RESUMO
The etiology of central precocious puberty (CPP) is multiple and heterogeneous, including congenital and acquired causes that can be associated with structural or functional brain alterations. All causes of CPP culminate in the premature pulsatile secretion of hypothalamic GnRH and, consequently, in the premature reactivation of hypothalamic-pituitary-gonadal axis. The activation of excitatory factors or suppression of inhibitory factors during childhood represent the 2 major mechanisms of CPP, revealing a delicate balance of these opposing neuronal pathways. Hypothalamic hamartoma (HH) is the most well-known congenital cause of CPP with central nervous system abnormalities. Several mechanisms by which hamartoma causes CPP have been proposed, including an anatomical connection to the anterior hypothalamus, autonomous neuroendocrine activity in GnRH neurons, trophic factors secreted by HH, and mechanical pressure applied to the hypothalamus. The importance of genetic and/or epigenetic factors in the underlying mechanisms of CPP has grown significantly in the last decade, as demonstrated by the evidence of genetic abnormalities in hypothalamic structural lesions (eg, hamartomas, gliomas), syndromic disorders associated with CPP (Temple, Prader-Willi, Silver-Russell, and Rett syndromes), and isolated CPP from monogenic defects (MKRN3 and DLK1 loss-of-function mutations). Genetic and epigenetic discoveries involving the etiology of CPP have had influence on the diagnosis and familial counseling providing bases for potential prevention of premature sexual development and new treatment targets in the future. Global preventive actions inducing healthy lifestyle habits and less exposure to endocrine-disrupting chemicals during the lifespan are desirable because they are potentially associated with CPP.
Assuntos
Doenças Hipotalâmicas , Puberdade Precoce , Humanos , Puberdade Precoce/diagnóstico , Puberdade Precoce/genética , Hormônio Liberador de Gonadotropina/metabolismo , Doenças Hipotalâmicas/complicações , Hipotálamo , Puberdade , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Objective: The transcription factor OTX2 is implicated in ocular, craniofacial, and pituitary development. Design: We aimed to establish the contribution of OTX2 mutations in congenital hypopituitarism patients with/without eye abnormalities, study functional consequences, and establish OTX2 expression in the human brain, with a view to investigate the mechanism of action. Methods: We screened patients from the UK (n = 103), international centres (n = 24), and Brazil (n = 282); 145 were within the septo-optic dysplasia spectrum, and 264 had no eye phenotype. Transactivation ability of OTX2 variants was analysed in murine hypothalamic GT1-7 neurons. In situ hybridization was performed on human embryonic brain sections. Genetically engineered mice were generated with a series of C-terminal OTX2 variants. Results: Two chromosomal deletions and six haploinsufficient mutations were identified in individuals with eye abnormalities; an affected relative of one patient harboured the same mutation without an ocular phenotype. OTX2 truncations led to significant transactivation reduction. A missense variant was identified in another patient without eye abnormalities; however, studies revealed it was most likely not causative. In the mouse, truncations proximal to aa219 caused anophthalmia, while distal truncations and the missense variant were tolerated. During human embryogenesis, OTX2 was expressed in the posterior pituitary, retina, ear, thalamus, choroid plexus, and partially in the hypothalamus, but not in the anterior pituitary. Conclusions: OTX2 mutations are rarely associated with hypopituitarism in isolation without eye abnormalities, and may be variably penetrant, even within the same pedigree. Our data suggest that the endocrine phenotypes in patients with OTX2 mutations are of hypothalamic origin.
