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 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 patients with Kallmann syndrome, in contrast to patients with idiopathic hypogonadotropic hypogonadism, whose sense of smell is normal.
Pathophysiology
Deficient hypothalamic GnRH secretion underlies the markedly abnormal gonadotropin secretion patterns in most patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism. The result is hypogonadism; infertility; and absent, incomplete, or partial pubertal maturation.
Some of the genes involved in the pathogenesis of Kallmann syndrome and idiopathic hypogonadotropic hypogonadism have been identified. However, the genes involved remain unidentified in over 50% of patients. [1] These conditions can be transmitted as autosomal dominant, autosomal recessive or X linked traits. Of note, oligogenic inheritance has been well-described.
Mutations of the KAL1 gene, which encodes a putative neural cell adhesion molecule (anosmin), have been described in several patients with X-linked Kallmann syndrome. In these patients, 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 been described in patients with autosomal dominant Kallmann syndrome. [2, 3] Heterozygous loss-of-function mutations of the gene encoding FGFR1 have also been described in individuals with idiopathic hypogonadotropic hypogonadism, normal smell sense, and normal MRI of the olfactory system. [4] Of note, anosmin may enhance fibroblast growth factor signaling through the fibroblast growth factor receptor 1.
Mutations of the gene encoding fibroblast growth factor 8 have been found in a small minority of patients with autosomal dominant Kallmann syndrome. [3] In addition, mutations of the gene encoding chromodomain-helicase DNA-binding protein 7 (CHD7) have been found in some patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism, some of whom have features of the CHARGE syndrome (characterized by delayed growth and development, congenital cardiac defects, dysmorphic ears, hearing loss, coloboma of the eyes).
Loss-of-function mutations of critical components of the prokineticin pathway have been implicated in the pathogenesis of Kallmann syndrome and idiopathic hypogonadotropic hypogonadism. [5, 6] Specifically, homozygous mutations of prokineticin 2 were found in 2 brothers with Kallmann syndrome and in their sister, who had idiopathic hypogonadotropic hypogonadism. [7] Homozygous, heterozygous or compound heterozygous mutations of the prokineticin receptor 2 have also been associated with Kallmann syndrome. [8] Digenic inheritance has been suggested in an individual carrying heterozygous mutations of prokineticin receptor 2 and KAL1. [8, 9]
Mutations of the DAX1 gene, which encodes a nuclear transcription factor, lead to X-linked idiopathic hypogonadotropic hypogonadism associated with adrenal hypoplasia congenita (AHC). [10] Mutations of genes encoding either leptin or the leptin receptor underlie isolated cases of autosomally transmitted idiopathic hypogonadotropic hypogonadism associated with early-onset obesity. [11] Several loss-of-function mutations of the GnRH receptor gene leading to GnRH resistance and autosomally transmitted hypogonadotropic hypogonadism have been described. [12] In addition, autosomal recessive mutations of the GnRH gene may underlie hypogonadotropic hypogonadism.
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 one patient, isolated bioinactive luteinizing hormone (LH) was present as a result of a homozygous mutation in the LH beta subunit gene, which prevented binding of LH to its receptor. This patient presented with hypogonadotropic hypogonadism, despite high levels of immunoreactive serum LH. A second patient had a different homozygous mutation in the LH beta subunit gene that prevented LH heterodimerization and secretion. He presented with hypogonadotropic hypogonadism and undetectable serum LH.
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 KISS1R (kisspeptin 1 receptor gene, also known as GPR54), a gene encoding a G protein–coupled receptor, which binds kisspeptin 1, have been reported as a cause of hypogonadotropic hypogonadism. [13] Inactivating mutations of the gene encoding kisspeptin 1 may also underlie hypogonadotropic hypogonadism. [14] Kisspeptin 1 and its receptor have an important role in the regulation of GnRH and the onset of puberty. [15, 16]
Homozygous mutations in the genes encoding neurokinin B (TAC3) or its receptor (TACR3) have also been described in some patients with autosomal recessive idiopathic hypogonadotropic hypogonadism. Interestingly, reversal of hypogonadism during adult life has been described in patients with these mutations.
Heterozygous missense mutations of the NSMF (NMDA receptor synaptonuclear signaling and neuronal migration factor, also known as NELF) gene have been associated with Kallmann syndrome. [17] Mutations of additional genes have been implicated in the pathogenesis of Kallmann syndrome and/or hypogonadotropic hypogonadism, including the following genes: WDR11, FGF17, IL17RD, DUSP6, SPRY4, FLRT3, AXL, SOX10,SEMA3A, and HS6ST11. [3, 18, 19, 20, 21, 22, 23]
A study by Turan et al that described the phenotype and prevalence of CCDC141 mutations in idiopathic hypogonadotropic hypogonadism/Kallmann syndrome confirmed that inactivating CCDC141 variants cause normosmic idiopathic hypogonadotropic hypogonadism but not Kallmann syndrome. [24]
Epidemiology
Frequency
International
The prevalence of idiopathic hypogonadotropic hypogonadism was approximately 1 in 10,000 men in a study of French conscripts. [25] A study of Sardinian military recruits reports the prevalence of hypogonadism associated with anosmia (Kallmann syndrome) as 1 in 86,000 men. [26] Methodological limitations of case ascertainment by medical record review should be kept in mind when interpreting these findings.
Mortality/Morbidity
Associated complications affect the patient's quality of life and his/her survival.
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Patients with Kallmann syndrome and those with idiopathic hypogonadotropic hypogonadism survive long term if they do not have associated conditions such as congenital heart disease or neurologic manifestations.
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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 Kallmann syndrome and idiopathic hypogonadotropic hypogonadism cases.
Age
Classic Kallmann syndrome and idiopathic hypogonadotropic hypogonadism are both congenital disorders.
Adult-onset or acquired idiopathic hypogonadotropic hypogonadism 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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MRI of the brain in patients with Kallmann syndrome (KS) and idiopathic hypogonadotropic hypogonadism (IHH). Panel A is a coronal T1-weighted image of a male with KS showing (abnormal) medially oriented olfactory sulci (black arrows) and normal appearing olfactory bulbs (white arrows). Panel B is an axial T1-weighted image of the same male with KS showing the presence of olfactory sulci (white arrows). Panel C is a coronal T1-weighted image of a female with IHH showing normal olfactory bulbs (large arrows) and sulci (small arrows). Panel D is a coronal T1-weighted image of a female with KS showing lack of olfactory bulbs with shallow olfactory sulci (arrows). (Images reproduced from Quinton R, et al: The neuroradiology of Kallmann's syndrome: a genotypic and phenotypic analysis. J Clin Endocrinol Metab 1996; 81: 3010-3017, with permission from the Endocrine Society).
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This is a frequently sampled serum luteinizing hormone (LH) profile in a male patient with Kallmann syndrome (KS) in comparison with a healthy individual. It shows lack of LH pulsatility in the former.
