RESUMO
The timing of pubertal development is strongly influenced by the genetic background, and clinical presentations of delayed puberty are often found within families with clear patterns of inheritance. The discovery of the underlying genetic regulators of such conditions, in recent years through next generation sequencing, has advanced the understanding of the pathogenesis of disorders of pubertal timing and the potential for genetic testing to assist diagnosis for patients with these conditions. This review covers the significant advances in the understanding of the biological mechanisms of delayed puberty that have occurred in the last two decades.
Assuntos
Hipogonadismo , Puberdade Tardia , Humanos , Hipogonadismo/genética , Puberdade/genética , Puberdade Tardia/diagnóstico , Puberdade Tardia/genéticaRESUMO
The initiation of puberty is orchestrated by an augmentation of gonadotropin-releasing hormone (GnRH) secretion from a few thousand hypothalamic neurons. Recent findings have indicated that the neuroendocrine control of puberty may be regulated by a hierarchically organized network of transcriptional factors acting upstream of GnRH. These include enhanced at puberty 1 (EAP1), which contributes to the initiation of female puberty through transactivation of the GnRH promoter. However, no EAP1 mutations have been found in humans with disorders of pubertal timing. We performed whole-exome sequencing in 67 probands and 93 relatives from a large cohort of familial self-limited delayed puberty (DP). Variants were analyzed for rare, potentially pathogenic variants enriched in case versus controls and relevant to the biological control of puberty. We identified one in-frame deletion (Ala221del) and one rare missense variant (Asn770His) in EAP1 in two unrelated families; these variants were highly conserved and potentially pathogenic. Expression studies revealed Eap1 mRNA abundance in peri-pubertal mouse hypothalamus. EAP1 binding to the GnRH1 promoter increased in monkey hypothalamus at the onset of puberty as determined by chromatin immunoprecipitation. Using a luciferase reporter assay, EAP1 mutants showed a reduced ability to trans-activate the GnRH promoter compared to wild-type EAP1, due to reduced protein levels caused by the Ala221del mutation and subcellular mislocation caused by the Asn770His mutation, as revealed by western blot and immunofluorescence, respectively. In conclusion, we have identified the first EAP1 mutations leading to reduced GnRH transcriptional activity resulting in a phenotype of self-limited DP.
Assuntos
Hormônio Liberador de Gonadotropina/fisiologia , Puberdade Tardia/genética , Securina/genética , Adolescente , Adulto , Animais , Criança , Feminino , Regulação da Expressão Gênica/genética , Hormônio Liberador de Gonadotropina/genética , Humanos , Hipotálamo/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Neurônios/metabolismo , Regiões Promotoras Genéticas/genética , Puberdade/genética , Puberdade/fisiologia , RNA Mensageiro/genética , Securina/fisiologia , Maturidade Sexual/genética , Transativadores/genética , Fatores de Transcrição/genética , Sequenciamento do Exoma , Adulto JovemRESUMO
Puberty is a process of transition from childhood to adult reproductive capacity, governed by the reactivation of the hypothalamic-pituitary-gonadal axis after a long period of dormancy in mid-childhood. As such, the reproductive hormones are in a state of flux during the adolescent years, and interpretation of both the onset of healthy, concordant puberty and the differentiation of precocious, delayed or disordered puberty, can be challenging. This review is focused on the description of the endocrine axes in healthy puberty and the markers of disorders of puberty that can aid diagnosis and management for patients with these conditions. It will cover the hypothalamic, pituitary and gonadal hormone systems, the dynamic changes that occur during puberty, conditions leading to precocious, delayed or absent puberty and other syndromes with disordered puberty, and the biochemical diagnosis of these different disorders of puberty.
