Sotos syndrome

Ghada M H Abdel-Salam MD (Dr. Abdel-Salam of the National Research Centre in Cairo, Egypt, has no relevant financial relationships to disclose.)
Harvey B Sarnat MD FRCPC MS, editor. (

Dr. Sarnat of the University of Calgary has no relevant financial relationships to disclose.

Originally released September 29, 2006; last updated April 4, 2017; expires April 4, 2020

This article includes discussion of Sotos syndrome, cerebral gigantism, Sotos 1, Sotos 2 or Malan syndrome, Sotos 3, and Sotos-like. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.


The author presents one of the overgrowth/developmental delay/multiple congenital anomalies that is caused by histone methylation machinery defect, 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 while 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 Sotos-like patients. The majority of cases are sporadic, but a few families that showed 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.


• Heterozygous mutations in SETD2 and DNMT3A were identified in Sotos-like patients.


• Unexpectedly, homozygous mutation of APC2 gene was described in 2 Egyptian siblings with Sotos-like features. APC2 is found to be a crucial downstream gene of NSD1.

Historical note and terminology

Sotos syndrome or cerebral gigantism has been recognized for over 50 years since the description of 5 children with macrocephaly, somatic overgrowth, characteristic facial appearance, and mental retardation by Juan Sotos and his colleagues (Sotos et al 1964). Thirty years later, the major diagnostic criteria of this syndrome were established (Cole and Hughes 1994). 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 (Imaizumi et al 2002; Kurotaki et al 2002). In 2010, patients with NFIX mutations have been identified in patients with Sotos like features and termed as Sotos 2 or Malan syndrome (Malan et al 2010; Priolo et al 2012; Yoneda et al 2012). Nevertheless, homozygous mutation in the APC2 gene was detected in 2 siblings with Sotos-like features (Almuriekhi et al 2015). 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 some patients with Sotos-like syndrome (Baujat et al 2005; Mayo et al 2012).

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