Clinical and Molecular Spectrum Along with Genotype-phenotype Correlation of 25 Patients Diagnosed with 3 M Syndrome: a Study from Turkey

Overview

Journal Eur J Pediatr

Specialty Pediatrics

Date 2024 Dec 6

PMID 39643721

Authors

Akcahan Akalin

Servan Ozalkak

Ruken Yildirim

Amine Aktar Karakaya

Baris Kolbasi

Enise Avci Durmusalioglu

Funda Kokali

Gizem Urel-Demir

Veysel Oz

Edip Unal

Tahir Atik

Pelin Ozlem Simsek-Kiper

Nursel H Elcioglu

Affiliations

Soon will be listed here.

Abstract

Conclusion: To date, genotype-phenotype correlations have been identified in a limited number of studies. Further research involving larger cohorts is necessary to solidify these correlations.

What Is Known: • 3M syndrome is a well-known skeletal dysplasia caused by biallelic pathogenic variants in CUL7, OBSL1, and CCDC8 genes. • Despite genetic heterogeneity, clinical, and radiologic features show homogeneity in affected individuals.

What Is New: • Genotype-phenotype correlations have been established in limited studies. • The CUL7 group exhibited significantly lower height SDS at both admission and the final evaluation and lower weight SDS at the final examination compared to the OBSL1 group. • The frequency of variants in the OBSL1 gene among Turkish patients exceeds the rates reported in the literature. • Gradenigo syndrome is being reported for the first time in a patient with 3M syndrome.

References

Miller J, MCKUSICK V, Malvaux P, Temtamy S, Salinas C . The 3-M syndrome: a heritable low birthweight dwarfism. Birth Defects Orig Artic Ser. 1975; 11(5):39-47. View

Unger S, Ferreira C, Mortier G, Ali H, Bertola D, Calder A . Nosology of genetic skeletal disorders: 2023 revision. Am J Med Genet A. 2023; 191(5):1164-1209. PMC: 10081954. DOI: 10.1002/ajmg.a.63132. View

Huber C, Munnich A, Cormier-Daire V . The 3M syndrome. Best Pract Res Clin Endocrinol Metab. 2011; 25(1):143-51. DOI: 10.1016/j.beem.2010.08.015. View

Yan J, Yan F, Li Z, Sinnott B, Cappell K, Yu Y . The 3M complex maintains microtubule and genome integrity. Mol Cell. 2014; 54(5):791-804. PMC: 4165194. DOI: 10.1016/j.molcel.2014.03.047. View

Davydov E, Goode D, Sirota M, Cooper G, Sidow A, Batzoglou S . Identifying a high fraction of the human genome to be under selective constraint using GERP++. PLoS Comput Biol. 2010; 6(12):e1001025. PMC: 2996323. DOI: 10.1371/journal.pcbi.1001025. View

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J . 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(5):405-24. PMC: 4544753. DOI: 10.1038/gim.2015.30. View

van der Wal G, Otten B, Brunner H, van der Burgt I . 3-M syndrome: description of six new patients with review of the literature. Clin Dysmorphol. 2001; 10(4):241-52. DOI: 10.1097/00019605-200110000-00002. View

Temtamy S, Aglan M, Ashour A, Ramzy M, Hosny L, Mostafa M . 3-M syndrome: a report of three Egyptian cases with review of the literature. Clin Dysmorphol. 2006; 15(2):55-64. DOI: 10.1097/01.mcd.0000198926.01706.33. View

Huber C, Dias-Santagata D, Glaser A, OSullivan J, Brauner R, Wu K . Identification of mutations in CUL7 in 3-M syndrome. Nat Genet. 2005; 37(10):1119-24. DOI: 10.1038/ng1628. View

10.

Huber C, Delezoide A, Guimiot F, Baumann C, Malan V, Le Merrer M . A large-scale mutation search reveals genetic heterogeneity in 3M syndrome. Eur J Hum Genet. 2009; 17(3):395-400. PMC: 2986175. DOI: 10.1038/ejhg.2008.200. View

11.

Simsek-Kiper P, Taskiran E, Kosukcu C, Arslan U, Cormier-Daire V, Gonc N . Further expanding the mutational spectrum and investigation of genotype-phenotype correlation in 3M syndrome. Am J Med Genet A. 2019; 179(7):1157-1172. DOI: 10.1002/ajmg.a.61154. View

12.

Tuysuz B, Alp Unkar Z, Turan H, Gezdirici A, Alkaya D, Kasap B . Natural history of facial and skeletal features from neonatal period to adulthood in a 3M syndrome cohort with biallelic CUL7 or OBSL1 variants. Eur J Med Genet. 2021; 64(12):104346. DOI: 10.1016/j.ejmg.2021.104346. View

13.

Keskin M, Muratoglu Sahin N, Kurnaz E, Bayramoglu E, Savas Erdeve S, Aycan Z . A Rare Cause of Short Stature: 3M Syndrome in a Patient with Novel Mutation in OBSL1 Gene. J Clin Res Pediatr Endocrinol. 2016; 9(1):91-94. PMC: 5363173. DOI: 10.4274/jcrpe.3238. View

14.

Lyford-Pike S, Hoover-Fong J, Tunkel D . Otolaryngologic manifestations of skeletal dysplasias in children. Otolaryngol Clin North Am. 2012; 45(3):579-98, vii. DOI: 10.1016/j.otc.2012.03.002. View

15.

Bano S, Nawaz A, Asmar A, Rehman M, Farooq H, Ali H . Gradenigo's syndrome presenting as IX and X cranial nerve palsy without clinically apparent ear infection: A case report and review of literature. eNeurologicalSci. 2022; 27:100397. PMC: 8938864. DOI: 10.1016/j.ensci.2022.100397. View

16.

Badina A, Pejin Z, Odent T, Buzescu A, Huber C, Cormier-Daire V . Hip dislocation in 3-M syndrome: risk of misdiagnosis. Clin Dysmorphol. 2011; 20(2):114-116. DOI: 10.1097/MCD.0b013e328343f958. View

17.

Lugli L, Bertucci E, Mazza V, Elmakky A, Ferrari F, Neuhaus C . Pre- and post-natal growth in two sisters with 3-M syndrome. Eur J Med Genet. 2016; 59(4):232-6. DOI: 10.1016/j.ejmg.2016.01.009. View

18.

Al-Dosari M, Al-Shammari M, Shaheen R, Faqeih E, AlGhofely M, Boukai A . 3M syndrome: an easily recognizable yet underdiagnosed cause of proportionate short stature. J Pediatr. 2012; 161(1):139-45.e1. DOI: 10.1016/j.jpeds.2011.12.051. View

19.

Demir K, Altincik A, Bober E . Severe short stature due to 3-M syndrome with a novel OBSL1 gene mutation. J Pediatr Endocrinol Metab. 2013; 26(1-2):147-50. DOI: 10.1515/jpem-2012-0239. View

20.

Guven A, Cebeci A . 3M syndrome: a report of four cases in two families. J Clin Res Pediatr Endocrinol. 2011; 3(3):154-9. PMC: 3184518. DOI: 10.4274/jcrpe.v3i3.30. View