Assuntos
Hipopituitarismo/fisiopatologia , Microftalmia/fisiopatologia , Neurônios/fisiologia , Fatores de Transcrição Otx/genética , Hipófise/fisiopatologia , Displasia Septo-Óptica/fisiopatologia , Adolescente , Animais , Animais Geneticamente Modificados , Brasil , Linhagem Celular , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Hipopituitarismo/embriologia , Hipopituitarismo/genética , Hipotálamo/citologia , Lactente , Masculino , Camundongos , Microftalmia/embriologia , Microftalmia/genética , Mutação , Neurônios/patologia , Linhagem , Hipófise/embriologia , Hipófise/patologia , Displasia Septo-Óptica/embriologia , Displasia Septo-Óptica/genética , Reino UnidoRESUMO
ABSTRACT Purpose: To evaluate the role of ARDT after surgical resection of ACC. Materials and Methods: Records of patients from our institutional ACC database were retrospectively assessed. A paired comparison analysis was used to evaluate the oncological outcomes between patients treated with surgery followed by ARDT or surgery only (control). The endpoints were LRFS, RFS, and OS. A systematic review of the literature and meta-analysis was also performed to evaluate local recurrence of ACC when ARDT was used. Results: Ten patients were included in each Group. The median follow-up times were 32 months and 35 months for the ARDT and control Groups, respectively. The results for LRFS (p=0.11), RFS (p=0.92), and OS (p=0.47) were similar among subsets. The mean time to present with local recurrence was significantly longer in the ARDT group compared with the control Group (419±206 days vs. 181±86 days, respectively; p=0.03). ARDT was well tolerated by the patients; there were no reports of late toxicity. The meta-analysis, which included four retrospective series, revealed that ARDT had a protective effect on LRFS (HR=0.4; CI=0.17-0.94). Conclusions: ARDT may reduce the chance and prolong the time to ACC local recurrence. However, there were no benefits for disease recurrence control or overall survival for patients who underwent this complementary therapy.
Assuntos
Humanos , Masculino , Feminino , Idoso , Idoso de 80 Anos ou mais , Adulto Jovem , Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical/radioterapia , Estudos de Casos e Controles , Estudos Retrospectivos , Seguimentos , Neoplasias do Córtex Suprarrenal/cirurgia , Carcinoma Adrenocortical/cirurgia , Adrenalectomia , Radioterapia Adjuvante/métodos , Intervalo Livre de Doença , Pessoa de Meia-IdadeRESUMO
PURPOSE: To evaluate the role of ARDT after surgical resection of ACC. MATERIALS AND METHODS: Records of patients from our institutional ACC database were retrospectively assessed. A paired comparison analysis was used to evaluate the oncological outcomes between patients treated with surgery followed by ARDT or surgery only (control). The endpoints were LRFS, RFS, and OS. A systematic review of the literature and meta-analysis was also performed to evaluate local recurrence of ACC when ARDT was used. RESULTS: Ten patients were included in each Group. The median follow-up times were 32 months and 35 months for the ARDT and control Groups, respectively. The results for LRFS (p=0.11), RFS (p=0.92), and OS (p=0.47) were similar among subsets. The mean time to present with local recurrence was significantly longer in the ARDT group compared with the control Group (419±206 days vs. 181±86 days, respectively; p=0.03). ARDT was well tolerated by the patients; there were no reports of late toxicity. The meta-analysis, which included four retrospective series, revealed that ARDT had a protective effect on LRFS (HR=0.4; CI=0.17-0.94). CONCLUSIONS: ARDT may reduce the chance and prolong the time to ACC local recurrence. However, there were no benefits for disease recurrence control or overall survival for patients who underwent this complementary therapy.
Assuntos
Neoplasias do Córtex Suprarrenal/radioterapia , Carcinoma Adrenocortical/radioterapia , Neoplasias do Córtex Suprarrenal/cirurgia , Adrenalectomia , Carcinoma Adrenocortical/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Radioterapia Adjuvante/métodos , Estudos Retrospectivos , Adulto JovemRESUMO
The genetic aetiology of congenital hypopituitarism (CH) is not entirely elucidated. FGFR1 and PROKR2 loss-of-function mutations are classically involved in hypogonadotrophic hypogonadism (HH), however, due to the clinical and genetic overlap of HH and CH; these genes may also be involved in the pathogenesis of CH. Using a candidate gene approach, we screened 156 Brazilian patients with combined pituitary hormone deficiencies (CPHD) for loss-of-function mutations in FGFR1 and PROKR2. We identified three FGFR1 variants (p.Arg448Trp, p.Ser107Leu and p.Pro772Ser) in four unrelated patients (two males) and two PROKR2 variants (p.Arg85Cys and p.Arg248Glu) in two unrelated female patients. Five of the six patients harbouring the variants had a first-degree relative that was an unaffected carrier of it. Results of functional studies indicated that the new FGFR1 variant p.Arg448Trp is a loss-of-function variant, while p.Ser107Leu and p.Pro772Ser present signalling activity similar to the wild-type form. Regarding PROKR2 variants, results from previous functional studies indicated that p.Arg85Cys moderately compromises receptor signalling through both MAPK and Ca(2) (+) pathways while p.Arg248Glu decreases calcium mobilization but has normal MAPK activity. The presence of loss-of-function variants of FGFR1 and PROKR2 in our patients with CPHD is indicative of an adjuvant and/or modifier effect of these rare variants on the phenotype. The presence of the same variants in unaffected relatives implies that they cannot solely cause the phenotype. Other associated genetic and/or environmental modifiers may play a role in the aetiology of this condition.
