medwireNews: Researchers report mutations in the growth hormone releasing hormone receptor gene (GHRHR) in patients with isolated growth hormone deficiency (IGHD) but a relatively mild phenotype.

Mehul Dattani (UCL Institute of Child Health, London, UK) and study co-authors identified the two novel compound homozygous mutations in three children in a consanguineous family of Pakistani origin. They also identified the mutations in a second patient from an unrelated consanguineous family from the same community, implying a founder effect.

All patients had anterior pituitary hypoplasia, yet restricted growth in the first family was not identified until the ages of 8.5 years in one boy and 6 years in another. By this age, their respective height standard deviation scores (SDSs) were –1.91 and –1.21, with growth velocities of 2.3 cm/year and 3.6 cm/year. The peak stimulated GH value was 2.9 µg/L for both boys.

The boys had a sister with the same mutations, but her IGHD was not identified until the age of 16 years, at which point her height was 144 cm and her height SDS was –3.0.

“Compared to the mean of ~114cm in the literature, this is the tallest untreated height reported for a patient with a GHRHR mutation to our knowledge”, write the researchers in The Journal of Clinical Endocrinology & Metabolism.

Both boys came to earlier medical attention with micropenis, bilateral undescended testes and hypoplastic scrotum. “The mechanism underlying this presentation is unknown”, say Dattani and team.

Mutational analysis revealed that all three siblings were homozygous for a novel missense variant in exon 1 of GHRHR, which resulted in arginine being replaced by glutamine (p.R4Q). They were also homozygous for a missense mutation in exon 3, in which proline was replaced by leucine (p.P79L).

However, only one of these mutations affected protein function: p.P79L, which caused a reduction in activity to 55.3% of that of wild-type GHRHR.

“All previously reported GHRHR mutations have been associated with complete loss of function”, the researchers note.

The p.R4Q variant had no effect on GHRHR function, and although the researchers say they cannot rule out it contributing to the patients’ phenotypes, they believe the symptoms are probably caused by the p.P79L variant alone.

“We show here the importance of performing functional studies in this highly unusual scenario where two variants are present in compound homozygosity in affected individuals”, they say.

With recombinant human GH treatment, the boys achieved adult height SDSs of –0.65 and +1.02 by adulthood, and their sister achieved a slight improvement, to –2.70. The unrelated patient was diagnosed with IGHD at the age of 6 years, and, with treatment, achieved an adult height SDS of +0.66.

By Eleanor McDermid

J Clin Endocrinol Metab 2016; Advance online publication

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