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A rare genetic overgrowth syndrome characterized by a typical facial appearance, overgrowth with macrocephaly and variable intellectual impairment.
ORPHA:821Classification level: Disorder
Prevalence at birth is estimated at 1/14,000.
Excessive growth is evident across life, especially in childhood, and can manifest since fetal life., with final adult height beyond or in the upper part of the normal ranges. Macrocephaly is usually striking and disproportioned with respect to height. The distinct facial appearance is most easily recognized in early childhood (long narrow face, flushed cheeks, prominent forehead with frontotemporal hair scarcity, down-slanting palpebral fissures, hypertelorism, a high arched palate, and pointed chin). Sotos syndrome is associated with mild to severe intellectual disability as well as a wide spectrum of behavioral disorders. Developmental milestones are commonly delayed. Additional features may include in the neonatal period hypotonia and poor feeding and subsequently advanced bone age, scoliosis, prognathia, premature dental eruption, large hands and feet. Seizures and electroencephalogram abnormalities are common. Less common features are conductive hearing loss, and cardiac and genitourinary anomalies. Cancer predisposition is debated: the increased risk, if any, appears to be low.
Sotos syndrome is caused by mutations or microdeletions in the NSD1 gene (5q35) in more than 95% of cases. NSD1 is involved in normal growth and development. Biallelic mutations in the APC2 gene (19p13.3) have also been reported in a few cases.
The diagnosis is based on the major clinical manifestations (characteristic facial features, learning disability, and overgrowth). It can be confirmed by molecular genetic testing of the causative genes. Overlap with other overgrowth syndromes may complicate diagnosis.
The differential diagnosis should include Malan syndrome, Simpson-Golabi-Behmal syndrome, Weaver syndrome, Tatton-Brown syndrome, Bannayan-Riley-Ruvalcaba syndrome, Fragile X syndrome and megalocephalic syndromes associated with mutations in the PI3K-AKT-mTOR pathway. A Sotos-like phenotype has been reported in patients with SETD2 mutations.
Prenatal diagnosis is possible if the disease-causing mutation has been identified in the family or if there is the strong suspicion of the condition (e.g. macrocephaly).
Sotos syndrome follows an autosomal dominant pattern of inheritance in the rare familial cases associated with NSD1; genetic counseling should be offered to affected individuals informing them that, for every pregnancy, there is a 50% risk of transmitting the disorder to offspring. The vast majority of patients have de novo mutations. In these cases, risk of recurrence is very low.
Management and treatment
There is no specific treatment for the syndrome. Management of Sotos syndrome requires a multidisciplinary approach.
Sotos syndrome shows a wide spectrum of intellectual impairment, with functioning from fully independent to fully dependent. Affected individuals are generally healthy with few medical issues.
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