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Context and objective: GH insensitivity with immune dysfunction caused by STAT5B mutations is an autosomal recessivecondition. Heterozygous mutations in other genes involved in growth regulation were previously associated with a mildheight reduction. Our objective was to assess for the first time the phenotype of heterozygous STAT5B mutations.Methods: We genotyped and performed clinical and laboratory evaluations in 52 relatives of two previously describedBrazilian brothers with homozygous STAT5B c.424_427del mutation (21 heterozygous). Additionally, we obtained heightdata and genotype from 1104 adult control individuals from the same region in Brazil and identified five additional familiesharboring the same mutation (18 individuals, 11 heterozygous). Furthermore, we gathered the available height data fromfirst-degree relatives of patients with homozygous STAT5B mutations (17 individuals from seven families). Data fromheterozygous individuals and non-carriers were compared.Results: Individuals carrying heterozygous STAT5B c.424_427del mutation were 0.6 SDS shorter than their non-carrierrelatives (PZ0.009). Heterozygous subjects also had significantly lower SDS for serum concentrations of IGF1 (PZ0.028) andIGFBP3 (PZ0.02) than their non-carrier relatives. The 17 heterozygous first-degree relatives of patients carrying homozygousSTAT5B mutations had an average height SDS of K1.4G0.8 when compared with population-matched controls (P! 0.001).Conclusions: STAT5B mutations in the heterozygous state have a significant negative impact on height (w3.9 cm). This effectis milder than the effect seen in the homozygous state, with height usually within the normal range. Our results support thehypothesis that heterozygosity of rare pathogenic variants contributes to normal height heritability. Fil: Scalco, Renata C.. Universidade de Sao Paulo; Brasil Fil: Hwa, Vivian. Cincinnati Center for Growth Disorders; Estados Unidos Fil: Domene, Horacio Mario. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; Argentina Fil: Jasper, Hector Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; Argentina Fil: Belgorosky, Alicia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Marino, Roxana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Pereira, Alberto M.. Leiden University Medical Center; Países Bajos Fil: Tonelli, Carlos A.. Universidade do Extremo Sul Catarinense; Brasil Fil: Wit, Jan M.. Leiden University Medical Center; Países Bajos Fil: Rosenfeld, Ron G.. Oregon Health and Science University; Estados Unidos Fil: Jorge, Alexander A. L. . Universidade de Sao Paulo; Brasil

The aim of the present work was to develop a method for maintaining prepubertal human testicular cells in culture. Seven pairs of testes of boys who died of causes unrelated to endocrine or metabolic diseases were obtained at necropsy. Histology of the testes was normal. Testes were digested with collagenase and dispersed cells were seeded in multi-well dishes in the presence of 5% bovine fetal serum. After the first day, cells were cultured for five days in serum-free medium in the presence or absence of 918 pmol/l insulin. At the end of culture, microscopic examination showed healthy looking cells with characteristics compatible with pre-Sertoli cells; peritubular cells were identified by immunocytochemistry. In the presence of insulin, cells were able to secrete either testosterone or estradiol into the medium, as well as to reveal aromatase activity. In order to study the effect of the time elapsed between death and beginning of cultures, steroidogenic activity was related to this post mortem time. It was found that, in the presence of insulin, cells obtained from testes with less than 24 h of post mortem time secreted testosterone (64±7.2 pmol/106 cells·24 h, mean±sd) while cells obtained from testes with more than 24 h of post mortem time did not secrete testosterone. With long post mortem times, aromatase activity under insulin increased from non-detectable to 35 pmol/106 cells·24 h. Time course studies showed that cells with capacity to secrete testosterone increase this secretion gradually up to day 10 of culture, while those with detectable aromatase activity showed increments in this activity during the first week of culture. It is concluded that it is possible to maintain cultures of prepubertal human testicular cells obtained at necropsy. In order to maintain testosterone secretion capacity, the time between death and initiation of culture should not exceed 24 h.

The adolescent growth spurt in boys is under hormonal control. It is accepted that androgens and growth hormone contribute to male pubertal growth, but the role of estrogens is uncertain even though low-dose estradiol administration stimulates growth in prepubertal boys. In the present work, the correlation of serum testosterone and serum estradiol with growth velocity was studied in 16 pubertal normal boys. The study included correlations of growth velocity with serum nonsex hormone-binding globulin-bound testosterone and with serum nonsex hormone-binding globulin-bound estradiol, which are parameters of serum bioavailable sex hormones. A statistically significant positive correlation was found between serum testosterone and growth velocity but not between serum estradiol and growth velocity. These findings are against the hypothesis that estrogens play a growth promoting role during male puberty.