Excerpt from Kallmann Syndrome and Idiopathic Hypogonadotropic Hypogonadism

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Background

Classic Kallmann syndrome (KS) and idiopathic hypogonadotropic hypogonadism (IHH) are rare genetic conditions that encompass the spectrum of isolated hypogonadotropic hypogonadism. Most patients have a gonadotropin-releasing hormone (GnRH) deficiency, as suggested by their response to pulsatile GnRH therapy. Hypothalamic-pituitary function is otherwise normal in most patients, and hypothalamic-pituitary imaging reveals no space-occupying lesions. By definition, either anosmia (lack of sense of smell) or severe hyposmia is present in KS patients, in contrast to patients with IHH, whose sense of smell is normal.

Pathophysiology

Deficient hypothalamic GnRH secretion underlies the markedly abnormal gonadotropin secretion patterns in most patients with KS or IHH. The result is hypogonadism; infertility; and absent, incomplete, or partial pubertal maturation.

Some of the genes involved in the pathogeneses of KS and IHH have been cloned. Mutations of the KAL gene, which encodes a putative neural cell adhesion molecule, have been described in several patients with X-linked KS. In these patients, both GnRH deficiency and anosmia are believed to be secondary to abnormalities of neuronal migration during development.

Loss-of-function mutations of the gene encoding fibroblast growth factor receptor 1 (FGFR1) have recently been described in patients with autosomal dominant KS.

Mutations of the DAX1 gene, which encodes a nuclear transcription factor, lead to X-linked IHH associated with adrenal hypoplasia congenita (AHC). Mutations of genes encoding either leptin or the leptin receptor underlie isolated cases of autosomally transmitted IHH associated with early-onset obesity. Mutations of the GnRH receptor gene leading to GnRH resistance and autosomally transmitted hypogonadotropic hypogonadism have been described.

Rarely, hypogonadotropic hypogonadism occurs as a result of isolated follicle-stimulating hormone (FSH) deficiency due to homozygous mutations in the FSH beta subunit gene. In 1 patient, isolated bioinactive luteinizing hormone (LH) was present because of a homozygous mutation in the LH beta subunit gene, which led to hypogonadotropic hypogonadism. In another patient, a mutation in the prohormone convertase gene (PC1) led to hypogonadotropic hypogonadism, in addition to extreme obesity, hypocortisolemia, and deficient conversion of proinsulin to insulin.

Homozygous mutations in GPR54, a gene encoding a G protein–coupled receptor, have recently been reported as a cause of hypogonadotropic hypogonadism. The physiologic role of kisspeptin-54, the endogenous neuropeptide agonist for this receptor, is under investigation. In addition, heterozygous missense mutations of the human nasal embryonic LHRH factor (NELF) gene may be associated with hypogonadotropic hypogonadism.

Frequency

International

The prevalence of IHH was approximately 1 in 10,000 men in a study of French conscripts (Fromantin, 1973). A study of Sardinian military recruits reports the prevalence of hypogonadism associated with anosmia (KS) as 1 in 86,000 men (Filippi, 1986). Methodological limitations of case ascertainment by medical record review should be kept in mind when interpreting these findings.

Mortality/Morbidity

• Associated complications affect both quality of life and survival.
• Both patients with KS and those with IHH survive long term if they do not have associated conditions such as congenital heart disease or neurologic manifestations.
• Adrenocortical insufficiency is fatal unless recognized and treated. Thyroid function must also be assessed. In patients who do not receive adequate gonadal steroid replacement, hypogonadal osteoporosis may develop insidiously.

Sex

• The male-to-female ratio ranges from 4:1 to 5:1.
• The male-to-female ratio is approximately 2.5:1 among strictly familial KS and IHH cases.

Age

• Classic KS and IHH are both congenital disorders.
• Adult-onset or acquired IHH has recently been described in men aged 30-50 years.
• Hypothalamic amenorrhea represents an acquired form of GnRH deficiency that occurs predominantly among young women and may be associated with excessive exercise, extreme weight loss, or psychogenic stress. This may occur particularly in patients with anorexia nervosa.

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