Kallmann Syndrome

[Includes: Kallmann Syndrome 1 (Kallmann Syndrome, X-Linked), Kallmann Syndrome 2, Kallmann Syndrome 3, Kallmann Syndrome 4]

Clinical Diagnosis

Kallmann syndrome (KS) is the association of idiopathic or isolated hypogonadotropic hypogonadism (IHH) and anosmia (absent sense of smell).

IHH is diagnosed clinically by the presence of the following:

• Clinical evidence of arrested sexual maturation or hypogonadism. Absence of secondary sexual characteristics; diminished libido; infertility; amenorrhea in women; erectile dysfunction in men

• Incomplete sexual maturation on physical examination as determined by Tanner staging (Table 1)

• Males with KS typically have Tanner stage I-II genitalia; females have Tanner stage I breasts; both males and females have Tanner stage II-III pubic hair since it is controlled in part by adrenal androgens.

• Men with KS often have pre-pubertal testicular volumes (<4mL).

• Low or normal serum concentration of LH (luteinizing hormone) and FSH (follicle stimulating hormone) in the setting of low circulating concentrations of sex steroids [total testosterone (T) <100 ng/dL in males and estradiol (E₂) <50 pg/mL in females]

• Normal pituitary and hypothalamus on MRI. MRI of the pituitary/olfactory region may indicate the absence of olfactory bulbs in individuals with KS and is needed to rule out secondary hypothalamic or pituitary causes of hormone deficiency.

• No other hypothalamic or pituitary abnormalities

• Absence of other causes of hypogonadotropic hypogonadism. See Hypogonadotropic Hypogonadism Overview.

Anosmia can be determined by history and confirmed using formal diagnostic smell tests, such as the University of Pennsylvania smell identification test (UPSIT) [Doty et al 1984]. This "scratch and sniff" test evaluates an individual's ability to identify 40 microencapsulated odorants and can be easily performed in most clinical settings.

Figure 1. Types of idiopathic hypogonadotropic hypogonadism (more...)

Figure 1. Types of idiopathic hypogonadotropic hypogonadism

Figure 1

Molecular Genetic Testing

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Genes. KAL1, FGFR1, PROKR2, and PROK2 are the only genes known to be associated with Kallmann syndrome (KS). Together, mutations in these genes account for about 20%-25% of KS.

Other loci. The gene(s) that account for the other 75%-80% of KS are unknown and unmapped.

Clinical testing

• KAL1 (Kallmann syndrome 1)

FISH or deletion testing. Detection of deletion of KAL1 by FISH or array CGH (comparative genomic hybridization) is possible [Hou et al 1999]; however, full deletions of KAL1 are an extremely rare cause of KS.

Sequence analysis. Mutations in KAL1 have been reported by several groups, making sequence analysis the favored approach for testing in individuals whose family history is highly suggestive of X-linked KS. In the authors' cohort of 250 individuals with IHH, approximately 5%-10% of familial and simplex (i.e., a single occurrence in a family) KS cases have been shown to have mutations in KAL1 [Waldstreicher et al 1996, Oliveira et al 2001].

• FGFR1 (Kallmann syndrome 2)

Sequence analysis. Mutations in FGFR1 have been reported in several persons with autosomal dominant KS by a number of groups [Dode et al 2003; Sato et al 2004; Pitteloud, Acierno et al 2006; Pitteloud, Meysing et al 2006; Trarbach et al 2006]. In the authors' cohort of 250 individuals with IHH, approximately 10% have mutations in FGFR1. Unlike KAL1, disruption of which generally leads to a severe phenotype, mutations in FGFR1 can have variable expressivity (see Genotype-phenotype Correlations).

• PROKR2 and PROK2

Sequence analysis. Recently, Dode et al (2006) reported several DNA sequence changes in the PROKR2 and PROK2 genes in persons with KS. Using sequence analysis in their research population, they found that approximately 5% of persons with KS had mutations in PROKR2 and fewer than 5% had mutations in PROK2. However, as appropriate numbers of ethnically matched controls and biologic assays were not studied, further confirmation is required.

Table 2 summarizes molecular genetic testing for this disorder.

Table 2. Molecular Genetic Testing Used in Kallmann Syndrome

Test Method	Mutations Detected	Mutation Detection Frequency 1	Test Availability
FISH	KAL1 deletion	Rare	Clinical
Sequence analysis	KAL1 sequence variant	~5%-10%
	FGFR1 sequence variant	~10%	Clinical
	PROKR2 sequence variant	~5%	Clinical
	PROK2 sequence variant	<5%	Clinical

1. Proportion of affected individuals with a mutation(s) as classified by gene/locus, phenotype, population group, genetic mechanism, and/or test method

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To establish the diagnosis of Kallmann syndrome (KS) in a proband. The clinical tests discussed in Molecular Genetic Testing can be offered to persons with findings of classic KS.

