CDKN1C-Related Beckwith-Wiedemann Syndrome: First Patient from India

Abstract

Beckwith-Wiedemann syndrome (BWS; MIM# 130650) is a well-characterized pediatric overgrowth disorder. In approximately 5% of the cases, it is caused by pathogenic variants in the CDKN1C (cyclin-dependent kinase inhibitor 1C). CDKN1C gene encodes for a protein p57 (KIP2) that acts as an inhibitor of cyclin-dependent kinases (CDK) that are expressed in the G and S-phase of the cell cycle, thus regulating cellular proliferation. Variants in CDKN1C gene lead to loss of inhibitory function of CDK and thus impair the inhibition of growth, resulting in BWS phenotype.

We describe here a 2.5-year-old boy with a maternally inherited variant c.182G > T, p.Trp61Cys in the CDKN1C gene causing BWS. The natural history of the disorder is described along with the gradual change in the facial features. An insight into the genotype–phenotype correlation and disorders to be considered in the differential diagnosis is provided. We describe a common overgrowth syndrome with its rare genetic mechanism and highlight the salient features that help in making a diagnosis and managing patients.

Keywords

BWS - CDKN1C - MS-MLPA - overgrowth syndrome - genotype–phenotype correlation

Publikationsverlauf

Eingereicht: 16. März 2022

Angenommen: 23. Januar 2023

Artikel online veröffentlicht:
31. März 2023

• References

• 1 Chen C-P, Chien S-C. Prenatal sonographic features of Beckwith-Wiedemann syndrome. J Med Ultrasound 2009; 17 (02) 98-106
• 2 Shuman C, Beckwith JB, Weksberg R. Beckwith-Wiedemann syndrome. In: Adam MP, Ardinger HH, Pagon RA. et al, eds. GeneReviews®. Seattle (WA): University of Washington; 2000
• 3 Wikipedia contributors. (2021, September 3). Beckwith–Wiedemann syndrome. Wikipedia, The Free Encyclopedia. Accessed February 9, 2023 at: https://en.wikipedia.org/w/index.php?title=Beckwith%E2%80%93Wiedemann_syndrome&oldid=1042221116
• 4 OMIM Entry - * 600856 - CYCLIN-DEPENDENT KINASE INHIBITOR 1C; CDKN1C. (n.d.). Omim.Org. Accessed February 9, 2023 at: https://omim.org/entry/600856
• 5 OMIM entry - * 607542 - POTASSIUM CHANNEL, VOLTAGE-GATED, KQT-LIKE SUBFAMILY, MEMBER 1; KCNQ1. (n.d.). Omim.Org. Accessed February 9, 2023 at: https://omim.org/entry/607542?search=KCNQ1&highlight=kcnq1
• 6 Elliott M, Bayly R, Cole T, Temple IK, Maher ER. Clinical features and natural history of Beckwith-Wiedemann syndrome: presentation of 74 new cases. Clin Genet 1994; 46 (02) 168-174
• 7 Greer KJ, Kirkpatrick SJ, Weksberg R, Pauli RM. Beckwith-Wiedemann syndrome in adults: observations from one family and recommendations for care. Am J Med Genet A 2008; 146 (13) 1707-1712
• 8 Gicquel C, Rossignol S, Le Bouc Y. Beckwith-Wiedemann syndrome. Orphanet encyclopedia; 2005. Accessed 16 March 2023 at: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=116
• 9 Wang KH, Kupa J, Duffy KA, Kalish JM. Diagnosis and management of Beckwith-Wiedemann syndrome. Front Pediatr 2020; 7: 562
• 10 Brioude F, Kalish JM, Mussa A. et al. Expert consensus document: Clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement. Nat Rev Endocrinol 2018; Apr;14 (04) 229-249 . Epub 2018 Jan 29. PMID: 29377879; PMCID: PMC6022848
• 11 Richards S, Aziz N, Bale S. et al; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17 (05) 405-424
• 12 Venselaar H, Te Beek TAH, Kuipers RKP, Hekkelman ML, Vriend G. Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces. BMC Bioinformatics 2010; 11 (01) 548
• 13 Lee MH, Reynisdóttir I, Massagué J. Cloning of p57KIP2, a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution. Genes Dev 1995; 9 (06) 639-649
• 14 Hatada I, Mukai T. Genomic imprinting of p57KIP2, a cyclin-dependent kinase inhibitor, in mouse. Nat Genet 1995; 11 (02) 204-206
• 15 Mussa A, Molinatto C, Cerrato F. et al. Assisted reproductive techniques and risk of Beckwith-Wiedemann syndrome. Pediatrics 2017; 140 (01) e20164311
• 16 Thompson JR, Williams CJ. Genomic imprinting and assisted reproductive technology: connections and potential risks. Semin Reprod Med 2005; 23 (03) 285-295