Hypogonadotropic hypogonadism, Kallmann syndrome

Clinical manifestations depend on the developmental stage at which the GnRH deficiency first manifests. In male infants, microphallus and cryptorchidism may indicate congenital GnRH deficiency, accompanied by low neonatal testosterone, LH, and FSH. Most affected individuals present at puberty: males have prepubertal testicular volume (<4 mL), absent facial and axillary hair, and reduced muscle mass; females have little or no breast development and primary amenorrhoea, although milder phenotypes with spontaneous menses are recognised. Failure of growth-plate fusion frequently results in eunuchoid skeletal proportions, with arm span exceeding height by ≥5 cm. The olfactory phenotype in Kallmann syndrome ranges from hyposmia to complete anosmia. Non-reproductive features depend on the underlying gene and may include bimanual synkinesis, renal agenesis (unilateral / bilateral), cleft lip or palate, dental agenesis, ear anomalies, congenital hearing loss, coloboma, and short stature.

The estimated incidence is approximately 1:125,000 in females and 1:30,000 in males. The condition shows a male predominance, with reported male-to-female ratios of approximately 4:1 in clinical cohorts.

More than 29 genes have been implicated in isolated GnRH deficiency, with frequent oligogenic inheritance and substantial overlap between the Kallmann and normosmic phenotypes. The most commonly involved genes include FGFR1 (~10%), ANOS1 (~7.5%, X-linked), CHD7 (~7.5%), GNRHR (~7.5%), PROKR2 (~5%), and TACR3 (~5%). Germline pathogenic variants disrupt GnRH-neuron specification and migration from the olfactory placode to the hypothalamus or impair GnRH/gonadotropin biosynthesis, secretion, or downstream signalling.

Multiple inheritance patterns are recognised: autosomal dominant, autosomal recessive, and X-linked (associated with ANOS1 variants in males). In families the causal variants can lied to phenotypic variability and reduced penetrance. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

Diagnosis rests on biochemical demonstration of hypogonadotropic hypogonadism: low total testosterone (<100 ng/dL in males) or low oestradiol (<50 pg/mL in females) with inappropriately low or normal LH and FSH and otherwise normal anterior pituitary function. Formal olfactory testing (using odorant panel and/or olfactometry) distinguishes Kallmann syndrome from normosmic IGD; Brain MRI characteristically shows olfactory-bulb aplasia or hypoplasia in Kallmann syndrome.

Main differential diagnoses include:

• Constitutional delay of puberty: spontaneous puberty eventually occurs; no test reliably distinguishes it from IGD
• : coloboma, heart defect, choanal atresia, growth retardation, ear abnormalities; CHD7
• Combined pituitary hormone deficiency: deficiencies of multiple anterior pituitary hormones with pituitary structural abnormalities; PROP1, POU1F1, LHX3, LHX4, HESX1

• Establishing the diagnosis: confirmation of the underlying genetic cause provides a definitive aetiological diagnosis.
• Specific and individualised clinical management: identification of the causative variant is a prerequisite for targeted medical care and informs management decisions made by the treating physicians in consultation with the affected individual.
• Family member testing: once the familial pathogenic variant has been identified, predictive testing of at-risk relatives becomes possible and can inform reproductive counselling.

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• Cangiano B, Swee DS, Quinton R, Bonomi M. Genetics of congenital hypogonadotropic hypogonadism: peculiarities and phenotype of an oligogenic disease. Human genetics. 2021;140(1):77-111. doi: 10.1007/s00439-020-02147-1. PMID: .
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