Overview
Sotos syndrome is a childhood growth disorder characterized by macrocephaly, specific facial features, mental retardation, and often advanced bone age. In 75-90% of cases, it is caused by pathogenic variants in the NSD1 gene, with the type of genetic mutation varying regionally. The prevalence is between 1:10,000 and 1:50,000.
Symptoms
Sotos syndrome is an overgrowth syndrome of childhood. The main symptoms are:
- Macrocephaly
- Distinctive craniofacial features: long and narrow head (dolichocephalic); high, broad forehead with a receding hairline, especially at the sides; prominent, pointed chin; pointed, high palate
- Appearance of wide-set eyes with eyelid axes that slope downwards
- Mild intellectual disability (IQ average 76)
- Advanced bone age and normal height in adulthood.
- Large hands and feet
- Hyperextensible joints
Feeding problems are common in infancy. About 50% of the children have seizures, and about half of them occur when they have a fever. Congenital malformations such as heart defects are rare. A slightly increased tumor rate has been reported, involving various tissues. Increased anxiety, hyperactivity and aggressiveness are often described.
Cause
In 75-90% of cases, Sotos syndrome is caused by nucleotide alterations or deletions in the NSD1 gene (nuclear receptor-binding SET domain-containing protein 1) in 5q35, with 60 to 80% of patients in Central Europe and the USA carrying nucleotide changes and approximately 10% carrying deletions.In Japanese patients, microdeletions are causal in over 50% of cases.
Frequency
The frequency of Sotos syndrome is estimated at 1:10,000 to 1:50,000. The recurrence risk for siblings is low, as the nucleotide changes or deletions usually arise de novo.
Differential Diagnosis
Weaver syndrome, a rare autosomal dominant disorder characterized by tall stature, variable intellectual disability, and characteristic facial dysmorphism, could be considered as a possible differential diagnosis. Pathogenic variants in the EZH2 gene (enhancer of zeste, Drosophila, homolog 2; OMIM 601573) are responsible for the majority of cases of Weaver syndrome. However, genetic heterogeneity cannot be ruled out.
References
Lane & Freeth 2019, Chromatin Signaling and Neurological Disorders, Vol 7, pp. 219 / Tatton-Brown et al., Sotos Syndrome. 2004 Dec 17 [Updated 2019 Aug 1]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021 / Imagawa et al. 2017, Hum Mutat 38:637 / Leventopoulos et al. 2009, Pediatr Neurol 40:357 / Tatton-Brown et al. 2007, Eur J Hum Genet 15:264 / Baujat et al. 2007, Orphanet J Rare Dis 2:36 / Visser et al. 2005, Am J Hum Genet 76:52 / Rio et al. 2003, J Med Genet 40:436 / Kurotaki et al. 2002, Nat Genet 30:365
