Sotos syndrome is a rare autosomal dominant congenital developmental disorder characterized by overgrowth with advanced bone age, craniofacial anomalies, developmental delay, and occasional seizures. The disease occurs at an incidence rate of nearly 1 in 14,000 births. The facial gestalt is very characteristic during childhood with macrocephaly, frontal bossing, prognathism, hypertelorism, and antimongoloid slant of the palpebral fissures. With increasing age, the face gradually lengthens, the jaw becomes more prominent, and macrocephaly is no longer pronounced. The hands and feet are usually large. In infancy growth is rapid, but settles down above the >97th centile in early childhood and tends to follow this during childhood. Height and weight tends to normalize in adulthood. Neurological features are variable and include hypotonia and delay in motor and language development, with a tendency for improvement with age. Sotos sysndrome is also frequently associated with brain, cardiovascular, and urinary anomalies and is occasionally accompanied with various malignancies, including acute lymphoblastic leukemia, lymphomas. Wilms tumor, and hepatocarcinoma.

Sotos syndrome is caused by haploinsufficiency of the NSD1 (nuclear receptor SET domain containing gene 1) gene. NSD1 is expressed in the fetal/adult brain, kidney, skeletal muscle, spleen, and the thymus, and faintly in the lung. The gene encodes 2696 amino acids with SET (su(var)3-9, enhancer-of-zeste, trithorax), PHD (plant homeodomain protein) finger, and PWWP (proline-tryptophan-tryptophan-proline) domains, all of which are possibly related to chromatin regulation, and possibly interact with nuclear receptors (Nrs). Among sporadic Sotos syndrome patients examined by direct sequencing, de novo point mutations predicting truncation of the protein and submicroscopic deletions involving the whole of NSD1 were identified. Two-thirds of Sotos syndrome cases showed NSD1 mutations, so haploinsufficiency of NSD1 is suggested to be the major molecular defect in Sotos syndrome.