Endocrine Abstracts

Introduction: Release of GH by the somatotroph cells of the anterior pituitary is stimulated by GHRH. GHRH acts via its transmembrane receptor, GHRHR, a G-protein coupled receptor that stimulates protein kinase A. Recessive mutations in GHRHR are associated with severe isolated GH deficiency (IGHD) with a final height in untreated patients between 130±10 cm (−7.2±1.6 SDS) and 114±0.7 cm (−8.3±0.1 SDS) in males and females respectively.

Objective: We hypothesised that a consanguineous Pakistani family with IGHD in three siblings (two males, one female) would have mutations in GH1 or GHRHR.

Methods: PCR amplification and direct sequencing analysis were used to screen both genes.

Results: In all three siblings we identified two novel homozygous missense mutations (c.11G>A (p.R4Q), c.236C>T (p.P79L)) absent from 200 Pakistani controls, in a conserved region of the extracellular domain of GHRHR, predicted to affect protein folding. The brothers were diagnosed with GHD at the age of 9.8 and 6.0 years with a height SDS of −2.24 and −1.23 respectively. Their peak GH to glucagon stimulation was 2.9 μg/l with low IGF1 and IGFBP3. Their sister first presented at the age of 16 years with untreated GHD (peak GH <0.1 μg/l, IGF1<3.3 mmol/l). She had classic GHD with abdominal fat deposition, a high pitched voice, frontal bossing and had a small anterior pituitary on MRI. Surprisingly, she attained an untreated final height of 144 cm (−3.0 SDS), which is the tallest untreated height reported to date. Their mother was compound heterozygous for both mutations; paternal DNA is currently unavailable. Screening of GH1 revealed no mutation.

Conclusion: We report for the first time to our knowledge the presence of two novel homozygous mutations in GHRHR. Contrary to previous reports the phenotype in this family appears to be relatively mild, despite the presence of the two mutations in the same gene.