Academic literature on the topic 'Hypogonadism/genetics'

Les hypogonadismes hypogonadotropes congénitaux (CHH) sont des maladies héréditaires caractérisées par un déficit de sécrétion des gonadotrophines par l’hypophyse, à l’origine d’une infertilité ou d’une absence complète de puberté. On distingue les formes isolées avec olfaction normale (nCHH) et les formes syndromiques associant au déficit gonadotrope d’autres signes, tel qu’un défaut d’olfaction dans le cas du syndrome de Kallmann (SK), la forme plus fréquente de CHH. Les gènes identifiés dans le SK participent au développement embryonnaire et les gènes des nCHH sont impliqués dans la régulation de la sécrétion de la GnRH ou de son action. A ce stade, deux populations de neurones hypothalamiques gonadotropes sont connues, le neurone à GnRH et le neurone KNDy, sécrétant les Kisspeptines et la Neurokinine B. On estimait que l’ensemble des gènes identifiés couvraient moins de 20% des étiologies génétiques. L’objectif de ce doctorat était d’étudier prévalences et mécanismes physiopathologiques des gènes connus et d’identifier de nouvelles étiologies génétiques de CHH. Dans la première partie, nous avons caractérisé la fonctionnalité de tous les variants identifiés sur les gènes KISS1R, TACR3 et TAC3. Cela a permis de préciser les prévalences chez 600 patients, d’identifier un profil neuroendocrinien propre à l’altération de la signalisation Neurokinine B et de démontrer l’implication des Kisspeptines au cours de la vie embryonnaire. Enfin, nous proposons un modèle d’interaction entre le neurone à GnRH et le neurone KNDy. Dans la seconde partie, nous avons identifié deux nouveaux gènes, SEMA3A dans une forme familiale de SK et PNPLA6 dans une forme familiale rare de CHH syndromique. En conclusion, notre connaissance accrue des formes génétiques de CHH, a permis de développer un panel d’exome ciblé dédié au diagnostic par séquençage nouvelle génération permettant l’analyse simultanée de gènes candidats et de gènes connus
Congenital hypogonadotropic hypogonadism (CHH) is characterized by deficient or absent pubertal development due to deficient or absent secretion of the pituitary gonadotropins. The many known genetic causes are generally classified into distinct nosological groups. One comprises abnormalities that affect the pre-natal development or migration of GnRH neurons, the paradigm of which is Kallmann syndrome. The other encompasses molecular abnormalities that only affect hypothalamic GnRH synthesis, GnRH release or GnRH signaling at pituitary level. At this stage, two populations of hypothalamic neurons implicated in a gonadotrop function are identified, GnRH neurons and KNDy neurons secreting kisspeptins and neurokinin B. All of the identified genes would represent less than 20% of genetic etiologies.The aim of this PhD was to study the prevalence and pathophysiology mechanisms of known genes and to identify new genetic etiologies of CHH.In the first part, we characterized the function of all molecular events identified on KISS1R, TACR3 and TAC3 genes. Prevalences were estimated in 600 patients. A particular neuroendocrine profile was identified in patients presenting an alteration of neurokinin B signaling. Importance of Kisspeptins during embryonic life was validated. According to these data, a model of interaction between GnRH and KNDy neurons was proposed.In the second part, we identified two new CHH genes using various molecular genetics approaches. SEMA3A was identified in a familial form of Kallmann syndrome and PNPLA6 in a rare familial form of CHH.Finally, our increased knowledge of the various genetic forms of CHH allows proposing a new genetic approach based on next generation sequencing to test together all known and several candidate genes

O Hipogonadismo hipogonadotrófico isolado (HHI) congênito é uma síndrome clínica rara causada por defeito na produção ou secreção do hormônio liberador de gonadotrofinas (GnRH) pelo hipotálamo ou por resistência hipofisária à ação do GnRH. O HHI é mais prevalente em homens e cerca de 50% a 60% dos indivíduos afetados apresentam anosmia ou hiposmia associada, caracterizando a síndrome de Kallmann. Diversos genes já foram associados à patogênese do HHI congênito, porém, a maioria dos casos ainda permanece sem diagnóstico molecular definido. Até recentemente, a identificação das causas genéticas dos pacientes com HHI era realizada por sequenciamento de genes candidatos, empregando a técnica de Sanger. No entanto, com o número