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Endocrine Abnormalities in a Case of Neurodegeneration with Brain Iron Accumulation

A 29-year-old man referred to our movement disorder clinic for slowness of movements, dysarthria, and dysphagia. His symptoms began at the age of 24 years with slowness of movements and difficulty in walking, progressing to the upper limbs and involving the face and bulbar areas. He also had 3 episodes of generalized tonic–clonic seizures in the past 2 years. Past medical history revealed mild intellectual disability, alopecia, azoospermia attributed to hypogonadotropic hypogonadism, and recently diagnosed diabetes mellitus (DM). He was the youngest child of unrelated parents and had 2 healthy brothers. On physical examination, he had dysmorphic features consisting of hypertelorism, sparse eyebrows and eyelashes, and temporal baldness. Neurological examination revealed hypophonic speech, hypokinesia more severe on the right limbs, and fine postural tremor of hands. His gait was abnormal as a result of a decreased right arm swing and limping gait attributed to a recent right knee trauma (Video S1). Brain magnetic resonance imaging (MRI) revealed a small pituitary gland (empty sella turcica) and bilateral hypointensity in globus pallidus on T2 and susceptibility-weighted images (SWI) compatible with iron deposition and proposing neurodegeneration with brain iron accumulation (NBIA) as the main differential diagnosis (Fig. 1). Genetic analysis using whole-exome sequencing (Illumina HiSeq 2500 system) identified a homozygous variant in DCAF17; NM_025000.3, c.1091 + 1G > A, confirming diagnosis of Woodhouse-Sakati syndrome (WSS). WSS (Online Mendelian Inheritance in Man 241080) is an autosomal recessive inherited neuroendocrine disorder caused by mutations in the DCAF17 gene. WSS belongs to the NBIA family, comprising a diverse and heterogenous category of diseases identified with excessive brain (mainly basal ganglia) iron accumulation. The endocrine system is affected in virtually all patients with WSS. The most common findings are hypogonadotropic hypogonadism, alopecia, DM, and primary hypothyroidism. Involvement of the neurological system happens in more than half of the patients, with extrapyramidal symptoms, intellectual disability, and sensory neural hearing loss being most commonly reported. Parkinsonism and dystonia are the main extrapyramidal manifestations. Seizure is an uncommon manifestation of WSS. Brain MRI demonstrates a small pituitary gland and bilateral hypointensity in globus pallidus on T2 and fluid attenuated inversion recovery sequences indicating iron deposition. Other features are nonenhancing frontoparietal and periventricular white matter changes that can help distinguish WSS from other NBIAs. WSS is not the only NBIA associated with endocrinopathy. Aceruloplasminemia is a form of NBIA characterized by DM and a wide range of neurological symptoms. Also consider Wilson disease in the setting of neurological and endocrine systems involvement, including DM and hypogonadotropic hypogonadism as a result of liver failure, and an NBIA-like brain MRI on SWI sequences caused by copper accumulation. Herein we present the first report of WSS from Iran. In accordance with previous reports, our case manifested with hypogonadotropic hypogonadism (azoospermia), diabetes mellitus, alopecia, intellectual disability, seizures, and parkinsonism with a typical brain MRI. To conclude, a combination of endocrine abnormalities, including hypogonadotropic hypogonadism and DM, together with alopecia and iron accumulation in the brain and basal ganglia make prominent clues to diagnose WSS.