Congenital Myopathy and Split-Foot Malformation: A Unique Case Without Mesoaxial Polydactyly
Laboratory Genetics and Genomics
-
Primary Categories:
- Genetic Counseling
-
Secondary Categories:
- Genetic Counseling
Introduction
Split-hand/foot malformation (SHFM), also known as ectrodactyly, is a rare congenital skeletal anomaly characterized by the division or absence of central digits in the hands or feet. SHFM is often associated with genetic mutations, making it significant for rare disease research and genetic counseling. While variants in the MAP3K20 gene are known to cause split-foot malformation with mesoaxial polydactyly (OMIM: 616890), the present case offers a novel phenotype, highlighting the genetic and phenotypic diversity associated with SHFM.
Case Presentation
A male patient from a consanguineous family presented with hallmark features of SHFM, including absent central digits in both hands and feet. Notably, the patient did not show signs of mesoaxial polydactyly. His medical history was unremarkable, except for the congenital limb abnormalities and muscle weakness, suggesting an underlying congenital myopathy. The patient exhibited developmental delay in motor functions such as walking, with weakness in the limbs.
Diagnostic Workup
Clinical assessments included X-rays that confirmed the absence of central digits in both the hands and feet. Biochemical tests ruled out metabolic causes. Whole exome sequencing (WES) followed by Sanger sequencing revealed a novel homozygous nonsense variant (c.1150G>T; p.Glu384*) in exon 6 of the MAP3K20 gene. The findings were validated through 3D protein modeling, which indicated significant structural alterations in the MAP3K20 protein. Additionally, RT-qPCR showed a decrease in MAP3K20 mRNA expression in the patient compared to other unaffected family members.
Treatment and Management
The patient was provided with supportive care, including physiotherapy and occupational therapy to aid motor function development. Since there is no established cure for SHFM, treatment focused on managing symptoms and improving the quality of life. No experimental treatments were administered, but genetic counseling was provided to the family due to the novel mutation's discovery.
Outcome and Follow-Up
After ongoing physiotherapy, the patient showed mild improvement in muscle strength, though significant functional limitations remained. Long-term follow-up will focus on monitoring muscular development and limb mobility, with periodic assessments to ensure appropriate intervention if further complications arise.
Discussion
This case expands the phenotypic spectrum associated with MAP3K20 gene mutations, which were previously linked to split-foot malformation with mesoaxial polydactyly. In contrast, this patient presented SHFM without polydactyly, alongside congenital myopathy, suggesting that MAP3K20 variants might contribute to a broader range of congenital abnormalities. The structural and functional impact of the p.Glu384* variant suggests its critical role in developmental pathways affecting both limb formation and muscular function. This discovery aligns with the growing understanding of how SHFM mutations impact not only limb morphology but also other organ systems, such as skeletal muscles.
Conclusion
This case report demonstrates the importance of MAP3K20 in limb development and congenital myopathies. The novel homozygous variant (c.1150G>T; p.Glu384*) expands the mutation spectrum of MAP3K20-associated SHFM and highlights a new phenotype without mesoaxial polydactyly. Future studies should further investigate the role of MAP3K20 in broader developmental signaling pathways and its potential contribution to myopathies.
Split-hand/foot malformation (SHFM), also known as ectrodactyly, is a rare congenital skeletal anomaly characterized by the division or absence of central digits in the hands or feet. SHFM is often associated with genetic mutations, making it significant for rare disease research and genetic counseling. While variants in the MAP3K20 gene are known to cause split-foot malformation with mesoaxial polydactyly (OMIM: 616890), the present case offers a novel phenotype, highlighting the genetic and phenotypic diversity associated with SHFM.
Case Presentation
A male patient from a consanguineous family presented with hallmark features of SHFM, including absent central digits in both hands and feet. Notably, the patient did not show signs of mesoaxial polydactyly. His medical history was unremarkable, except for the congenital limb abnormalities and muscle weakness, suggesting an underlying congenital myopathy. The patient exhibited developmental delay in motor functions such as walking, with weakness in the limbs.
Diagnostic Workup
Clinical assessments included X-rays that confirmed the absence of central digits in both the hands and feet. Biochemical tests ruled out metabolic causes. Whole exome sequencing (WES) followed by Sanger sequencing revealed a novel homozygous nonsense variant (c.1150G>T; p.Glu384*) in exon 6 of the MAP3K20 gene. The findings were validated through 3D protein modeling, which indicated significant structural alterations in the MAP3K20 protein. Additionally, RT-qPCR showed a decrease in MAP3K20 mRNA expression in the patient compared to other unaffected family members.
Treatment and Management
The patient was provided with supportive care, including physiotherapy and occupational therapy to aid motor function development. Since there is no established cure for SHFM, treatment focused on managing symptoms and improving the quality of life. No experimental treatments were administered, but genetic counseling was provided to the family due to the novel mutation's discovery.
Outcome and Follow-Up
After ongoing physiotherapy, the patient showed mild improvement in muscle strength, though significant functional limitations remained. Long-term follow-up will focus on monitoring muscular development and limb mobility, with periodic assessments to ensure appropriate intervention if further complications arise.
Discussion
This case expands the phenotypic spectrum associated with MAP3K20 gene mutations, which were previously linked to split-foot malformation with mesoaxial polydactyly. In contrast, this patient presented SHFM without polydactyly, alongside congenital myopathy, suggesting that MAP3K20 variants might contribute to a broader range of congenital abnormalities. The structural and functional impact of the p.Glu384* variant suggests its critical role in developmental pathways affecting both limb formation and muscular function. This discovery aligns with the growing understanding of how SHFM mutations impact not only limb morphology but also other organ systems, such as skeletal muscles.
Conclusion
This case report demonstrates the importance of MAP3K20 in limb development and congenital myopathies. The novel homozygous variant (c.1150G>T; p.Glu384*) expands the mutation spectrum of MAP3K20-associated SHFM and highlights a new phenotype without mesoaxial polydactyly. Future studies should further investigate the role of MAP3K20 in broader developmental signaling pathways and its potential contribution to myopathies.