Target System: Endocrine System
Specific Target Glands: Pituitary Gland and Hypothalamus
Alternative titles; symbols
KMS
KS
Hypogonadotropic Hypogonadism and Anosmia; HHA
Dysplacia Olfactogenitalis of De Morsier
Anosmic Hypogonadism
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Kallmann syndrome is an example of hypogonadism (decreased functioning of the sex hormone-producing glands) caused by a deficiency of gonadotropin-releasing hormone (GnRH), which is created by the hypothalamus. Kallmann syndrome is also known as hypothalamichypogonadism, familial hypogonadism with anosmia, or hypogonadotropic hypogonadism, reflecting its disease mechanism.
Kallmann syndrome is a form of secondary hypogonadism reflecting the fact the primary cause of the defect in sex hormone production lies within the pituitary and hypothalamus rather than a physical defect of the testes or ovaries themselves.
Kallmann syndrome consists of congenital, isolated, idiopathic hypogonadotropic hypogonadism and anosmia. The gene responsible for the X-linked form of Kallmann syndrome, KAL1, encodes a protein, anosmin, that plays a key role in the migration of GnRH neurons and olfactory nerves to the hypothalamus.
Kallmann syndrome was described in 1944 by Franz Josef Kallmann, a German-American geneticist. However, others - such as the Spanish doctor Aureliano Maestre de San Juan - had noticed a correlation between anosmia and hypogonadism in 1856.
The most well known person who has Kallmann syndrome in modern times is the jazz vocalist Jimmy Scott. In 2004, Canadian writer Brian Brett published a memoir, Uproar's Your Only Music, about growing up with Kallmann syndrome.
Clinical Features
Males with Kallmann syndrome show anosmia due to agenesis of the olfactory lobes, and hypogonadism secondary to deficiency of hypothalamic gonadotropin-releasing hormone (GnRH). 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. 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 and of testosterone to human chorionic gonadotropin. A maternal uncle had hypogonadism and anosmia and also showed an impaired LH and FSH response to LHRH. MRI showed hypoplasia of the rhinencephalon in both cases.
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. 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 KAL2.
Biochemical Features
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 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.
Diagnosis
The diagnosis is often one of exclusion found during the workup of delayed puberty. The presence of anosmia together with micropenis in boys should suggest Kallmann syndrome (although micropenis alone may have other causes).
Pathogenesis
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 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. Luteinizing-hormone-releasing hormone (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. Dode et al. (2003) found that loss-of-function mutations in fibroblast growth factor receptor-1 (FGFR1; 136350) caused an autosomal form of Kallmann syndrome. They proposed that the KAL1 gene product, the extracellular matrix protein anosmin-1, is involved in FGF signaling, that there is an interaction between anosmin-1 and FGFR1, and that the higher prevalence of the disease in males is due to gender difference in anosmin-1 dosage, because KAL1 partially escapes X inactivation.
Pathophysiology
Under normal conditions, GnRH travels to the pituitary gland via the hypophyseal portal system, where it triggers production and release of gonadotropins (LH and FSH) from the gonadotropes. When GnRH is low, the pituitary does not create the normal amount of gonadotropins. The gonadotropins normally increase the production of gonadal steroids, so when they are low, these steroids will be low as well.
In Kallmann syndrome, the GnRH neurons do not migrate properly from the olfactory placode to the hypothalamus during development. The olfactory bulbs also fail to form or have hypoplasia, leading to anosmia or hyposmia.
Kallmann syndrome can be inherited as an X-linked recessive trait, in which case there is a defect in the KAL1 gene, which maps to chromosome Xp22.3. KAL encodes a neural cell adhesion molecule, anosmin-1. Anosmin-1 is normally expressed in the brain, facial mesenchyme, mesonephros and metanephros. It is required to promote migration of GnRH neurons into the hypothalamus. It also allows migration of olfactory neurons from the olfactory bulbs to the hypothalamus.