In familial KS cases, the mode of inheritance is useful in assessing the predictive value of the available tests:

• X-linked pattern of inheritance. Sequence analysis of the coding regions of KAL1 may have higher yield than sequence analysis of FGFR1.

• Autosomal dominant pattern of inheritance or for families with both anosmic IHH and normosmic IHH. Testing of FGFR1 may have higher yield than sequence analysis of KAL1.

For simplex KS cases:

• Males. Sequence analysis of the coding exons of KAL1, FGFR1, PROKR2, and PROK2

• Females. Sequence analysis of FGFR1, PROKR2, and PROK2

Carrier testing for relatives at-risk for Kallmann syndrome 1 requires identification of the disease-causing KAL1 mutation in an affected family member.

Note: Carrier testing is relevant for an X-linked disorder but not for an autosomal dominant disorder.

Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutation in an affected family member.

Genetically Related (Allelic) Disorders

KAL1. Deletions in the terminal arm of Xp22.3 cause a contiguous gene syndrome including short stature, chondrodysplasia punctata, mental retardation, steroid sulfatase deficiency, and Kallmann syndrome [Ballabio et al 1989, Hou 2005].

FGFR1. In addition to KS with highly variable expressivity, the only other phenotype associated with mutations in FGFR1 is Pfeiffer syndrome type 1. However, of the mutations that cause Pfeiffer syndrome, 95% occur in FGFR2 and only 5% occur in FGFR1. (See FGFR-Related Craniosynostosis Syndromes.) Pfeiffer syndrome type 1 is characterized by coronal craniosynostosis with moderate-to-severe midface hypoplasia, usually normal intellect, broad and medially deviated thumbs and great toes with variable degree of brachydactyly. Hearing loss and hydrocephalus can be seen on occasion.

Natural History

Gonadal function

• Infancy. Some individuals exhibit clues to the diagnosis of KS in early childhood. In boys, micropenis (stretched penile length <1.9 cm) and cryptorchidism are common features and can be associated with abnormally low serum concentrations of gonadotropins and testosterone in the first months of life.

• Adolescence. Individuals with KS display abnormal sexual maturation at puberty, usually with incomplete or absent development of secondary sexual characteristics.

• Adulthood. Adult males with KS tend to have pre-pubertal testicular volume (i.e., <4 mL), absence of secondary sexual features such as facial and axillary hair growth and deepening of the voice, and decreased muscle mass. Adult females have little or no breast development and primary amenorrhea. Since adrenal maturation proceeds normally, the low levels of androgens produced in the adrenal glands may allow normal onset of pubic hair growth (adrenarche) in both sexes.

  Individuals with hypogonadotropic hypogonadism typically have a eunuchoidal body habitus with arm span exceeding height by 5 cm or more. Although skeletal maturation is delayed, the rate of linear growth is usually normal (except for the absence of a distinct pubertal growth spurt) [Van Dop et al 1987].

• Fertile eunuch variant. Not all individuals manifest the same severity of IHH and some individuals demonstrate some degree of pubertal development. This clinical variability is supported by analyses of the pulsatile pattern of gonadotropins in IHH, which demonstrate a spectrum of absent to arrested developmental patterns ranging from completely absent GnRH-induced LH pulses to sleep-entrained GnRH release that is indistinguishable from that of early puberty [Spratt et al 1987]. This variable level of endogenous GnRH activity permits spermatogenesis to occur with the potential to achieve fertility with little or no treatment [Smals et al 1978]. This extreme of the spectrum of abnormal pubertal development is referred to as the "fertile eunuch" phenotype of IHH. Although individuals with this syndrome exhibit clinical evidence of hypogonadism associated with low serum concentration of testosterone, they do have partial pubertal development with normal or near-normal testicular volumes.

Anosmia. Individuals with anosmia may or may not be aware of their olfactory deficiency; thus, formal testing is required to evaluate the ability to smell (see Diagnosis). Although family members sometimes comment on their relative's olfactory deficiency, the ability to smell is often culturally valued and may be down-played by the affected individual.

