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  • Updated 11.29.2023
  • Released 09.29.2006
  • Expires For CME 11.29.2026

Sotos syndrome



Sotos syndrome is a Mendelian disorder of the epigenetic machinery that is classically characterized by the triad of distinctive craniofacial features, overgrowth, and intellectual disability. NSD1 haploinsufficiency was determined to be the major cause of typical Sotos syndrome. Microdeletions of NSD1 were identified in Japanese Sotos patients whereas intragenic mutations were found in most non-Japanese patients. A Sotos-like presentation can also be associated with a number of other genes, most commonly variants of NFIX (Malan syndrome). The majority of Sotos syndrome cases are sporadic, but a few families with an autosomal dominant transmission have been reported. The clinical phenotypes of Sotos syndrome, Malan syndrome, and Sotos-like syndromes are discussed. In addition, the diagnostic and management guidelines are reviewed.

Key points

• Overgrowth, characteristic facial gestalt, and learning disability or behavioral abnormalities are considered the cardinal clinical criteria of Sotos syndrome.

• Cardiac anomalies, renal anomalies, hypodontia, seizures, or scoliosis are considered as major features.

• Genetic testing to confirm the diagnosis is highly recommended because of the remarkable clinical overlap with other overgrowth syndromes.

NSD1 is the most commonly implicated gene in patients with Sotos-like presentation and should be included in the first step when testing any patient with Sotos syndrome.

Historical note and terminology

Sotos syndrome, historically referred to as cerebral gigantism, has been recognized for over 50 years, since the description of five children with macrocephaly, somatic overgrowth, characteristic facial appearance, and intellectual disability by Juan Sotos and his colleagues (49). Thirty years later, the major diagnostic criteria of this syndrome were established (10). In 2002, the genetic etiology of Sotos syndrome was unraveled in a patient carrying an apparently balanced de novo reciprocal translocation t(5; 8)(q35; q24). Since then, heterozygous inactivating variants of the gene NSD1 (nuclear receptor binding SET domain protein 1) have been identified as a major cause and are identified in about 90% of patients with Sotos-like presentation (22; 26). In 2010, pathogenic variants in NFIX were identified in patients with Sotos-like features and initially referred to as Sotos syndrome 2 (31; 42; 60). Subsequently, homozygous variants in the APC2 gene were detected in two siblings with Sotos-like features (03). This autosomal recessive type was originally known as Sotos 3. Further, DNMT3A, SETD2, and GPC3 gene variants or hypomethylation of KCNQ1OT1 may be responsible for clinical features in a few patients with Sotos-like presentation (05; 34).

Terminology. The Sotos syndrome 1/2/3 nomenclature is now nonpreferred. Instead, Sotos syndrome generally refers to affected individuals with NSD1 pathogenic variants, though this term is also used to describe individuals with a clinical diagnosis in the absence of confirmatory genetic testing. Malan syndrome is the current preferred nomenclature for individuals with Sotos-like phenotype and NFIX pathogenic variants. For optimal clarity, it is appropriate to use nomenclature that includes both the genetic etiology and the clinical phenotype in cases in which both are known, eg, NSD1-associated Sotos syndrome or APC2-associated Sotos-like syndrome.

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