Alternative titles; symbols
SNOMEDCT: 93559003; ICD10CM: E23.0; ORPHA: 432, 478; DO: 0090094;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xp22.31 | Hypogonadotropic hypogonadism 1 with or without anosmia (Kallmann syndrome 1) | 308700 | X-linked recessive | 3 | ANOS1 | 300836 |
A number sign (#) is used with this entry because hypogonadotropic hypogonadism-1 with or without anosmia (HH1) is caused by mutation in the KAL1 gene (ANOS1; 300836) on chromosome Xp22.3, sometimes in association with mutation in another gene, e.g., PROKR2 (607123).
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). 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.
Bardin et al. (1969) concluded that patients with Kallmann syndrome have a defect in both pituitary and Leydig cell function. They demonstrated impaired secretion of FSH and LH and thought there to be Leydig cell insensitivity to gonadotropin. Treatment with chorionic gonadotropin can correct cryptorchidism and establish fertility, even in adult males. Schroffner and Furth (1970) found failure of response to clomiphene, as measured by plasma levels of gonadotropins.
With respect to neuroendocrine phenotype, Oliveira et al. (2001) observed that 8 Kallmann syndrome men with documented KAL1 (300836) mutations had completely apulsatile LH secretion, whereas those with autosomal modes of inheritance demonstrated a more variable spectrum with evidence of enfeebled (but present) GnRH-induced LH pulses. They concluded that patients with KAL1 mutations have apulsatile LH secretion consistent with a complete absence of GnRH migration of GnRH cells into the hypothalamus, whereas evidence of enfeebled GnRH-induced LH pulses may be present in autosomal Kallmann syndrome cases.
Sparkes et al. (1968) described X-linked inheritance of hypogonadotropic hypogonadism with anosmia in 2 brothers and their half sister. The 3 affected sibs had the same mother who, despite having minor signs of the disorder (late menarche and irregular menses), had 9 liveborn children. The affected girl had no menses or breast development at age 18 and her ovaries were histologically exactly like those of the fetus. The father had anosmia. This may have been an autosomal recessive form with heterozygous expression in the father or an autosomal dominant form (see 147950).
Hermanussen and Sippell (1985) reported a presumably X-linked recessive kindred. All carrier females had normal sexual and olfactory function. Hipkin et al. (1990) described male twins who were identical by DNA fingerprinting; one had full-blown manifestations of Kallmann syndrome, whereas the other showed normal sexual development and only hyposmia. In a second family, Hermanussen and Sippell (1985) observed 16-year-old twin sisters of whom one had retarded pubertal development and total anosmia, and the other, proven to be monozygotic by blood grouping and HLA typing, had undergone a normal menarche but showed total anosmia. The authors pointed out that sporadic cases of Kallmann syndrome have appeared only in families in which isolated anosmia (see 301700, 107200) is present. They suggested that there is an acquired hypothalamic GnRH deficiency on the basis of preexisting anosmia.
Oliveira et al. (2001) observed that of their X-linked cases confirmed by mutation analysis, only 1 of 3 pedigrees appeared X-linked by inspection, whereas the other 2 contained only affected brothers. Female members of 3 known KAL1 mutation families exhibited no reproductive phenotype and were not anosmic, whereas 3 families with anosmic women were not found to carry KAL1 mutations. The authors concluded that obligate female carriers in families with KAL1 mutations have no discernible phenotype.
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.
The mean age at diagnosis in the patients of Pawlowitzki et al. (1987) and in those reported in the literature was 24.8 and 24.9 years, respectively. Since therapeutic success with substitution therapy, leading to endogenous sex-steroid secretion and even reproduction, is probably age dependent (Rogol et al., 1980), early diagnosis is important. In a 28-year-old man with Kallmann syndrome, Oppermann et al. (1987) caused the induction and maintenance of spermatogenesis and biologic paternity by intranasal administration of gonadotropin-releasing hormone (152760) in low dose.
Guioli et al. (1992) described a patient with Kallmann syndrome who carried an X;Y translocation resulting from abnormal pairing and recombination between the X-linked Kallmann syndrome gene and its homolog on the Y. The translocation created a recombinant, nonfunctional KAL gene identical to the normal X-linked gene with the exception of the 3-prime end that was derived from the Y. The findings indicated that the 3-prime portion of the Kallmann syndrome gene is essential for its function and cannot be substituted by the Y-derived homologous region, although a 'position effect' remained a formal possibility.
Maya-Nunez et al. (1998) described a contiguous gene syndrome due to deletion of the first 3 exons of the KAL1 gene and complete deletion of the steroid sulfatase gene (300747). The 20-year-old subject had hypogonadism, anosmia, and generalized ichthyosis. They found reports of complete deletion of both the STS and the KAL genes in 6 families, and 1 previous description of 3 sibs with complete deletion of the STS gene and partial deletion of the KAL gene. The KAL gene is proximal to the STS gene, with its 3-prime end oriented toward the telomere. It was therefore surprising that the 5-prime end of the KAL gene was deleted. This was said to be the first report of a deletion (or a point mutation) in this region of the KAL gene. The involvement of the conserved cysteine-rich N-terminal region which corresponds to the whey acidic protein motif of the KAL gene demonstrated the importance of this specific region for the function of the gene.