Other. The non-reproductive phenotypes in males with KAL1 mutations include the following [Wegenke et al 1975, Quinton et al 2001, Massin et al 2003]:

• Synkinesia of the digits (present in approximately 80% of males with KAL1 mutations). This can be demonstrated clinically by asking the individual to fully extend both arms and hands, and then move the fingers of one hand in isolation. The inability of the individual to move the fingers of one hand without exhibiting mirror movements of the digits of the other hand is synkinesia. An inability to play a musical instrument because of synkinesia is often obtained in the history.

• Unilateral renal agenesis (present in approximately 30% of males with KAL1 mutations but also reported in persons with KS of unknown cause). This is often asymptomatic, and must be evaluated by ultrasound examination.

• Sensorineural hearing loss

• High-arched palate

The non-reproductive phenotypes caused by FGFR1 mutations include the following [Dode et al 2003]:

• Synkinesia in about 10% of persons

• Cleft lip and/or palate

• Agenesis of one or more teeth

• Digit malformations (brachydactyly, syndactyly)

• Agenesis of the corpus callosum seen on MRI

Genotype-Phenotype Correlations

KAL1 (Kallmann syndrome 1). Males with a KAL1 mutation generally have a severe reproductive phenotype. In frequent sampling studies using serum concentration of LH as a surrogate marker of GnRH secretion, males with KAL1 mutations have complete absence of GnRH pulsations. Males with KAL1 mutations also have smaller testes at presentation and higher rates of cryptorchidism than males with normosmic IHH [Oliveira et al 2001; Pitteloud, Hayes, Boepple et al 2002].

FGFR1 (Kallmann syndrome 2). The IHH phenotype associated with FGFR1 mutations often has variable expressivity within and across families with identical mutations. Absent puberty, partial puberty, or delayed puberty can be seen in individuals with the same mutation. Further, some persons with an FGFR1 mutation are asymptomatic, denoting incomplete penetrance (see Penetrance). Thus, among individuals with the same FGFR1 mutation in a family, some have an abnormal reproductive phenotype, while others do not [Pitteloud, Meysing et al 2006]. The IHH phenotype is more predominant in males with FGFR1 mutations than in females.

Penetrance

Penetrance for the IHH phenotype is complete in males with KAL1 mutations. Penetrance is incomplete in individuals with FGFR1 mutations: individuals with normal gonadal function and an FGFR1 mutation have been documented.

Penetrance for anosmia in men with mutations in KAL1 is generally complete. In contrast, individuals with IHH and FGFR1 mutations may be normosmic, hyposmic, or anosmic [Pitteloud, Acierno et al 2006].

Nomenclature

KS is a subset of idiopathic hypogonadotropic hypogonadism (IHH) and is sometimes referred to as anosmic IHH, hypogonadotropic hypogonadism and anosmia, or anosmic hypogonadism.

"Dysplasia olfactogenitalis of De Morsier" is a previously used term originating from an autopsy report describing 14 individuals with KS.

Prevalence

Estimates of the overall incidence of KS vary from approximately 1:10,000 to 1:86,000 [Seminara et al 1998].

One estimate of KS frequency utilized Sardinian conscripts. The overall incidence of testicular atrophy was 344 out of 600,000 (1:1174), although not all of the affected men could be investigated to determine the cause. Seven of the 265 men examined were anosmic, leading the authors to conclude that the incidence of KS was 1:86,000 men [Filippi 1986].

One study that assessed the incidence of KS in 24 individuals with anosmia found one previously undiagnosed case of KS, indicating that the incidence of KS may be high among individuals with anosmia [Pawlowitzki et al 1987].

In the authors' cohort of 250 individuals with IHH, the male predominance was significant, with a male-to-female ratio of nearly 4:1 [Seminara et al 1998]; approximately two-thirds of those with IHH have anosmia/hyposmia (Kallmann syndrome) and one-third have normosmic IHH (nIHH) [Authors, unpublished observation].

Evaluations Following Initial Diagnosis

If a mutation in KAL1 or FGFR1 has been identified, appropriate initial clinical evaluation would include the following:

• Assessment of sexual maturation by Tanner stage (Table 1)

• Measurement of testicular volume in men

• Measurement of serum concentrations of LH, FSH, total testosterone (T) in men and estradiol (E₂) in women to determine the severity of GnRH deficit

• Assessment of non-reproductive phenotypes such as: severity of anosmia, presence of unilateral renal agenesis, synkinesia and/or skeletal abnormalities, agenesis of the corpus callosum (as seen on MRI)

Treatment of Manifestations

Treatment options for individuals with IHH include sex steroids, gonadotropin therapy, or pulsatile GnRH administration. Choice of therapy is determined by the goal(s) of treatment, i.e., to induce and maintain secondary sex characteristics and/or to bring about fertility.

