Sotos syndrome is a member of a group of conditions called overgrowth syndromes. In general, these syndromes are often very different from one another, but they all share overgrowth of either the whole body (such as excessive length and weight at birth) or a part of the body (such as abdominal organs or the tongue). Other members of this group include but are not limited to) Beckwith-Wiedemann syndrome, Pallister-Killian syndrome, Proteus syndrome, neurofibromatosis type I (NF1), Weaver syndrome, Simpson-Golabi-Behmel syndrome, Sturge-Weber syndrome, macrocephaly-capillary malformation, and fragile X syndrome.

Fragile X syndrome and NF1 are the most common members of this group, but Sotos is also one of the more common overgrowth conditions (1). It is estimated at 1 birth in 14,000 (2). Thus, while it may be relatively common among the overgrowth syndromes, it is nonetheless a rare condition.

Clinical information

The signs of Sotos syndrome may be evident at birth or on a prenatal ultrasound. Specifically, at birth, infants are often larger than most others of the same sex and gestational age. They may particularly have large heads. A review paper on Sotos syndrome noted that head size at birth is often past the 99th percentile, while length may be ~84th percentile, and weight at ~96th percentile. However, while large size is common, not all newborns with Sotos syndrome will be large.

Other common clinical features of Sotos syndrome are listed below.

Common clinical features of Sotos syndrome

•  Growth (height) may be very rapid in the early years and slow later
•  Tall stature (may normalize in adulthood, especially in females)
•  Frequent upper respiratory infections (including ear infections)
•  Enlarged brain ventricles (visible on a brain scan)
•  A high hairline and sparse hair over the forehead
•  Advanced bone age (bones mature rapidly)
•  Problems breathing at birth or soon after
•  Large size at birth (especially the head)
•  Very large head (macrocephaly)
•  Delayed speech development
•  Delayed motor development
•  Intellectual disability
•  Behavioral problems
•  Early tooth eruption
•  Feeding difficulties
•  Clumsiness
•  Flat feet

People with Sotos syndrome have a similar facial appearance. They tend to have prominent foreheads and eyes that slant downward. Their faces may be triangular, tapering from a large forehead to a prominent chin that may jut forward or be somewhat pointed. They may appear to have wideset eyes, but measurement may show that the distance between their eyes is normal. Their ears may be large. Infants with Sotos syndrome sometimes have rounded faces with very prominent foreheads (for example, see the photo below). As these children get older, their faces become long and relatively narrow (see photo at top right). In addition, many people with Sotos syndrome may develop rosiness over their noses and cheeks.

Cause

Sotos syndrome is associated with the gene NSD1 (3). It can be caused by mutations in NSD1 or by a deletion in the chromosomal region containing it (reviewed in 4). Most cases of Sotos syndrome are sporadic, meaning that they occur without apparently at random and with no known cause. However, a few cases have been reported in families (5-9). In familial cases, the condition is autosomal dominant. This term means that only one copy of a mutated gene is needed to cause the disorder. In the case of Sotos syndrome, the problematic gene is inherited from a parent who also has the disease.

Diagnosis and Testing

Until the identification of the NSD1 gene in 2002 (3), diagnosis of Sotos syndrome was based on clinical features. Today, testing can confirm the diagnosis. The links at the right provide information about testing centers around the world.

A large study performed in 2005 estimated the frequency of different clinical features in people with Sotos syndrome (4). There were 266 patients in the study, and abnormalities in NSD1 had been found in all of them. The study found that the following were present in at least 90% of study subjects:

• Characteristic facial appearance (see above for details)
• Overgrowth (height and/or head circumference at or above the 98th percentile)
• Learning disabilities

These findings are used as informal aids to diagnosis, as there are no formal diagnosis criteria for Sotos syndrome (2). The condition should be suspected in people with the three main features noted directly above this paragraph. As noted, molecular testing can confirm that a person definitely has Sotos syndrome.

Differential Diagnosis

A number of other conditions resemble Sotos syndrome.

Beckwith-Wiedemann syndrome (BWS). BWS is another overgrowth syndrome. Like infants with Sotos syndrome, babies with BWS may be very large at birth. Unlike Sotos syndrome, in some newborns with BWS, intestines or other abdominal organs protrude through the navel. This condition is called omphalocele or exomphalos. It results from rapid fetal growth and a failure of the abdominal wall to fully close during development. Umbilical hernias and other abdominal wall abnormalities also occur in BWS but are are relatively rare in Sotos syndrome.