An autosomal dominant gene on chromosome 8 {8p12} (KAL-2 or FGFR-1 (fibroblast growth factor receptor 1)) is thought to cause about 10% of cases. There is some recent evidence to suggest a degree of linkage between the KAL-1 and FGFR-1 genes.
An additional autosomal cause of Kallmann syndrome has been reported Dode et al.2006) by a mutations in the prokineticin receptor-2 gene (PROKR2)(KAL-3) at position 20p13 and its ligand prokineticin 2 (PROK2)(KAL-4) at position 3p21.1. It was noted that mutations in these genes brought about various degrees of olfactory and reproductive dysfunction, but not the other symptoms seen in KAL-1 and KAL-2 forms of Kallmann Syndrome. The authors of the paper suggested that up to 30% of all Kallmann Syndrome cases can be linked to known genetic mutations.
Inheritance
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 the autosomal recessive form with heterozygous expression in the father or the autosomal dominant form.
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 is present. (Whether a heritable form of anosmia distinct from the Kallmann syndrome exists is unclear.) 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.
Epidemiology
Kallmann syndrome occurs at a rate of 1 in 10,000 male births and 1 in 50,000 female births. It may be inherited as an X-linked condition, an autosomal dominant condition or as an autosomal recessive condition. Statistics are sparse, but it seems that autosomal dominant is the most common form of heredity.
One recent paper (Quinton, 2004) quoted an incidence in males of 0.025%, or 1 in 4,000, with the female incidence being 3 to 5 times less.
Even though mutations in the KAL-1 gene on the X chromosome can cause Kallmann syndrome, only 11-14% of patients with Kallmann syndrome have detectable KAL-1 mutations.
Autosomal dominant mutations have been described with the FGFR-1 (8p12) gene, sometimes referred to as the KAL-2 gene. This is thought to cause about 10% of cases.
Autosomal recessive mutations of the GnRH receptor gene (4q13.2) have also been reported (Quinton, 2004). This defect appears to produce a wider spectrum of physical symptoms than with the other gene defects, and the defect lies in the ability of the pituitary gland to recognize GnRH, rather than the ability of the hypothalamus to produce GnRH. It is debateable as to whether this is in fact Kallmann syndrome since the GnRH receptor development is not related to anosmia.
There may also be no obvious family history of inheritance (sporadic cases). However, it is possible for Kallmann syndrome genes to be passed on to children of a sporadic case.
Treatment
Treatment is directed at restoring the deficient hormones -- known as hormone replacement therapy (HRT). Males are administered human chorionic gonadotropin (hCG) or testosterone. Females are treated with oestrogen (estrogen) and progestins.
To induce fertility in males or females, GnRH (aka LHRH) is administered by an infusion pump, or hCG/hMG/FSH/LH combinations are administered through regular injections. Fertility is only maintained whilst actually being treated with these hormones. Once fertility treatment stops it is necessary to revert to the normal HRT of testosterone for men and oestrogen + progestins for women.
The main health risk, for both men and women, of untreated Kallmann Syndrome is osteoporosis. Therefore, regular bone density scans (every 2 years or so) are advisable, even if being treated with HRT. Additional medication specifically for osteoporosis is necessary in some cases.
Cytogenetics
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. In a clinical assessment and molecular analysis of KAL1 and FGFR1 (136350, mutations in which cause KAL2, 147950) in 28 patients with Kallmann syndrome, Sato et al. (2004) found submicroscopic deletions at Xp22.3 involving VCXA (300533), STS (308100), KAL1, and OA1 (300500) in 3 familial cases and 1 sporadic male case affected by a contiguous gene syndrome.
Mapping
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 (STS; 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. Franco et al. (1991) mapped a gene, which they called KALIG1 (Kallmann syndrome interval gene-1), to the Kallmann syndrome critical region on the distal short arm of the human X chromosome. They showed that the gene shares homology with molecules involved in cell adhesion and axonal pathfinding, further supporting the notion that a molecular defect in this gene causes the neuronal migration defect underlying the syndrome.
