Sotos syndrome

Abstract

Sotos syndrome is an overgrowth condition characterized by cardinal features including excessive growth during childhood, macrocephaly, distinctive facial gestalt and various degrees of learning difficulty, and associated with variable minor features. The exact prevalence remains unknown but hundreds of cases have been reported. The diagnosis is usually suspected after birth because of excessive height and occipitofrontal circumference (OFC), advanced bone age, neonatal complications including hypotonia and feeding difficulties, and facial gestalt. Other inconstant clinical abnormalities include scoliosis, cardiac and genitourinary anomalies, seizures and brisk deep tendon reflexes. Variable delays in cognitive and motor development are also observed. The syndrome may also be associated with an increased risk of tumors. Mutations and deletions of the NSD1 gene (located at chromosome 5q35 and coding for a histone methyltransferase implicated in transcriptional regulation) are responsible for more than 75% of cases. FISH analysis, MLPA or multiplex quantitative PCR allow the detection of total/partial NSD1 deletions, and direct sequencing allows detection of NSD1 mutations. The large majority of NSD1 abnormalities occur de novo and there are very few familial cases. Although most cases are sporadic, several reports of autosomal dominant inheritance have been described.

Malan syndrome: Sotos-like overgrowth with de novo NFIX sequence variants and deletions in six new patients and a review of the literature

“…Overgrowth is therefore often postnatal in onset and is typically less marked than in Sotos syndrome with a median height in Malan syndrome of 2.0 SD above the mean (range À0.5 to þ 3.8 SD) compared to a median of 4 þ 2.5 SD in Sotos syndrome (Table 3). [12][13][14] Median head circumference is 2.3 SD above the mean (range À0.7 to 3.9 SD) and may also be more mildly increased than in Sotos syndrome where it is 4 þ 2.5 SD. Median weight is 0.6 SD above the mean (range À0.9 to þ 2.9 SD).…”

Epigenetic inactivation of the Sotos overgrowth syndrome gene histone methyltransferase NSD1 in human neuroblastoma and glioma

“…cancer ͉ DNA methylation ͉ epigenetics ͉ histone ͉ overgrowth S otos syndrome is an autosomal dominant condition characterized by physical overgrowth during the first years of life, a distinctive facial appearance, and learning disability (1, 2) with an increased incidence of malignant neoplasms (1)(2)(3)(4). The distinctive head shape and size has led to Sotos syndrome sometimes being called cerebral gigantism (1,2).…”

“…The distinctive head shape and size has led to Sotos syndrome sometimes being called cerebral gigantism (1,2). Mutations in the nuclear receptor SET [su(var)3-9, enhancer-of-zeste, trithorax] domain containing protein-1 (NSD1) gene are found in patients exhibiting the clinical symptoms of Sotos syndrome (1,2,5).…”

“…There are occasional individuals with NSD1 defects that overlap clinically with Sotos syndrome and other conditions such as Weaver syndrome (6,7). The vast majority of NSD1 mutational mechanisms, including truncating, missense, and splice-site mutations and deletions, result in loss of function of the NSD1 protein (1,2).…”

“…There is growing evidence that deregulation of SET domain-containing proteins, such as NSD1, has an important role in cellular transformation (11), with the leukemia-translocated H3-K4 and H3-K36 histone methyltransferases hDOT1L and MLL, respectively, being further examples (12,13). The case for NSD1 is even more interesting because its genetic disruption in Sotos syndrome is associated with an elevated risk of cancer (1)(2)(3)(4), as occurs with other childhood overgrowth conditions such as BeckwithWiedemann (14). Because patients with NSD1 germ-line genetic disruption have an increased risk of developing malignancy before adulthood, including neuroblastoma, Wilms tumors, and hematological malignancies, a tumor-suppressor function for NSD1 might be proposed.…”