicism, which is difficult to diagnose through peripheral blood sample by conventional cytogenetic methods and fluorescence in situ hybridization.MethodsHere, we report five patients with PKS. We delineate their clinical phenotypes and we compare them with previously published cases. We used array Comparative Genomic Hybridization (aCGH) with DNA extracted from peripheral blood samples. The five patients have also been tested by conventional cytogenetics techniques.ResultsFour out of five patients showed tetrasomy 12p by aCGH. Three of the four patients have typical i(12p) and one of the four demonstrated atypical tetrasomy 12p. The percentage of mosaicism was as low as 20%. Our cohort exhibited the typical PKS phenotypes.ConclusionOur results demonstrate the efficacy of aCGH for the diagnosis of PKS from DNA extracted from lymphocytes. Thus, for patients suspected of PKS, we recommend performing aCGH on lymphocytes at an early age before proceeding to skin biopsy. aCGH on peripheral blood samples is sensitive in detecting low level of mosaicism and it is less invasive method than skin biopsy. We reviewed also the literature concerning the previously published PKS patients diagnosed by aCGH.

Highlights

Pallister–Killian syndrome (OMIM 601803; PKS) is a rare disorder which was first described by Philip Pallister (Pallister et al, 1977)
Array Comparative Genomic Hybridization on DNA extracted from lymphocytes showed the presence of tetrasomy 12p in mosaic state in four patients out of five
The mosaicism percentages in array Comparative Genomic Hybridization (aCGH) analysis were 20 for patient 1, 28 for patient 2, and 50 for patient 5. aCGH in patient 3 revealed a distal gain of 12p with log2 ratio of 0.888 (85%) and proximal gain of short and long arm of chromosome 12 with log2 ratio of 0.281 (43%; Figure S1). aCGH result for patient 4 was normal; the PKS was confirmed using karyotyping and FISH on fibroblasts

Summary

Introduction

Pallister–Killian syndrome (OMIM 601803; PKS) is a rare disorder which was first described by Philip Pallister (Pallister et al, 1977). PKS is caused by the presence of a supernumerary isochromosome i(12p), in mosaic status This extra chromosome can generally be detected on cultured fibroblast by karyotype or FISH, but the detection of i(12p) might be complicated on cultured lymphocyte. Several publications show that array Comparative Genomic Hybridization (aCGH) on DNA extracted from lymphocytes could identify tetrasomy 12p at mosaic level (Blyth et al, 2015; Chen et al, 2014; Lee, Lee, Yu, Lee, & Kim, 2017; Theisen et al, 2009). PKS is associated with tissue mosaicism, which is difficult to diagnose through peripheral blood sample by conventional cytogenetic methods and fluorescence in situ hybridization. ACGH on peripheral blood samples is sensitive in detecting low level of mosaicism and it is less invasive method than skin biopsy. We reviewed the literature concerning the previously published PKS patients diagnosed by aCGH

Results

Discussion

Conclusion