Cloning
Legouis et al. (1991) sequenced 67 kb of genomic DNA corresponding to a deletion interval containing at least part of the Kallmann gene. They found 2 candidate exons, identified by multiparameter computer programs, in a cDNA encoding a protein of 679 amino acids. This candidate gene, ADMLX (adhesion molecule-like, X-linked), was interrupted in its 3-prime coding region in the Kallmann patient, in which the proximal end of the KAL deletion interval was previously defined. A 5-prime-end deletion was detected in another Kallmann patient. The predicted protein sequence showed homologies with the fibronectin type III repeat. Thus, ADMLX encodes a putative adhesion molecule consistent with the defect of embryonic neuronal migration. Del Castillo et al. (1992) demonstrated that the KAL1 gene consists of 14 exons spanning 120 to 200 kb that correlate with the distribution of domains in the predicted protein including 4 fibronectin type III repeats. The homologous locus, KALP, on Yq11 has several large deletions and a number of small insertions, deletions, and base substitutions which indicate that it is a nonprocessed pseudogene. The sequence divergence between KAL1 and KALP in humans, and the chromosomal location of KAL homologous sequences in other primates, suggest that KALP and the steroid sulfatase pseudogene on Yq11 were involved in the same rearrangement event on the Y chromosome during primate evolution. Incerti et al. (1992), who localized the KALP pseudogene to Yq11.2, came to similar conclusions.
Legouis et al. (1993) determined the entire coding sequence of chicken and quail KAL cDNAs and demonstrated an overall identity of 73% and 72%, respectively, with human KAL cDNA. This corresponds to 76% and 75% identity at the protein level.
Gene Function
Soussi-Yanicostas et al. (1996) showed that the KAL protein is N-glycosylated, secreted in the cell culture medium, and localized at the cell surface. Upon transfection of Chinese hamster ovary (CHO) cells with human KAL cDNA, the corresponding encoded protein was produced. Several lines of evidence indicated that heparan-sulfate chains of proteoglycan(s) are involved in the binding of the KAL protein to the cell membrane. The authors generated polyclonal and monoclonal antibodies to the purified KAL protein. With these, they detected and characterized the protein encoded by the KAL gene in the chicken central nervous system at late stages of embryonic development. The protein is synthesized by definite neuronal cell populations, including Purkinje cells in the cerebellum, mitral cells in the olfactory bulbs, and several subpopulations in the optic tectum, and the striatum. The protein, with an approximate molecular mass of 100 kD, was named anosmin-1 by the authors in reference to the deficiency of the sense of smell that characterizes Kallmann disease. Anosmin-1 was thought to be an extracellular matrix component. Since heparin treatment of cell membrane fractions from cerebellum and tectum resulted in the release of the protein, Soussi-Yanicostas et al. (1996) suggested that 1 or several heparan-sulfate proteoglycans are involved in the binding of anosmin-1 to the membranes in vivo.
reported that KAL is localized on the cell surface and it appears to be secreted as a diffusible molecule. They demonstrated that KAL undergoes proteolytic cleavage to yield a diffusible component and that this diffusible form is incorporated into the extracellular matrix. Rugarli et al. (1996) reported that KAL encodes a predicted 680-amino acid polypeptide with a protease inhibitor domain that is followed by 4 fibronectin type III repeats. Because the low abundance of this protein hampered biochemical characterization, they carried out transfection experiments to overexpress human and chick KAL in eukaryotic cells. Rugarli et al. (1996) postulated that once incorporated into the extracellular matrix of the olfactory bulb, KAL might promote the ultimate migration and target recognition of olfactory axons.
Soussi-Yanicostas et al. (2002) showed that anti-anosmin-1 antibodies blocked the formation of the collateral branches of rat olfactory bulb output neurons (mitral and tufted cells) in organotypic cultures. Moreover, anosmin-1 greatly enhanced axonal branching of these dissociated neurons in culture. Coculture experiments with either piriform cortex or anosmin-1-producing CHO cells demonstrated that anosmin-1 is a chemoattractant for the axons of these neurons, suggesting that this protein, which is expressed in the piriform cortex, attracts their collateral branches in vivo. The authors concluded that anosmin-1 has a dual branch-promoting and guidance activity and is involved in the patterning of mitral and tufted cell axon collaterals to the olfactory cortex.