Surveillance

Gonadal function. Individuals diagnosed with KS in infancy or childhood need to be evaluated at puberty as follows:

• Assessment of sexual maturation by Tanner staging (Table 1) and, in men, testicular volume

• Measurement of serum concentration of LH and FSH; total testosterone (T) in males and estradiol (E₂) in females

Bone mineral density. In addition to treating hypogonadism, the potential deterioration in bone health that may have resulted from periods of low circulating sex hormones should be addressed. Depending on the timing of puberty, duration of hypogonadism, and other osteoporotic risk factors (e.g., glucocorticoid excess, smoking) a bone mineral density study should be considered. Specific treatment for decreased bone mass should be considered depending on the degree of bone mineralization.

Agents/Circumstances to Avoid

When using topical androgen replacement in men, care must be taken to avoid exposure of treated skin to other individuals in the household. Anecdotal reports suggest that the transmission of clinically effective levels of testosterone from the patient to other family members, including women and children, is possible.

Testing of Relatives at Risk

Testing at-risk relatives may be indicated when a mutation has been identified in a family (e.g., testing the brother of a proband with a known KAL1 mutation whose mother is a known carrier). Because of variable expressivity, however, it is unknown if a pre-pubertal child with a known mutation will progress through puberty in a normal or delayed fashion, or not at all. Therefore, hormone treatment should only be initiated when IHH is diagnosed with impaired pubertal development.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.

Mode of Inheritance

Kallmann syndrome 1 (caused by mutations in KAL1) is inherited in an X-linked manner.

Kallmann syndrome 2 (caused by mutations in FGFR1), Kallmann syndrome 3 (caused by mutations in PROKR2), and Kallmann syndrome 4 (caused by mutations in PROK2) are inherited in an autosomal dominant manner.

Risk to Family Members — X-Linked Inheritance

Parents of a proband

• The father of an affected male will not have the disease nor will he be a carrier of the mutation.

• In a family with more than one affected individual, the mother of an affected male is an obligate carrier.

• If pedigree analysis reveals that the proband is the only affected family member, the mother may be a carrier or the affected male may have a de novo gene mutation and, thus, the mother is not a carrier. The frequency of de novo mutations is unknown.

• If a woman has more than one affected son and the disease-causing mutation cannot be detected in her DNA, she may have germline mosaicism. Germline mosaicism in mothers has not been reported, but the possibility exists.

• Pedigree analysis reveals that about 70% of affected males are simplex cases (i.e., a single occurrence in a family).

• When an affected male is the only affected individual in the family, several possibilities regarding his mother's carrier status need to be considered:

  • He has a de novo disease-causing mutation in the KAL1 gene and his mother is not a carrier.

  • His mother is a carrier and has a de novo disease-causing mutation in the KAL1 gene, either a) as a "germline mutation" (i.e., present at the time of her conception and therefore in every cell of her body); or b) as "germline mosaicism" (i.e., present only in some of her cells, including germ cells).

  • His mother is a carrier and has a disease-causing mutation that she inherited from her parents, most commonly from maternal transmission.

Sibs of a proband

• The risk to sibs depends upon the carrier status of the mother.

• If the mother of the proband has a disease-causing mutation, the chance of transmitting it in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers.

• If the disease-causing mutation cannot be detected in the DNA of the mother of a simplex male, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband

• With appropriate treatment, males with Kallmann syndrome can be fertile.

• Males with X-linked Kallmann syndrome will pass the disease-causing mutation to all of their daughters and none of their sons.

Other family members of a proband. The proband's maternal uncles may be at risk of being affected and the maternal aunts may be at risk of being carriers. The aunts' offspring, depending upon their gender, may be at risk of being carriers or of being affected.

Carrier Detection

Carrier testing of at-risk female relatives is available on a clinical basis if the mutation has been identified in the family.

Risk to Family Members — Autosomal Dominant Inheritance

Parents of a proband

• Some individuals diagnosed with Kallmann syndrome 2, 3, or 4 have an affected parent, although the severity of the phenotype can differ.

• A proband with Kallmann syndrome 2, 3, or 4 may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is unknown.

• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include: (1) a detailed pubertal history of both parents and (2) FGFR1, PROKR2, or PROK2 sequence analysis of both parents. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be fully confirmed until appropriate evaluations have been performed.

Note: Although some individuals diagnosed with Kallmann syndrome 2, 3, or 4 have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members due to early death before the onset of symptoms, incomplete penetrance, or late onset of the disease in an affected relative.

