RESUMEN

Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.

Asunto(s)

Frecuencia de los Genes , Menarquia , Pubertad , Humanos , Femenino , Menarquia/genética , Pubertad/genética , Animales , Herencia Multifactorial/genética , Ratones , Estudio de Asociación del Genoma Completo , Adolescente , Pubertad Precoz/genética , Polimorfismo de Nucleótido Simple , Receptores Acoplados a Proteínas G/genética , Pubertad Tardía/genética , Niño

RESUMEN

PURPOSE: 17α Hydroxylase/17,20 lyase deficiency (17OHD) is a rare form of congenital adrenal hyperplasia, typically diagnosed in late adolescence with symptoms of pubertal delay and hypertension. This study aimed to determine the clinical and laboratory characteristics of 17OHD cases and gather data on disease management. METHODS: Data from 97 nationwide cases were analyzed using the CEDD-NET web system. Diagnostic, follow-up findings, and final heights of patients were evaluated. RESULTS: Mean age at admission was 13.54 ± 4.71 years, with delayed puberty as the most common complaint. Hypertension was detected in 65% at presentation; hypokalemia was present in 34%. Genetic analysis revealed Exon 1-6 homozygous deletion as the most frequent mutation, identified in 42 cases. Hydrocortisone replacement was universal; pubertal replacement was administered to 66 cases. Antihypertensive treatment was required in 57 (90%) patients. Thirty-seven cases reached final height, with an average SD of 0.015 in 46,XX and -1.43 in 46,XY. Thelarche and pubarche did not develop properly in some cases despite estradiol treatment. CONCLUSION: This study represents the largest cohort of pediatric cases of 17-hydroxylase deficiency (17OHD) documented in the literature. Hypertension and hypokalemia can serve as guiding indicators for early diagnosis.The final height is typically considered to be normal. The relationship between genotype and phenotype remains elusive. The initial genetic test for exon 1-6 deletions may be MLPA in our region.

Asunto(s)

Hiperplasia Suprarrenal Congénita , Adolescente , Niño , Preescolar , Femenino , Humanos , Masculino , Hiperplasia Suprarrenal Congénita/genética , Estudios de Cohortes , Hipertensión/genética , Hipopotasemia/genética , Pubertad Tardía/genética , Esteroide 17-alfa-Hidroxilasa/genética , Turquía/epidemiología

RESUMEN

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.

Asunto(s)

Hipogonadismo , Pubertad Tardía , Adolescente , Humanos , Femenino , Animales , Ratones , Receptor de Melanocortina Tipo 3 , Prevalencia , Hipogonadismo/epidemiología , Hipogonadismo/genética , Hipogonadismo/complicaciones , Pubertad Tardía/epidemiología , Pubertad Tardía/genética , Pubertad Tardía/diagnóstico , Pubertad/genética , Trastornos del Crecimiento/genética

RESUMEN

OBJECTIVES: Although at least 598 genes are involved in the development of the hypothalamo-pituitary-testicular (HPT) axis, mutations in only 75 genes have so far been shown to cause delayed puberty. METHODS: Six male patients with failed puberty, manifested as absence of pubertal changes by 18 years of age, underwent whole exome sequencing of genomic DNA with subsequent bioinformatics analysis and confirmation of selected variants by Sanger sequencing. Genes having plausibly pathogenic non-synonymous variants were characterized as group A (previously reported to cause delayed puberty), group B (expressed in the HPT-axis but no mutations therein were reported to cause delayed puberty) or group C (not reported previously to be connected with HPT-axis). RESULTS: We identified variants in genes involved in GnRH neuron differentiation (2 in group A, 1 in group C), GnRH neuron migration (2 each in groups A and C), development of GnRH neural connections with supra-hypothalamic and hypothalamic neurons (2 each in groups A and C), neuron homeostasis (1 in group C), molecules regulating GnRH neuron activity (2 each in groups B and C), receptors/proteins expressed on GnRH neurons (1 in group B), signaling molecules (3 in group C), GnRH synthesis (1 in group B), gonadotropins production and release (1 each in groups A, B, and C) and action of the steroid hormone (1 in group A). CONCLUSIONS: Non-synonymous variants were identified in 16 genes of the HPT-axis, which comprised 4 in group A that contains genes previously reported to cause delayed puberty, 4 in group B that are expressed along HPT-axis but no mutations therein were reported previously to cause delayed puberty and 8 in group C that contains novel candidate genes, suggesting wider genetic causes of failed male puberty.