crescente de genes descritos nos últimos anos, esse processo vem se tornando impraticável. Novas metodologias de sequenciamento (sequenciamento paralelo em larga escala) foram desenvolvidas permitindo a genotipagem simultânea de diversas regiões, com maior velocidade e menor custo relativo. O atual projeto foi desenvolvido com o objetivo de rastrear genes candidatos em pacientes portadores de HHI congênito utilizando-se o sequenciamento paralelo em larga escala, visando ampliar o conhecimento genético do HHI. Realizamos o sequenciamento paralelo em larga escala (SPLE) de 130 pacientes com HHI congênito utilizando um painel contendo 36 genes relacionados ao HHI. Inicialmente, identificamos 104 variantes, potencialmente patogênicas em 77 pacientes (59,2%). Após a filtragem inicial, foi realizada uma análise individualizada de cada variante e com isso foram mantidos 41 (31,5%) pacientes com variantes classificadas como patogênicas ou provavelmente patogênicas. Os genes KAL1, FGFR1, CHD7 e GNRHR foram os mais frequentemente afetados. Esses resultados confirmam a importância dos genes classicamente associados ao HHI congênito. Destaca-se a alta prevalência de variantes no CHD7 (10,8%), gene bastante extenso, levando à dificuldade técnica de sequenciá-lo pelos métodos tradicionais, até então sem estudos nessa coorte. O CHD7 é um gene originalmente associado à complexa síndrome de CHARGE, porém, nos últimos anos vem sendo cada vez mais associados ao HHI congênito. Dentre os resultados, ressaltamos a identificação de uma mutação inédita no gene GNRH1, causa rara de HHI, e a identificação de variantes deletérias no gene IGSF10, recentemente descrito associado ao atraso puberal, mas sem papel claro no fenótipo de HHI, em dois pacientes que tiveram reversibilidade do hipogonadismo. Variantes provavelmente patogênicas em genes com poucas descrições ou até mesmo sem relatos de associação ao fenótipo de HHI (SPRY4, FLRT3, IGSF1, NSMF, SOX10 e OTX2) também foram identificadas nessa coorte, ampliando nosso conhecimento genético do HHI. A oligogenicidade, previamente descrita com prevalência de 2,5% a 7%, em nosso estudo esteve presente em 22% dos pacientes, demonstrando uma ampliação das descrições de oligogenicidade quando comparados aos estudos prévios utilizando somente a técnica de Sanger. A nova técnica de sequenciamento genético (SPLE), utilizada em nosso estudo, foi capaz de ampliar de 22% para 31,5% (41 em 130 pacientes) a porcentagem de pacientes com diagnóstico molecular definido, quando comparado aos dados prévios utilizando a técnica de Sanger, mostrando-se rápida, confiável e eficaz
Congenital isolated hypogonadotropic hypogonadism (IHH) is a rare condition caused by GnRH deficiency, due to defective hypothalamic gonadotropin-releasing hormone (GnRH) production or secretion, or by pituitary resistance to the GnRH action. Congenital IHH is more prevalent in men and about 50% to 60% of affected individuals present with associated anosmia or hyposmia, characterizing Kallmann\'s syndrome. Several genes have already been associated with the pathogenesis of congenital IHH, but most cases still remain without a molecular diagnosis. Until recently, identification of the genetic causes of IHH was performed by sequencing candidate genes using the Sanger technique. However, with the growing number of genes and the genetic complexity of IHH, it has become almost impossible to keep the screening of all candidate genes updated using the traditional techniques. The advent of next-generation sequencing (NGS) has allowed the simultaneous genotyping of several regions, faster and with lower relative cost. The present project was developed with the objective of tracking candidate genes in patients with congenital IHH using large-scale parallel sequencing, in aiming to increase the genetic knowledge of this rare condition. A total of 130 unrelated patients with IHH was studied by targeted NGS, using a panel containing 36 IHH associated genes. Initially, 104 potentially pathogenic variants were identified in 77 patients (59.2%). However, after an individualized analysis of each variant, the number of patients considered to carry pathogenic or probably pathogenic variants dropped to 41 (31.5%). The genes KAL1, FGFR1, CHD7 and GNRHR were the most frequently affected and these results confirm the importance of genes classically associated with IHH. It is noteworthy the high prevalence of variants in CHD7 (10.8%), a rather extensive gene, leading to technical