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  • Updated 06.17.2020
  • Released 09.29.2006
  • Expires For CME 06.17.2023

Sotos syndrome


This article includes discussion and comparison between Sotos 1 and Sotos 2 (also called Malan syndrome). The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.


The author presents one of the Mendelian disorders of the epigenetic machinery that is characterized by overgrowth and intellectual disability, Sotos syndrome. Typically, it is characterized by distinctive facial features, macrodolichocephaly, learning disability, and a variable range of associated abnormalities. 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. Patients with few features of Sotos syndrome are known as Sotos-like, NFIX gene was found in 10% of patients (referred as Sotos-like) and those patients harboring NFIX gene mutations are also known as Malan syndrome or Sotos 2. Mutations of the DNMT3A and SETD2 genes were also identified in few patients with Sotos-like syndrome. The majority of cases are sporadic, but few families with an autosomal dominant mode of inheritance have been reported. The clinical phenotypes of Sotos 1, Sotos 2, Sotos 3, and Sotos-like syndrome 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 cardinal clinical criteria of Sotos syndrome.

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

• Genetic testing is mandatory for the diagnosis because of the remarkable clinical overlap with other overgrowth syndromes.

NSD1 gene is the most common implication in Sotos patients and should be taken as a first step when testing any patient with Sotos syndrome.

• Negative Sotos patients for NSD1 should be tested for NFIX gene.

• Unexpectedly, homozygous mutation of APC2 gene was described in two Egyptian siblings with Sotos-like features. APC2 is found to be a crucial downstream gene of NSD1.

• Few patients with heterozygous mutations in SETD2 and DNMT3A were identified in Sotos-like patients.

Historical note and terminology

Sotos syndrome or cerebral gigantism has been recognized for over 50 years, since the description of five children with macrocephaly, somatic overgrowth, characteristic facial appearance, and mental retardation by Juan Sotos and his colleagues (43). Thirty years later, the major diagnostic criteria of this syndrome were established (09). 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, haploinsufficiency of NSD1 gene (nuclear receptor binding SET domain protein 1) has been identified as a major causative role in about 90% of patients and considered as Sotos 1 (18; 22). In 2010, patients with NFIX mutations were identified in patients with Sotos like features and termed as Sotos 2 or Malan syndrome (26; 36; 54). Nevertheless, homozygous mutation in the APC2 gene was detected in two siblings with Sotos-like features (03). This autosomal recessive type is known as Sotos 3. Further, DNMT3A, SETD2, and GPC3 gene mutations or hypomethylation of KCNQ1OT1 may be responsible for clinical features in a few patients with Sotos-like features (Baujat et al 2005; 28).

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