Asunto(s)

Pubertad Tardía , Humanos , Masculino , Pubertad Tardía/genética , Secuenciación del Exoma , Hormona Liberadora de Gonadotropina/genética , Gonadotropinas , Pubertad

RESUMEN

Puberty marks the end of childhood and is a period when individuals undergo physiological and psychological changes to achieve sexual maturation and fertility. The onset of puberty is first detected as an increase in pulsatile secretion of gonadotropin-releasing hormone (GnRH). Pubertal onset is regulated by genetic, nutritional, environmental, and socio-economic factors. Disturbances affecting pubertal timing result in adverse health conditions later in life. Human genetic studies show that around 50-80% of the variation in pubertal onset is genetically determined. The genetic control of pubertal timing has been a field of active investigation in attempt to better understand the neuroendocrine control of this relevant period of life. Large populational studies and patient cohort-based studies have provided insights into the genetic regulation of pubertal onset. In this review, we discuss these discoveries and discuss potential mechanisms for how implicated genes may affect pubertal timing.

Asunto(s)

Pubertad Tardía , Pubertad , Hormona Liberadora de Gonadotropina/genética , Humanos , Pubertad/genética , Pubertad Tardía/genética , Maduración Sexual/genética

RESUMEN

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.

Asunto(s)

Hipogonadismo , Pubertad Tardía , Humanos , Hipogonadismo/genética , Pubertad/genética , Pubertad Tardía/diagnóstico , Pubertad Tardía/genética

RESUMEN

Distinguishing between self limited delayed puberty (SLDP) and congenital hypogonadotropic hypogonadism (CHH) may be tricky as they share clinical and biochemical characteristics. and appear to lie within the same clinical spectrum. However, one is classically transient (SDLP) while the second is typically a lifetime condition (CHH). The natural history and long-term outcomes of these two conditions differ significantly and thus command distinctive approaches and management. Because the first presentation of SDLP and CHH is very similar (delayed puberty with low LH and FSH and low sex hormones), the scientific community is scrambling to identify diagnostic tests that can allow a correct differential diagnosis among these two conditions, without having to rely on the presence or absence of phenotypic red flags for CHH that clinicians anyway seem to find hard to process. Despite the heterogeneity of genetic defects so far reported in DP, genetic analysis through next-generation sequencing technology (NGS) had the potential to contribute to the differential diagnostic process between SLDP and CHH. In this review we will provide an up-to-date overview of the genetic architecture of these two conditions and debate the benefits and the bias of performing genetic analysis seeking to effectively differentiate between these two conditions.

Asunto(s)

Hipogonadismo , Pubertad Tardía , Humanos , Pubertad Tardía/diagnóstico , Pubertad Tardía/genética , Hipogonadismo/diagnóstico , Hipogonadismo/genética , Hipogonadismo/congénito , Diagnóstico Diferencial

RESUMEN

The pubertal development onset is controlled by a network of genes that regulate the gonadotropin releasing hormone (GnRH) pulsatile release and the subsequent increase of the circulating levels of pituitary gonadotropins that activate the gonadal function. Although the transition from pre-pubertal condition to puberty occurs physiologically in a delimited age-range, the inception of pubertal development can be anticipated or delayed due to genetic and epigenetic changes or environmental conditions. Most of the genetic and epigenetic alterations concern genes which encode for kisspeptin, GnRH, LH, FSH and their receptor, which represent crucial factors of the hypothalamic-pituitary-gonadal (HPG) axis. Recent data indicate a central role of the epigenome in the regulation of genes in the hypothalamus and pituitary that could mediate the flexibility of pubertal timing. Identification of epigenetically regulated genes, such as Makorin ring finger 3 (MKRN3) and Delta-like 1 homologue (DLK1), respectively responsible for the repression and the activation of pubertal development, provides additional evidence of how epigenetic variations affect pubertal timing. This review aims to investigate genetic, epigenetic, and environmental factors responsible for the regulation of precocious and delayed puberty.

