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Writer’s Cramp Presentation of Woodhouse–Sakati Syndrome – “Out of the Woods”

Woodhouse–Sakati syndrome (WSS) is a rare autosomal recessive multi-system disorder, included under neurodegeneration with brain iron accumulation (NBIA), characterized by hypogonadism, alopecia, diabetes mellitus, sensorineural deafness, mental retardation, and extrapyramidal symptoms caused by mutations in the DCAF17 (previously known as C2orf37) gene, which encodes a poorly characterized nucleolar protein. We describe a South Indian family with two affected siblings suffering from WSS presenting with childhood-onset writer’s cramp. A 25-year-old lady (proband), born of third-degree consanguineous parentage, presented with writer’s cramp since 10 years of age which later progressed to affect other activities. By 13 years, she had difficulty in tasks with the left upper limb as well. There was no neck dystonia or bradykinesia. She was a school dropout without any behavioral issues or seizures. She had never attained menarche and had sparse scalp hair noticed since childhood. Examination showed a high-arched palate, facial dysmorphism with triangular facies, hypertelorism, alopecia over the frontal and temporal regions, and poorly developed secondary sexual characters. She had action dystonia of both upper limbs (left > right) with writer’s cramp and dystonia of both lower limbs (Video segment 1 and 2). There were no features of parkinsonism, pyramidal or cerebellar dysfunction. Her routine blood investigations were normal except for hyperglycemia. Electrocardiogram and echocardiography were within normal limits. Pure tone audiometry showed bilateral mild sensorineural hearing loss. Magnetic resonance imaging (MRI) brain showed mineralization in bilateral globus pallidus interna, substantia nigra, and red nucleus on susceptibility-weighted images (SWI) (Figure 1A and B) along with bilateral frontoparietal discrete white matter hyperintensities on T2-weighted images(Figure 1C) and partial empty sella with small-sized hypophysis (Figure 1D). Serum estradiol level of 23.2 pg/mL (normal range in premenopausal females being 30–400 pg/mL) and progesterone levels of 0.04 ng/mL (normal range being 0.1– 0.7 ng/mL in the follicular stage and 2–25 ng/mL in the luteal stage) were low, whereas serum follicular stimulating hormone (FSH) level of 33 IU/L(normal range 3–10 ), luteinizing hormone (LH) level of 27.4 IU/L (normal range 2–8 ) were high suggesting a hypergonadotropic hypogonadism secondary to ovarian failure. Ultrasound pelvis showed a small infantile uterus with ill-defined ovaries. The proband’s 19-year-old brother also had writer’s cramp since 8 years of age which later became non-task specific. He did not have lower limb symptoms, tremors, parkinsonism, or ataxia. He was poor scholastically, had similar sparse scalp hair and impaired secondary sexual characters. Examination revealed action dystonia of both upper extremities (right > left) on writing and other tasks (Video segment 3 and 4). His MRI brain showed iron deposition in bilateral globus pallidus and substantia nigra on SWI images (Figure 2A, B) and a small-sized pituitary gland on T2 weighted images (Figure 2C) with no white matter changes. He had diabetes and a hormonal profile suggesting hypogonadotropic hypogonadism. Targeted gene sequencing (which includes 11 genes implicated in NBIA namely AP4M1, ATP13A2, C19ORF12, COASY, CP, DCAF17, FA2H, FTL, PANK2, PLA2G6, and WDR45) revealed a homozygous pathogenic nonsense mutation c.85C>T (p. Gln29Ter) in exon 1 of DCAF17 gene on chromosome 2q31.1 in the proband and sibling, which causes a premature truncation of the protein, confirmingWSS. They were initiated on metformin and low dose insulin for diabetes mellitus, local application of minoxidil for hair growth, a combination pill containing low-dose estrogen and progesterone in monthly cycles for proband and testosterone depo injections once monthly for the brother. WSS is characterized by facial dysmorphism (long triangular face, hypertelorism, prominent nasal bridge), alopecia, hypogonadism, diabetes mellitus, hypothyroidism, intellectual disability, sensorineural deafness, extrapyramidal features, and ECG abnormalities (ST segment lengthening and flattened or negative T waves). WSS has been reported from North-East Europe, India, Turkey, Saudi Arabia, Kuwait, Portugal, and Israel and onset is