Simpson-Golabi-Behmel syndrome (SGBS). SGBS is caused by a mutation in the gene GPC3, which controls growth. SGBS is an X-linked recessive condition. This term means that it is passed from mothers to sons via the X chromosome. However, some signs of disease may be seen in female carriers. SGBS shares many features with Sotos syndrome (most importantly, overgrowth and intellectual disabilities). Clinical features of SGBS that are not generally found in Sotos syndrome include extra fingers or toes (polydactyly), extra nipples, and a sunken chest. A test for mutations in the GPC3 can distinguish BWS and Sotos.

Fragile X syndrome. Fragile X syndrome is characterized by intellectual disability (generally moderate in males and mild in females), as well as the long face with a prominent forehead that occur in Sotos syndrome. Other clinical features that are shared with Sotos syndrome include behavior problems and floppiness/hypotonia. Infants with fragile X syndrome generally do no have the sucking/feeding sucking problems that are common in Sotos syndrome. Again, genetic testing can distinguish the two conditions.

Bannayan-Riley-Ruvalcaba syndrome (BRRS). Like Sotos syndrome, BRRS is an overgrowth syndrome. Most patients have a large head/macrocephaly. They may also be tall and have intellectual disabilities and some facial features that also occur in Sotos syndrome (wideset eyes, a large or prominent forehead, and downslanting eyes. People with BRRS tend to develop multiple noncancerous tumors called hamartomas. These growths are not associated with Sotos synrome. In addition, males with BRRS may aso have dark freckle-like areas on the penis. Unlike Sotos syndrome, BRRS patients do not have enlargment of the brain ventricles. This finding is common in Sotos patients.

Other conditions in the differential diagnosis of Sotos syndrome are described in reference 2.

References

1. 1. Baujat G & Cormier-Daire V (2007) Sotos syndrome. Orphanet J Rare Dis 2:36. doi: 10.1186/1750-1172-2-36. Full text on PubMed.
2. 2. Tatton-Brown K et al. (2004) Sotos Syndrome. Updated November 19, 2015. GeneReviews [Internet] Pagon RA et al., editors. Seattle (WA): University of Washington, Seattle; 1993-2016. Full text.
3. 3. Kurotaki N et al. (2002) Haploinsufficiency of NSD1 causes Sotos syndrome. Nature Genet 30(4):365-366. Abstract on Pubmed.
4. 4. Tatton-Brown K et al. (2005) Genotype-phenotype associations in Sotos syndrome: an analysis of 266 individuals with NSD1 aberrations. Am J Hum Genet 77(2):193-204. Full text on Pubmed.
5. 5. de Boer L et al. (2004) Genotype-phenotype correlation in patients suspected of having Sotos syndrome. Horm Res 62(4):197-207. Full text from publisher.
6. 6. Hoglund P et al. (2003) Familial Sotos syndrome is caused by a novel 1 bp deletion of the NSD1 gene. J Med Genet 40(1):51-54. Full text on Pubmed.
7. 7. Opitz JM et al. (1998) The syndromes of Sotos and Weaver: reports and review. Am J Med Genet 79(4):294-304. Abstract on PubMed.
8. 8. Tei S et al. (2006) The first Japanese familial Sotos syndrome with a novel mutation of the NSD1 gene. Kobe J Med Sci 52(1-2):1-8. Full text from publisher.
9. 9. Türkmen S et al. (2003) Mutations in NSD1 are responsible for Sotos syndrome, but are not a frequent finding in other overgrowth phenotypes. Eur J Hum Genet 11(11):858-865. Full text from publisher.
10. 10. Sogaard M et al. (2005) Subtelomeric study of 132 patients with mental retardation reveals 9 chromosomal anomalies and contributes to the delineation of submicroscopic deletions of 1pter, 2qter, 4pter, 5qter and 9qter. BMC Med Genet 6:21. doi: 10.1186/1471-2350-6-21. Full text on Pubmed.
11. 11. Photo by user Wikifan256 and found in the Wikimedia Commons.
12. 12. Türkuçar S et al. (2014) Sotos syndrome: a case report. (Article in Turkish; abstract in English) Turk J Ped Dis 2:94-97. doi: 10.12956/tjpd.2014.52. Full text from publisher.