Asunto(s)

Pubertad Tardía , Pubertad Precoz , Humanos , Pubertad Precoz/genética , Pubertad Tardía/genética , Hormona Liberadora de Gonadotropina/genética , Hormona Liberadora de Gonadotropina/metabolismo , Pubertad/genética , Epigénesis Genética , Ubiquitina-Proteína Ligasas/genética

RESUMEN

BACKGROUND: Variants of chromodomain helicase DNA binding protein 7 (CHD7) gene are commonly associated with Kallmann syndrome (KS) and account for 5-6% of idiopathic hypogonadotropic hypogonadism (IHH) cases. Here we report a novel mutation of CHD7 gene in a patient with KS, which may contribute to the better understanding of KS. CASE PRESENTATION: A 29-year-old male patient with KS and a chief complaint of delayed puberty for 13 years (Tanner B Stage< 4) was admitted to the Department of Endocrinology of the First Affiliated Hospital of Zhejiang University (Hangzhou, China) in September 2019. Dual-energy X-ray absorptiometry (DEXA) showed low bone density in both lumbar spine (L1 ~ L5 mean Z-score - 3.0) and femoral neck (Z-score - 2.7). Dynamic contrast-enhanced magnetic resonance imaging (MRI) of pituitary and contrast-enhanced computed tomography (CT) showed no abnormal findings. Ophthalmological evaluation showed that his both eyes showed exotropia, and no sight loss was noted. Heterozygous c.1619G > T mutation of TCD7 gene (p.G4856V) was detected, whereas none of his family members had this mutation. Human chorionic gonadotropin (HCG) and human menopausal gonadotropin (HMG) were injected for three times/week to treat idiopathic hypogonadotropic hypogonadism (IHH). After several months of therapy, the patient's health condition improved. His testicles became larger, and his secondary sexual characteristics improved after treatment. CONCLUSION: Exploration of the novel splice-site mutation of CHD7 may further our current understanding of KS.

Asunto(s)

ADN Helicasas/genética , Proteínas de Unión al ADN/genética , Síndrome de Kallmann/genética , Mutación Missense , Adulto , China , Análisis Mutacional de ADN , Heterocigoto , Humanos , Hipogonadismo/diagnóstico , Hipogonadismo/genética , Hipogonadismo/terapia , Síndrome de Kallmann/complicaciones , Síndrome de Kallmann/diagnóstico , Síndrome de Kallmann/terapia , Imagen por Resonancia Magnética , Masculino , Polimorfismo de Nucleótido Simple , Pubertad Tardía/diagnóstico , Pubertad Tardía/etiología , Pubertad Tardía/genética , Pubertad Tardía/terapia , Tomografía Computarizada por Rayos X

RESUMEN

OBJECTIVE: The diagnosis of growth hormone deficiency (GHD) in children is not always straightforward because insulin-like growth factor 1 (IGF-I) or GH stimulation tests may not be able to discriminate GHD from constitutional delay of growth and puberty (CDGP) or other causes of short stature. DESIGN: Boys and girls (n = 429, 0.7-16 years) who attended our department for short stature participated in this study. They were followed up for an average period of 9 years. At the end of follow-up after reaching the final height, a definitive diagnosis was assigned, and all the components of ternary complex (IGF-I, IGF-binding protein-3 (IGFBP-3), acid-labile subunit (ALS), and IGF-I/IGFBP-3 ratio) were evaluated as biomarkers for the respective diagnosis. RESULTS: All the components of the ternary complex were tightly correlated with each other and were positively related to age. IGF-I, IGFBP-3, ALS, and IGF-I/IGFBP-3 ratio differed significantly between GHD and normal groups. IGF-I and ALS levels were lower in GHD compared to children with familial short stature, while IGF-I and IGF-I/IGFBP-3 ratio was significantly lower in GHD compared to children with CDGP. IGF-I and IGF-I/IGFBP-3 receiver operating curve cutoff points were unable to discriminate between GHD and normal groups or between GHD and CDGP groups. CONCLUSION: Despite the tight correlation among all the components of the ternary complex, each one shows a statistically significant diagnosis-dependent alteration. There is a superiority of IGF-I, ALS, and IGF-I/IGFBP-3 ratio in the distinction between GHD and CDGP or between GHD and normal groups but without usable discriminating power, making auxology as the primary criterion for establishing the diagnosis.

Asunto(s)

Estatura/genética , Factor I del Crecimiento Similar a la Insulina/análisis , Adolescente , Biomarcadores , Niño , Preescolar , Enanismo Hipofisario/genética , Femenino , Estudios de Seguimiento , Hormona de Crecimiento Humana/deficiencia , Humanos , Lactante , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/análisis , Factor I del Crecimiento Similar a la Insulina/genética , Masculino , Pubertad Tardía/genética , Curva ROC

RESUMEN

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.