Assuntos
Puberdade Precoce , Adolescente , Adulto , Criança , Hormônio Foliculoestimulante , Hormônio Liberador de Gonadotropina , Humanos , Hormônio Luteinizante , PuberdadeRESUMO
The genetic control of puberty remains an important but mostly unanswered question. Late pubertal timing affects over 2% of adolescents and is associated with adverse health outcomes including short stature, reduced bone mineral density, and compromised psychosocial health. Self-limited delayed puberty (DP) is a highly heritable trait, which often segregates in an autosomal dominant pattern; however, its neuroendocrine pathophysiology and genetic regulation remain unclear. Some insights into the genetic mutations that lead to familial DP have come from sequencing genes known to cause gonadotropin-releasing hormone (GnRH) deficiency, most recently via next-generation sequencing, and others from large-scale genome-wide association studies in the general population. Investigation of the genetic control of DP is complicated by the fact that this trait is not rare and that the phenotype is likely to represent a final common pathway, with a variety of different pathogenic mechanisms affecting the release of the puberty "brake." These include abnormalities of GnRH neuronal development and function, GnRH receptor and luteinizing hormone/follicle-stimulating hormone abnormalities, metabolic and energy homeostatic derangements, and transcriptional regulation of the hypothalamic-pituitary-gonadal axis. Thus, genetic control of pubertal timing can range from early fetal life via development of the GnRH network to those factors directly influencing the puberty brake during mid-childhood.
Assuntos
Predisposição Genética para Doença , Puberdade Tardia/genética , Animais , Humanos , Puberdade Tardia/metabolismoRESUMO
Patients with congenital hypogonadism will encounter many health care professionals during their lives managing their health needs; from antenatal and infantile periods, through childhood and adolescence, into adult life and then old age. The pubertal transition from childhood to adult life raises particular challenges for diagnosis, therapy and psychological support, and patients encounter many pitfalls. Many patients with congenital hypogonadism and delayed or absent puberty are only diagnosed and treated after long diagnostic journeys, and their management across different centres and countries is not well standardised. Here we reconsider the management of pubertal delay, whilst addressing problematic diagnostic issues and highlighting the limitations of historic pubertal induction protocols - from the perspective of both an adult and a paediatric endocrinologist, dealing in our everyday work with the long-term adverse consequences to our hypogonadal patients of an incorrect and/or late diagnosis and treatment in childhood.
Assuntos
Hipogonadismo , Puberdade Tardia , Gravidez , Adulto , Adolescente , Criança , Humanos , Feminino , Puberdade Tardia/diagnóstico , Puberdade Tardia/etiologia , Puberdade Tardia/terapia , Hipogonadismo/diagnóstico , Hipogonadismo/terapia , Hipogonadismo/congênito , PuberdadeRESUMO
Central precocious puberty (CPP) is the premature activation of the hypothalamus-pituitary-gonadal axis, resulting in the early development of secondary sexual characteristics. CPP classically occurs before the age of 8 years in girls and 9 years in boys. The aetiology of this precocious onset of puberty is governed by complex mechanistic interactions between genetic and environmental factors. The rates of CPP have been documented to have been rising before the COVID-19 pandemic; despite this, the incidence of CPP has increased exponentially since the start of the pandemic. There are multiple theories potentially explaining this change in incidence of CPP over COVID-19. These include the direct effect of SARS-coV-2 infection, increasing body mass index of adolescents over sequential lockdowns, changes in sleep patterns, increased use of electronic devices and levels of stress, and additionally potential earlier detection of signs of CPP by parents and carers. Whilst there is evidence from observational cohorts, case studies and animal models for each of these factors, it is difficult to definitively prove which has had the greatest impact due to the mainly retrospective nature of the human research that has been conducted. Moreover, studies set in diverse settings with varying population make comparison complex. Additionally, each country responded differently to the COVID-19 pandemic and the lockdowns varied between locations, hence the effect of lockdown was not equal or universal. Despite this, similar trends have been identified, with various lifestyle changes that occurred over the pandemic being potentially influential factors on the development of CPP.
Assuntos
COVID-19 , Puberdade Precoce , Masculino , Feminino , Humanos , Adolescente , Criança , COVID-19/epidemiologia , COVID-19/complicações , Puberdade Precoce/epidemiologia , Puberdade Precoce/etiologia , Puberdade Precoce/diagnóstico , Pandemias , Estudos Retrospectivos , Incidência , SARS-CoV-2 , Controle de Doenças Transmissíveis , Hormônio Liberador de GonadotropinaRESUMO
Infants born with severe central disorders of the hypothalamic-pituitary-gonadal axis leading to gonadotropin deficiency not only lack pubertal development in adolescence, but also lack infantile mini-puberty. This period of mini-puberty, where infants have gonadotropin and sex steroid concentrations up into the adult range, is vital for future reproductive capacity, particularly in boys. At present, there is no consensus on the diagnosis or management of infants with gonadotropin deficiency due to congenital hypogonadotropic hypogonadism or multiple pituitary hormone deficiency. Case series suggest that gonadotropin treatment in male infants with absent mini-puberty is effective in promoting both testicular descent in those with undescended testes and also facilitating increased penile size. Moreover, replacement with follicle-stimulating hormone increases the testicular Sertoli cell population, measurable as an increase in testicular volume and inhibin B, thus hypothetically increasing the capacity for spermatogenesis in adult life for these patients. However, long-term follow-up data is limited for both outcomes pertaining to fertility and nonreproductive sequelae, including neurodevelopment and psychological well-being. The use of international registries for patients with gonadotropin deficiency is a key element in the collection of high-quality, geographically widespread data to inform best-practice management from birth to adulthood.
