Novel mutation points to a hot spot in CDKN1C causing Silver-Russell syndrome

Abstract

Background: Pathogenic CDKN1C gain-of-function variants on the maternal allele were initially reported as a cause of IMAGe syndrome characterized by intrauterine growth retardation, metaphyseal dysplasia, primary adrenal insufficiency and genital anomalies. Recently, a maternally inherited CDKN1C missense mutation (p.Arg279Leu) was identified in several members of a single family clinically diagnosed with Silver-Russell syndrome (SRS) but without adrenal insufficiency. Thereafter, two half siblings from UK with familial SRS were described who carried the same mutation. This specific amino acid change is located within a narrow functional region containing the mutations previously associated with IMAGe syndrome.

Results: Here, we describe a third familial case with maternally inherited SRS due to a missense variant affecting the same amino acid position 279 but leading to a different amino acid substitution (p. (Arg279Ser)). The two affected family members (mother and son) presented with the complete SRS phenotype (both Netchine-Harbison CSS score 5 of 6) but without body asymmetry or adrenal insufficiency.

Conclusions: In comparison with loss-of-function genomic IGF2 mutations, CDKN1C gain-of-function mutations are a less frequent cause of SRS and seem to affect a cluster of few amino acids.

Keywords: CDKN1C; Growth retardation; Silver–Russell syndrome.

Fig. 1

Pedigree of the family. The two affected family members (index IV,1 and mother III,2) carry the mutation c.835C > A as well as the unaffected maternal grandmother (II,2) who is likely to have the mutation de novo. The arrow indicates the index patient

Fig. 2

Photographs of index patient, his affected mother and his unaffected maternal grandmother

Fig. 3

Growth charts of index patient and his affected mother. The percentiles shown are according to Prader et al. [18]. The “rhGH” arrows indicate the start and the cessation of treatment with recombinant GH. The “LHRHa” arrows indicate the start and the cessation of treatment with an LHRH agonist. The “TH” arrow indicates the target height of the mother. The index patient’s target height could not be determined, because his mother is affected