Asunto(s)

Pubertad Tardía/diagnóstico , Pubertad Tardía/genética , Adolescente , Estudios de Cohortes , Biología Computacional , Simulación por Computador , Diagnóstico Diferencial , Exoma/genética , Femenino , Pruebas Genéticas , Variación Genética , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Hipogonadismo/genética , Masculino , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Estudios Retrospectivos , Secuenciación del Exoma

RESUMEN

The semaphorin protein family is a diverse set of extracellular signaling proteins that perform fundamental roles in the development and operation of numerous biological systems, notably the nervous, musculoskeletal, cardiovascular, endocrine, and reproductive systems. Recently, recessive loss-of-function (LoF) variants in SEMA3A (semaphorin 3A) have been shown to result in a recognizable syndrome characterized by short stature, skeletal abnormalities, congenital heart defects, and variable additional anomalies. Here, we describe the clinical and molecular characterization of a female patient presenting with skeletal dysplasia, hypogonadotropic hypogonadism (HH), and anosmia who harbors a nonsense variant c.1633C>T (p.Arg555*) and a deletion of exons 15, 16, and 17 in SEMA3A in the compound heterozygous state. These variants were identified through next-generation sequencing analysis of a panel of 26 genes known to be associated with HH/Kallmann syndrome. Our findings further substantiate the notion that biallelic LoF SEMA3A variants cause a syndromic form of short stature and expand the phenotypic spectrum associated with this condition to include features of Kallmann syndrome.

Asunto(s)

Anomalías Múltiples/genética , Anosmia/genética , Codón sin Sentido , Enanismo/genética , Cardiopatías Congénitas/genética , Hipogonadismo/genética , Mutación con Pérdida de Función , Semaforina-3A/genética , Alelos , Pie Equinovaro/genética , Codón sin Sentido/genética , Femenino , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Recién Nacido , Síndrome de Kallmann/genética , Hipotonía Muscular/genética , Pectus Carinatum/genética , Fenotipo , Pubertad Tardía/genética , Escoliosis/genética , Semaforina-3A/deficiencia , Síndrome

RESUMEN

Delayed puberty may signify a common variation of normal development, or indicate the presence of a pathologic process. Constitutional delay of growth and puberty is a strongly familial type of developmental pattern and accounts for the vast majority of children who are "late bloomers." Individuals with sex chromosomal abnormalities frequently have hypergonadotropic hypogonadism. There are currently 4 known monogenic causes of central precocious puberty. The primary treatment goal in children with hypogonadism is to mimic normal pubertal progression, while the primary aims for the management of precocious puberty are preservation of height potential and prevention of further pubertal development.

Asunto(s)

Hipogonadismo/tratamiento farmacológico , Hipogonadismo/genética , Pubertad Tardía/tratamiento farmacológico , Pubertad Tardía/genética , Pubertad Precoz/tratamiento farmacológico , Pubertad Precoz/genética , Adolescente , Niño , Humanos

RESUMEN

Acid-labile subunit (ALS) deficiency (ACLSD) constitutes the first monogenic defect involving a member of the Insulin-like Growth Factor (IGF) binding protein system. The lack of ALS completely disrupts the circulating IGF system. Autocrine/paracrine action of local produced IGF-I could explain the mild effect on growth. In the present work we have revised the more relevant clinical and biochemical consequences of complete ACLSD in 61 reported subjects from 31 families. Low birth weight and/or length, reduced head circumference, height between -2 and -3 SD, pubertal delay and insulin resistance are commonly observed. Partial ACLSD could be present in children initially labeled as idiopathic short stature, presenting low IGF-I levels, suggesting that one functional IGFALS allele is insufficient to stabilize ternary complexes. Dysfunction of the GH-IGF axis observed in ACLSD may eventually result in increased risk for type-2 diabetes and tumor progression. Consequently, long term surveillance is recommended in these patients.

Asunto(s)

Proteínas Portadoras/fisiología , Glicoproteínas/fisiología , Hormona de Crecimiento Humana/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Estatura/efectos de los fármacos , Estatura/genética , Proteínas Portadoras/genética , Proteínas Portadoras/farmacología , Niño , Femenino , Glicoproteínas/deficiencia , Glicoproteínas/genética , Glicoproteínas/farmacología , Trastornos del Crecimiento/genética , Trastornos del Crecimiento/metabolismo , Humanos , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Masculino , Pubertad Tardía/genética , Pubertad Tardía/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología

