Clinical characteristics: Virtually all individuals with Woodhouse-Sakati syndrome (WSS) have the endocrine findings of hypogonadism (evident at puberty) and progressive childhood-onset hair thinning that often progresses to alopecia totalis in adulthood. More than half of individuals have the neurologic findings of progressive extrapyramidal movements (dystonic spasms with dystonic posturing with dysarthria and dysphagia), moderate bilateral postlingual sensorineural hearing loss, and mild intellectual disability. To date, more than 40 families (including 33 with a molecularly confirmed diagnosis) with a total of 88 affected individuals have been reported in the literature.

Diagnosis/testing: The diagnosis of WSS is established in a proband with suggestive clinical, neuroimaging, and neurophysiologic findings by identification of biallelic pathogenic variants in DCAF17 on molecular genetic testing.

Management: Treatment of manifestations: Treatment is symptomatic and should be managed by a multidisciplinary team. Hypogonadism requires hormone replacement therapy to induce secondary sex characteristics and promote bone health at the usual age of puberty. Alopecia is treated symptomatically for cosmetic reasons only. Treatment for dystonia is routine; oral medications are tried first and followed in some instances by botulinum toxin injection and/or deep-brain stimulation. Dysarthria often benefits from consultation with a speech therapist. Those with dysphagia often require measures to reduce oral secretions, use of thickened liquids and pureed foods to avoid aspiration, and eventually a gastrostomy to help maintain caloric intake. Standard treatment for diabetes mellitus, hypothyroidism, hearing loss, and intellectual disability.

Surveillance: Monitoring for endocrine abnormalities is recommended at the following ages: hypogonadism beginning at age 12-14 years; diabetes mellitus and hypothyroidism beginning at age 20 years; serum IGF-1 every three to five years following diagnosis; annual neurologic assessment for dystonia; speech and language assessment for dysarthria and dysphagia as needed; annual developmental assessment throughout childhood; annual audiology evaluation.

Agents/circumstances to avoid: Persons with dystonia should avoid situations in which the risk of falling is increased.

Evaluation of relatives at risk: Molecular genetic testing for the DCAF17 pathogenic variants identified in the proband is appropriate for evaluation of apparently asymptomatic older and younger sibs to identify as early as possible those who would benefit from early identification and treatment of potential complications.

Genetic counseling: WSS is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the pathogenic DCAF17 variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.