Assuntos
Hipogonadismo , Humanos , Masculino , Hipogonadismo/tratamento farmacológico , Hipogonadismo/congênito , Lactente , Gonadotropinas/uso terapêutico , Gonadotropinas/deficiência , Puberdade/fisiologia , Terapia de Reposição Hormonal/métodos , Testículo/metabolismo , Recém-NascidoRESUMO
There are 3 physiological waves of central hypothalamic-pituitary-gonadal (HPG) axis activity over the lifetime. The first occurs during fetal life, the second-termed "mini-puberty"-in the first months after birth, and the third at puberty. After adolescence, the axis remains active all through adulthood. Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder characterized by a deficiency in hypothalamic gonadotropin-releasing hormone (GnRH) secretion or action. In cases of severe CHH, all 3 waves of GnRH pulsatility are absent. The absence of fetal HPG axis activation manifests in around 50% of male newborns with micropenis and/or undescended testes (cryptorchidism). In these boys, the lack of the mini-puberty phase accentuates testicular immaturity. This is characterized by a low number of Sertoli cells, which are important for future reproductive capacity. Thus, absent mini-puberty will have detrimental effects on later fertility in these males. The diagnosis of CHH is often missed in infants, and even if recognized, there is no consensus on optimal therapeutic management. Here we review physiological mini-puberty and consequences of central HPG axis disorders; provide a diagnostic approach to allow for early identification of these conditions; and review current treatment options for replacement of mini-puberty in male infants with CHH. There is evidence from small case series that replacement with gonadotropins to mimic "mini-puberty" in males could have beneficial outcomes not only regarding testis descent, but also normalization of testis and penile sizes. Moreover, such therapeutic replacement regimens in disordered mini-puberty could address both reproductive and nonreproductive implications.
Assuntos
Hipogonadismo , Humanos , Masculino , Hipogonadismo/terapia , Hipogonadismo/tratamento farmacológico , Hipogonadismo/fisiopatologia , Sistema Hipotálamo-Hipofisário , Puberdade/fisiologia , Terapia de Reposição Hormonal , Hormônio Liberador de Gonadotropina/metabolismoRESUMO
OBJECTIVE: Hypogonadotropic hypogonadism is characterized by inadequate secretion of pituitary gonadotropins, leading to absent, partial, or arrested puberty. In males, classical treatment with testosterone promotes virilization but not testicular growth or spermatogenesis. To quantify treatment practices and efficacy, we systematically reviewed all studies investigating gonadotropins for the achievement of pubertal outcomes in males with hypogonadotropic hypogonadism. DESIGN: Systematic review and meta-analysis. METHODS: A systematic review of Medline, Embase, Global Health, and PsycINFO databases in December 2022. Risk of Bias 2.0/Risk Of Bias In Non-randomized Studies of Interventions/National Heart, Lung, and Blood Institute tools for quality appraisal. Protocol registered on PROSPERO (CRD42022381713). RESULTS: After screening 3925 abstracts, 103 studies were identified including 5328 patients from 21 countries. The average age of participants was <25 years in 45.6% (n = 47) of studies. Studies utilized human chorionic gonadotropin (hCG) (n = 93, 90.3% of studies), human menopausal gonadotropin (n = 42, 40.8%), follicle-stimulating hormone (FSH) (n = 37, 35.9%), and gonadotropin-releasing hormone (28.2% n = 29). The median reported duration of treatment/follow-up was 18 months (interquartile range 10.5-24 months). Gonadotropins induced significant increases in testicular volume, penile size, and testosterone in over 98% of analyses. Spermatogenesis rates were higher with hCG + FSH (86%, 95% confidence interval [CI] 82%-91%) as compared with hCG alone (40%, 95% CI 25%-56%). However, study heterogeneity and treatment variability were high. CONCLUSIONS: This systematic review provides convincing evidence of the efficacy of gonadotropins for pubertal induction. However, there remains substantial heterogeneity in treatment choice, dose, duration, and outcomes assessed. Formal guidelines and randomized studies are needed.