In a clinical assessment and molecular analysis of KAL1 and FGFR1 (136350, mutations in which cause KS (HH2), 147950) in 28 patients with Kallmann syndrome, Sato et al. (2004) found submicroscopic deletions at Xp22.3 involving VCXA (300533), STS (300747), KAL1, and OA1 (300808) in 3 familial cases and 1 sporadic male case affected by a contiguous gene syndrome.
Bick et al. (1989) described a male infant with the combination of ichthyosis, Kallmann syndrome, and chondrodysplasia punctata as a contiguous gene syndrome due to deletion of the terminal part of Xp, with the breakpoint at Xp22.31. The mother showed the same deletion of one X chromosome. Bick et al. (1989) studied an 18-week-old male fetus from this mother affected with the deletion syndrome (contiguous gene syndrome) that included steroid sulfatase deficiency, chondrodysplasia punctata, and Kallmann syndrome. The olfactory bulbs and tracts were absent and a horseshoe kidney was found. Wray et al. (1989) presented results of studies in the mouse supporting the hypothesis that all luteinizing-hormone-releasing hormone (LHRH) cells in the central nervous system arise from a discrete group of progenitor cells in the olfactory placode and that a subpopulation of these cells migrate into forebrain areas where they subsequently establish an adult-like distribution. During normal embryologic development, the olfactory placode in the nose gives rise to the olfactory nerve and nervus terminalis. LHRH-secreting cells of the hypothalamus arise from the nervus terminalis and migrate from the nose through the cribriform plate along the olfactory tract to the hypothalamus. In the aborted fetus, Bick et al. (1989) showed by immunocytochemical analysis that the LHRH-immunoreactive cells and the olfactory nerve failed to reach their normal position, ending prematurely at the meninges. Absence of LHRH-secreting cells in the hypothalamus explains the deficiency of this hormone in Kallmann syndrome. Failure of the olfactory nerve to induce the formation of the olfactory bulb and tract explains the absence of the latter structures. Thus, Bick et al. (1989) appear to have demonstrated that Kallmann syndrome is a defect in neuronal migration. See also Schwanzel-Fukuda et al. (1989).
Krams et al. (1999) used a quantitative MRI protocol to determine if the mirror movements characteristic of X-linked Kallmann syndrome result from loss of transcallosal inhibition, as proposed by Nass (1985), or from an abnormal ipsilateral corticospinal tract, as suggested by electrophysiologic studies. Volumetric comparisons were made of men with X-linked Kallmann syndrome, all of whom had mirror movements, with normal controls, and men with autosomal Kallmann syndrome (147950, 244200), which is not associated with mirror movements. Bilateral hypertrophy of the corticospinal tracts was found in the X-linked patients only. Hypertrophy of the corpus callosum was found in both the X-linked and autosomal Kallmann syndrome patients. The findings of Krams et al. (1999) supported the hypothesis that the mirror movements seen in X-linked Kallmann syndrome result from abnormal development of ipsilateral corticospinal tracts.
Ballabio et al. (1986) studied a large Italian pedigree in which 5 males had a syndrome, following a pattern of X-linked inheritance, characterized by steroid sulfatase-deficient ichthyosis (308100) and Kallmann syndrome. No crossing-over with Xg or with the probe DXS143 was found. No evidence of deletion was found in the probe studies. Thus, the Kallmann locus appears to be in the distal region of Xp, although Ballabio et al. (1986) did not reject the possibility that the Kallmann syndrome in their family was due to an allele at the STS locus. By linkage to the hypervariable repeat sequence CRI-S232 (DXS278), Meitinger et al. (1990) narrowed the location of the KAL1 gene to Xp22.3; maximum lod score = 6.5 at theta = 0.03. Using pulsed field gel analysis of DNAs from patients with terminal deletions of Xp, Petit et al. (1990) mapped the Kallmann syndrome locus to a deletion interval of 350 kb at most, located between 8,600 and 8,950 kb from Xpter.
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.
Possible Association with Functional Hypothalamic Amenorrhea in Carrier Females
Caronia et al. (2011) studied 55 women with functional hypothalamic amenorrhea, who had all completed puberty spontaneously and had a history of secondary amenorrhea for 6 months or more, with low or normal gonadotropin levels and low serum estradiol levels. All had 1 or more predisposing factors, including excessive exercise, loss of more than 15% of body weight, and/or a subclinical eating disorder, and all had normal results on neuroimaging. The authors screened 7 HH-associated genes in the 55 affected women and identified 7 patients from 6 families who carried heterozygous mutations, including 1 in KAL1, 2 in FGFR1, 2 in PROKR2, and 1 in the GNRHR gene. Since these women with mutations resumed regular menses after discontinuing hormone-replacement therapy, Caronia et al. (2011) concluded that the genetic component of hypothalamic amenorrhea predisposes patients to, but is not sufficient to cause, GnRH deficiency.
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.
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