RESUMO
BACKGROUND: Children initially diagnosed with isolated GH deficiency (IGHD) have a variable rate to progress to combined pituitary hormone deficiency (CPHD) during follow-up. OBJECTIVE: To evaluate the development of CPHD in a group of childhood-onset IGHD followed at a single tertiary center over a long period of time. PATIENTS AND METHODS: We retrospectively analyzed data from 83 patients initially diagnosed as IGHD with a mean follow-up of 15.2 years. The Kaplan-Meier method and Cox regression analysis was used to estimate the temporal progression and to identify risk factors to development of CPHD over time. RESULTS: From 83 patients initially with IGHD, 37 (45%) developed CPHD after a median time of follow up of 5.4 years (range from 1.2 to 21 years). LH and FSH deficiencies were the most common pituitary hormone (38%) deficiencies developed followed by TSH (31%), ACTH (12%) and ADH deficiency (5%). ADH deficiency (3.1 ± 1 years from GHD diagnosis) presented earlier and ACTH deficiency (9.3 ± 3.5 years) presented later during follow up compared to LH/FSH (8.3 ± 4 years) and TSH (7.5 ± 5.6 years) deficiencies. In a Cox regression model, pituitary stalk abnormalities was the strongest risk factor for the development of CPHD (hazard ratio of 3.28; p = 0.002). CONCLUSION: Our study indicated a high frequency of development of CPHD in patients initially diagnosed as IGHD at childhood. Half of our patients with IGHD developed the second hormone deficiency after 5 years of diagnosis, reinforcing the need for lifelong monitoring of pituitary function in these patients.
Assuntos
Hormônio Adrenocorticotrópico/deficiência , Nanismo Hipofisário/epidemiologia , Hormônio Foliculoestimulante/deficiência , Hormônio do Crescimento Humano/deficiência , Hipopituitarismo/epidemiologia , Hormônio Luteinizante/deficiência , Tireotropina/deficiência , Vasopressinas/deficiência , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Progressão da Doença , Feminino , Seguimentos , Humanos , Hipopituitarismo/patologia , Hipotálamo/patologia , Estimativa de Kaplan-Meier , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Hipófise/patologia , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND: The onset of puberty is first detected as an increase in pulsatile secretion of gonadotropin-releasing hormone (GnRH). Early activation of the hypothalamic-pituitary-gonadal axis results in central precocious puberty. The timing of pubertal development is driven in part by genetic factors, but only a few, rare molecular defects associated with central precocious puberty have been identified. METHODS: We performed whole-exome sequencing in 40 members of 15 families with central precocious puberty. Candidate variants were confirmed with Sanger sequencing. We also performed quantitative real-time polymerase-chain-reaction assays to determine levels of messenger RNA (mRNA) in the hypothalami of mice at different ages. RESULTS: We identified four novel heterozygous mutations in MKRN3, the gene encoding makorin RING-finger protein 3, in 5 of the 15 families; both sexes were affected. The mutations included three frameshift mutations, predicted to encode truncated proteins, and one missense mutation, predicted to disrupt protein function. MKRN3 is a paternally expressed, imprinted gene located in the Prader-Willi syndrome critical region (chromosome 15q11-q13). All affected persons inherited the mutations from their fathers, a finding that indicates perfect segregation with the mode of inheritance expected for an imprinted gene. Levels of Mkrn3 mRNA were high in the arcuate nucleus of prepubertal mice, decreased immediately before puberty, and remained low after puberty. CONCLUSIONS: Deficiency of MKRN3 causes central precocious puberty in humans. (Funded by the National Institutes of Health and others.).
