OR20-4 Mild growth and immunological phenotypes in individuals heterozygous for STAT5B mutations

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR20-Genetics of Growth
Bench to Bedside
Sunday, June 16, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 12:00 PM
Room 122 (Moscone Center)
Renata Da Cunha Scalco1, Carlos A Tonelli2, Patricia Pugliese-Pires3, Julio Cechinel4, Ivo J Arnhold5 and Alexander Augusto Lima Jorge*3
1Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo - SP, Brazil, 2Faculdade de Medicina da Universidade do Extremo Sul de Santa Catarina (UNESC), Criciuma, Brazil, 3Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil, 4Laboratorio Pasteur, Criciuma, Brazil, 5Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
Background: STAT5b is a protein involved in the signaling pathway of growth hormone (GH) and interleukins. Homozygous inactivating mutations in STAT5B gene cause GH insensitivity with chronic pulmonary disease and/or other immune dysfunctions. The effect of heterozygous STAT5Bmutations on phenotype is still poorly characterized.

Objective and hypothesis: To test the hypothesis that STAT5B haploinsufficiency could cause an intermediate phenotype between patients with homozygous mutations and controls.

Methods: Direct relatives of two patients homozygous for the p.L142fsX161 (c.424_427del) STAT5B mutation were evaluated (1). We compared clinical and laboratory characteristics between relatives heterozygous for the STAT5Bmutation and non-carriers. In this way the differences related to different genetic backgrounds could be minimized.

Results: We investigated a total of 32 direct relatives of the index patient. Fourteen of them carry the heterozygous c.424_427del STAT5B mutation. Individuals carrying STAT5B mutation and the ones homozygous for the wild type (WT) allele have similar gender distribution and ages. However, individuals heterozygous for STAT5B mutation (height SDS = -0.9 ± 0.6) were significantly shorter than WT ones (height SDS = 0.0 ± 1.1; p = 0.012; 95% confidence interval: -1.6 to -0.2). Additionally, IGF-1 levels had a tendency to be lower in relatives carrying the mutation (IGF-1 SDS = -0.5 ± 1.1 vs. +0.2 ± 1.1, p = 0.086). There were no differences between the two groups of relatives regarding basal GH, PRL, IGFBP-3, glucose, insulin, C-peptide levels, serum immunoglobulins. A lower lymphocyte concentration was observed in relatives heterozygous for STAT5B mutation (1738 ± 368 per ml vs 2218 ± 690 per ml in WT; p = 0.026). Interestingly, two relatives carrying STAT5B mutation were diagnosed with “idiopathic” pulmonary fibrosis.

Conclusions: Individuals heterozygous for the studied STAT5B mutation are shorter than their non-carrier relatives, although in the normal height range. In the same direction, IGF-1 SDS was lower in heterozygous individuals, although without reaching significance. A tendency toward more respiratory allergy and a decrease of serum lymphocytes were also observed in carriers. These results suggest a mild phenotype in individuals heterozygous for STAT5B mutations, but it is necessary to expand the number of studied relatives in this and other families to confirm the present findings.

(1) Pugliese-Pires PN et al. European Journal of Endocrinology, v. 163, p. 349-355, 2010.

Nothing to Disclose: RDCS, CAT, PP, JC, IJA, AALJ

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: This work was supported by grants from Fundacao de Amparo a Pesquisa do Estado de Sao Paulo – FAPESP (010/19809-6 and 2011/15078-0) and fromConselho Nacional de Desenvolvimento Cientifico e Tecnologico –CNPq (300982/2009-7 to IJPA and 304678/2012-0 to AALJ).