Assuntos
Hipogonadismo , Síndrome de Klinefelter , Humanos , Masculino , Gonadotropina Coriônica/uso terapêutico , Hormônio Foliculoestimulante , Hormônio Liberador de Gonadotropina , Gonadotropinas/uso terapêutico , Hipogonadismo/tratamento farmacológico , Espermatogênese , Testículo , Testosterona , Adulto JovemRESUMO
Congenital hypogonadotropic hypogonadism (CHH) is a rare endocrine disorder that results in reproductive hormone deficiency and reduced potential for fertility in adult life. Discoveries of the genetic aetiology of CHH have advanced dramatically in the past 30 years, with currently over 40 genes recognised to cause or contribute to the development of this condition. The genetic complexity of CHH is further increased by the observation of di- and oligogenic, as well as classic monogenic, inheritance and incomplete penetrance. Very recently in the UK, a panel of 14 genes has been curated for the genetic diagnosis of CHH within the NHS Genomic Medicine Service programme. The aim of this review is to appraise the advantages and potential pitfalls of the use of a CHH panel in clinical endocrine diagnostics, and to consider the future avenues for developing this panel including the potential of whole exome or whole genome sequencing data analysis in this condition.
Assuntos
Hipogonadismo , Adulto , Humanos , Hipogonadismo/diagnóstico , Hipogonadismo/genética , Hipogonadismo/congênito , Biologia MolecularRESUMO
Background: Fibroblast growth factor 21 (FGF21) is an essential metabolic regulator that adapts to changes in nutritional status. Severe childhood undernutrition induces elevated FGF21 levels, contributing to growth hormone (GH) resistance and subsequent linear growth attenuation potentially through a direct action on chondrocytes. Methods: In this study, we assessed expression of the components of both GH and FGF21 pathways in rare and unique human growth plates obtained from children. Moreover, we investigated the mechanistic interplay of FGF21 on GH receptor (GHR) signaling in a heterologous system. Results: Chronic FGF21 exposure increased GH-induced GHR turnover and SOCS2 expression, leading to the inhibition of STAT5 phosphorylation and IGF-1 expression. The clinical significance of FGF21 signaling through GH receptors was tested in nutritionally driven growth failure seen in very preterm (VPT) infants right after birth. VPT infants display an immediate linear growth failure after birth followed by growth catch-up. Consistent with the in vitro model data, we show that circulating FGF21 levels were elevated during deflection in linear growth compared to catch-up growth and were inversely correlated with the length velocity and circulating IGF1 levels. Conclusions: This study further supports a central role of FGF21 in GH resistance and linear growth failure and suggests a direct action on the growth plate.
Assuntos
Hormônio do Crescimento , Fator de Crescimento Insulin-Like I , Lactente , Criança , Humanos , Recém-Nascido , Hormônio do Crescimento/metabolismo , Recém-Nascido Prematuro , Fatores de Crescimento de Fibroblastos/metabolismo , Receptores da Somatotropina/genética , Receptores da Somatotropina/metabolismoRESUMO
Gonadotropin-releasing hormone (GnRH) deficiency (GD) is a disorder characterized by absent or delayed puberty, with largely unknown genetic causes. The purpose of this study was to obtain and exploit gene expression profiles of GnRH neurons during development to unveil novel biological mechanisms and genetic determinants underlying GD. Here, we combined bioinformatic analyses of immortalized and primary embryonic GnRH neuron transcriptomes with exome sequencing from GD patients to identify candidate genes implicated in the pathogenesis of GD. Among differentially expressed and filtered transcripts, we found loss-of-function (LoF) variants of the autism-linked neuroligin 3 (NLGN3) gene in two unrelated patients co-presenting with GD and neurodevelopmental traits. We demonstrated that NLGN3 is upregulated in maturing GnRH neurons and that NLGN3 wild-type, but not mutant, protein promotes neuritogenesis when overexpressed in developing GnRH cells. Our data represent proof of principle that this complementary approach can identify new candidate GD genes and demonstrate that LoF NLGN3 variants can contribute to GD. This novel genotype-phenotype correlation implies common genetic mechanisms underlying neurodevelopmental disorders, such as GD and autistic spectrum disorder.
