Clinical characteristics: SOST-related sclerosing bone dysplasias include SOST-related sclerosteosis and SOST-related endosteal hyperostosis, van Buchem type (van Buchem disease), both disorders of progressive bone overgrowth due to increased bone formation.

The major clinical features of SOST-related sclerosteosis are progressive skeletal overgrowth, most pronounced in the skull and mandible, and variable syndactyly, usually of the second (index) and third (middle) fingers. Affected individuals appear normal at birth except for syndactyly. Facial distortion due to frontal bossing and mandibular overgrowth is seen in nearly all individuals and becomes apparent in early childhood with progression into adulthood. Hyperostosis of the skull results in narrowing of the foramina, causing entrapment of the seventh cranial nerve (leading to facial palsy) with other, less common nerve entrapment syndromes including visual loss (2nd cranial nerve), neuralgia or anosmia (5th cranial nerve), and sensorineural hearing loss (8th cranial nerve). In SOST-related sclerosteosis, hyperostosis of the calvarium reduces intracranial volume, increasing the risk for potentially lethal elevation of intracranial pressure. Survival of individuals with SOST-related sclerosteosis into old age is unusual but not unprecedented.

The manifestations of van Buchem disease are generally milder than SOST-related sclerosteosis. Stature is typically normal, cranial nerve entrapment of the seventh and eighth cranial nerves are common, and increased intracranial pressure is rare, seen only in severely affected individuals. Individuals with van Buchem disease do not have syndactyly or other digit deformities. Life span appears not to be altered.

Diagnosis/testing: The diagnosis of a SOST-related sclerosing bone dysplasia is established in a proband with typical clinical and radiographic findings and biallelic pathogenic variants in SOST (in individuals with SOST-related sclerosteosis) or a biallelic 52-kb deletion downstream of SOST (in individuals with van Buchem disease) identified on molecular genetic testing.

Management: Treatment of manifestations: Hearing aids with middle ear surgery or cochlear implant depending on the nature of the hearing loss; surgical decompression as needed for entrapped facial nerves; surgical reduction of mandibular overgrowth; orbital decompression for proptosis; treatment of dental manifestations per orthodontist and/or craniofacial team; craniectomy and ventriculoperitoneal drain for increased intracranial pressure; surgical correction of syndactyly.

Surveillance: Intermittent assessment of bone mineral density and biochemical markers of bone turnover until age 18 years and then every five years in adulthood; annual audiologic assessment in childhood and as needed in adults; examination for evidence of cranial nerve entrapment and increased intracranial pressure every six months until age 18 years and then annually in adulthood; annual ophthalmology examination to assess for proptosis, intraocular pressure, and evaluation of the optic nerve papilla; annual dental and orthodontic evaluation to assess for tooth malalignment and malocclusion until age 18 years; routine dental screening in adults.

Agents to avoid: Agents known to suppress bone resorption (e.g., bisphosphonates, denosumab, selective estrogen receptor modulators) and agents known to stimulate bone formation (e.g., teriparatide, abaloparatide, romozosumab).

Genetic counseling: SOST-related sclerosing bone dysplasias are inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a pathogenic variant associated with a SOST-related sclerosing bone dysplasia, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the pathogenic variants associated with a SOST-related sclerosing bone dysplasia have been identified in an affected family member, carrier testing for at-risk family members and prenatal/preimplantation genetic testing are possible.