Assuntos
Mutação da Fase de Leitura , Mutação de Sentido Incorreto , Puberdade Precoce/genética , Ribonucleoproteínas/genética , Animais , Núcleo Arqueado do Hipotálamo/química , Criança , Pré-Escolar , Exoma , Feminino , Estudos de Associação Genética , Heterozigoto , Humanos , Hipotálamo/metabolismo , Masculino , Camundongos , Linhagem , RNA Mensageiro/análise , Ribonucleoproteínas/deficiência , Análise de Sequência de DNA , Ubiquitina-Proteína LigasesRESUMO
Pituitary stalk interruption and ectopic posterior lobe on magnetic resonance imaging (MRI) are frequently observed in patients with GH deficiency (GHD), but their pathogenesis remains controversial. We performed pituitary stimulation tests, MRI, and studied GH-1, GHRH receptor (GHRH-R), and Prophet of Pit-1 (PROP-1) genes in 76 patients with GHD. Of 33 patients with isolated GHD, 4 had GH-1 deletions and 4 had GHRH-R mutations; of 43 patients with combined pituitary hormone deficiency, 1 had PIT-1 and 5 had PROP-1 mutations. Compared with the 62 patients without mutations, 14 patients with mutations had higher frequency of consanguinity (57 vs. 2%, P < 0.001), familial cases (21 vs. 3%, P < 0.05), and lower frequency of breech delivery or hypoxemia at birth (0 vs. 39%, P < 0.005). On MRI, all patients with mutations had an intact stalk, whereas it was interrupted or thin in 74% without mutations (P < 0.001). The posterior pituitary lobe was in normal position in 92% of patients with mutations against 13% without mutations (P < 0.001). Among patients with combined pituitary hormone deficiency, hormonal deficiencies were of pituitary origin in all with PROP-1 and PIT-1 mutations and suggestive of hypothalamic origin in 81% without mutations. Perinatal insults were associated with thin/interrupted pituitary stalk, ectopic posterior lobe, and hypothalamic origin of hormonal deficiencies. In contrast, GH-1, GHRH-R, and PROP-1 mutations were associated with consanguineous parents, intact pituitary stalk, normal posterior lobe, and pituitary origin of hormonal deficiencies. We conclude that pituitary MRI and hormonal response to stimulation tests are useful in selection of patients and candidate genes to elucidate the etiological diagnosis of GHD.
Assuntos
Proteínas de Homeodomínio/genética , Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/genética , Mutação , Hipófise/patologia , Receptores de Neuropeptídeos/genética , Receptores de Hormônios Reguladores de Hormônio Hipofisário/genética , Adolescente , Adulto , Criança , Pré-Escolar , Consanguinidade , Feminino , Deleção de Genes , Humanos , Hipotálamo/fisiopatologia , Lactente , Imageamento por Ressonância Magnética , Masculino , Hipófise/fisiopatologia , Neuro-Hipófise/patologiaRESUMO
Dopamine (DA) and zinc (Zn++) share common mechanisms in their inhibition of prolactin (PRL) secretion. Both substances are present in the same brain areas, where Zn++ is released together with DA, suggesting a modulatory effect of Zn++ on dopaminergic receptors. The aim of the present study was to evaluate the effect of Zn++ supplementation on basal and PRL secretion stimulated by metoclopramide (MCP), a dopaminergic antagonist. Seven healthy men were evaluated in controlled study, where MCP (5 mg) was given intravenously, before and after 3 months of oral Zn++ (25 mg) administration. Our results indicate that chronic Zn++ administration does not change basal or MCP-stimulated plasma PRL secretion suggesting that, in humans, Zn++ does not interfere on PRL secretion mediated through dopaminergic receptors.