Introduction: Constitutional delay of growth and puberty (CDGP) is the most prevalent cause of delayed puberty in both sexes. Family history of delayed puberty (2 or more affected members in a family) has been evidenced in 50-75% of patients with CDGP and the inheritance is often consistent with autosomal dominant pattern, with or without complete penetrance. However, the molecular basis of CDGP is not completely understood. Objective: To characterize the clinical and genetic features of a CDGP cohort. Methods: Fiftynine patients with CDGP (48 boys and 11 girls) underwent careful and long-term clinical evaluation. Genetic analysis was performed using a custom DNA target enrichment panel designed to capture 36 known and candidate genes implicated with pubertal development. Results: All patients had spontaneous or induced pubertal development (transient hormonal therapy) prior to 18 years of age. The mean clinical follow-up time was 46 ± 28 months. Male predominance (81%), short stature (91%), and family history of delayed puberty (59%) were the main clinical features of this CDGP cohort. Genetic analyses revealed 15 rare heterozygous missense variants in 15 patients with CDGP (25%) in seven different genes (IGSF10, GHSR, CHD7, SPRY4, WDR11, SEMA3A, and IL17RD). IGSF10 and GHSR were the most prevalent affected genes in this group. Conclusions: Several rare dominant variants in genes implicated with GnRH migration and metabolism were identified in a quarter of the patients with familial or sporadic CDGP, suggesting genetic heterogeneity in this frequent pediatric condition.
Context The management of youth with delayed puberty is hampered by difficulty in predicting who will eventually progress through puberty and who will fail to attain adult reproductive endocrine function. The neuropeptide kisspeptin, which stimulates gonadotropin-releasing hormone (GnRH) release, can be used to probe the integrity of the reproductive endocrine axis. Objective We sought to determine whether responses to kisspeptin can predict outcomes for individuals with pubertal delay. Design, Setting, and Participants We conducted a longitudinal cohort study in an academic medical center of 16 children (3 girls and 13 boys) with delayed or stalled puberty. Intervention and Outcome Measures Children who had undergone kisspeptin- and GnRH-stimulation tests were followed every 6 months for clinical evidence of progression through puberty. Inhibin B was measured in boys. A subset of participants underwent exome sequencing. Results All participants who had responded to kisspeptin with a rise in luteinizing hormone (LH) of 0.8 mIU/mL or greater subsequently progressed through puberty (n = 8). In contrast, all participants who had exhibited LH responses to kisspeptin ≤ 0.4 mIU/mL reached age 18 years without developing physical signs of puberty (n = 8). Thus, responses to kisspeptin accurately predicted later pubertal outcomes (P = .0002). Moreover, the kisspeptin-stimulation test outperformed GnRH-stimulated LH, inhibin B, and genetic testing in predicting pubertal outcomes. Conclusion The kisspeptin-stimulation can assess future reproductive endocrine potential in prepubertal children and is a promising novel tool for predicting pubertal outcomes for children with delayed puberty.
Testotoxicosis is a rare cause of peripheral precocious puberty in boys caused by constitutively activating mutations of the LHCG receptor. Affected males usually have normal gonadotropin profiles and fertility in their adult life. Here, we described the long-term follow-up of a 24-year-old young man with severe testotoxicosis due to a de novo activating mutation in the third transmembrane helix of the LHCGR (p.Leu457Arg). This patient was treated with different medications, including medroxyprogesterone acetate, ketoconazole, cyproterone acetate and aromatase inhibitor from age 2.5 to 9.5 years. His basal and GnRH-stimulated gonadotropin levels were continually suppressed during and after medical treatment. At adulthood, extremely high serum testosterone levels (>35 nmol/L), undetectable gonadotropin levels (LH < 0.15 IU/L and FSH < 0.6 IU/L) and oligozoospermia were evidenced. Despite his suppressed FSH levels and an unfavorable spermogram, the patient fathered a healthy girl and biological paternity was confirmed through analysis of microsatellites. Spontaneous fertility in a young man with severe testotoxicosis and chronic suppression of FSH levels reinforces the key role of high intratesticular testosterone levels in human spermatogenesis.
