CDKN1C gene mutation causing familial Silver-Russell syndrome: A case report and review of literature

Abstract

Background: Cyclin-dependent kinase inhibitor 1C (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 restriction, metaphyseal dysplasia, adrenal hypoplasia congenital, and genitourinary malformations). We present a Silver-Russell syndrome (SRS) pedigree that was due to a missense mutation affecting the same amino acid position, 279, in the CDKN1C gene, resulting in the amino acid substitution p.Arg279His (c.836G>A). The affected family members had 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 contained mutations previously associated with IMAGe syndrome. In familial SRS patients, the PCNA region of CDKN1C should be analysed. Adrenal insufficiency should be excluded in all patients with functional CDKN1C variants.

Case summary: We describe the case of an 8-year-old girl who initially presented with short stature. Her height was 91.6 cm, and her weight was 10.2 kg. Physical examination revealed that she had a relatively large head, an inverted triangular face, a protruding forehead, a low ear position, sunken eye sockets, and irregular cracked teeth but no limb asymmetry. Family history: The girl's mother, great-grandmother, and grandmother's brother also had a prominent forehead, triangular face, and severely proportional dwarfism but no limb asymmetry or adrenal insufficiency. Exome sequencing of the girl revealed a new heterozygous CDKN1C (NM_000076. 2) c.836G>A mutation, resulting in a variant with a predicted evolutionarily highly conserved arginine substituted by histidine (p.Arg279His). The same causative mutation was found in both the proband's mother, great-grandmother, and grandmother's brother, who had similar phenotypes. Thus far, we found an SRS pedigree, which was due to a missense mutation affecting the same amino acid position, 279, in the CDKN1C gene, resulting in the amino acid substitution p.Arg279His (c.836G>A). Although the SRS-related CDKN1C mutation is in the IMAGe-related mutation hotspot region [the proliferating cell nuclear antigen (PCNA) domain], no adrenal insufficiency was reported in this SRS pedigree. The reason may be that the location of the genomic mutation and the type of missense mutation determines the phenotype. The proband was treated with recombinant human growth hormone (rhGH). After 1 year of rhGH treatment, the height standard deviation score of the proband increased by 0.93 standard deviation score, and her growth rate was 8.1 cm/year. No adverse reactions, such as abnormal blood glucose, were found.

Conclusion: 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.

Keywords: CDKN1C; Case report; Gene; Mutation; Silver-Russell syndrome.

Figure 1

Photographs of the index patient, her affected mother, great grandmother, and grandmother's brother. A: Index patient IV,1 (8 years old); B: Mother of the index patient III,2 (32.0 years old); C: Great grandmother of the index patient I,1 (91.0 years old); D: Grandmother's brother II,1 (58.0 years old).

Figure 2

Pedigree of the family. The proband (index IV,1) and her four affected family members (mother III; grandmother II,3; grandmother’s brother II,1; great-grandmother I,1) carried the mutation c.836G>A. The arrow indicates the index patient.

Figure 3

Sequencing map of CDKN1C gene c.836G>A locus. The orange arrow indicates the mutation site. Both the proband and her mother were heterozygous mutations. The proband's father was normal.

Figure 4

Growth chart of the index patient. Black dots are postnatal height measurements, black arrows indicate initiation of recombinant human growth hormone treatment, and red dots indicate height measurements after growth hormone treatment.