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 June 7, 2016; expires June 7, 2019

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


The author presents 1 of the uncommon overgrowth/developmental delay/multiple congenital anomalies, Sotos syndrome. Typically, it is characterized by distinctive facial features, macrodolichocephaly, learning disability, and a variable range of associated abnormalities. Atypical patients with normal growth parameters and mild facial features were reported. NSD1 haploinsufficiency was determined to be the major cause of typical and atypical Sotos syndrome. Microdeletions of NSD1 were identified in Japanese Sotos syndrome patients whereas intragenic mutations were found in most non-Japanese patients. The NFIX gene was found in 10% of patients (referred as Sotos-like), and it is also known as Malan syndrome or Sotos 2 syndrome. The majority of cases are sporadic, but a few families have been reported so far, most of whom show an autosomal dominant mode of inheritance. The clinical phenotype of Sotos 1 and Sotos 2 syndrome is discussed. In addition, the diagnostic and management guidelines are reviewed.

Key points


• Overgrowth, typical facial gestalt, and learning disability 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.


• The NDS1 gene is the most common implicated in Sotos syndrome patients (known as Sotos 1). Microdeletions of the NSD1 gene are more prevalent in Japanese patients whereas intragenic mutations are more common in non-Japanese. Thus, genetic testing for NSD1 should be taken as a first step when testing any patient with Sotos syndrome.


• Sotos syndrome patients negative for NSD1 should be tested for the NFIX gene, as haploinsufficiency or loss-of-function mutation in the NFIX gene have been found in patients with Sotos 2 syndrome.


• Unexpectedly, homozygous mutation of the 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 45 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 gene for Sotos syndrome was identified 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 approximately 90% of patients and is considered as with Sotos 1 syndrome (Imaizumi et al 2002; Kurotaki et al 2002). In 2010, NFIX mutations were identified in patients with Sotos-like features and termed Sotos 2 syndrome or Malan syndrome (Malan et al 2010; Priolo et al 2012; Yoneda et al 2012). Further, GPC3 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). Homozygous mutation in the APC2 gene was detected in 2 siblings with Sotos-like features (Almuriekhi et al 2015).

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