• familial Sotos syndrome
• NSD1

Sotos syndrome (SS) or cerebral gigantism (OMIM *117550) is characterised by excessive growth, advanced bone age, typical facial gestalt, and developmental delay.^1,2 In infancy growth is rapid, but settles down above the >97th centile in early childhood^3,4 and tends to follow this during childhood. The adult height remains close to normal.⁴ The hands and feet are large. The facial gestalt is very characteristic during childhood with macrocephaly (>97th centile), 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.^5,6 Neurological features are variable and include hypotonia and delay in motor and language development, with a tendency for improvement with age.^1,2,5–9 Familial SS is rare. Only 17 families have been reported, most of which show an autosomal dominant mode of inheritance.^5,6,10–19

Recent advances have shown a molecular genetic basis for sporadic SS. Initially, two SS patients carrying de novo balanced translocations suggested 5q35 as a possible locus for the SS gene.^20,21 Subsequently, the NSD1 gene was isolated from the 5q35 breakpoint of the patient with t(5;8)(q35;q24.1) by positional cloning.^22,23NSD1 has an open reading frame of 8088 bp and consists of at least 23 exons (GenBank accession No AF395588). NSD1 is expressed in the fetal/adult brain, kidney, skeletal muscle, spleen, and the thymus, and faintly in the lung.²² 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).²² Among 42 sporadic SS patients examined by direct sequencing, altogether four de novo point mutations predicting truncation …