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Familial Dwarfism due to a Novel Mutation of the Growth Hormone-Releasing Hormone Receptor Gene¹

Division of Endocrinology, Departments of Medicine (R.S., M.A.L.) and Pediatrics (M.A.L.) The Johns Hopkins University School of Medicine, Baltimore Maryland 21287; Unit of Endocrine Genetics (C.Y.H, R.G.G., S.P.A.T.), University of São Paulo, São Paulo, Brazil 01246-903; Division of Endocrinology (M.H.A.-O., A.H.O.S., M.M.C.), Federal University of Sergipe, Aracaju Brazil 49060-100; Department of Pediatrics (J.A.P., M.P.), Vanderbilt University, Nashville, Tennessee 37232; Division of Endocrinology (H.G.M., G.B.), Northwestern University, Chicago, Illinois 60611

Address correspondence and requests for reprints to: Dr. Roberto Salvatori, Division of Endocrinology, The Johns Hopkins School of Medicine, Blalock 904, 600 N. Wolfe Street, Baltimore, Maryland 21287. E-mail: salvator{at}jhmi.edu

Isolated growth hormone (GH) deficiency (IGHD) is a rare cause of short stature. The same mutation of the gene encoding the growth hormone-releasing hormone 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 105 affected members with autosomal recessive short stature underwent extensive endocrine evaluation, which confirmed markedly reduced or undetectable serum concentrations of GH that did not increase in response to different stimuli.

DNA sequences of the 13 exons and intron-exon boundaries of the GHRHR gene were determined in an index patient. A novel homozygous 5' splice site mutation (GA at position +1) in IVS1 was found. Thirty of the affected subjects tested were homozygous for this mutation, and 64 clinically unaffected patients were either heterozygous for the mutation (n = 41, including 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.

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