Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary ... Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. Idiopathic hypogonadotropic hypogonadism can be caused by an isolated defect in gonadotropin-releasing hormone (GNRH; 152760) release, action, or both. Other associated nonreproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss, occur with variable frequency. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism has been called 'Kallmann syndrome (KS),' whereas in the presence of a normal sense of smell, it has been termed 'normosmic idiopathic hypogonadotropic hypogonadism (nIHH)' (summary by Raivio et al., 2007). Because families have been found to segregate both KS and nIHH, the disorder is here referred to as 'hypogonadotropic hypogonadism with or without anosmia.' For information on the autosomal forms of hypogonadotropic hypogonadism with or without anosmia, see 147950.
Males with Kallmann syndrome show anosmia due to agenesis of the olfactory lobes, and hypogonadism secondary to deficiency of hypothalamic gonadotropin-releasing hormone (see GNRH1, 152760). Transmitting females have partial or complete anosmia. In the course of molecular genetic ... Males with Kallmann syndrome show anosmia due to agenesis of the olfactory lobes, and hypogonadism secondary to deficiency of hypothalamic gonadotropin-releasing hormone (see GNRH1, 152760). Transmitting females have partial or complete anosmia. In the course of molecular genetic studies of X-linked Kallmann syndrome, Hardelin et al. (1992) found instances of renal agenesis and also pointed to mirror movements of the hands (bimanual synkinesia), pes cavus, high-arched palate, and cerebellar ataxia. Synkinesia, which is one of the more frequent findings, may be attributable to lack of inhibitory fibers connecting the 2 hemispheres through the corpus callosum (Nass, 1985). Colorblindness was also segregating in families described by Kallmann et al. (1944); however, the information was too limited to give conclusive evidence on possible X-linkage of this syndrome. De Morsier (1954) collected 28 reported cases of agenesis of the olfactory lobes in which complete autopsy was performed and found that abnormalities of the sexual organs, mainly cryptorchidism and testicular atrophy, had been noted in 14. He suggested that the genital atrophy is secondary to involvement of the hypothalamus as well as the olfactory lobes. Hockaday (1966) described 2 cases. In the second case, the father was found to have 'complete anosmia on testing.' Thus, this may have been an autosomal dominant form of the disorder (see 147950). Anosmia must be inquired about in cases of hypogonadism since patients rarely volunteer the information. Indeed, the patient is sometimes unaware of anosmia so that tests are necessary. Pittman (1966) found anosmia in 16 of 28 cases of hypogonadotropic hypogonadism. Ballabio (1993) reported the consensus from an NIH conference on Kallmann syndrome that no patient of molecularly confirmed X-linked Kallmann syndrome has intact smell. In a single family, 1 brother was hyposmic and had normal gonadal development, whereas 2 brothers and 2 maternal cousins had the full-blown Kallmann syndrome phenotype. There was agreement that the intrafamilial variability of the phenotype in the autosomal forms of Kallmann syndrome (for which no molecular test is available) is extensive. Several families have been described in which affected individuals have either hypogonadism or anosmia or both. On the contrary, in the X-linked families, the phenotype seems to be consistent within families. Males et al. (1973) studied 6 unrelated subjects, 5 males and 1 female, with hypogonadism and anosmia. All the males had small genitals and decreased sexual hair. Gynecomastia and eunuchoid habitus were seen in 4. All 6 had a radiographically normal sella turcica. Testicular biopsies of the males showed decreased numbers of germ cells and a spermatogenic state at the primary spermatocyte stage. Leydig cells were not histologically identifiable. The affected female had 2 brothers with anosmia and hypogonadism. Urine