Posted: February 9, 2019 at 5:42 pm

A number sign (#) is used with this entry because of evidence that Woodhouse-Sakati syndrome is caused by homozygous mutation in the C2ORF37 gene (DCAF17; 612515) on chromosome 2q31.

Woodhouse and Sakati (1983) reported a total of 7 Saudi Arabian individuals from 2 consanguineous families with a combination of hypogonadism, partial alopecia, diabetes mellitus, mental retardation, and deafness. The first family had 2 affected males and 2 affected females ranging in age from 16 to 22 years. The second family had 1 affected male and 1 affected female aged 47 and 40 years, respectively. One female from each family initially presented with primary amenorrhea and failure of sexual development. All patients were subsequently found to have hypogonadism with low estradiol or testosterone levels. Luteinizing hormone (LHB; 152780) and follicle-stimulating hormone (FSH; 136530) were increased in 2 women (hypergonadotropic ovarian failure) and normal in all the other patients. Three males had hypothalamic hypogonadotrophic testicular failure, and the remaining female had both hypothalamic and ovarian failure. Examination of 1 woman showed hypoplastic uterus, rudimentary fallopian tubes, and streak ovaries. Testicular histology of 1 man showed hypospermatogenesis and prominent Sertoli cells. There was variable loss of eyebrow and scalp hair, the latter being short, sparse, and fine. Hair loss was most severe in the older patients. All patients were diabetic with inappropriately low serum insulin levels. All patients had some degree of mental retardation, ranging from mild to severe. Four patients tested had sensorineural hearing loss. Electrocardiogram (ECG) showed flattening of the T wave in all patients.

Devriendt et al. (1996) reported a brother and sister with a progressive extrapyramidal movement disorder with onset in adolescence associated with progressive alopecia and primary hypogonadism. The parents were first cousins once removed. Of 9 children total, 2 were affected and 1 died immediately after birth with severe arthrogryposis. Progressive learning problems, speech difficulties, and gait disturbance were first observed at age 12 years in the brother. He had decreased muscle strength and hand control, resulting in difficulties in fine motor skills such as writing. He was trained vocationally as a plumber. At age 17 years, he was seen by an endocrinologist for delayed puberty with absence of pubic and facial hair growth and prepubertal testes and penis. Neurologic examination at age 17 showed dystonia of the left arm and dysarthria. Progressive alopecia was observed in the early 20s. At age 47, he was able to walk very little and could produce only a few vocal sounds and had difficulty eating and drinking. His uncontrolled movements were dystonic and choreoathetotic, especially in the upper limbs. The sister showed learning difficulties in primary school and she required special education. At age 14 she developed progressive gait disturbance and was wheelchair-bound by her early 20s. Around the age of 14, a slowly progressive dysarthria and alopecia developed. There was primary amenorrhea, with no development of secondary female sexual characteristics. Facial appearance was very similar to that of her brother.

Gul et al. (2000) reported a 32-year-old Turkish man with mental retardation, partial alopecia, diabetes mellitus, hypogonadotrophic hypogonadism, deafness, and nervous system involvement. He had a eunuchoid appearance, flat occiput, triangular face, thin and sparse scalp hair (microscopic examination showed pili annulati), high forehead, frontal bossing, mild hypertelorism, and short and sparse eyebrows. Other features included downslanting palpebral fissures, a prominent nasal root, dental malocclusion, and a high-arched palate. Neurologic examination showed dysarthria, mild weakness in the distal muscles, sensory polyneuropathy, and equivocal Babinski sign. Other studies, such as central motor conduction time and brainstem auditory evoked responses, indicated involvement of both the central and peripheral nervous systems. A younger and older brother of the proband had diabetes mellitus and similar facial features, and the older brother died at age 30 of unknown cause. The parents were first cousins. Gul et al. (2000) referred to the disorder in the proband as 'Woodhouse and Sakati syndrome' and suggested autosomal recessive inheritance.

Al-Semari and Bohlega (2007) reported 12 Saudi families with an autosomal recessive multisystem disorder reminiscent of that described by Devriendt et al. (1996). Ten of the families were consanguineous. One of the families had been previously reported by Woodhouse and Sakati (1983) and 3 affected members had since developed a neurologic extrapyramidal syndrome with choreoathetoid movements and dystonia. The proband was unable to stand or walk, had scoliosis, hyperreflexia, and extensor plantar responses. Brain MRI of the proband, 1 sister, and 1 cousin showed diffuse white matter disease. Characteristic features in affected members of the other families included partial alopecia, dystonia, hypogonadism with lack of secondary sexual characteristics, cognitive impairment, deafness, diabetes mellitus, and signal abnormalities on brain MRI. Pelvic examination in female members of affected families showed infantile uterus and/or small ovaries. ECG showed abnormal T waves in 4 patients. Laboratory studies showed that 7 patients had increased FSH and LH, 4 men had low testosterone, and 2 women had low estradiol. Eight patients had biochemical evidence of hypothyroidism. The most striking and consistent laboratory abnormality was low serum insulin growth factor-1 (IGF1; 147440) with normal growth hormone (GH; 139250). Al-Semari and Bohlega (2007) suggested that the disorder could be an undescribed type of neuro-endocrine-ectodermal syndrome.