difficulty of sequencing by traditional methods, which had not been studied in this cohort. CHD7 is the causative gene of CHARGE syndrome, however it has been recently identified in a growing number of congenital IHH patients with or without additional features of the syndrome. Among the results, we emphasize a novel mutation in the GNRH1 gene, a rare cause of IHH, and the identification of deleterious variants in the IGSF10 gene, recently associated with pubertal delay but without a clear role in the IHH phenotype, in two patients with reversible hypogonadism. Probably pathogenic variants in genes with few descriptions or even no reports of association with the IHH phenotype (SPRY4, FLRT3, IGSF1, NSMF, SOX10 and OTX2) were also identified in this cohort, increasing the genetic knowledge of IHH. Oligogenicity, previously described with a prevalence of 2.5% to 7%, was observed in 22% of our patients, demonstrating an increase in oligogenicity cases when compared to previous studies using only the Sanger sequencing. In conclusion, targeted NGS was able to increase the percentage of patients with molecular diagnosis from 22% to 31.5% in our cohort when compared to the previous data using the Sanger sequencing, and has been shown to be a fast, reliable and effective tool in the molecular diagnosis of congenital IHH

A resposta do LH e do FSH ao estímulo com GnRH, realizado em estádio pré-puberal em pacientes com hipopituitarismo acompanhados até a idade puberal, são úteis para predizer o diagnóstico da deficiência de gonadotrofinas, principalmente nas meninas. O estudo da região codificadora do gene LH em pacientes com hipogonadismo hipogonadotrófico e concentrações normais de LH revelou 5 variantes alélicas. A freqüência das variantes alélicas Arg8 e Thr15 foi similar entre hipogonádicos e adultos normais e a sua presença não interferiu nas concentrações séricas do LH. O estudo das isoformas do LH mostrou um predomínio das isoformas ácidas do LH em hipogonádicos e indivíduos normais, não permitindo atribuir à sua presença a baixa atividade biológica do LH imunorreativo encontrado em 13% dos hipogonádicos
LH and FSH responses to GnRH stimulation carried out in the pre-pubertal stage in patients with hypopituitarism followed until the pubertal stage are useful tools for predicting the gonadotropin deficiency diagnosis, especially in girls. The study of the codifying region of the LH gene in patients with hypogonadotropic hypogonadism and normal LH levels disclosed 5 allelic variants. The frequencies of the allelic variants Arg8 and Thr15 were similar between hypogonadic and normal adults, and their presence did not alter serum LH levels. The study of LH isoforms showed a predominance of acid LH isoforms in hypogonadic and normal subjects, which does not allow us to ascribe to their presence the low biological activity of the immunoreactive LH, found in 13% of the hypogonadic individuals

Although the female menopause has been extensively characterized as a well-defined symptomatic state of oestrogen deficiency, which responds relatively well to oestrogen replacement therapy, the symptomatic state of androgen deficiency in men is poorly defined and uncertainty exists whether it responds to testosterone replacement. It has been proposed that hypothalamic-pituitary-testicular (HPT)-axis function (responsible for the production of androgens) and regulation could be viewed as a ‘barometer’ of health status in older men and that potential alterations in HPT-axis function and regulation reflect subclinical and clinical deficits in function and health, which may result in an aged phenotype of human health and disease in older men. The HPT-axis constitutes a well-defined, tractable, clinically-relevant, biological system, which may permit insight into the mechanisms underlying the expression of ageing-related phenotypes of human health and disease. By using a different lens – such as the genetic background; the compensatory responses within the HPT-axis; the syndromes of androgen deficiency; the ethnic background of an individual or the life course trajectory of function and health from conception into older age – to magnify potential dysregulation in the HPT-axis will it be possible to visualize and understand the phenotypic expression of human male ageing as a gradient of functional and health outcomes. This will allow for a better understanding of the physiological mechanics underlying symptomatic expression of dysregulation in the HPT-axis.