Assuntos
Transtorno Autístico , Humanos , Transtorno Autístico/genética , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Hormônio Liberador de Gonadotropina/metabolismoRESUMO
Introduction: Delayed puberty (DP) is a frequent concern for adolescents. The most common underlying aetiology is self-limited DP (SLDP). However, this can be difficult to differentiate from the more severe condition congenital hypogonadotrophic hypogonadism (HH), especially on first presentation of an adolescent patient with DP. This study sought to elucidate phenotypic differences between the two diagnoses, in order to optimise patient management and pubertal development. Methods: This was a study of a UK DP cohort managed 2015-2023, identified through the NIHR clinical research network. Patients were followed longitudinally until adulthood, with a definite diagnosis made: SLDP if they had spontaneously completed puberty by age 18 years; HH if they had not commenced (complete, cHH), or had commenced but not completed puberty (partial, pHH), by this stage. Phenotypic data pertaining to auxology, Tanner staging, biochemistry, bone age and hormonal treatment at presentation and during puberty were retrospectively analysed. Results: 78 patients were included. 52 (66.7%) patients had SLDP and 26 (33.3%) patients had HH, comprising 17 (65.4%) pHH and 9 (34.6%) cHH patients. Probands were predominantly male (90.4%). Male SLDP patients presented with significantly lower height and weight standard deviation scores than HH patients (height p=0.004, weight p=0.021). 15.4% of SLDP compared to 38.5% of HH patients had classical associated features of HH (micropenis, cryptorchidism, anosmia, etc. p=0.023). 73.1% of patients with SLDP and 43.3% with HH had a family history of DP (p=0.007). Mean first recorded luteinizing hormone (LH) and inhibin B were lower in male patients with HH, particularly in cHH patients, but not discriminatory. There were no significant differences identified in blood concentrations of FSH, testosterone or AMH at presentation, or in bone age delay. Discussion: Key clinical markers of auxology, associated signs including micropenis, and serum inhibin B may help distinguish between SLDP and HH in patients presenting with pubertal delay, and can be incorporated into clinical assessment to improve diagnostic accuracy for adolescents. However, the distinction between HH, particularly partial HH, and SLDP remains problematic. Further research into an integrated framework or scoring system would be useful in aiding clinician decision-making and optimization of treatment. .
Assuntos
Hipogonadismo , Puberdade Tardia , Adolescente , Humanos , Masculino , Adulto , Feminino , Puberdade Tardia/diagnóstico , Estudos Retrospectivos , Testosterona , Hipogonadismo/diagnósticoRESUMO
BACKGROUND: Identification of genetic causes of central precocious puberty have revealed epigenetic mechanisms as regulators of human pubertal timing. MECP2, an X-linked gene, encodes a chromatin-associated protein with a role in gene transcription. MECP2 loss-of-function mutations usually cause Rett syndrome, a severe neurodevelopmental disorder. Early pubertal development has been shown in several patients with Rett syndrome. The aim of this study was to explore whether MECP2 variants are associated with an idiopathic central precocious puberty phenotype. METHODS: In this translational cohort study, participants were recruited from seven tertiary centres from five countries (Brazil, Spain, France, the USA, and the UK). Patients with idiopathic central precocious puberty were investigated for rare potentially damaging variants in the MECP2 gene, to assess whether MECP2 might contribute to the cause of central precocious puberty. Inclusion criteria were the development of progressive pubertal signs (Tanner stage 2) before the age of 8 years in girls and 9 years in boys and basal or GnRH-stimulated LH pubertal concentrations. Exclusion criteria were the diagnosis of peripheral precocious puberty and the presence of any recognised cause of central precocious puberty (CNS lesions, known