6. SOTO’S syndrome: A unique cerebral gigantism

Abstract

Soto’s syndrome is a rare genetic disorder caused by a mutation in the NSD1 gene. 95% are sporadic, the rest have Autosomal Dominance pattern of inheritance. In the Japanese population, genetic material is deleted from the region of chromosome 5, containing the NSD1 gene. The NSD1 gene provides instructions for making a protein that is involved in normal growth and development. Excessive physical growth during the first few years of life, macrocrania, mild mental retardation and unusual aggressiveness are the main features of the syndrome. The pathogenesis of this syndrome is not yet fully understood. A 41 year old right handed man was referred for behavioural disorder, eyelid flutter and headaches, and question of seizures. Patient was born full-time after prolonged labour, assisted with forceps. He had cardiac failure at 7 weeks of life, due to Wolff–Parkinson–White syndrome, was treated at SickKids. Tonsillectomy and Adenoidectomy was performed at 4 years, and Orchidectomy for testicular carcinoma at 18 years. Operation for Cholesteatoma was performed due to induced right hearing impairment at 36 years. The patient was diagnosed in early childhood with Soto’s syndrome with autistic spectrum disorder. Methods used to conclude the diagnoses included MRI studies, with EEG’s and Polysomnography. He had global developmental delay with cognitive impairment requiring special education. Patient has mildly dysmorphic features due to macrocrania with anti-mongoloid slant eyes. Diffuse hypotonia with symmetrical deep tendon reflexes, flexor plantars, and apraxic gait are also present. Aggressive behaviour is increasing as he ages. His MRI showed mild ventricular enlargement and sulcal enlargement with cerebellar tonsils of Arnold Chiari type I. The EEG had a generalised irregular spike wave paroxysm with a suggestion of a frontal prominence at 18 years, and then normalized with maturation. The Polysomnography showed a disordered sleep pattern with spontaneous arousals from slow-wave sleep and periodic limb movements. This case of Soto’s syndrome with typical phenotype and neuroimaging is unique for neurophysiologic studies, including several EEGs over four decades showing paroxysmal activity that resolved with cerebral maturation. Global developmental delay with cognitive impairment could be the result of ventricular and sulcal enlargement, and autistic spectrum disorder may be associated with this abnormality. Detailed studies of the mechanisms whereby NSD1 mutation produced the phenotype of cerebral gigantism remain to be analysed. The lack of clarity of how a reduced amount of protein from the NSD1 gene leads to Soto’s syndrome is perhaps one of the biggest questions. Maybe with more potential cases and genetic studies performed, we’ll be able to figure out the exact pathogenesis of the protein involved.