Woodhouse and Sakati (1983) were the first to describe patients with this syndrome. The first family had two affected males and two affected females ranging in age from 16 to 22 years. The second family had one affected male and one affected female aged 47 and 40 years, respectively. All patients suffered from abnormalities affecting six unrelated systems; hypogonadism, diabetes mellitus, alopecia, mental retardation, sensorineural deafness, and ECG abnormalities. All patients, especially the females, showed a failure of sexual maturation. The affected members showed a distinctive facial appearance, variable loss of eyebrow and scalp hair, intellectual impairment, ranging from mild to severe, and hyperglycemia. The females had a complete absence of breast tissue and sexual hair, hypoplastic uterus, rudimentary fallopian tubes, and streak ovaries. The males had moderate growth of pubic hair and genital development, moderately severe hypospermatogenesis and prominent Sertoli cells. Woodhouse and Sakati (1983) differentiated this condition from other similar disorders and suggested that this was a previously unreported condition, inherited as an autosomal recessive trait.
Al-Semari and Bohlega (2007) described the clinical manifestations of affected patients with Woodhouse-Sakati syndrome from 12 Saudi families. Ten of the families were consanguineous. One of the families had been previously reported by Woodhouse and Sakati (1983) and three 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, one sister, and one cousin showed diffuse white matter disease. The onset of the disease was in early adolescence, with males showing a more rapid progression. Patients showed alopecia, hypogonadism, and low IGF-1. Some patients had diabetes mellitus and/or sensorineural deafness. There was a progressive extra-pyramidal disorder, white matter disease, and abnormal signals of the basal ganglia. Pelvic examination in female members of affected families showed infantile uterus and/or small ovaries. ECG showed abnormal T waves in four patients. Laboratory studies showed that seven patients had increased FSH and LH, four men had low testosterone, and two 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) with normal growth hormone (GH). Al-Semari and Bohlega (2007) hinted on the high prevalence of this condition in the country.
The molecular basis for Woodhouse Sakati Syndrome was investigated by Alazami et al. (2008). Genome-wide linkage analysis on three affected siblings from one of the original Saudi families enabled the identification of an extended autizygous region on chromosome 2q. This region was further narrowed to a 1.2 Mb region by the inclusion of an additional family with four affected siblings. Sequencing of a hypothetical gene, C2ORF37, in this region revealed a 1bp deletion mutation that fully segregated with the phenotype. This mutation was found in six additional affected Saudi families, but not in 274 Saudi control chromosomes.
Hdiji et al., (2016) described two sisters with Woodhouse-Sakati syndrome born to healthy first cousin parents. The index patient was a 25-year-old woman who presented with generalized dystonia involving the trunk and all four limbs. She had dysmorphic facial features including a triangular shape with a large forehead, sparse eyebrows and eyelashes, alopecia predominant in the fronto-temporal region of the scalp, hypertelorism, large ears, prominent nasal root, precocious skin aging and partial edentulism. She also had mild intellectual disabilities. Her secondary sexual characteristics were absent with minimal breast budding and marked vulvar hypoplasia, as well as no facial, axillary or pubic hair. She was severely disabled and wheelchair dependent because of her movement disorder. Her laboratory tests revealed hypogonadotropic hypogonadism. Her 30-year-old sister presented at the age of 12 years with dystonic movement of the left upper limb. Eight years later, her right side became affected. At the age of 27 years she had walking difficulties with frequent falls, and one year later she became bedridden. She had intellectual disabilities. She had a primary amenorrhea and alopecia. She had the same dysmorphic facial characteristics as her sister. Sequencing of the C2orf37 gene revealed a homozygous mutation c.436delC in exon 4 in the two affected sisters, and in a heterozygous state in the parents and the healthy sister.