gonadotropins were low in the 2 patients tested. Basal urinary 17-hydroxycorticosteroids were normal in those tested. A metyrapone test suggested low levels of ACTH in 2. One male patient at operation showed agenesis of the olfactory bulbs and tracts. The authors stated that the Kallmann syndrome is probably the expression of a disorder of hypothalamic regulation involving the control of those releasing factors needed for effective pituitary function. Additionally, it is interesting to note that there is some evidence for a relationship between olfactory acuity (perhaps to detect pheromones) and the gonadal and adrenal system in laboratory test animals. Unilateral renal agenesis has been described in several patients with Kallmann syndrome (Wegenke et al., 1975; Hermanussen and Sippell, 1985). Kirk et al. (1994) reported a systematic study of kidneys in 17 affected persons from 6 families with Kallmann syndrome, including a family with an association of Kallmann syndrome and ichthyosis and interstitial deletion within the short arm of the X chromosome. Unilateral renal agenesis was found in 6 males in 4 families. Moreover, in 2 families (including a family in which all 4 patients demonstrated normal kidneys), there were male infants who died with bilateral renal agenesis. In the family with an association of Kallmann syndrome and ichthyosis, unilateral renal agenesis was found in 2 of 4 affected persons, although all 4 had the same X-chromosome deletion. Presumably, normal renal development requires expression of the Kallmann product (Kalig1/AMDLX), but mutation or absence of this product is not invariably associated with renal agenesis. Birnbacher et al. (1994) made the diagnosis of X-linked Kallmann syndrome in a 3-month-old infant who presented with hypogonadism, a small penis, and bilateral cryptorchidism. He showed an inadequate response of luteinizing hormone and follicle stimulating hormone to the administration of luteinizing hormone-releasing hormone (LHRH; 152760) and of testosterone to human chorionic gonadotropin. A maternal uncle had hypogonadism and anosmia and also showed an impaired LH (152780) and FSH (136530) response to LHRH. MRI showed hypoplasia of the rhinencephalon in both cases. Massin et al. (2003) described clinical heterogeneity in 3 brothers with Kallmann syndrome who carried a large deletion in the KAL1 gene (300386.0011). All 3 had a history of hypogonadotropic hypogonadism with delayed puberty. Although brain MRI showed hypoplastic olfactory bulbs in the 3 sibs, variable degrees of anosmia/hyposmia were shown by olfactometry. In addition, these brothers had different phenotypic anomalies, i.e., unilateral renal aplasia (sibs B and C), high-arched palate (sib A), brachymetacarpalia (sib A), mirror movements (sibs A and B), and abnormal eye movements (sib C). Sib A suffered from a severe congenital hearing impairment, a feature that had been reported in Kallmann syndrome but had not yet been ascribed unambiguously to the X-linked form of the disease. The authors concluded that the variable phenotype, both qualitatively and quantitatively, in this family further emphasizes the role of putative modifier genes, and/or epigenetic factors, in the expressivity of X-linked Kallmann syndrome. Dode et al. (2003) stated that bimanual synkinesia had been observed in 75% of X-linked Kallmann syndrome cases; they described bimanual synkinesia, i.e., mirror movements of the hands, in 2 affected members in a family with an autosomal dominant form of Kallmann syndrome (HH2; 147950). Highly arched palate, which can be regarded as a mild anomaly of palatal fusion, is a common feature of KAL1. Dode et al. (2003) found cleft palate or cleft lip in several individuals with HH2. Kaplan et al. (2010) studied 5 patients with features of Kallmann syndrome and reviewed reported patients. Noting that the diagnosis can be difficult to make before puberty, they suggested that it should be considered when a patient presents a combination of features that includes microphallus, cryptorchidism, hearing loss, renal agenesis, and oral clefting or dental agenesis.