monogenic causes, genetic syndromes, or early exposure to sex steroids). All patients included were followed up at the outpatient clinics of participating academic centres. We used high-throughput sequencing in 133 patients and Sanger sequencing of MECP2 in an additional 271 patients. Hypothalamic expression of Mecp2 and colocalisation with GnRH neurons were determined in mice to show expression of Mecp2 in key nuclei related to pubertal timing regulation. FINDINGS: Between Jun 15, 2020, and Jun 15, 2022, 404 patients with idiopathic central precocious puberty (383 [95%] girls and 21 [5%] boys; 261 [65%] sporadic cases and 143 [35%] familial cases from 134 unrelated families) were enrolled and assessed. We identified three rare heterozygous likely damaging coding variants in MECP2 in five girls: a de novo missense variant (Arg97Cys) in two monozygotic twin sisters with central precocious puberty and microcephaly; a de novo missense variant (Ser176Arg) in one girl with sporadic central precocious puberty, obesity, and autism; and an insertion (Ala6_Ala8dup) in two unrelated girls with sporadic central precocious puberty. Additionally, we identified one rare heterozygous 3'UTR MECP2 insertion (36_37insT) in two unrelated girls with sporadic central precocious puberty. None of them manifested Rett syndrome. Mecp2 protein colocalised with GnRH expression in hypothalamic nuclei responsible for GnRH regulation in mice. INTERPRETATION: We identified rare MECP2 variants in girls with central precocious puberty, with or without mild neurodevelopmental abnormalities. MECP2 might have a role in the hypothalamic control of human pubertal timing, adding to the evidence of involvement of epigenetic and genetic mechanisms in this crucial biological process. FUNDING: Fundação de Amparo à Pesquisa do Estado de São Paulo, Conselho Nacional de Desenvolvimento Científico e Tecnológico, and the Wellcome Trust.
Assuntos
Puberdade Precoce , Síndrome de Rett , Animais , Criança , Feminino , Humanos , Masculino , Camundongos , Brasil , Estudos de Coortes , Hormônio Foliculoestimulante , Hormônio Liberador de Gonadotropina , Hormônio Luteinizante/metabolismo , Puberdade Precoce/genética , Puberdade Precoce/diagnóstico , Síndrome de Rett/genética , Síndrome de Rett/complicaçõesRESUMO
CONTEXT: The melanocortin 3 receptor (MC3R) has recently emerged as a critical regulator of pubertal timing, linear growth, and the acquisition of lean mass in humans and mice. In population-based studies, heterozygous carriers of deleterious variants in MC3R report a later onset of puberty than noncarriers. However, the frequency of such variants in patients who present with clinical disorders of pubertal development is currently unknown. OBJECTIVE: This work aimed to determine whether deleterious MC3R variants are more frequently found in patients clinically presenting with constitutional delay of growth and puberty (CDGP) or normosmic idiopathic hypogonadotropic hypogonadism (nIHH). METHODS: We examined the sequence of MC3R in 362 adolescents with a clinical diagnosis of CDGP and 657 patients with nIHH, experimentally characterized the signaling properties of all nonsynonymous variants found and compared their frequency to that in 5774 controls from a population-based cohort. Additionally, we established the relative frequency of predicted deleterious variants in individuals with self-reported delayed vs normally timed menarche/voice-breaking in the UK Biobank cohort. RESULTS: MC3R loss-of-function variants were infrequent but overrepresented in patients with CDGP (8/362 [2.2%]; OR = 4.17; P = .001). There was no strong evidence of overrepresentation in patients with nIHH (4/657 [0.6%]; OR = 1.15; P = .779). In 246 328 women from the UK Biobank, predicted deleterious variants were more frequently found in those self-reporting delayed (aged ≥16 years) vs normal age at menarche (OR = 1.66; P = 3.90E-07). CONCLUSION: We have found evidence that functionally damaging variants in MC3R are overrepresented in individuals with CDGP but are not a common cause of this phenotype.