Medica et al. (2007) reported a 52-year-old woman of Croatian origin who had the phenotypic findings of Woodhouse-Sakati syndrome, including hypogonadism, sparse hair, diabetes mellitus, sensorineural hearing impairment, mild mental retardation, and flattened T waves on EKG.

Koshy et al. (2008) reported 3 sibs from a consanguineous Indian family with Woodhouse-Sakati syndrome who showed phenotypic variability. The female proband presented with idiopathic thrombocytopenic purpura and had camptodactyly of the fourth and fifth fingers as did her affected brother. She and her affected sister had hypergonadotropic hypogonadism, whereas their brother had hypogonadotropic hypogonadism. A female cousin of the sibs was reported to have had alopecia and amenorrhea, and was pale and edematous when she died of severe diarrhea and dehydration at 32 years of age.

Schneider and Bhatia (2008) described a brother and sister from a consanguineous Middle Eastern family with adult-onset dystonia associated with sensorineural deafness, seizures, sensory neuropathy, mental retardation, alopecia, hypogonadism, and diabetes mellitus. The authors stated that although these features were suggestive of Woodhouse-Sakati syndrome, they also considered a diagnosis of mitochondrial disease, but mitochondrial mutations and muscle biopsy were negative; other causes of secondary dystonia were also excluded.

Steindl et al. (2010) studied 3 affected members of an Italian family with Woodhouse-Sakati syndrome who were found to have a homozygous nonsense mutation in the C2ORF37 gene (612515.0006) by Alazami et al. (2010) (see MOLECULAR GENETICS). The proband was a 58-year-old man who exhibited the full constellation of hypogonadism, alopecia, diabetes mellitus, cognitive impairment, and dystonia. His sister, who was reported to have died at 46 years of age of myocardial infarction and heart block, had autopsy findings that suggested the presence of alopecia and hypogonadism, with complete absence of the uterus. There was also a distant female relative in this pedigree who had similar clinical features to those of the proband; laparoscopy revealed absence of fallopian tubes, streak gonads, and hypoplastic uterus. She also had psychosis and hallucinations; Steindl et al. (2010) stated that psychiatric features should be added to the clinical spectrum of Woodhouse-Sakati syndrome. Examination of photographs at different ages demonstrated the appearance of progressive aging, a triangular face shape with prominent nasal root, and prominent ears with large ear lobes. There was progressive cognitive decline in these patients after normal development in childhood, culminating in severe cognitive impairment with little spontaneous speech in adulthood. In addition, anodontia presented from an early age in all 3 patients.

Alazami et al. (2008) performed genomewide linkage analysis on 3 affected sibs from 1 of the original Saudi families described by Woodhouse and Sakati (1983) and identified an extended autozygous region encompassing chromosome 2q22.3-q35. Inclusion of another Saudi family with 4 affected sibs confirmed the homozygosity and yielded a maximum multipoint lod score of 6.13 from markers D2S2284 to D2S1791; fine mapping further narrowed the critical region to a 1.2-Mb interval containing 13 known and predicted genes and pseudogenes.

In affected members of 2 Saudi families with Woodhouse-Sakati syndrome, including 1 of the original families described by Woodhouse and Sakati (1983), Alazami et al. (2008) identified homozygosity for a 1-bp deletion in the C2ORF37 gene (612515.0001); 6 additional Saudi families with the disorder were also found to be homozygous for the mutation. SNP-based haplotype analysis confirmed a founder effect, and the deletion likely arose approximately 55 generations earlier. Alazami et al. (2008) subsequently identified homozygosity of a different 1-bp deletion in the C2ORF37 gene (612515.0002) in the Eastern European patient previously reported by Medica et al. (2007), and respective homozygous splice site mutations (612515.0003-612515.0004) in the Indian family reported by Koshy et al. (2008) and the Middle Eastern family reported by Schneider and Bhatia (2008). The mutations segregated fully with disease in all families, and were not found in ethnically matched controls.

Alazami et al. (2010) analyzed the C2ORF37 gene in 7 patients with Woodhouse-Sakati syndrome from 4 unrelated families, 2 of Italian origin, 1 of French-Gypsy origin, and 1 of Turkish origin, and identified homozygosity for 3 nonsense mutations (612515.0005-612515.0007) and 1 deletion/insertion mutation (612515.0008). Screening of the C2ORF37 gene in a cohort of 11 patients with deafness and dystonia but no hypogonadism, alopecia, or mental retardation did not reveal any mutations, suggesting that mutation in C2ORF37 does not contribute significantly to cases presenting with isolated elements of Woodhouse-Sakati syndrome. Alazami et al. (2010) found no correlation between clinical expressivity and site of mutation, and noted that the intrafamilial variability in the mutation-positive patients indicated that modifiers likely play an important role in this disease.

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