O hipogonadismo hipogonadotrófico idiopático (HHI) é definido pela falência completa ou parcial do desenvolvimento pubertário devido à deficiente secreção de gonadotrofinas (FSH e LH) e hormonas sexuais (testosterona e estradiol), na ausência de qualquer causa orgânica hipotalâmico-pituitária. As formas congénitas do HHI incluem a Síndrome de Kallmann (SK), caracterizada pela deficiência gonadotrófica e uma deficiência do sentido de olfato (anósmia ou hipósmia), e HHI sem defeitos olfactivos (HHI normósmico). Esta condição pode ser detetada na infância pela presença de micropénis e/ou criptorquidia, em associação com baixos níveis de gonadotrofinas ou, mais frequentemente, na adolescência ou na idade adulta, pela ausência do desenvolvimento pubertário. Podem, ainda, surgir outros fenótipos não-reprodutivos, como defeitos da linha média facial, agenesia dentária, surdez, agenesia renal, sincinesia e anomalias ósseas digitais. Cerca de um terço dos pacientes com HHI revela um defeito genético em genes que regulam o desenvolvimento embrionário ou a migração dos neurónios secretores da hormona libertadora de gonadotrofinas (GnRH), ou a síntese, secreção ou ação da GnRH. Esta doença pode ter ainda um carácter oligogénico, uma vez que têm sido descritos casos de indivíduos com HHI e alterações genéticas em mais do que um gene. Embora raramente, existem pacientes, que após tratamento hormonal, evidenciam reversão espontânea do quadro de hipogonadismo. O objetivo deste estudo foi determinar a prevalência de mutações e prever as suas consequências funcionais, numa coorte de pacientes com HHI. Neste sentido, 50 pacientes com HHI foram estudados por sequenciação de genes associados a esta doença: KAL1, FGFR1, FGF8, CHD7, PROK2, PROKR2, KISS1R, TAC3, TACR3, GNRH1 e GNRHR. As consequências funcionais das mutações foram previstas por análises estruturais e de conservação in silico. Foram identificadas 43 variantes consideradas patogénicas (das quais 18 nunca foram descritas) em 30 dos 50 pacientes estudados, o que corresponde a uma frequência de causas genéticas de 60%. As variantes foram identificadas com diferentes frequências consoante o gene: KAL1 (7%), FGFR1 (25,6%), FGF8 (2,3%), CHD7 (39,5%), PROK2 (2,3%), PROKR2 (11,6%), KISS1R (2,3%) e GNRHR (9,3%). As análises in silico foram consistentes com um papel crítico das mutações na atividade das proteínas codificadas. Em sete famílias foram encontrados casos de oligogenia e num caso ocorreu reversão da doença, após interrupção do tratamento de reposição com testosterona. Não foi observada uma clara relação genótipo/fenótipo, no entanto, verificou-se que, tal como descrito na literatura existente, mutações no gene KAL1 podem ocorrer em pacientes com problemas renais e mutações no FGFR1 e CHD7 podem estar associadas a surdez. Em suma, neste estudo foi encontrada uma prevalência de 60% de mutações em casos de SK e de HHI normósmico. Identificaram-se 18 novas mutações patogénicas nos genes KAL1, FGFR1, CHD7, KISS1R, GNRHR e PROKR2, ampliando o espectro de mutações associadas ao HHI. O estudo possibilitou, ainda, confirmar o crescente carácter oligogénico que explica os casos de penetrância incompleta e variabilidade fenotípica, presentes em algumas famílias estudadas. Estes estudos poderão revelar-se de grande importância no aconselhamento genético, uma vez que pacientes em que foram identificadas mutações, podem ser alertados para a possível coexistência de outras malformações e para a probabilidade de outros familiares serem afetados pela mesma doença, podendo ser tomadas medidas que minimizem os seus efeitos nocivos.
