Dyggve–Melchior–Clausen syndrome in three siblings: a unique case series with dual diagnosis of Down syndrome and Hirschsprung disease
-
,
,
,
,
,
,
,
,
and
Abstract
Objectives
Dyggve–Melchior–Clausen (DMC) syndrome is a rare autosomal recessive skeletal dysplasia caused by mutations in the DYM gene. It is characterized by progressive spondyloepimetaphyseal dysplasia, short stature, coarse facial features, microcephaly and intellectual disability. While it clinically resembles Morquio syndrome (mucopolysaccharidosis type IV, MPS IV), DMC is distinguished by cognitive impairment, absence of corneal clouding, normal urinary glycosaminoglycans and distinctive radiological features.
Case presentation
We reported three siblings with DMC syndrome. Two 4-year-old monozygotic male twins, born to consanguineous parents, presented with growth retardation and developmental delay. Radiographs showed generalized platyspondyly, rhizomelic shortening and metaphyseal dysplasia, while biochemical tests excluded MPS IV. Molecular tests revealed a homozygous deletion in exon 16 of the DYM gene. The third sibling, with Down syndrome, also exhibited similar skeletal features and carried the same DYM deletion.
Conclusions
The clinical and radiological features of our patients were consistent with DMC syndrome, with partial overlap with MPS IV. This case series represents the first reported coexistence of DMC and Down syndrome. In addition, we identified a novel homozygous deletion in exon 16 of the DYM gene, which broadens the known mutational spectrum. This finding also highlights the importance of comprehensive genetic testing when standard sequencing results are inconclusive. The presence of neurological findings, such as seizures, further supports the need for combined genetic and neurological evaluation in these patients.
Acknowledgments
Meryem Halis, MD is the corresponding author of this study. I would like to extend my sincere thanks to my professors and colleagues who supported me in preparing this case article.
-
Research ethics: As this was a retrospective study limited to members of a single family, Institutional Review Board approval was not required. The study was conducted in accordance with the principles of the Declaration of Helsinki (2013 revision).
-
Informed consent: Written informed consent was obtained from the parents for participation and for the publication of clinical data and photographs.
-
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
-
Use of Large Language Models, AI and Machine Learning Tools: Artificial intelligence (AI) tools were used solely to improve the clarity and fluency of the language.
-
Conflict of interest: The authors state no conflict of interest.
-
Research funding: None declared.
-
Data availability: The datasets generated and/or analyzed during the current study are not publicly available due to concerns regarding participant/patient anonymity.
References
1. Beighton, P. Dyggve–Melchior–Clausen syndrome. J Med Genet 1990;27:512–15. https://doi.org/10.1136/jmg.27.8.512.Search in Google Scholar PubMed PubMed Central
2. Spranger, J, Maroteaux, P, Der Kaloustian, VM. The Dyggve–Melchior–Clausen syndrome. Radiology 1975;114:415–21. https://doi.org/10.1148/114.2.415.Search in Google Scholar PubMed
3. El Ghouzzi, V, Dagoneau, N, Kinning, E, Thauvin-Robinet, C, Chemaitilly, W, Prost-Squarcioni, C, et al.. Mutations in a novel gene dymeclin (FLJ20071) are responsible for Dyggve–Melchior–Clausen syndrome. Hum Mol Genet 2003;12:357–64. https://doi.org/10.1093/hmg/ddg029.Search in Google Scholar PubMed
4. Denais, C, Dent, CL, Southgate, L, Hoyle, J, Dafou, D, Trembath, RC, et al.. Dymeclin, the gene underlying Dyggve–Melchior–Clausen syndrome, encodes a protein integral to extracellular matrix and golgi organization and is associated with protein secretion pathways critical in bone development. Hum Mutat 2011;32:231–9. https://doi.org/10.1002/humu.21413.Search in Google Scholar PubMed
5. Paupe, V, Gilbert, T, Le Merrer, M, Munnich, A, Cormier-Daire, V, El Ghouzzi, V. Recent advances in Dyggve–Melchior–Clausen syndrome. Mol Genet Metabol 2004;83:51–9. https://doi.org/10.1016/j.ymgme.2004.08.012.Search in Google Scholar PubMed