Quinton et al. (1996) performed detailed neurologic examinations of Kallmann syndrome subjects for phenotype-genotype correlation. They studied 27 Kallmann syndrome subjects, including 12 males with X-linked disease and 3 females; 6 male and 2 female normosmics with isolated ... Quinton et al. (1996) performed detailed neurologic examinations of Kallmann syndrome subjects for phenotype-genotype correlation. They studied 27 Kallmann syndrome subjects, including 12 males with X-linked disease and 3 females; 6 male and 2 female normosmics with isolated GnRH (152760) deficiency; 1 male with a KMS variant; and 1 obligate female carrier. Evidence for X-linked disease came from pedigree analysis and mutation analysis of the KAL locus. All 8 normosmics, 3 males with KMS, and the female carrier had normal olfactory bulbs and sulci. Three new mutations at the KAL locus were identified, including 2 single exon deletions and 1 point mutation. No coding sequence mutations were found in 2 pedigrees with clear X-linked inheritance, suggesting that these cases may be due to mutations in pKAL, the 5-prime promoter region. No clear phenotype-genotype relationship was made between specific phenotypic anomalies and KAL mutations. Involuntary mirror movements of the upper limbs were present in 10 of 12 cases of X-linked KMS but in none of the other subjects. Although a mental or intellectual disturbance was described in the original report of Kallmann syndrome (Kallmann et al., 1944), analyses of the genotype-phenotype relationship showed that Kallmann syndrome patients with mental disorders have large deletions on Xp22.3 that extend beyond the KAL1 locus (Nagata et al., 2000). In contrast, almost all patients with mutations restricted to the KAL1 locus are free of mental disturbance. Prager and Braunstein (1993) speculated that another gene located close to KAL1 is responsible for the mental disturbance. Salenave et al. (2008) studied the endocrine features reflecting gonadotropic-testicular axis function in 39 men; 21 had mutations in KAL1 and 18 in FGFR1, but none had additional mutations in PROK2 (607002) or PROKR2 (607123) genes. Puberty failed to occur in the patients with KAL1 mutations, all of whom had complete congenital hypogonadotropic hypogonadism (CHH). Three with FGFR1 (KAL2) mutations had normal puberty, were eugonadal, and had normal testosterone and gonadotropin levels. Cryptorchidism was more frequent and testicular volume was smaller in CHH subjects with KAL1 mutations than in subjects with FGFR1 mutations. The mean basal plasma FSH (see 136530) level, serum inhibin B (see 147290) level, basal LH (see 152780) plasma level, and GnRH-stimulated LH plasma level were significantly lower in the subjects with KAL1 mutations. LH pulsatility was studied in 13 CHH subjects with KAL1 mutations and 7 subjects with FGFR1/KAL2 mutations; LH secretion was nonpulsatile in all the subjects, but mean LH levels were lower in those with KAL1 mutations.
In a patient and his brother with Kallmann syndrome, Bick et al. (1992) detected a 3,300-bp deletion in the KAL1 gene (300836.0001).
Hardelin et al. (1993) reported results of a mutation search of the KAL gene ... In a patient and his brother with Kallmann syndrome, Bick et al. (1992) detected a 3,300-bp deletion in the KAL1 gene (300836.0001). Hardelin et al. (1993) reported results of a mutation search of the KAL gene (300836) in 21 unrelated males with familial Kallmann syndrome. In 2 families, large Xp22.3 deletions that included the entire KAL gene were detected by Southern blot analysis. By sequencing each of the 14 coding exons and splice site junctions in the other 19 patients, they found 9 point mutations at separate locations in 4 exons and 1 splice site. They emphasized the high frequency of unilateral renal aplasia in X-linked Kallmann patients; 6 of 11 males with identified alterations of the KAL gene showed this feature. Parenti et al. (1995) reported the cases of 3 brothers with X-linked ichthyosis and variable expression of Kallmann syndrome. All 3 had the same deletion, which spared the first exon of the KAL1 gene; however, 1 brother had only mild hyposomia and