Case Report
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Cases. Jul 6, 2023; 11(19): 4655-4663
Published online Jul 6, 2023. doi: 10.12998/wjcc.v11.i19.4655
CDKN1C gene mutation causing familial Silver–Russell syndrome: A case report and review of literature
Jie Li, Li-Na Chen, Hai-Lan He
Jie Li, Li-Na Chen, Hai-Lan He, Department of Paediatrics, Sichuan Academy of Medical Sciences, Sichuan Provincial People’s Hospital, Chengdu 610000, Sichuan Province, China
Author contributions: Li J and Chen LN wrote the study plan, requested ethical approval, and contacted the family; Chen LN examined the patients; Li J wrote the first draft; Li J, Chen LN and He HL performed the corrections on the different versions of the draft, revised the literature, and updated the manuscript; All the authors approved the final version of the manuscript.
Supported by the China Foundation for International Medical Exchange, Pediatric Endocrinology Young and Middle-Aged Doctors’ Growth Research Fund, No. Z-2019-41-2101-01.
Informed consent statement: We obtained written informed consent from the patients or the patients’ parents to publish patients’ clinical and molecular information as well as facial photographs.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
CARE Checklist (2016) statement: The authors have read CARE Checklist (2016), and the manuscript was prepared and revised according to CARE Checklist (2016).
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Li-Na Chen, MD, Doctor, Department of Paediatrics, Sichuan Academy of Medical Sciences, Sichuan Provincial People’s Hospital, No. 32, West Section 2, Yihuan Road, Qingyang District, Chengdu 610000, Sichuan Province, China. linachen9755@163.com
Received: February 1, 2023
Peer-review started: February 1, 2023
First decision: April 19, 2023
Revised: May 5, 2023
Accepted: May 31, 2023
Article in press: May 31, 2023
Published online: July 6, 2023
Processing time: 148 Days and 23.9 Hours
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; Gene; Silver-Russell syndrome; Mutation; Case report

Core Tip: This is the fourth reported case of familial Silver–Russell syndrome (SRS) caused by a new missense mutation in the PCNA-binding domain of CDKN1C.The SRS pedigree, which was due to missense mutation affecting the amino acid position, 279, of the PCNA-binding domain of the CDKN1C gene, resulting in the amino acid substitution p.Arg279His (c.836G>A). Five affected family members also showed SRS phenotypes (small for gestational age, proportionately severe short stature, certain facial features (protruding forehead, triangular face, micrognathia), but without limb asymmetry or adrenal insufficiency. Initial efficacy and safety of growth hormone were observed in the proband treated with growth hormone.