ソトス症候群

Sotos syndrome is a rare autosomal dominant disorder characterized by childhood overgrowth, including tall stature and macrocephaly, distinctive facial appearance, and neuropsychiatric manifestations. These features include intellectual disability and a broad spectrum of behavioral disturbances. Traumatic brain injury (TBI) is also known to cause various neuropsychiatric symptoms, including behavioral disturbances, even in individuals without underlying medical conditions. However, the influence of pre-existing neurodevelopmental disorders such as Sotos syndrome on behavioral outcomes following TBI remains incompletely understood. We report the case of a 35-year-old man with previously undiagnosed Sotos syndrome who developed severe behavioral disturbances following TBI. Based on his history of childhood overgrowth and characteristic dysmorphic facial features, Sotos syndrome was suspected and subsequently confirmed by genetic testing, which demonstrated a heterozygous whole-gene deletion of the causative gene, NSD1. Initial treatment with yokukansan and olanzapine did not improve his symptoms. However, subsequent treatment with valproate and propranolol resulted in marked improvement. The total Neuropsychiatric Inventory Questionnaire (NPI-Q) score decreased from 43 to 15 after one year of treatment. This report suggests that TBI may unmask or exacerbate behavioral disturbances in individuals with underlying neurodevelopmental disorders such as Sotos syndrome. In addition, a combination of valproate and propranolol may represent a potential therapeutic option for managing severe behavioral symptoms following TBI, although further accumulation of cases is required to establish its efficacy.

Sotos syndrome is an overgrowth disorder caused by heterozygous NSD1 variants, partial-gene deletions, or 5q35 microdeletions. Malan syndrome, a phenotypically overlapping condition, results from haploinsufficiency of the NFIX gene due to either heterozygous chromosomal microdeletions involving the 19p13.2 region or heterozygous loss-of-function variants. This multicenter study aimed to characterize the clinical and molecular features of individuals with Sotos and Malan syndromes in Türkiye. We retrospectively analyzed clinical and molecular data from 48 individuals with genetically confirmed Sotos or Malan syndrome across 14 centers. Molecular analyses included whole-exome sequencing, clinical exome sequencing, targeted gene panels, multiplex ligation-dependent probe amplification, and chromosomal microarray analysis. Forty-two individuals were diagnosed with Sotos syndrome and six with Malan syndrome. All exhibited characteristic facial features, and 97.9% had developmental delay or intellectual disability. We identified a total of 38 NSD1 variants, of which 35 were classified as pathogenic or likely pathogenic and three as variants of uncertain significance; notably, 23 of these variants were novel. Three patients carried 5q35 microdeletions, and one had an intragenic deletion involving exons 10-11. Four distinct NFIX variants (two novel) were detected in five patients, and one carried a 19p13.13 deletion encompassing the entire gene. This nationwide study expands the genotype-phenotype spectrum of Sotos and Malan syndromes in Türkiye and supports improved diagnostic and clinical management strategies.

Sotos syndrome is an autosomal dominant genetic disorder that causes an overgrowth of the body characterized by distinctive craniofacial features, excessive growth, and neurodevelopmental delay. We present a 49-year-old man diagnosed with Sotos syndrome and with a previous history of lymphoma in remission who developed a high-grade malignant peripheral nerve sheath tumor (MPNST) affecting the right upper extremity. Due to the tumor recurrence of a high-grade malignant peripheral nerve sheath tumor (MPNST) in the right arm and shoulder, the patient underwent a right shoulder disarticulation. This aggressive clinical course was further complicated by a pathological fracture, persistent local neoplastic disease, and the eventual development of pulmonary lesions radiographically highly suggestive of metastatic disease, though tissue biopsy was not performed. The patient originally refused amputation despite advice for early definitive surgical therapy, which caused the condition to worsen. Palliative radiation therapy, multi-agent chemotherapy, and supportive care for pain and psychological distress were part of the subsequent management. This case underscores the aggressive clinical course and the importance of early diagnosis, prompt surgical intervention, multidisciplinary care, and effective patient counseling.

Simpson-Golabi-Behmel syndrome (SGBS) is an overgrowth syndrome associated with an increased risk of certain malignancies; however, gliomas have not previously been reported in patients with SGBS. Loss-of-function variants in glypican-3 (GPC3) represent the primary molecular mechanism underlying SGBS-related overgrowth and tumorigenesis, although their relationship with gliomas remains unclear. We report a case of an 18-year-old male who had been clinically diagnosed with Sotos syndrome in childhood. He presented with sudden impaired consciousness, and neuroimaging revealed a large tumor in the left occipitoparietal lobe, which was subsequently resected. Histopathological analysis demonstrated a pediatric-type diffuse hemispheric glioma, H3 G34-mutant (CNS WHO grade 4). Next-generation sequencing of peripheral blood DNA identified a germline hemizygous deletion encompassing exons 3-5 of GPC3, leading to a revised diagnosis of SGBS. To our knowledge, this is the first reported case of SGBS associated with a glioma. This case raises the possibility that GPC3 alterations may contribute to gliomagenesis, including in H3 G34-mutant diffuse hemispheric glioma.

[This corrects the article DOI: 10.3389/fped.2023.1184529.].