Assuntos
Hipogonadismo , Puberdade Tardia , Adolescente , Humanos , Feminino , Animais , Camundongos , Receptor Tipo 3 de Melanocortina , Prevalência , Hipogonadismo/epidemiologia , Hipogonadismo/genética , Hipogonadismo/complicações , Puberdade Tardia/epidemiologia , Puberdade Tardia/genética , Puberdade Tardia/diagnóstico , Puberdade/genética , Transtornos do Crescimento/genéticaRESUMO
This guideline is written as a reference document for clinicians presented with the challenge of managing paediatric patients with differentiated thyroid carcinoma up to the age of 19 years. Care of paediatric patients with differentiated thyroid carcinoma differs in key aspects from that of adults, and there have been several recent developments in the care pathways for this condition; this guideline has sought to identify and attend to these areas. It addresses the presentation, clinical assessment, diagnosis, management (both surgical and medical), genetic counselling, follow-up and prognosis of affected patients. The guideline development group formed of a multi-disciplinary panel of sub-speciality experts carried out a systematic primary literature review and Delphi Consensus exercise. The guideline was developed in accordance with The Appraisal of Guidelines Research and Evaluation Instrument II criteria, with input from stakeholders including charities and patient groups. Based on scientific evidence and expert opinion, 58 recommendations have been collected to produce a clear, pragmatic set of management guidelines. It is intended as an evidence base for future optimal management and to improve the quality of clinical care of paediatric patients with differentiated thyroid carcinoma.
Assuntos
Neoplasias da Glândula Tireoide , Adulto , Criança , Humanos , Prognóstico , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/terapia , Reino Unido , Adulto JovemRESUMO
CONTEXT: Pubertal delay can be the clinical presentation of both idiopathic hypogonadotropic hypogonadism (IHH) and self-limited delayed puberty (SLDP). Distinction between these conditions is a common but important diagnostic challenge in adolescents. OBJECTIVE: To assess whether gene panel testing can assist with clinical differential diagnosis and to allow accurate and timely management of delayed puberty patients. DESIGN: Retrospective study. METHODS: Patients presenting with delayed puberty to UK Paediatric services, followed up to final diagnosis, were included. Whole-exome sequencing was analysed using a virtual panel of genes previously reported to cause either IHH or SLDP to identify rarely predicted deleterious variants. Deleterious variants were verified by in silico prediction tools. The correlation between clinical and genotype diagnosis was analysed. RESULTS: Forty-six patients were included, 54% with a final clinical diagnosis of SLDP and 46% with IHH. Red flags signs of IHH were present in only three patients. Fifteen predicted deleterious variants in 12 genes were identified in 33% of the cohort, with most inherited in a heterozygous manner. A fair correlation between final clinical diagnosis and genotypic diagnosis was found. Panel testing was able to confirm a diagnosis of IHH in patients with pubertal delay. Genetic analysis identified three patients with IHH that had been previously diagnosed as SLDP. CONCLUSION: This study supports the use of targeted exome sequencing in the clinical setting to aid the differential diagnosis between IHH and SLDP in adolescents presenting with pubertal delay. Genetic evaluation thus facilitates earlier and more precise diagnosis, allowing clinicians to direct treatment appropriately.
Assuntos
Puberdade Tardia/diagnóstico , Puberdade Tardia/genética , Adolescente , Estudos de Coortes , Biologia Computacional , Simulação por Computador , Diagnóstico Diferencial , Exoma/genética , Feminino , Testes Genéticos , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Hipogonadismo/genética , Masculino , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sequenciamento do ExomaRESUMO
Developmental abnormalities of the gonadotropin-releasing hormone (GnRH) neuronal network result in a range of conditions from idiopathic hypogonadotropic hypogonadism to self-limited delayed puberty. We aimed to discover important underlying regulators of self-limited delayed puberty through interrogation of GnRH pathways. Whole exome sequencing (WES) data consisting of 193 individuals, from 100 families with self-limited delayed puberty, was analysed using a virtual panel of genes related to GnRH development and function (n = 12). Five rare predicted deleterious variants in Coiled-Coil Domain Containing 141 (CCDC141) were identified in 21 individuals from 6 families (6% of the tested cohort). Homology modeling predicted all five variants to be deleterious. CCDC141 mutant proteins showed atypical subcellular localization associated with abnormal distribution of acetylated tubulin, and expression of mutants resulted in a significantly delayed cell migration, demonstrated in transfected HEK293 cells. These data identify mutations in CCDC141 as a frequent finding in patients with self-limited delayed puberty. The mis-localization of acetylated tubulin and reduced cell migration seen with mutant CCDC141 suggests a role of the CCDC141-microtubule axis in GnRH neuronal migration, with heterozygous defects potentially impacting the timing of puberty.