normal pubertal progression, whereas the others were severely affected. The reason for the variability was unclear. Georgopoulos et al. (1997) determined the frequency of KAL1 gene mutations in subjects with sporadic GNRH deficiency. Only 1 of 21 (5%) with sporadic GNRH deficiency had a KAL1 gene mutation (a deletion of 14 bases starting at codon 464). In each of 3 different patients with an X-linked mode of inheritance, 3 mutations were detected. These were a single-base substitution introducing a stop codon at position 328, another encoding a phe517-to-leu substitution and a 9-base deletion at the 3-prime exon-intron splice site of exon 8. These data indicated that the incidence of mutations in the coding region of the KAL1 gene in patients with sporadic GNRH deficiency is low. Oliveira et al. (2001) examined 101 individuals with idiopathic hypogonadotropic hypogonadism with or without anosmia and their families to determine their modes of inheritance, incidence of KAL1 mutations, genotype-phenotype correlations, and, in a subset of 38 individuals, their neuroendocrine phenotype. Of the 101 patients, 59 had true Kallmann syndrome (hypogonadotropic hypogonadism and anosmia/hyposmia), whereas, in the remaining 42, no anosmia was evident in the patients or their families. Of the 59 Kallmann syndrome patients, 21 were familial and 38 were sporadic cases. Mutations in the coding sequence of KAL1 were identified in only 3 familial cases (14%) and 4 of the sporadic cases (11%). Oliveira et al. (2001) concluded that confirmed mutations in the coding sequence of the KAL1 gene occur in the minority of Kallmann syndrome cases, and that the majority of familial (and presumably sporadic) cases of Kallmann syndrome are caused by defects in at least 2 autosomal genes. Sato et al. (2004) studied 25 male and 3 female Japanese individuals with Kallmann syndrome aged 10 to 53 years. Ten males were from 5 families, and the remaining 15 males and 3 females were apparently sporadic cases. Sequencing all exons of the KAL1 and FGFR1 (136350) genes showed 6 novel and 2 recurrent intragenic KAL1 mutations in 7 familial and 4 sporadic male cases and 2 novel intragenic FGFR1 mutations in 2 sporadic male cases. Clinical assessment in the 15 males with KAL1 mutations showed normal and borderline olfactory function in 2 males and right-side dominant renal lesion in 7 males, in addition to variable degrees of hypogonadotropic hypogonadism in all the 15 males and olfactory dysfunction in 13 males. Clinical features in the remaining 11 cases with no demonstrable KAL1 or FGFR1 mutations included right renal aplasia in 1 female and cleft palate, cleft palate with perceptive deafness, and dental agenesis with perceptive deafness in 1 male each, in addition to a variable extent of hypogonadotropic hypogonadism and olfactory dysfunction. Dode et al. (2006) described a patient with Kallmann syndrome who was heterozygous for 2 mutations: one in the KAL1 gene (300836.0012) and the other in the PROKR2 gene (607123.0001), raising the possibility of digenic inheritance. Trarbach et al. (2006) investigated 80 Brazilian patients with isolated hypogonadotropic hypogonadism (IHH), 46 of whom had olfactory abnormalities, for mutations in the KAL1 and FGFR1 genes. Two novel mutations in the KAL1 gene were found among the 46 patients with Kallmann syndrome (300386.0013 and 300386.0014). Eight novel FGFR1 mutations were found in 8 patients with Kallmann syndrome and in 1 with IHH and normal olfactory status.
Pawlowitzki et al. (1987) attempted to estimate the frequency of the Kallmann syndrome, which they referred to by the acronym HHA for hypogonadotropic hypogonadism and anosmia. Among 791 hypogonadal males, they found 19 persons with HHA. They reported ... Pawlowitzki et al. (1987) attempted to estimate the frequency of the Kallmann syndrome, which they referred to by the acronym HHA for hypogonadotropic hypogonadism and anosmia. Among 791 hypogonadal males, they found 19 persons with HHA. They reported that HHA is about one-tenth as common as the Klinefelter syndrome. Among 24 patients presenting with anosmia, they found one hitherto undiagnosed case of HHA.