RESUMEN

Objectives Congenital hypogonadotropic hypogonadism (CHH) is a rare condition resulting from GnRH deficiency. Gonadotropin Releasing Hormone 1 (GNRH1) homozygous mutations are an extremely rare cause of normosmic CHH (nCHH). Most heterozygous individuals are asymptomatic, with the notable exception of individuals heterozygous for a p.R31C GNRH1 mutation. Case presentation The patient is an index case from a consanguineous family, presenting with severe CHH and his parents presenting with late puberty and normal fertility. The index case is homozygous for a p.R31H GNRH1 variant, both parents being heterozygous. The analysis of a panel of genes implicated in CHH does not show any other clinically relevant variant in any other gene tested. Conclusions GNRH1 mutations are a rare cause of nCHH. Five different mutations have been reported so far in homozygous individuals. Most are frameshift in nature but the one reported here causes an amino acid change in the Gonadotropin-releasing hormone (GnRH) decapeptide. Both independently reported patients with the p.R31H mutation are from Turkish origin. The question of the possible role of this mutation in the late puberty of the heterozygous parents needs further documentation. An analogy is made with the heterozygous individuals carrying the p.R31C and displaying partial CHH. No nonreproductive disorder is noted.

Asunto(s)

Hormona Liberadora de Gonadotropina/genética , Homocigoto , Hipogonadismo/genética , Mutación , Precursores de Proteínas/genética , Pubertad Tardía/genética , Adolescente , Adulto , Femenino , Heterocigoto , Humanos , Hipogonadismo/congénito , Hipogonadismo/patología , Lactante , Masculino , Pronóstico , Adulto Joven

RESUMEN

The initiation of puberty is driven by an upsurge in hypothalamic gonadotropin-releasing hormone (GnRH) secretion. In turn, GnRH secretion upsurge depends on the development of a complex GnRH neuroendocrine network during embryonic life. Although delayed puberty (DP) affects up to 2% of the population, is highly heritable, and is associated with adverse health outcomes, the genes underlying DP remain largely unknown. We aimed to discover regulators by whole-exome sequencing of 160 individuals of 67 multigenerational families in our large, accurately phenotyped DP cohort. LGR4 was the only gene remaining after analysis that was significantly enriched for potentially pathogenic, rare variants in 6 probands. Expression analysis identified specific Lgr4 expression at the site of GnRH neuron development. LGR4 mutant proteins showed impaired Wnt/ß-catenin signaling, owing to defective protein expression, trafficking, and degradation. Mice deficient in Lgr4 had significantly delayed onset of puberty and fewer GnRH neurons compared with WT, whereas lgr4 knockdown in zebrafish embryos prevented formation and migration of GnRH neurons. Further, genetic lineage tracing showed strong Lgr4-mediated Wnt/ß-catenin signaling pathway activation during GnRH neuron development. In conclusion, our results show that LGR4 deficiency impairs Wnt/ß-catenin signaling with observed defects in GnRH neuron development, resulting in a DP phenotype.

Asunto(s)

Neuronas , Pubertad Tardía , Receptores Acoplados a Proteínas G/deficiencia , Vía de Señalización Wnt , Animales , Femenino , Estudios de Seguimiento , Hormona Liberadora de Gonadotropina/genética , Hormona Liberadora de Gonadotropina/metabolismo , Humanos , Masculino , Ratones , Neuronas/metabolismo , Neuronas/patología , Pubertad Tardía/genética , Pubertad Tardía/metabolismo , Pubertad Tardía/patología , Receptores Acoplados a Proteínas G/metabolismo , beta Catenina/genética , beta Catenina/metabolismo

RESUMEN

Delayed puberty is a common reason of pediatric endocrinological consultation. It is often a self-limited (or constitutional) condition with a strong familial basis. The type of inheritance is variable but most commonly autosomal dominant. Despite this strong genetic determinant, mutations in genes implicated in the regulation of hypothalamic-pituitary-gonadal axis have rarely been identified in cases of self-limited delayed puberty and often in relatives of patients with congenital hypogonadotropic hypogonadism (i.e., FGFR1 and GNRHR genes). However, recently, next-generation sequencing analysis has led to the discovery of new genes (i.e., IGSF10, HS6ST1, FTO, and EAP1) that are implicated in determining isolated self-limited delayed puberty in some families. Despite the heterogeneity of genetic defects resulting in delayed puberty, genetic testing may become a useful diagnostic tool for the correct classification and management of patients with delayed puberty. This article will discuss the benefits and the limitations of genetic testing execution in cases of delayed puberty.