Bulow et al. (2002) showed that expression of the C. elegans homolog of KAL1 in selected sensory and interneuron classes caused a highly penetrant, dosage-dependent, and cell autonomous axon-branching phenotype. In a different cellular context, heterologous C. elegans Kal1 expression caused a highly penetrant axon-misrouting phenotype. The axon-branching and -misrouting activities required different domains of the KAL1 protein. In a genetic modifier screen, Bulow et al. (2002) isolated several loci that either suppressed or enhanced the Kal1-induced axonal defects, 1 of which codes for an enzyme that modifies specific residues in heparan sulfate proteoglycans, namely heparan 6-O-sulfotransferase (604846). Bulow et al. (2002) hypothesized that KAL1 binds by means of a heparan sulfate proteoglycan to its cognate receptor or other extracellular cues to induce axonal branching and axon misrouting.
Molecular Genetics
Isolated GNRH deficiency is a heritable condition characterized by a functional deficit in GNRH secretion. 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.
Hardelin et al. (1993) reported results of a mutation search of the KAL gene 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.
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 (308100). 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.
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 (308700.0012) and the other in the PROKR2 gene (607123.0001), raising the possibility of digenic inheritance.
Other Features
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.
Genotype/Phenotype Correlations
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 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.
Allelic Variants
.0001 Kallmann Syndrome 1 [KAL1, 3300-BP DEL]
Bick et al. (1992) studied 77 families in which one or more men had hypogonadotropic hypogonadism, characterized by hypogonadism and low serum concentrations of testosterone, luteinizing hormone, and follicle-stimulating hormone. None had evidence of deficiency of any other pituitary hormone or of a hypothalamic or pituitary mass lesion. Among the 77 families, the probands had anosmia in 52, hyposmia in 7, and a normal sense of smell in 18. In 10 of the families some affected members were brothers, and in 6 families some belonged to at least 2 generations related through female members, indicating a pattern of X-linked inheritance. In only 1 family was an abnormality on Southern blot analysis discovered. Bick et al. (1992) demonstrated that this patient and his brother had inherited from their mother a 3,300-bp deletion entirely confined within the 210-kb KALIG1 gene. They sequenced the 5-prime and 3-prime boundaries of the deleted region. A 6-bp homology (CAAATT) was found at the deletion breakpoint. It is possible that this short stretch of sequence homology was involved in the molecular mechanism that underlay the event producing the deletion. Similar nonhomologous recombinations as the basis of intragenic deletions have been postulated (Woods-Samuels et al., 1991; Bernatowicz et al., 1992). The deletion included the penultimate exon which encodes one of the domains of the KALIG1 gene that is homologous with molecules involved in neural cell adhesion. In this family, 1 brother was born with microphallus, scrotal hypoplasia, and an undescended testis. His brother had normal genitalia at birth, but by 4 months of age his testes had retracted and his penis appeared involuted, closely resembling his brother's genitalia at the same age. Both had anosmia; their mother had a normal sense of smell.
.0002 Kallmann Syndrome 1 [KAL1, TRP237TER]
Hardelin et al. (1992) sought intragenic mutations in the KAL candidate gene in 18 unrelated patients. With the PCR, 2 exons of the gene were amplified in genomic DNA. They identified 3 different base substitutions--all leading to a stop codon--and 1 single-base deletion responsible for a frameshift. In 1 patient with a rather extensively affected family, they found a TGG-to-TGA transition at codon 237 converting tryptophan to stop. In addition to bilateral cryptorchidism and anosmia, the boy had synkinesia, minor motor epilepsy, and unilateral renal aplasia. A brother who had died at 1 day of age had only one kidney.
.0003 Kallmann Syndrome 1 [KAL1, ARG257TER]
In a patient in whom micropenis and bilateral cryptorchidism was recognized at birth and who later showed anosmia, typical mirror movements of the hands (bimanual synkinesia) and mild bilateral pes cavus, Hardelin et al. (1992) found a CGA-to-TGA transition at codon 257 resulting in a change of arginine to stop.
