Autosomal dominant isolated growth hormone deficiency resulting from a recurrent GH1 gene mutation (p.Arg183His) in three unrelated families

ALICIA MARTÍNEZ; PAULA SCAGLIA; MARÍA GABRIELA ROPELATO; JUAN J HEINRICH; MIGUEL BLANCO; HÉCTOR JASPER; HORACIO DOMENÉ

Milan

Congreso; 9th Joint Meeting of Paediatric Endocrinology (ESPE, PES, APEG, APPES, ASPAE, JSPE, SLEP); 2013

ESPE

Background: Isolated Growth Hormone Deficiency (IGHD) type II results from autosomal dominant (AD) GH1 gene molecular defects.Objective and hypotheses: To investigate GH1 gene mutations in patients with severe IGHD having at least one affected first degree relative.Methods: We were able to perform biochemical and genetic studies in 7 out of 10 adults and 4 children from 3 unrelated families. IGHD was confirmed by low stimulated GH (GHmax < 3.0 ng/ml), low IGF-I levels, normal TSH response to TRH and normal levels of prolactin and cortisol. The whole GH1 gene was PCR amplified and automatically sequenced.Results: In adults, heights ranged from -5.41 to -2.28 SDS in 6 affected and from -2.03 to -0.28 in 3 unaffected. While in children, heights in 3 affected were -3.36, -3.28 and -2.83 and in 2 not affected heights were -0.10 and -0.40. GH1 gene sequencing revealed a c.626G>A transition in exon 5, predicted to result in the missense mutation p.Arg183His in every affected family member. Two patients who received adequate rhGH replacement therapy for 1.5 and 9.3 years showed good growth response and improved height SDS from -3.80 to -2.29 and -3.36 to -0.88, respectively. Two other heterozygous uncommon intronic variants were also found in affected subjects: c.10+52A>G (rs201477005) and c.10+56A>T (rs200389180).Conclusions: As it has been previously reported for carriers of the p.Arg183His GH1 mutation, we found a large variability among affected individuals, with adult heights ranging from -5.41 to -2.28. Due to the highly frequent report of this mutation, both worldwide and in our country, it would be advisable to search for this variant as the first molecular study for type II-IGHD.