Partial loss of function of the GHRH Receptor leads to mild Growth Hormone Deficiency

Introduction Recessive mutations in GHRHR are associated with severe isolated GH deficiency (IGHD), with a final height in untreated patients of 130cm±10cm (-7.2±1.6SDS; males) and 114±0.7cm (-8.3±0.1SDS; females). Objective We hypothesised that a consanguineous Pakistani family with IGHD in 3 siblings (2 males, 1 female) would have mutations in GH1 or GHRHR. Results Two novel homozygous missense variants [c.11G>A (p.R4Q), c.236C>T (p.P79L)] at conserved residues were identified in all 3 siblings. Both were absent from control databases, aside from pR4Q appearing once in heterozygous form in the ExAc Browser. The brothers were diagnosed with GHD at 9.8 and 6.0 years (height SDS: -2.24 and -1.23 respectively), with a peak GH of 2.9 μ g/l with low IGF-1/IGFBP3. Their sister presented at 16 years with classic GHD (peak GH <0.1μ g/l, IGF-1<3.3mmol/L) and attained an untreated near-adult height of 144 cm (-3.0 SDS); the tallest untreated patient with GHRHR mutations reported. An unrelated Pakistani female IGHD patient was also compound homozygous. All patients had a small anterior pituitary on MRI. Functional analysis revealed a 50% reduction in maximal cAMP response to stimulation with GHRH by the p.R4Q/p.P79L double mutant receptor, with a 100 fold increase in EC50. Conclusion We report the first co-existence of two novel compound homozygous GHRHR variants in 2 unrelated pedigrees associated with a partial loss of function. Surprisingly, the patients have a relatively mild IGHD phenotype. Analysis revealed that the pP79L mutation is associated with the compromise in function, with the residual partial activity explaining the mild phenotype.