.0004 Kallmann Syndrome 1 [KAL1, TRP258TER]
In an 11-year-old boy with unilateral cryptorchidism, anosmia, left ptosis, synkinesia, and unilateral renal aplasia, Hardelin et al. (1992) found a TGG-to-TGA transition resulting in conversion of tryptophan-258 to stop.
.0005 Kallmann Syndrome 1 [KAL1, 1-BP DEL, PRO277FS]
In an 8-year-old boy with micropenis, bilateral cryptorchidism, anosmia, and bilateral pes cavus, Hardelin et al. (1992) found deletion of one C from codon 277 (CCC-to-CC, which normally codes for proline) resulting in frameshift. The brother of the patient also had Kallmann syndrome and marked pes cavus, and both had high-arched palate.
.0006 Kallmann Syndrome 1 [KAL1, EX3-5DEL ]
Maya-Nunez et al. (1998) found KAL gene defects in 7 of 12 unrelated males studied with X-linked KMS. One had a deletion from exon 3 to exon 5. The deletion comprised only part (exon 5) of the coding region of the first fibronectin type III-like repeat of the KAL protein. The rest of the deletion comprised part of the conserved cysteine-rich N-terminal region that corresponds to the whey acidic protein motif.
.0007 Kallmann Syndrome 1 [KAL1, GLU514LYS]
Maya-Nunez et al. (1998) found KAL gene defects in 7 of 12 unrelated males studied with X-linked KMS. Six patients had a previously unidentified missense mutation in exon 11, which was a G-to-A transition at codon 514 (GAA to AAA) resulting in a glu514-to-lys substitution. The fact that the same missense mutation was found in 6 of the 12 patients indicated that the mutation was derived from a common ancestor or resulted from a mutation hotspot.
.0008 Kallmann Syndrome 1 [KAL1, EX5DEL]
In a male patient with Kallmann syndrome, Soderlund et al. (2002) identified a complete deletion of exon 5 of the KAL1 gene, which occurred within the region encoding the first fibronectin type III-like repeat of the KAL1 protein.
.0009 Kallmann Syndrome 1 [KAL1, 11-BP DUP, NT158]
In a male patient with Kallmann syndrome, Soderlund et al. (2002) identified a novel duplication of nucleotides 158-168 in exon 1 of the KAL1 gene; this 11-bp insertion caused a termination codon (TGA) within the same exon. The duplication was located in the conserved cysteine-rich N-terminal region that corresponds to the whey acidic protein motif, affecting the KAL1 protein either by interrupting the normal transcription or by stopping the translation at the stop codon.
.0010 Kallmann Syndrome 1 [KAL1, ARG262TER]
In a male patient with Kallmann syndrome, Soderlund et al. (2002) identified a novel arg262-to-ter (R262X) mutation in exon 6 of the KAL1 gene. The stop codon in exon 6 was located within the region encoding the first fibronectin type III-like repeat of the KAL1 protein.
.0011 Kallmann Syndrome 1 [KAL1, EX3-13 DEL ]
Massin et al. (2003) described clinical heterogeneity in 3 brothers with Kallmann syndrome who carried a large deletion (exons 3-13) in KAL1. 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), brachymetacarpia (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.
.0012 Kallmann Syndrome 1 [KAL1, SER396LEU ]
In a sporadic case of Kallmann syndrome, Dode et al. (2006) identified heterozygosity for a ser396-to-leu mutation in the KAL1 gene and heterozygosity for a leu173-to-arg mutation in the PROKR2 gene (607123.0001). The mutation in the KAL1 gene modifies the first amino acid residue of the linker between the second and third fibronectin-like type III repeats of the predicted protein; this residue is conserved among orthologous proteins from vertebrates and invertebrates. The mutation in the PROKR2 gene was identified in 6 unrelated Kallmann syndrome patients. Neither mutation was found in control individuals, raising the possibility of digenic inheritance.
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