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

Clin Epigenetics. 2020 Oct 19;12(1):152. doi: 10.1186/s13148-020-00945-y.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Insufficiency / diagnosis
  • Adrenal Insufficiency / genetics*
  • Alleles
  • Amino Acid Substitution / genetics
  • Child, Preschool
  • Cyclin-Dependent Kinase Inhibitor p57 / genetics*
  • Female
  • Fetal Growth Retardation / diagnosis
  • Fetal Growth Retardation / genetics*
  • Genetic Variation / genetics
  • Heterozygote
  • Human Growth Hormone / therapeutic use
  • Humans
  • Insulin-Like Growth Factor II / genetics*
  • Male
  • Mothers
  • Mutation, Missense
  • Osteochondrodysplasias / diagnosis
  • Osteochondrodysplasias / genetics*
  • Pedigree
  • Phenotype
  • Silver-Russell Syndrome / diagnosis
  • Silver-Russell Syndrome / drug therapy
  • Silver-Russell Syndrome / genetics*
  • Treatment Outcome
  • Urogenital Abnormalities / diagnosis
  • Urogenital Abnormalities / genetics*


  • CDKN1C protein, human
  • Cyclin-Dependent Kinase Inhibitor p57
  • IGF2 protein, human
  • Human Growth Hormone
  • Insulin-Like Growth Factor II

Supplementary concepts

  • Intrauterine Growth Retardation, Metaphyseal Dysplasia, Adrenal Hypoplasia Congenita, And Genital Anomalies