Asunto(s)

Marcadores Genéticos , Hipogonadismo/fisiopatología , Pubertad Tardía/diagnóstico , Niño , Estudios de Evaluación como Asunto , Humanos , Hipogonadismo/congénito , Pubertad Tardía/etiología , Pubertad Tardía/genética

RESUMEN

Distinguishing between constitutional delay of growth and puberty (CDGP) and congenital hypogonadotropic hypogonadism (CHH) may be challenging. CDGP and CHH appear to belong to the same clinical spectrum (with low sex hormones and low LH and FSH), although one is classically transient and known as a self-limited form of delayed puberty (CDGP) while the other is permanent (CHH). Thus, the clinical history and the outcomes of these two conditions require different approaches, and an adequate and timely management for the patients is mandatory. Since the initial presentation of CDGP and CHH is almost identical and given the similarities of CDGP and partial forms of CHH (i.e. patients with partial and early interrupted pubertal development) the scientific community has been struggling to find some diagnostic tests able to allow an accurate differential diagnosis between these two conditions in delayed puberty. In this review we provide an up to date insight on the tests available, their meanings and accuracy, as well as some clues to effectively differentiate between constitutional pubertal delay and pathologic CHH.

Asunto(s)

Trastornos del Crecimiento/diagnóstico , Hipogonadismo/diagnóstico , Pubertad Tardía/diagnóstico , Diagnóstico Diferencial , Femenino , Hormona Folículo Estimulante/sangre , Humanos , Hipogonadismo/sangre , Hipogonadismo/congénito , Hipogonadismo/genética , Inhibinas/sangre , Insulina/sangre , Kisspeptinas/sangre , Hormona Luteinizante/sangre , Masculino , Proteínas , Pubertad Tardía/etiología , Pubertad Tardía/genética , Receptores de Péptidos/sangre , Receptores de Factores de Crecimiento Transformadores beta/sangre , Factores Sexuales , Factores de Tiempo

RESUMEN

Pathogenic variants in components of the minor spliceosome have been associated with several human diseases. Recently, it was reported that biallelic RNPC3 variants lead to severe isolated growth hormone deficiency and pituitary hypoplasia. The RNPC3 gene codes for the U11/U12-65K protein, a component of the minor spliceosome. The minor spliceosome plays a role in the splicing of minor (U12-type) introns, which are present in ~700-800 genes in humans and represent about 0.35% of all introns. Here, we report a second family with biallelic RNPC3 variants in three siblings with a growth hormone deficiency, central congenital hypothyroidism, congenital cataract, developmental delay/intellectual deficiency and delayed puberty. These cases further confirm the association between biallelic RNPC3 variants and severe postnatal growth retardation due to growth hormone deficiency. Furthermore, these cases show that the phenotype of this minor spliceosome-related disease might be broader than previously described.

Asunto(s)

Hipotiroidismo Congénito/genética , Discapacidades del Desarrollo/genética , Enanismo Hipofisario/genética , Proteínas Nucleares/genética , Proteínas de Unión al ARN/genética , Adolescente , Adulto , Catarata , Niño , Preescolar , Hipotiroidismo Congénito/complicaciones , Hipotiroidismo Congénito/patología , Discapacidades del Desarrollo/complicaciones , Discapacidades del Desarrollo/patología , Enanismo Hipofisario/complicaciones , Enanismo Hipofisario/diagnóstico , Enanismo Hipofisario/patología , Femenino , Hormona del Crecimiento/deficiencia , Hormona del Crecimiento/genética , Humanos , Intrones/genética , Masculino , Fenotipo , Pubertad Tardía/complicaciones , Pubertad Tardía/genética , Pubertad Tardía/patología , Empalme del ARN/genética , Empalmosomas/genética , Empalmosomas/patología , Adulto Joven

RESUMEN

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.

Asunto(s)

Técnicas de Diagnóstico Endocrino , Kisspeptinas/administración & dosificación , Hormona Luteinizante/sangre , Pubertad Tardía/diagnóstico , Adolescente , Femenino , Hormona Folículo Estimulante/sangre , Estudios de Seguimiento , Pruebas Genéticas/métodos , Hormona Liberadora de Gonadotropina/administración & dosificación , Humanos , Inhibinas/sangre , Estudios Longitudinales , Masculino , Valor Predictivo de las Pruebas , Estudios Prospectivos , Pubertad Tardía/sangre , Pubertad Tardía/genética , Valores de Referencia , Secuenciación del Exoma