Heterozygous GH1 p.R209H Variant Challenges the Assessment of Short Stature

SCAGLIA, PAULA; ROPELATO, MARÍA GABRIELA; VISHNOPOLSKA, SEBASTIAN; REY, RODOLFO A.; BRASLAVSKY, DÉBORA; KESELMAN, ANA; SUCO, SOFIA; MARTI, MARCELO; PÉREZ MILLÁN, MARIA I.; SANGUINETI, NORA; BALLERINI, MARÍA GABRIELA; KITZMAN, J; DOMENÉ, HORACIO; CAMPER, SALLY A.

Florianópolis

Congreso; Congreso anual Sociedad Latinoamericana de Endocrinología Pediátrica (SLEP); 2019

Sociedad Latinoamericana de Endocrinología Pediátrica

Background: Short stature due to classical growth hormonedeficiency (GHD) has typical clinical and biochemical features,with GH provocative tests (GHPT) as the gold standard to confirmits diagnosis. Autosomal dominant GHD type II is caused by GH1gene defects. GH1 p.R209H variant impairs GH secretion despitenormal GH synthesis and bioactivity.Aim: to describe a large pedigree with a marked variability inclinical and biochemical phenotype due to p.R209H GH1 missensevariant, making the diagnosis of GHD elusive. Case: We report anon-consanguineous 4 generation pedigree. Four siblings hadshort stature (median height -3.8 SDS, range -2.6 to -4.02) withouttypical features of GHD; normal response to GHPT (GH peaks5.46 to 10.9 ng/ml; IS 98/574, Immulite), low serum IGF-1 (median -3.05; range -2.49 to -4.54 SDS) and low IGFBP-3 (median-2.10; range -1.04 to -2.95 SDS) levels, thus resembling a pattern ofgrowth hormone insensitivity. IGF-1 generation tests (rhGH dose33 µg/kg.d) showed a mean increment in IGF-1 of 3 times overbasal, revealing adequate GH sensitivity. Within the same pedigree, two members presented classical IGHD phenotype: height-4.74 and -2.27 SDS, at 5.4 and 1.8 yrs, respectively; non-detectableIGF-1, low IGFBP-3 levels (-2.83 and -2.28 SDS, respectively) andinsufficient response to GHPT (GH peak 3.62 and 2.65 ng/ml, respectively). Brain MRI showed anterior pituitary hypoplasia inone. Both responded adequately to rhGH treatment (0.17 mg/kg.w). These IGHD patients were studied by a customized panelfor congenital hypopituitarism using single molecule molecularinversion probes sequencing (smMIPS), revealing a c.626G>A(p.R209H) GH1 variant, confirmed by Sanger sequencing. Despitethe absence of complete GHD phenotype in the four former siblings, data from the extended pedigree suggested GH1 as the initialcandidate gene, identifying the same GH1 variant in all of them.Conclusion: The identification of short stature disorders requires the integration of all clinical, biochemical, radiological dataand it is critical to ascertain an extended family history. The widespectrum of clinical and biochemical presentation in individualscarrying the p.R209H variant could hinder the diagnosis of a GHD,therefore misleading the genetic diagnosis approach. Our resultshighlight the need to explore GH1 gene in children with short stature associated to low IGF-I and IGFBP-3 serum levels, even in thecontext of normal response to GHPT.