Endocrine Abstracts

JOINT3674

Background: Growth hormone secretagogue receptor (GHSR) mutations are implicated in growth disorders due to disrupted growth hormone (GH) regulation. We describe three pediatric cases with short stature, all carrying the same genetic variant in GHSR (c.422G>T; p.Arg141Leu). This variant, classified as a variant of uncertain significance (VUS), is suspected to have clinical relevance, particularly in cases from a geographically clustered region with consanguineous backgrounds and consistent phenotypic features of partial growth hormone deficiency (GHD).

Cases and Clinical Details: We evaluated three unrelated consanguineous cases from nearly the same geographic area within the United Arab Emirates:

• Case 1: 4-year-old female, birth weight 3.2 kg, height SDS -2.5, weight SDS -2.97. Bone age lagged at -1.24 SDS. Arginine-stimulated peak GH level was 6.71 ng/ml. Serum IGF-1 was 57 ng/ml, and IGFBP-3 was 1,767 ng/ml. NGS stature panel revealed a heterozygous GHSR c.422G>T variant. MRI of the sella showed a small anterior pituitary gland.

• Case 2: 7-year-old male, birth weight 3.2 kg, height SDS -2.42, weight SDS -2.4. Bone age lagged at -1.52 SDS. Peak GH with arginine stimulation was 6.78 ng/ml. IGF-1 was 31.8 ng/ml, and IGFBP-3 was 1,847 ng/ml. The stature panel identified a homozygous GHSR c.422G>T variant. MRI revealed a small anterior pituitary.

• Case 3: 9-year-old male, birth weight 3.2 kg, height SDS -2.87, weight SDS -3.13. Bone age lagged at -1.87 SDS. Peak GH level was 2.95 ng/ml. IGF-1 was 42.1 ng/ml, and IGFBP-3 was 2,486 ng/ml. A homozygous GHSR c.422G>T variant was identified. MRI of the sella also showed anterior pituitary hypoplasia.

Results: All three patients exhibited features of isolated partial GHD, with suboptimal peak GH responses on stimulation testing despite low-normal IGF-1 and IGFBP-3 levels. The shared GHSR mutation (p.Arg141Leu), identified as autosomal dominant or recessive, may contribute to impaired GH axis regulation. The small anterior pituitary volumes in all cases suggest a structural component related to the variant’s pathogenicity.

Conclusion: The recurrent GHSR c.422G>T (p.Arg141Leu) variant in patients from nearly the same geographic area with consistent phenotypic presentations highlights a potential disease-causing role. While classified as a VUS, our findings support further investigation of its contribution to partial GHD. Longitudinal follow-up and functional studies may help clarify its pathogenicity and guide therapeutic decision-making.