Sotos syndrome

Sotos syndrome is inherited in an autosomal dominant manner. Approximately 95% of affected individuals have the disorder as a result of a de novo pathogenic NSD1 variant or a deletion encompassing NSD1, while about 5% have an affected parent. Each child of an affected individual has a 50% risk of inheriting the pathogenic variant. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

Sotos syndrome is diagnosed primarily by molecular genetic testing, as no formal clinical diagnostic criteria are established. A disorder-specific DNA methylation signature in peripheral blood leukocytes has been identified and may support diagnostic clarification when molecular testing is inconclusive or identifies a variant of uncertain significance.

Main differential diagnoses include:

• EZH2-related Weaver syndrome: pre- and postnatal overgrowth with variable intellectual disability, advanced bone age, scoliosis and joint hypermobility; distinguishable from Sotos syndrome between ages 1–3 years by round face shape, ocular hypertelorism, a chin that appears “stuck on” with a horizontal crease, camptodactyly/contractures and a hoarse, low-pitched cry in infancy; EZH2.
• Malan syndrome: dolichocephaly, prominent forehead and downslanting palpebral fissures with scoliosis and increased childhood height that overlap markedly with Sotos syndrome; distinguished by more frequent ophthalmic abnormalities and by tall stature being less common in older children and adults; NFIX.
• Tatton-Brown-Rahman syndrome (DNMT3A-related ): overgrowth, variable intellectual disability, joint hypermobility and scoliosis; distinguished from Sotos syndrome by a round face with coarse features, prominent central incisors, narrow palpebral fissures, thick low-set eyebrows and a tendency to overweight/obesity; DNMT3A.

• Establishing the diagnosis: confirming a molecular cause ends the diagnostic odyssey, secures the clinical picture and provides a basis for prognostic counselling.
• Specific and individualised surveillance: a confirmed molecular diagnosis enables condition-specific surveillance and clinical monitoring for evolving manifestations and is a prerequisite for targeted medical care, the scope and timing of which are determined by the treating physicians in consultation with the affected individual.
• Family member testing: identification of the familial pathogenic variant enables predictive testing of at-risk relatives and supports informed reproductive planning.

• Ocansey S, Cole TRP, Rahman N, Tatton-Brown K. Sotos Syndrome. 2025 Jun 5. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. PMID: 20301652. Available from:
• Testa B, Conteduca G, Grasso M, Cecconi M, Lantieri F, Baldo C, et al. Molecular Analysis and Reclassification of NSD1 Gene Variants in a Cohort of Patients with Clinical Suspicion of Sotos Syndrome. Genes. 2023;14(2). doi: 10.3390/genes14020295. PMID: . PMCID: PMC9956575.
• Tatton-Brown K, Douglas J, Coleman K, Baujat G, Cole TR, Das S, et al. Genotype-phenotype associations in Sotos syndrome: an analysis of 266 individuals with NSD1 aberrations. American journal of human genetics. 2005;77(2):193-204. doi: 10.1086/432082. PMID: . PMCID: PMC1224542.