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Expanding the Phenotype of Dyggve-Melchior-Clausen Syndrome and Smith-McCort Dysplasia: A Rare Case of Skeletal Dysplasia

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical- Pediatric
  • Secondary Categories:
    • Clinical- Pediatric
Introduction
Dyggve-Melchior-Clausen syndrome (DMC) is a rare and progressive genetic skeletal disorder first described in 1962. Approximately 100 cases have been reported worldwide. Smith-McCort dysplasia (SMS), a variant of DMC with a slightly higher prevalence, is a disorder that is nearly identical but lacks intellectual disability. DMC and SMS are autosomal recessive spondyloepimetaphysal dysplasias resulting from mutations in the DYM gene. The product of this gene, dymeclin, plays a role in Golgi-associated secretory pathways and bone formation. Characteristic features include: coarse facies, short neck, short trunk, barrel-shaped chest, rhizomelic limb shortening, and pathognomonic radiological features. The progressive features often resemble those of a lysosomal storage disorder. We hereby present the unique case of a 10-year-old boy with a long time undiagnosed skeletal dysplasia.

Case Presentation
A 10-year-old nonverbal male was referred for genetics evaluation due to developmental delay, growth delay, and multiple osseous abnormalities suggestive of an underlying skeletal dysplasia. He was born preterm to a 21-year-old G1P0 mother via normal spontaneous vaginal delivery. Family history was unremarkable and consanguinity was denied. The patient came to the United States from the Dominican Republic in March of 2024 for medical care. His milestones were mostly unrecalled, though likely grossly abnormal as he did not sit up until age two. He previously attended school for one year in a kindergarten class and has not attended school since. On physical examination, the following features were noted: sloping forehead, midface flattening, hypertelorism, broad chest, wide spaced nipples, pectus carinatum, flexion elbow contractures, finger contractures, leg length discrepancy (right two centimeters shorter than left) causing a significant limp, prominent genu valgum, and broad flat feet. No words were spoken during examination, though he appeared socially appropriate and engaged.

Diagnostic Workup
In light of these findings, a skeletal dysplasia panel was sent, which identified a pathogenic variant, c.208C>T (p.Arg70*), and a likely pathogenic variant, gain (exons 3-10), in DYM gene. The phase of these variants have not yet been resolved, though they are most likely in trans as the patient’s phenotype aligns with the skeletal findings of both DMC and SMS.

Treatment and Management
Treatment of individuals with DMC and SMS is symptomatic and supportive. Spinal fusion, among other surgical techniques, are commonly indicated. In some cases, invasive surgery is contraindicated due to bone quality.

Outcome and Follow-Up
Although the patient’s presentation is consistent with a diagnosis of DCM or SMS, parental DYM gene testing would confirm this. Regardless, the patient will require long-term follow up with multiple specialties, particularly orthopedics as the condition is progressive and complications are common.

Discussion
The cases highlight the diagnostic challenge in evaluating nonverbal patients with DYM pathogenic variants due to overlapping clinical features of DYM-related conditions. At present, the patient is undergoing evaluation for intellectual disability. It remains to be seen which DYM-related condition is affecting this individual.

Conclusion
In this unique case, a 10-year-old boy was living with a rare and undiagnosed genetic disease. The patient’s phenotype suggests both Dyggve-Melchior-Clausen syndrome and Smith-McCort dysplasia, which share overlapping features but differ in intellectual involvement. Additional research is needed to better understand genotype-phenotype correlations in DYM-related disorders. Precise diagnosis for this individual remains to be determined.

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