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Congenital isolated hypogonadotropic hypogonadism (IHH) is a rare reproductive disorder caused by the deficient production, secretion or action of gonadotropin-releasing hormone (GnRH).
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Kallmann syndrome, a disorder that combines congenital IHH and anosmia or hyposmia, is caused by abnormal embryonic migration of GnRH and olfactory neurons.
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Congenital IHH is clinically and genetically heterogeneous with different modes of inheritance and several causative genes.
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Spontaneous recovery of
Molecular and Genetic Aspects of Congenital Isolated Hypogonadotropic Hypogonadism
Section snippets
Key points
Genes implicated with development and migration of gonadotropin-releasing hormone neurons
The development of GnRH neurons is unusual, because they originate outside the central nervous system in the olfactory placode and then migrate in close association with the olfactory fibers into the brain during embryonic development to their ultimate destination in the hypothalamus. This route provides a developmental link between the central control of reproduction and the sense of smell, which are both affected in Kallmann syndrome. Several genes associated to congenital IHH affect the fate
Gonadotropin-Releasing Hormone 1
The human GNRH1 gene encodes the preprohormone that is ultimately processed to produce GnRH decapeptide.57 Although it may be considered the most obvious candidate gene for congenital IHH, GNRH1 mutations are a very rare cause of normosmic IHH. Despite a large number of individuals screened, only 3 homozygous GNRH1 mutations were described in patients with normosmic IHH, in an autosomal-recessive mode of inheritance.58, 59, 60 In addition, one heterozygous GNRH1 (p.R31C) mutation that affects
Leptin, Leptin Receptor, and PCSK1
The early onset of severe obesity associated with IHH may suggest loss-of-function mutations in the LEP, LEPR, or PCSK1 genes. Leptin is a fat-derived hormone that regulates body weight by inhibiting food intake and stimulating energy expenditure. Leptin acts through the leptin receptor, a single transmembrane domain peptide expressed on human pituitary cells, as well as in many different sites of the central nervous system (choroid plexus, and the arcuate, ventromedial, dorsomedial and
Reversal of hypogonadism
Congenital IHH has been traditionally considered a lifelong and permanent condition. However, anecdotal reports of spontaneous recovery of the reproductive function after testosterone therapy have been described for many years.102, 103 Currently, the prevalence of IHH reversal is observed in 10% to 15%, occurring in both males and females.104 Reversal of congenital IHH has been reported in patients with normosmic IHH and Kallmann syndrome, but is more common in patients with a phenotype of
Oligogenic inheritance
There are several disorders that were thought initially to be monogenic, but have subsequently proven to be caused by more than one gene defect.7 Over the years, the traditional Mendelian view of congenital IHH as a monogenic disorder has been revised after the identification of oligogenic forms of congenital IHH. Mutations in more than 1 gene have been reported in several cases in normosmic IHH/Kallmann syndrome, involving different combinations of genes.7, 9, 30, 33, 106, 107 The genes more
Summary
Congenital IHH is a rare disease with an uncovered complex model of genetics (monogeniticy and oligogenicity) that might apply to a large proportion of patients. At present, more than 25 different genes have been implicated in congenital IHH, which accounts for approximately 50% of cases.8, 9 The greater accessibility of new genetic sequencing methods probably will increase the percentage of patients with defined molecular diagnosis through the use of gene panels and new genes not yet described
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2022, Best Practice and Research: Clinical Endocrinology and MetabolismCitation Excerpt :The main defect may involve the embryogenesis of the gonadotrophin-releasing hormone (GnRH) neuron, the expression of GnRH or its regulation, or the function of the gonadotroph. Alternatively, a defective development of the hypothalamic-pituitary region results in multiple pituitary hormone deficiencies [1–5]. In most cases, central hypogonadism is generalised, affecting all testicular populations.
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The authors have nothing to disclose.
This work was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq # 302849/2015-7); Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP # 2013/03236-5) to A.C. Latronico.