Sotos syndrome is a relatively common neurologic disorder characterized by prenatal and postnatal overgrowth, advanced bone maturation, large skull with acromegalic features, and significant developmental delay.  Most cases are sporadic, but autosomal dominant inheritance has been suggested in some instances and autosomal inheritance in a few rare instances.  Reports of balanced translocations have pointed to several chromosomal sites as the location of a gene responsible for the syndrome.  One of these has led to the identification of mutations of a nuclear hormone receptor cofactor as a major cause of this syndrome.

Kurotaki et al analyzed DNA from a patient with a de novo translocation 46,XX,t(5;8)(q35;q24.1) that had been reported previously by Imaizumi et al.  From analysis of a series of overlapping clones, a contig, that covered the break point, they identified a partial sequence that corresponded to a gene originally cloned in mice, NSD1.  They then isolated and characterized the human NSD1 showing that it encoded a protein of 2,696 amino acids that is expressed in many tissues including fetal brain, skeletal muscle and kidney, and that the 5q35 breakpoint is located within NSD1. 

The group next analyzed DNA from 38 patients with the clinical diagnosis of Sotos syndrome.  De novo point mutations that would predict truncated gene products with loss of function were identified in four individuals.  Fluorescent in situ hybridization (FISH) analysis revealed a common 2.2 Mb deletion in 18 and a smaller deletion in one of 30 patients in whom a suitable chromosomal spread was available.  These deletions included the entire NSD1 gene.  In total, a loss of function mutation or a deletion of NSD1 was found in 77% of patients implicating haploinsufficiency of NSD1 as a cause of Sotos syndrome. 

NSD1 is thought to act as a co-activator or co-repressor of nuclear hormone receptors, such as the androgen receptor, depending on the promoter context of the target gene and the cellular context.  In other words, in one cell type NSD1 may interact with a combination of regulatory factors unique to the cell type to activate a target gene, whereas it may interact with another set of factors to inhibit expression of target genes in another cell type.  The mutations thus alter expression of target genes in relevant tissues.

Clinically, the authors state that the identification of a deletion or mutation of this mutated gene on chromosome 5 will sometimes help in the diagnosis of Sotos syndrome.  Investigatively, the knowledge reported in this article will eventually shed light on some of the underlying mechanisms producing human mental retardation and physical growth.

Imaizumi K et al. Sotos syndrome associated with a de novo balanced reciprocal translocation t(5;8)(q35;q24.1). Am J Med Genet 107:58-60, 2002.

Kurotaki N et al. Haploinsufficiency of NSD1 causes Sotos syndrome. Nat Gen 30:365-366, 2002.

First Editor’s Comments:  Sotos syndrome has been considered to be a relatively heterogeneous entity. The identification of the responsible gene(s) will undoubtedly lead to a better definition of the syndrome and a better understanding of the features observed. Sotos syndrome can now be added to the growing list of disorders with microdeletions in which fluorescent probes are available to identify affected individuals.

In the last few years, identification of individuals with translocations has been instrumental in identifying the genes responsible for many genetic disorders. Sotos syndrome has been considered to be sporadic, even though there were a few reports of parent/child involvement. This discovery clearly confirms that an abnormality in only one allele leads to the syndrome. As in other microdeletions, the size of the deletion may indicate how severely an individual is affected.

Judith G. Hall, OC, MD

Second Editor’s Comment:  The results reported in this paper argue strongly that Sotos syndrome is caused by a partial loss of NSD1 function.  The range of nuclear receptors whose action is affected by NSD1 is not known, nor are the target genes whose level of expression are influenced by NSD1.  Given the overgrowth features of Sotos syndrome, one would conclude that the relevant genes are involved in controlling growth and maturation, probably at a very basic level.  Moreover, one would expect that the mutations lead to loss of co-activation of growth inhibiting genes, loss of repression of growth promoting genes, or some combination of the two.  Questions still remain regarding which cell types are involved.  NSD1 is known to be expressed in the fetal brain, which presumably explains the CNS manifestations, but the cells responsible for the skeletal features are still not known.

William A. Horton, MD