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Genetic basis and variable phenotypic expression of Kallmann syndrome: towards a unifying theory

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Idiopathic hypogonadotropic hypogonadism (IHH) is defined by absent or incomplete puberty and characterised biochemically by low levels of sex steroids, with low or inappropriately normal gonadotropin hormones. IHH is frequently accompanied by non-reproductive abnormalities, most commonly anosmia, which is present in 50–60% of cases and defines Kallmann syndrome. The understanding of IHH has undergone rapid evolution, both in respect of genetics and breadth of phenotype. Once considered in monogenic Mendelian terms, it is now more coherently understood as a complex genetic condition. Oligogenic and complex genetic–environmental interactions have now been identified, with physiological and environmental factors interacting in genetically susceptible individuals to alter the clinical course and phenotype. These potentially link IHH to ancient evolutionary pressures on the ancestral human genome.

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Idiopathic hypogonadotropic hypogonadism: clinical features and classification

Idiopathic hypogonadotropic hypogonadism (IHH) is defined by absent or delayed sexual development, with puberty being either absent or incomplete by the age of 18 years. This is associated with low or ‘inappropriately normal’ levels of the pituitary gonadotropin hormones luteinising hormone (LH) and follicle-stimulating hormone (FSH) [1]. In at least one genetic form of the disease, deficiency in human gonadotropin results from arrest in the migration of gonadotropin-releasing hormone (GnRH)

The physiological basis of IHH

Fundamental to understanding abnormalities of GnRH production or action is an understanding of the ontogeny and physiology of the GnRH neurons themselves. GnRH is secreted in discrete pulses into the hypophyseal portal circulation from nerve terminals at the median eminence by neurons having their cell bodies in the mediobasal hypothalamus. It stimulates pulsatile gonadotropin release from the anterior pituitary gland. GnRH neurons originate extracranially in the olfactory placode, and must

Overview of the genetic basis of IHH

Most unrelated cases of IHH are sporadic, with up to one-third showing some form of familial inheritance 1, 3. To date, mutations in one or more of a number of genes have been found in just over 50% of cases, with rare genetic variants encoding regulatory molecules within the FGFR1–FGF8 network (the FGF8 synexpression group, which appears to be crucial to olfactory-bulb ontogeny) accounting for the majority 36, 37; in the remainder, the underlying genetic susceptibility is not understood.

The

Hierarchical relationships among ligand–receptor systems determining GnRH secretion

The precise hierarchical relationships between the KISS1−KISS1R, GNRH1−GNRHR, tachykinin 3/tachykinin receptor 3 (TAC3−TACR3) systems in maintaining pulsatile GnRH secretion remain to be fully elucidated, but some of the underlying physiology is now known in some detail [47] (Figure 2). For instance, it is well established that exogenous pulsatile GnRH can normalise gonadotropin-mediated gonadal activity in the vast majority of patients with IHH, including some with GNRHR mutations [1], as well

Oligogenic inheritance in IHH

That inheritance of IHH was unlikely to be strictly mendelian was evident from the wide variations in reproductive and non-reproductive phenotypes exhibited by autosomal kindreds in historic studies [3]. This impression was reinforced with each new piece of the emerging IHH genetic puzzle. FGFR1 was originally thought to be a gene for autosomal KS [11], but detailed phenotyping of individuals carrying identical FGFR1 mutations later revealed a broad range of phenotypes, both within and between

Modulation of phenotype through genotype–environment interactions

Compound heterozygotes for a single IHH locus carry the same implications for the human gene pool as do the digenic/oligogenic cases. Their existence indicates that the population prevalence of mutated IHH alleles is sufficient to generate a stream of new autosomal recessive IHH cases even without consanguinity. Indeed, Sykiotis et al [27] found that 10% of their control group carried a single mutated allele, and this proportion will surely rise with the characterisation of novel IHH loci. That

Concluding remarks

Currently, about 65% of cases of IHH remain without a definite genetic cause and further genes undoubtedly remain to be discovered. Even those IHH cases with a single monoallelic variant are likely to harbour variants of undiscovered or unrecognised IHH-associated genes. Of the known genetic defects, most are unlikely to be causative per se in the heterozygous state, but can result in IHH when combined with other genetic susceptibilities, or can predispose to reversible HPG-axis suppression in

Acknowledgments

We would like to thank W Dhillo, London, UK for help with preparation of Figure 2.

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