Background: The management of youth presenting with delayed puberty is challenging because it can be difficult to predict which children will eventually progress through puberty and which children will not. We have previously shown that exogenous administration of the neuropeptide kisspeptin, which stimulates GnRH release, can be used to probe the integrity of the reproductive endocrine axis. We hypothesized that responses to kisspeptin could predict outcomes for individuals with pubertal delay. Methods: We conducted a longitudinal study of 16 children (3 girls and 13 boys) with delayed or stalled puberty who had undergone stimulation testing with kisspeptin and GnRH. Participants were followed with serial physical examinations and laboratory studies every six months for evidence of progression through puberty. Inhibin B was measured in boys. A subset of participants underwent exome sequencing. Results: “Kisspeptin responders” who had responded to kisspeptin with a rise in LH of 0.8 mIU/mL or greater all subsequently progressed through puberty (n = 8). In contrast, “kisspeptin nonresponders” who had exhibited LH responses to kisspeptin ≤0.4 mIU/mL all reached age 18 years without developing physical signs of puberty (n = 8). Thus, responses to kisspeptin accurately predicted later pubertal outcomes (p = 0.0002), with sensitivity and specificity of 100% (95% CI 74-100%). Moreover, the kisspeptin-stimulation test outperformed overnight LH measurements, GnRH-stimulated LH, inhibin B, and genetic testing in predicting pubertal outcomes. Conclusion: The kisspeptin-stimulation test can be used to reveal future reproductive endocrine potential in prepubertal children and is a promising novel tool for predicting pubertal outcomes for children with delayed puberty. Trial registration: ClinicalTrials.gov NCT01438034
Aos meus pais, Giovanni e Ely, que sempre apoiaram as minhas escolhas e me ensinaram desde cedo a amar os estudos e a lutar pelos meus objetivos. Ao meu esposo, Vladimir, pelo apoio incondicional nesta jornada, compreensão e companheirismo. Aos meus irmãos, George e Victor, pela amizade mais sincera que pode existir. Ao meu avô Olimar (in memorian), que nos deixou em junho deste ano, e à minha avó Miriam, por sempre terem me incentivado a estudar e aprender. À minha querida orientadora Dra. Ana Claudia Latronico, por ter me dado a oportunidade de realizar este trabalho inovador e por ter me ajudado em todos os momentos, das dúvidas mais simples às maiores angústias. Com certeza, sem essa ótima orientação, eu não teria conseguido conquistar tantas vitórias ao longo desses quatro anos de estudos e aprendizado. Ao meu coorientador Dr. Alexander A. L. Jorge pelos ensinamentos valiosíssimos no campo da genética médica e pela dedicação aos pacientes. À Profa. Berenice Bilharinho Mendonça, que desde a residência em endocrinologia tem sido um exemplo de pesquisadora e médica dedicada aos pacientes e à Medicina. Ao Dr. Vinícius Nahime Brito, pelos ensinamentos no ambulatório e na vida, pelas conversas leves e apoio desde o início do meu doutorado. À Luciana Montenegro, pela amizade, paciência e ensinamentos no trabalho de bancada, parte fundamental no sucesso desta tese. À Miriam Nishi e à Mariana Funari, por esclarecerem minhas dúvidas e pela ajuda nas questões de biologia molecular e de laboratório. Ao grupo de pós-graduandos da puberdade, Delanie Macedo, Danielle Bessa, Carolina Ramos e Carlos Seraphim pela amizade, apoio e ajuda. Ao grupo de pesquisa de hipogonadismo, Dra. Elaine Costa, Alessandra Renck e Caroline Schnoll por terem me recebido tão bem no ambulatório e me ensinado muito. Às minhas amigas Lorena Lima Amato e Marina Cunha que desde a residência médica em endocrinologia têm sido parceiras nas horas boas e ruins.
