A Novel Mutation in SOST Gene Causes Sclerosteosis

Background: Sclerostin is a SOST gene product that inhibits osteoblasts activity and prevents excessive bone formation by antagonizing Wnt signaling pathway. Sclerosteosis has been linked to the loss of function mutation in SOST gene. It is a rare autosomal recessive disorder characterized by craniotubular hyperostosis leading to gigantism, cranial nerves entrapment, and fatal cerebellar herniation. Objectives To report a novel mutation of SOST gene in a patient with sclerosteosis. Clinical Case: A 25-year-old female was referred to the endocrine clinic for suspected GH excess. The patient noted the onset of headache, progressive bilateral blurred vision and hearing disturbance, irregular menses, and generalized arthralgia; at the age of 23 years. Subsequently, she observed a progressive increase in the size of shoes and hands, proptosis, and protrusion of the chin. She was the second of seven siblings from non-consanguineous parents with normal antenatal and neonatal history except for syndactyly. All family members were phenotypically normal except for a sister with similar physical appearance who had cranial decompression 20 years back. MRI pituitary was done initially due the suspicion of pituitary adenoma and it revealed an enlarged sella turcica with normal pituitary gland. Surprisingly, the MRI showed diffuse osseous thickening with narrowing of skull base foramina, narrowing of optic and internal auditory canals, secondary compression of cerebral parenchyma and bilateral cerebellar tonsillar herniation. Further image revealed extremely increased bone mass density with Z-score values of +12, generalized increase cortical thickness, vertebral end plates sclerosis, and deformed left index finger. Biochemical and endocrine tests revealed normal GH, IGF -1, TSH, prolactin, short Synacthen test, FSH, LH, estradiol, calcium, phosphorus, PTH and alkaline phosphatase. Due to progressive worsening of vision with compressive optic neuropathy, optic nerve fenestration with decompression hemicraniotomy was performed. Sclerosteosis was suspected due to the predominant craniotubular hyperostosis with syndactyly. There was no definite therapy. Management aimed at relieving symptoms and preventing complications, so she was commenced on calcitriol and prednisolone to suppress the osteoclasts. Genomic sequencing of the SOST was performed. We identified a novel deletion mutation in SOST gene (c.387delG, p.D131fs*) which disrupts the sclerostin function causing sclerosteosis in this patient. Conclusion: We describe a novel mutation in the SOST gene in a patient with sclerosteosis in Saudi Arabia, that has not been previously described. Closing the gap between the genomic knowledge and clinical applications will add the benefit of success in development of targeted therapies in such a fatal disease.