Sclerosteosis

Sclerosteosis (also known as cortical hyperostosis with syndactyly, or van Buchem disease type 2) is an extremely rare autosomal recessive skeletal disorder characterized by progressive bone overgrowth (hyperostosis and sclerosis), particularly affecting the skull and mandible. The condition is caused by loss-of-function mutations in the SOST gene on chromosome 17q21.31, which encodes sclerostin, a protein that normally inhibits bone formation. Without functional sclerostin, osteoblastic bone formation proceeds unchecked, leading to excessive bone density and skeletal overgrowth. The disease typically manifests in early childhood with syndactyly (fusion of the skin or bones of the fingers), which is often present at birth, and progressive skeletal overgrowth that becomes more apparent over time. Key clinical features include tall stature, a large and heavy jaw (mandibular overgrowth), facial distortion due to cranial hyperostosis, and cranial nerve entrapment. The overgrowth of skull bones can compress cranial nerves, leading to facial nerve palsy (often the seventh cranial nerve), hearing loss, and in severe cases, raised intracranial pressure that can be life-threatening. The long bones also show increased cortical thickness and density. Sclerosteosis is most prevalent among the Afrikaner population of South Africa, though cases have been reported in other populations. There is no cure for sclerosteosis. Treatment is primarily supportive and symptomatic, including surgical decompression of cranial nerves to address facial palsy and hearing loss, and neurosurgical intervention for raised intracranial pressure. Notably, the understanding of sclerostin's role in this disease has led to the development of anti-sclerostin antibody therapies (such as romosozumab) for osteoporosis, representing a significant pharmacological advance derived from rare disease research.

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