Familial dwarfism due to a novel mutation of the growth hormone-releasing hormone receptor gene

Isolated growth hormone (GH) deficiency (IGHD) is a rare cause of short sta ture. The same mutation of the gene encoding the growth hormone-releasing h ormone receptor (GHRHR) has been identified as the basis for IGHD in three families from the Indian subcontinent. The prevalence and heterogeneity of defects in the GHRHR gene are not known. Twenty-two dwarf members of a large, extended kindred containing at least 1 05 affected members with autosomal recessive short stature underwent extens ive endocrine evaluation, which confirmed markedly reduced or undetectable serum concentrations of GH that did not increase in response to different s timuli. DNA sequences of the 13 exons and intron-exon boundaries of the GHR HR gene were determined in an index patient. A novel homozygous 5' splice s ite mutation (G-->A at position +1) in IVS1 was found. Thirty of the affect ed subjects tested were homozygous for this mutation, and 64 clinically una ffected patients were either heterozygous for the mutation (n = 41, includi ng 9 obligate carriers) or homozygous for the wild-type sequence (n = 23). We describe a novel mutation in the GHRHR gene as cause of dwarfism in the largest kindred with familial IGHD described to date.