Constitutional delay of growth and puberty (CDGP) is the most prevalent cause of delayed puberty in both sexes. It has a strong family history, however, its genetic basis is still poorly understood. Objective : To characterize the clinical and genetic features of a CDGP cohort. Methods: 59 unrelated probands with CDGP were selected. They underwent careful and long-term clinical evaluation. Genetic analysis was performed using a custom DNA target enrichment panel (NextSeq 500 next-generation sequencing, Illumina Inc) designed to capture 36 known and candidate genes implicated with delayed puberty. Results: All CDGP patients had spontaneous pubertal development or it was induced by a transient sexual steroid replacement. Male predominance (81%), short stature (91%) associated with delayed bone age and positive family history (59%) were the major clinical features of this cohort. Genetic analyses revealed 16 rare heterozygous predicted to be deleterious variants in 15 CDGP patients (25%) in 8 distinct genes ( HS6ST1 , IGSF10, GHSR, CHD7, SEMA3A, IL17RD, SPRY4 and WDR11) . IGSF10 and GHSR were the most prevalent affected genes in this group (3 variants in 4 patients each one). The vast majority of variants were missense. We identified a stop-gain variant, likely pathogenic, in HS6ST1 gene (p.Cys27X) in a male proband with no family history of delayed puberty. 5% of the subjects had oligogenicity (variants in more than one gene). Conclusions: The classic phenotype of CDGP has as clinical features short stature in the prepubertal period, higher prevalence in males and more than a half of the individuals had a positive family history. Genetic heterogeneity was demonstrated in typical CDGP phenotype.
A boy presented with delayed puberty at age 13.5 years. His mother had idiopathic hypogonadotropic hypogonadism (IHH) with a heterozygous mutation in the gene TACR3 that the son had inherited. He had a normal sense of smell, no chronic diseases, and no use of medications. At his first physical examination, testicular volumes were 1 mL bilaterally. Blood tests revealed FSH 0.99 IU/L (prepubertal <3.1 IU/L), LH 0.03 IU/L (prepubertal <0.7 IU/L), total testosterone 5 ng/dL (prepubertal <10 ng/dL). At age 14.5 years, he started treatment with testosterone enanthate 50 mg every 4 weeks. Because his genetic testing suggested that he may have IHH like his mother, he underwent full pubertal induction with gradual increases in the testosterone dose and a plan to withdraw treatment to assess endogenous function when growth was finished. Treatment induced appropriate pubertal growth and development of secondary sex characteristics such as voice breaking and pubic and body hair. At 16 years 11 months of age, he was noted to have testicular enlargement to 3 mL. Laboratory tests on that occasion, collected 2 weeks after the last dose of testosterone enanthate 120 mg, showed elevated gonadotropins: LH 13.5 IU/L (adult male: 1.4 - 11.1 IU/L) and FSH 17.1 IU/L (adult male: 1.3 - 12.7 IU/L). Repeat tests at age 17 years and 2 months, after 2 months without testosterone treatment, showed an increase in FSH to 23 IU/L, LH within the normal range (6.8 IU/L) and testosterone 466 ng/dL (adult male: 700 +/- 300 ng/dL). After stopping testosterone treatment, testicular volume continued to increase, most recently 8 mL on the right and 10 mL on the left at age 17.5 years. Blood tests at that time showed FSH 13.9 IU/L and inhibin B 84 pg/mL (11-18 years: 50 - 475 pg/mL). We present a boy with self-limited delayed puberty and a heterozygous mutation in TACR3 who underwent full pubertal induction with exogenous testosterone. After almost 2.5 years of treatment, he had testicular enlargement and a surprising finding of hypergonadotropism. His LH and testosterone normalized, but to date his FSH remains elevated. We hypothesize that this patient had spontaneous pubertal maturation of the hypothalamus and pituitary, but a delay in gonadal development because of suppression of gonadotropins by exogenous testosterone. He now appears to be slowly acquiring gonadal function, with Leydig cell function developing faster than Sertoli cell function. Alternatively or in addition, he may have a primary gonadal defect (either related or unrelated to his TACR3 mutation); he has no history of chemotherapy or radiation treatment, testicular injury or surgeries, or mumps in childhood, and a karyotype to evaluate for Klinefelter syndrome is pending. Another possibility is that his TACR3 mutation is affecting the balance of FSH/LH secretion, as has been reported in IHH patients with TACR3 mutations, though hypergonadotropism...
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