Idiopathic hypogonadotropic hypogonadism (IHH) is defined by complete or partial failure of pubertal development due to the compromised secretion of gonadotropins (FSH and LH) and sex hormones (testosterone and estradiol), in the absence of any hypothalamic-pituitary organic cause. Congenital forms of IHH include Kallmann Syndrome (KS), which is characterized by gonadotropin deficiency with a defective sense of smell (anosmia or hyposmia), and IHH without olfactory defects (normosmic IHH). This condition can be detected in childhood by the presence of micropenis and/or cryptorchidism, in combination with low levels of gonadotropins and sex hormones or, more frequently, in adults due to absent secondary sexual characteristics. Other non-reproductive phenotypes may be present, such as midline facial defects, tooth agenesis, hearing loss, renal agenesis, synkinesis and digital bone abnormalities. About one third of patients with IHH reveal a genetic defect in genes that regulate the embryonic development or migration of gonadotropin-releasing hormone (GnRH) neurons, or the synthesis, secretion or action of GnRH. This disease can have an oligogenic character, since there have been reports of individuals with IHH with genetic alterations in more than one gene. Although rarely, there are patients that show spontaneous reversal of hypogonadism after hormone treatment. The aim of this study was to determine the prevalence of mutations and to predict their functional consequences in a cohort of patients with IHH. In this regard 50, unrelated patients with IHH were studied by sequencing genes associated with this disease: KAL1, FGFR1, FGF8, CHD7, PROK2, PROKR2, KISS1R, TAC3, TACR3, GNRH1 and GNRHR. The functional consequences of mutations were predicted by in silico structural and conservation analysis. A total of 43 variants considered pathogenic (of which 18 have never been described) were identified in 30 of the 50 studied patients, which correspond to a frequency of genetic causes of 60%. The variants were recognized with different frequencies depending on the gene: KAL1 (7%), FGFR1 (25,6%), FGF8 (2,3%), CHD7 (39,5%), PROK2 (2,3%), PROKR2 (11,6%), KISS1R (2,3%) and GNRHR (9,3%). In silico analyses were consistent with a critical role for the mutations in the activity of the encoded proteins. In addition oligogenic cases were found in seven families, as well as a case of reversal of the disease after interruption of testosterone replacement therapy. Although we did not observe a clear genotype/phenotype relationship, we observed that, in agreement to that described in the literature, mutations in the KAL1 gene may occur in patients with kidney problems and mutations in FGFR1 and CHD7 may be associated with hearing loss. In summary, this study identified 18 new pathogenic mutations in KAL1, FGFR1, CHD7, KISS1R GNRHR and PROKR2 genes, thereby expanding the spectrum of mutations associated with IHH. It also confirmed the increasingly oligogenic character of this disease, that explains cases of incomplete penetrance and phenotypic variability, present in some studied families. These studies may prove to be of great importance for genetic counselling, since patients with known mutations can be alerted for the possible coexistence of other malformations and for the probability of recurrence in other family members, so that measures can be taken to minimize the harmful effects.

Haemochromatosis is a hereditary disorder generally caused by inappropriate absorption of iron by the small intestine which leads to iron deposition in the viscera, endocrine organs, and other sites, causing structural injury and impaired function. The most common form is classical adult haemochromatosis, but juvenile and neonatal forms are recognized, and several other genetic syndromes associated with iron storage have been identified; these may rarely involve specific tissues selectively, such as the lens of the eye or basal ganglia of the brain, or a characteristic range of tissues including the liver, heart, and endocrine system. Early-onset (juvenile) haemochromatosis has a predilection for the heart, pituitary gonadotrophs and the pancreatic islet—thus myocardial disease (which may be fatal if untreated), hypogonadism and diabetes mellitus are prominent features. Prompt diagnosis and depletion of tissue iron by chelating agents—and venesection where possible—may be life-saving. Unravelling the molecular genetics of haemochromatosis is underpinning promising new therapies for disorders of iron homeostasis....

Hereditary haemochromatosis syndromes are inherited disorders whereby inappropriate absorption of iron by the small intestine leads to iron deposition in the viscera, endocrine organs, and other sites, causing structural injury and impaired function. The most common form is classical adult (HFE-related) haemochromatosis, but other forms are recognized. Extended genetic platforms are increasingly used for specific diagnosis and noninvasive methods are increasingly used to evaluate hepatic damage. The mainstay of treatment is venesection although iron chelation therapy is an emerging oral alternative. Unravelling the molecular genetics of haemochromatosis is underpinning promising new therapies for disorders of iron homeostasis. Classical adult (HFE-related) haemochromatosis: aetiology and pathogenesis—inherited as a recessive trait and due to mutations in the major histocompatibility complex class I-related HFE gene that appear to reduce liver production of hepcidin. The principal mutant allele of HFE, designated C282Y, is carried by approximately 1 in 10 individuals of European ancestry, hence around 1 in 200 are homozygotes, usually with biochemical abnormalities of iron storage that may lead to full-blown clinical haemochromatosis. Clinical features—expression of disease may range from slight abnormalities of blood parameters that reflect iron metabolism to the established clinical syndrome of cutaneous pigmentation, cardiomyopathy, endocrine failure (especially diabetes mellitus and hypogonadism), arthritis, and pigment cirrhosis. Diagnosis—usually established by demonstrating abnormalities of iron metabolism. Molecular analysis of the HFE gene, in particular for homozygosity for the C282Y allele, is confirmatory. Management and prognosis—this is directed to the removal of iron by phlebotomy until the serum ferritin concentration is reduced to within the low normal range, after which the frequency of phlebotomy is reduced. Family members—first-degree relatives should be offered screening.