Abstract

Sotos syndrome is a genetic disorder resulting from heterozygous pathogenic variants or deletions in the nuclear receptor-binding SET domain protein 1 (NSD1) gene. It is characterized by prenatal and postnatal overgrowth, macrocephaly, distinctive craniofacial features, learning disability, and advanced bone maturation. In contrast, Reverse Sotos syndrome, arises from duplications within the NSD1 gene, presenting with an opposite clinical phenotype, including microcephaly, developmental delay, short stature and delayed bone maturation. To date, the reverse clinical phenotype associated with the 5q35.2q35.3 microduplication encompassing the NSD1 gene has been reported in 43 cases. We present a novel case of a 4-year-11-month-old patient with a 5q35.2q35.3 duplication involving the NSD1 gene. The patient, exhibited clinical features of microcephaly, short stature, low-normal weight, delayed bone age, developmental delay, attention deficit hyperactivity disorder, alongside normal routine biochemical tests, nutritional parameters, and insulin-like growth factor-1 levels. Chromosomal microarray analysis (CMA) identified a 714.1 kb duplication in the 5q35.2q35.3 region, including NSD1.  This case underscores the significance of NSD1 gene dosage alterations in manifesting a reverse clinical phenotype typified by microcephaly and short stature. Furthermore, it highlights the utility of CMA as a robust diagnostic tool for detecting microrearrangements and guiding clinical evaluation.