Sibs of a proband

• The risk to the sibs of the proband depends upon the genetic status of the proband's parents.

• If a parent of the proband is affected, the risk to the sibs is 50% although the manifestations may be variable.

• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.

• If the disease causing mutation found in the proband cannot be detected in the DNA of either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism. Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a proband. Each child of an individual with Kallmann syndrome 2, 3, or 4 has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends upon the status of the proband's parents. If a parent is found to be affected, his or her family members may be at risk.

Related Genetic Counseling Issues

Family planning. The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.

Prenatal Testing

Prenatal testing is possible for pregnancies of women who are carriers of a KAL1 mutation. The usual procedure is to determine fetal sex by performing chromosome analysis on fetal cells obtained by chorionic villus sampling (CVS) at about ten to 12 weeks' gestation or by amniocentesis usually performed at about 15-18 weeks' gestation. If the karyotype is 46,XY, DNA from fetal cells can be analyzed for the known KAL1 disease-causing mutation.

Prenatal diagnosis for pregnancies at increased risk for Kallmann syndrome 2 (caused by FGFR1 mutations) is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. The disease-causing FGFR1 allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

No laboratories offering molecular genetic testing for prenatal diagnosis of Kallmann syndrome 3 or 4 (caused by mutations in PROKR2 and PROK2, respectively) are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available for families in which the disease-causing mutation has been identified. For laboratories offering custom prenatal testing, see .

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Molecular Genetic Pathogenesis

Anosmia results because the olfactory axons and GnRH-secreting neurons depend on each other to migrate to the brain from the olfactory placode during development. Defects in this migration result in the co-development of GnRH deficiency and anosmia.

KAL1

Normal allelic variants: KAL1 has 14 exons

Pathologic allelic variants: Reported pathologic mutations in KAL1 include deletion of the entire gene, deletion of several nucleotides, missense mutations, nonsense mutations, and mutations predicted to cause splice variants.

For more information, see Genomic Databases table.

Normal gene product: The protein encoded by KAL1, also known as anosmin, has 680 amino acids with functional similarities with molecules involved in neural development [Rugarli et al 1993]. The N-terminus domains share homologies with a consensus sequence of the whey acid protein family and a motif found in protease inhibitors. The C terminus contains a series of fibronectin type III repeats similar to those found in neural cell adhesion molecules.

Abnormal gene product: Impaired function of anosmin results in a migratory defect of the olfactory and GnRH neurons from the olfactory placode during development [Cariboni et al 2004]. The obstructed migration of these neurons accounts for the tell-tale symptoms of KS, IHH, and anosmia, and leads to olfactory bulb malformation detectable by MRI in the majority of individuals.

FGFR1

Normal allelic variants: FGFR1 has 18 exons with a known splice variant at the end of exon 10.

Pathologic allelic variants: Pathologic mutations in FGFR1 include deletions, missense, nonsense, and splice variant mutations.

For more information, see Genomic Databases table.

Normal gene product: The FGFR1 gene encodes a membrane receptor with three extracellular immunoglobulin-like domains and an intracellular tyrosine kinase domain [Lee et al 1989]. Ligand binding results in receptor dimerization and recruitment of intracellular signaling proteins.

Abnormal gene product: Abnormal FGFR1 gene products result in impaired receptor signaling. The gene dose effect of anosmin and its interaction with FGFR1 in guiding GnRH neuronal migration have been proposed as explanations for the greater predominance of the IHH phenotype in males than females [Dode et al 2003].

PROKR2

Normal allelic variants: PROKR2 has two exons.

Pathologic allelic variants: Pathologic variants of PROKR2 described include missense and nonsense mutations.

Normal gene product: The normal gene product encodes the prokineticin receptor 2, a G protein-coupled transmembrane receptor for PROK2.

Abnormal gene product: Functional effects of mutations identified in humans are unknown. Knockout mice lack olfactory bulbs and have severe atrophia of the reproductive system related to the absence of gonadotropin-releasing hormone-synthesizing neurons in the hypothalamus [Masumoto et al 2006].

PROK2

Normal allelic variants: PROK2 has four coding exons, including an alternative exon 3.

Pathologic allelic variants: Pathologic variants of PROK2 include missense and nonsense mutations, as well as alterations of translation start sites.

Normal gene product: The normal gene product is prokineticin-2, the main ligand of PROKR2.

Abnormal gene product: The functional effects of mutations identified in humans are unknown.

Literature Cited

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

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