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Novel mutation and white matter involvement in an Indian child with pycnodysostosis
Ankur Singh1, Sergio Cuevas-Covarrubias, Gaurav Pradhan
1Department of Pediatrics, LHMC and associated Kalawati Saran Children Hospital, New Delhi, India.
Insights
Pycnodysostosis, a genetic disorder affecting the cathepsin K gene, presents with skeletal and extraskeletal features. A novel mutation expands the known spectrum of this rare disease.
Area of Science:
- Genetics
- Molecular Biology
- Medical Science
Background:
- Pycnodysostosis (OMIM # 265800) is an inherited lysosomal disorder caused by mutations in the cathepsin K gene (CTSK).
- The disorder is characterized by skeletal abnormalities and can involve extraskeletal manifestations.
Observation:
- The index patient exhibited typical features of pycnodysostosis, including short stature, dental and digital anomalies, and a history of multiple fractures.
- Neuroimaging revealed white matter hyperintensities, suggesting dysmyelination, an unreported finding in this condition.
Findings:
- Molecular analysis identified a novel homozygous frameshift mutation (c.480_481insT, p.L160fsX173) in the CTSK gene.
- This mutation leads to a premature stop codon, altering the cathepsin K protein structure and function.
Implications:
- This case expands the known phenotypic spectrum of pycnodysostosis.
- The discovery of this novel mutation contributes to the understanding of CTSK gene mutations and their associated pathologies.
Abstract:
Pycnodysostosis (OMIM # 265800) is an inherited lysosomal disorder due to affection of cathepsin K gene, localised to 1q21. Pycnodysostosis can present with both skeletal and extraskeletal features. The index patient presented with cardinal features of short stature, dental and digital anomalies with history of multiple fractures. He, in addition had an unreported finding of white matter hyperintensity suggesting dysmyelination on neuroimaging. Molecular analysis revealed a homozygous insertion of single nucleotide in exon 5 of the CTSK gene that produces the substitution of phenylalanine instead of leucine at position 160 of protein and a premature termination of protein synthesis due to insertion of a stop codon. This mutation (c.480_481insT), (p.L160fsX173) is a novel frameshift mutation. The index case extends the phenotypic spectrum and the list of previously reported mutations in the CTSK gene.
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