SAT-217 Severe Short Stature and Growth Hormone (GH) Insensitivity in an Adolescent Male Associated with a Novel Homozygous Variant in the GH Receptor Gene: A Unique Case of Laron Syndrome

Abstract Disclosure: V.X. Yu: None. M.E. Geffner: Diurnal, Novo Nordisk, Neurocrine Biosciences: Research support, Advisory board/Consultant, Spruce Biosciences: Research support, Advisory board/Consultant, Ascendis: Advisory board/Consultant, Eton Pharmaceuticals: Advisory board/Consultant, Theratechnologies, Inc: Advisory board/Consultant, McGraw-Hill: Royalties, Up To Date. L.M. Randolph: BioMarin Pharmaceuticals- Advisory board/consultant. Z. Laron: None. A. Ryabets-Lienhard: Ultragenyx, Principal investigator receiving grant support for research, Takeda, Principal investigator receiving grant support for research, Alexion Pharmaceuticals, Inc., Advisory board/consultant, BioMarin Pharmaceuticals- Advisory board/consultant. Introduction: Laron syndrome (LS) is a rare autosomal recessive disorder with an estimated 500 global cases, characterized by GH resistance due to pathogenic variants in the GH receptor (GHR) gene, resulting in primary IGF-1 deficiency. Affected patients exhibit severe short stature, distinctive facial features, and extremely low levels of IGF-1 despite normal or elevated GH levels. The broad spectrum of pathogenic GHR variants in LS includes missense, nonsense, splice-site, and deletion variants that often involve the extracellular (EC) GH binding domain of the GHR (exons 1-7) and result in low GH-binding protein (GHBP) levels. We present a unique case of an adolescent male with severe LS associated with a novel missense variant in GHR exon 7, but normal GHBP levels. Case: An almost 16-yr-old male of Mexican ancestry with no known significant family history or consanguinity presented with severe relatively proportional short stature (height -7.06 SD, BMI 0.37 SD). He had an infantile face with round cheeks, depressed nasal bridge, high-pitched voice, slightly blue sclerae, Tanner Stage (TS) 2 puberty with testosterone 77 ng/dL (8-66), and bone age 11.6 yr. He was found to have undetectable IGF-1 (<10 ng/mL, 201-609) and low IGFBP-3 (0.8 mg/L, 3.5-10.0) with normal GH stimulation (peak GH 10.9 ng/mL) and GHBP (1446 pmol/L, 290-3140). TSH was elevated (6.43 mlU/mL, 0.50-5.00) with normal FT4 (1.09 ng/dL, 0.70-1.65). Genetic testing using the Discover Dysplasias gene panel (Invitae) identified a novel homozygous c.650T>G (p.Val217Gly) variant in GHR exon 7, classified as a variant of uncertain significance, in the last codon of the EC binding domain. There was no response in IGF-1 generation testing to GH 33 mg/kg/day x 7 days (IGF-1 averaged 11 ng/dL, 201-609; -5.5 SD), further supporting a diagnosis of LS. After 3 mo, height remained -7.08 SD while puberty progressed to TS3 with increased testosterone (526 ng/dL, 26-800). TSH increased further to 9.74 mlU/mL with normal FT4 1.13 ng/dL. Patient started recombinant human IGF-1 therapy at 0.1 mg/kg once daily x 1 wk, then increased to 0.18 mg/kg once daily x 1 wk and subsequently to 0.12 mg/kg twice daily (with no hypoglycemia or other side effects). Letrozole (2.5 mg daily) was also started to delay epiphyseal fusion. Conclusion: This unique case of severe Laron syndrome involves a novel homozygous missense variant of uncertain significance in the EC GH binding domain of GHR with unexpectedly normal GHBP levels, potentially expanding the scope of known GHR pathogenic variants. Its position in the last codon of the EC domain adjacent to the transmembrane domain may explain normal GHBP levels with disruption of GH action downstream. Functional studies are planned to further analyze this novel variant and confirm its pathogenicity. The co-occurrence of subclinical hypothyroidism also warrants further study regarding its contribution to the LS phenotype. Presentation: Saturday, July 12, 2025