CDKN1C gene mutation causing familial Silver–Russell syndrome, with family pedigree

Abstract

Abstract Background: CDKN1C is a cell proliferation inhibitor that regulates the cell cycle and cell growth through G1 cell cycle arrest. CDKN1C mutations can lead to IMAGe syndrome (CDKN1C allele gain-of-function mutations lead to intrauterine growth retardation, primary adrenal insufficiency, metaphyseal dysplasia, and genital malformations). So far,There are three reported pedigrees worldwide had CDKN1C missense mutations that caused silver Russell syndrome (SRS) (p.Arg279Leu, p.Arg279Ser). The affected family members showed an SRS phenotype but did not have limb asymmetry or adrenal insufficiency. The amino acid changes in this specific region were located in a narrow functional region that contains mutations previously associated with IMAGe syndrome. Results: We found an SRS pedigree, which was due to missense mutation affecting the same amino acid position , 279, of the CDKN1C gene, resulting in the amino acid substitution p.Arg279His (c.836G>A). Five affected family members also showed SRS phenotypes , but without limb asymmetry or adrenal insufficiency. Two affected member had diabetes mellitus. Although the SRS-related CDKN1Cmutation is in the IMAGe-related mutation hotspot region(the proliferating cell nuclear antigen (PCNA) domain), no adrenal insufficiency has been reported in this SRS pedigree. The reason may be that the location of genomic mutation and the type of missense mutation determine the phenotype. Conclusions: Functional mutations in CDKN1C can lead to familial SRS without limb asymmetry, and some patients may have glucose abnormalities. In familial SRS patients, the PCNA region of CDKN1C should be analysed. Adrenal insufficiency should be excluded in all patients with functional CDKN1C variants.