6. Neumann, LM, El Ghouzzi, V, Paupe, V, Weber, HP, Fastnacht, E, Leenen, A, et al.. Dyggve–Melchior–Clausen syndrome and Smith-McCort dysplasia: clinical and molecular findings in three families supporting genetic heterogeneity in Smith-McCort dysplasia. Am J Med Genet A 2006;140:421–6. https://doi.org/10.1002/ajmg.a.31090.Search in Google Scholar PubMed
7. Dyggve, HV, Melchior, JC, Clausen, J. Morquio-Ullrich’s disease: an inborn error of metabolism? Arch Dis Child 1962;37:525–34. https://doi.org/10.1136/adc.37.195.525.Search in Google Scholar PubMed PubMed Central
8. Dyggve, HV, Melchior, JC, Clausen, J, Rastogi, SC. The Dyggve–Melchior–Clausen (DMC) syndrome. A 15 year follow-up and a survey of the present clinical and chemical findings. Neuropadiatrie 1977;8:429–42. https://doi.org/10.1055/s-0028-1091538.Search in Google Scholar PubMed
9. Aglan, MS, Temtamy, SA, Fateen, E, Ashour, AM, Eldeeb, K, Hosny, GA. Dyggve–Melchior–Clausen syndrome: clinical, genetic, and radiological study of 15 Egyptian patients from nine unrelated families. J Child Orthop 2009;3:451–8. https://doi.org/10.1007/s11832-009-0211-8.Search in Google Scholar PubMed PubMed Central
10. Varshney, K, Narayanachar, SG, Girisha, KM, Bhavani, GS, Narayanan, D, Phadke, S, et al.. Clinical, radiological and molecular studies in 24 individuals with Dyggve–Melchior–Clausen dysplasia and Smith-McCort dysplasia from India. J Med Genet 2023;60:204–11. https://doi.org/10.1136/jmedgenet-2021-108098.Search in Google Scholar PubMed
11. Lyulcheva-Bennett, E, Kershaw, C, Baker, E, Gillies, S, McCarthy, E, Higgs, J, et al.. Dual diagnosis of achondroplasia and mandibulofacial dysostosis with microcephaly. BMC Med Genom 2024;17:226. https://doi.org/10.1186/s12920-024-01999-0.Search in Google Scholar
12. Kar, SK, Bansal, S, Kumar, D. An extremely rare association of Dyggve–Melchior–Clausen syndrome with mania: coincidence or comorbidity. Indian J Psychol Med 2015;37:226–9. https://doi.org/10.4103/0253-7176.155644.Search in Google Scholar
13. Alquraishi, AS, Abdelmogeit, SE, Asiri, K, Alasmari, BG, Mohammed, M, Alghubishi, SA. Dyggve–Melchior–Clausen syndrome with celiac disease: a rare entity. Cureus 2025;17:e78881. https://doi.org/10.7759/cureus.78881.Search in Google Scholar
14. Dupuis, N, Fafouri, A, Bayot, A, Kumar, M, Lecharpentier, T, Ball, G, et al.. Dymeclin deficiency causes postnatal microcephaly, hypomyelination, and reticulum-to-golgi trafficking defects in mice and humans. Hum Mol Genet 2015;24:2771–83. https://doi.org/10.1093/hmg/ddv038.Search in Google Scholar
15. Diposarosa, R, Bustam, NA, Sahiratmadja, E, Susanto, PS, Sribudiani, Y. Literature review: enteric nervous system development, genetic and epigenetic regulation in the etiology of Hirschsprung’s disease. Heliyon 2021;7:e07308. https://doi.org/10.1016/j.heliyon.2021.e07308.Search in Google Scholar
16. Reyes-Silva, C, Gallardo-Vizuete, J, Guzmán-Acán, J, Jaramillo-Koupermann, G, Cabrera-Andrade, A. Dyggve–Melchior–Clausen syndrome in Ecuador: expanding knowledge on a rare genetic disorder. Genes (Basel) 2025;16:490. https://doi.org/10.3390/genes16050490.Search in Google Scholar
17. Bergant, G, Maver, A, Lovrecic, L, Čuturilo, G, Hodzic, A, Peterlin, B. Comprehensive use of extended exome analysis improves diagnostic yield in rare disease: a retrospective survey in 1,059 cases. Genet Med 2018;20:303–12. https://doi.org/10.1038/gim.2017.142.Search in Google Scholar
18. Riggs, ER, Andersen, EF, Cherry, AM, Kantarci, S, Kearney, H, Patel, A, et al.. Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med 2020;22:245–57. https://doi.org/10.1038/s41436-019-0686-8.Search in Google Scholar
19. McLaren, W, Gil, L, Hunt, SE, Riat, HS, Ritchie, GR, Thormann, A, et al.. The ensembl variant effect predictor. Genome Biol 2016;17:122. https://doi.org/10.1186/s13059-016-0974-4.Search in Google Scholar
20. ClinVar. Variation ID: rs780873164, c.1762C>T (p.Arg588Ter) in DYM. National Center for Biotechnology Information. https://www.ncbi.nlm.nih.gov/clinvar/variation/rs780873164 [Accessed 30 Nov 2025].Search in Google Scholar
21. Khosravi, M, Weaver, DD, Bull, MJ, Lachman, R, Rimoin, DL. Lethal syndrome of skeletal dysplasia and progressive central nervous system degeneration. Am J Med Genet 1998;77:63–71. https://doi.org/10.1002/(sici)1096-8628(19980428)77:1<63::aid-ajmg14>3.0.co;2-m.10.1002/(SICI)1096-8628(19980428)77:1<63::AID-AJMG14>3.0.CO;2-MSearch in Google Scholar
© 2025 Walter de Gruyter GmbH, Berlin/Boston
