ESPE Abstracts

Background: Isolated GH deficiency (IGHD) may be due to several different causes. Mutations in the GHRH receptor (GHRHR) gene are a relatively rare cause of IGHD.

Objective and hypotheses: To understand the molecular cause of severe short stature in a large highly consanguineous family with IGHD.

Method: Affected patients were evaluated for GH secretion and other anterior pituitary function. Anterior pituitary size was measured using magnetic resonance imaging (MRI). Homozygosity mapping was performed on two affected and one unaffected member from subfamily-1 and subfamily-2. A shared homozygous region overlapping between affected members from both subfamilies and absent in the unaffected individuals was found on chromosome 7. This region contained the GHRHR gene which was subsequently sequenced. Sequence analysis of the whole GHRHR coding regions and the intron–exon boundaries from peripheral DNA showed a novel homozygous missense mutation in exon-4 of GHRHR gene in two affected patients from each subfamily.

Results: The maximum stimulated serum GH peak was 1.01 μg/l with serum IGF1 and IGFBP3 levels <2 SDS in all affected members. Eight subjects (five from subfamily-1 and three from subfamily-2) were homozygous for a novel missense mutation in the coding sequence of exon-4 (p.C64G). The parents and two unaffected from each subfamily were heterozygous Evaluation of anterior pituitary with MRI showed marked anterior pituitary hypoplasia in affected subjects from subfamily-1 whereas normal anterior pituitary size in the subfamily-2. In addition basal IGF1 levels of subjects from subfamily-1 with AHP were lower than those of the subfamily-2.

Conclusion: We describe a novel mutation in the GHRHR in a large consanguineous family with IGHD. The variability between the AP sizes showed that phenotypic expression of GHRHR gene mutations can be quite different even in same family members carrying the identical mutation.