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Extensive Phenotypic Analysis of a Family with Growth Hormone (GH) Deficiency Caused by a Mutation in the GH-Releasing Hormone Receptor Gene¹

Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 468 (I.N., F.D., M.G., S.A.), Centre Hospitalier Universitaire Henri Mondor, 94010 Créteil, France; Service de Pédiatrie (P.T.) and Laboratoire de Radio-Immunologie (F.V.), Hôpital de Montfermeil, 93370, Montfermeil, France; and Service d’Endocrinologie Pédiatrique (I.N.), Hôpital Necker-Enfants Malades, 75743 Paris, France

Address all correspondence and requests for reprints to: Serge Amselem, INSERM U. 468, C.H.U. Henri Mondor, 94010 Créteil, France. E-mail: amselem{at}im3.inserm.fr

GH secretion and release are complex phenomena depending on activation of several genes, including those encoding GH, GHRH, and its receptor (GHRH-R). The GH gene, which is the most extensively analyzed sequence in patients with familial GH deficiency (GHD), represents the main known target of mutations. To test the involvement of the GHRH-R gene in this disease phenotype, we investigated one candidate Tamoulean family originating from Sri Lanka. Two brothers, with extremely short stature (<-4 SD) and no dysmorphy, were diagnosed as having complete GHD, unresponsive to exogenous GHRH and associated with PRL levels within the lower normal range. Magnetic resonance imaging examination showed anterior pituitary hypoplasia with a normal pituitary stalk. Both patients increased their growth rate while under GH therapy. Molecular investigations revealed a homozygous GHRH-R gene mutation that introduces a stop codon at residue 72. This mutation, which predicts a severely truncated receptor lacking the seven membrane-spanning domains, is identical to that recently reported in one Indian Moslem family, raising the possibility of a founder effect. There was no clear evidence for height reduction in the three heterozygous individuals studied. This observation, which underlines the phenotypic criteria associated with a loss of GHRH-R function, raises the question of the frequency of GHRH-R abnormalities among GHD patients.

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