Clinical Diagnosis

Kallmann syndrome (KS) is the association of isolated GnRH deficiency (IGD) and anosmia (impaired sense of smell).

IGD 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 (see Table 1):
  • Stage I-II genitalia in males, stage I-II breasts in females
  • Stage II-III pubic hair in both males and females, since it is controlled in part by adrenal androgens
  • Pre-pubertal testicular volume (stage I; <4mL) in males

• Low or normal serum concentration of LH (luteinizing hormone) and FSH (follicle stimulating hormone) in the presence 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 Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency Overview.

Sense of smell can be evaluated by history and by formal diagnostic smell tests, such as the University of Pennsylvania smell identification test (UPSIT) [Doty 2007]. This "scratch and sniff" test evaluates an individual's ability to identify 40 microencapsulated odorants and can be easily performed in most clinical settings. Identification of anosmia, hyposmia, or normosmia is based on the individual’s score, age at testing, and gender.

• In general, individuals with IGD scoring at the fifth percentile or lower (typically either hyposmic or anosmic) receive a diagnosis of Kallmann syndrome.
• Individuals scoring above the 5^th percentile (could be hyposmic or normosmic) are considered to have normosmic IGD.

Figure 1 differentiates the two types of IGD, Kallmann syndrome and normosmic IGD.

Figure

Figure 1. Genes associated with isolated GnRH deficiency (IGD) by sense of smell and mode of inheritance

Molecular Genetic Testing

Genes. KAL1, FGFR1, PROKR2, PROK2, CHD7, and FGF8 are the only genes known to be associated with Kallmann syndrome (KS). Together, mutations in these genes account for about 25%-35% of KS.

Other loci. The gene(s) that account for the other 65%-75% of KS are unknown and unmapped.

Clinical testing

KAL1 (Kallmann syndrome 1)

• FISH or deletion/duplication analysis. Detection of deletion of KAL1 by FISH or CMA (chromosomal microarray) is possible [Hou et al 1999]. Most deletions include an exon or multiple exons. Whole-gene deletions of KAL1 are a 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 IGD, 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 [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 [Dodé et al 2003, Sato et al 2004, Pitteloud et al 2006a, Pitteloud et al 2006b, Trarbach et al 2006]. In the authors' cohort of 250 individuals with IGD, approximately 10% have mutations in FGFR1. FGFR1 deletions are rare [Trarbach et al 2010b]. 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 (Kallmann syndrome 3 and Kallmann syndrome 4, respectively)

• Sequence analysis. Dodé et al [2006] reported several DNA sequence changes in PROKR2 and PROK2 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. In the authors’ cohort of 170 individuals with KS, approximately 2% have loss of function mutations in PROK2 and approximately 4% have loss of function mutations in PROKR2 [Cole et al 2008]. Mutations in these genes also give rise to normosmic IGD [Pitteloud et al 2007b, Abreu et al 2008, Cole et al 2008].

CHD7 (Kallmann syndrome 5)

• Sequence analysis. Heterozygous mutations in CHD7 have been reported in approximately 5% of persons with KS or normosmic IGD [Kim et al 2008, Jongmans et al 2009].

FGF8 (Kallmann syndrome 6)

• Sequence analysis. Loss-of-function mutations in FGF8 have recently been associated with KS and normosmic IGD [Falardeau et al 2008, Trarbach et al 2010a]. In the author’s cohort of 451 individuals with normosmic and anosmic IGD, fewer than 2% have mutations in FGF8.

Table 2. Summary of Molecular Genetic Testing Used in Kallmann Syndrome

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Gene Symbol	Proportion of KS Attributed to Mutations in This Gene	Test Method	Mutations Detected	Mutation Detection Frequency by Gene and Test Method 1	Test Availability
KAL1	Rare	Deletion / duplication analysis 2, including FISH	Partial- or whole-gene deletion	>95% 4	Clinical
	5%-10%	Sequence analysis	Sequence variants 3	>95%
FGFR1	~10%	Sequence analysis	Sequence variants 3	>95%	Clinical
		Deletion / duplication analysis 2	Deletion	Rare 4
PROKR2	~5%	Sequence analysis	Sequence variants 3	>95%	Clinical
PROK2	<5%	Sequence analysis	Sequence variants 3	>95%	Clinical
CHD7	5%-10%	Sequence analysis	Sequence variants 3	>95%	Clinical
FGF8	<5%	Sequence analysis	Sequence variants 3	>95%	Clinical

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. See CMA.

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

4. Extent of deletion detected may vary by method and by laboratory.

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

Testing Strategy

Establishing 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 would be the highest-yield genetic test.
• Autosomal dominant pattern of inheritance or families with both anosmic IGD and normosmic IGD. Testing of FGFR1, PROKR2, PROK2, CHD7, and FGF8 mutations may have higher yield than sequence analysis of KAL1.
• Autosomal recessive or oligogenic pattern of inheritance. Testing for PROKR2 and PROK2 mutations may be of use when evaluating familial KS cases inherited in an autosomal recessive or dominant manner. Although additional sequence analysis for FGFR1 and FGF8 may be useful because of possible digenic inheritance, the yield is substantially lower.

For simplex KS cases:

• Males. Sequence analysis of the coding exons of KAL1, FGFR1, PROKR2, PROK2, CHD7, and FGF8
• Females. Sequence analysis of FGFR1, PROKR2, PROK2, CHD7, and FGF8

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

Note: Carriers are heterozygotes for this X-linked disorder and may develop clinical findings related to the disorder.

Identification of female carriers requires either (1) prior identification of the disease-causing mutation in the family or (2) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and if no mutation is identified, then by methods to detect gross structural abnormalities.

Family members of individuals with a known FGFR1, PROKR2, PROK2, CHD7, or FGF8 mutation may also be candidates for testing for a familial mutation resulting from incomplete penetrance or variable expressivity of mutations.

Prenatal diagnosis /preimplantation genetic diagnosis (PGD) for at-risk pregnancies requires prior identification of the disease-causing mutation in an affected family member.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

KAL1. Deletions in the terminal arm of Xp22.3 cause a contiguous gene syndrome including short stature, chondrodysplasia punctata, intellectual disability, steroid sulfatase deficiency, and Kallmann syndrome [Hou 2005].

FGFR1. In addition to KS with highly variable expressivity, other phenotypes associated with mutations in FGFR1 include Pfeiffer syndrome type 1 and osteoglophonic dwarfism.

• 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.
• Osteoglophonic dwarfism involves rhizomelic dysplasia, dysmorphic facial features, fibrous dysplasia, and clover-leaf skull.

CHD7. Heterozygous mutations or microdeletions in CHD7 can also cause CHARGE syndrome. The syndrome is characterized (and named) by coloboma, heart abnormalities, choanal atresia, retardation of growth and development, genital hypoplasia, and ear abnormalities [Vissers et al 2004]. The genital abnormalities in CHARGE syndrome are caused by hypogonadotropic hypogonadism and are frequently accompanied by olfactory defects and cleft lip/palate [Pinto et al 2005].

Natural History

Gonadal function

• Infancy. Some individuals exhibit clues to the diagnosis of Kallmann syndrome (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 including 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 IGD and some individuals demonstrate some degree of pubertal development. This clinical variability is supported by analyses of the pulsatile pattern of gonadotropins in IGD, 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 IGD. 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.
• Reversal. The presence of normal serum testosterone levels after a period of treatment cessation has been reported in about 10% of men with either Kallmann syndrome or normosmic IGD [Raivio et al 2007]. While the mechanisms of this reversal remain unclear, such demonstration of normal activity of the hypothalamic-pituitary-gonadal axis after cessation of gonadal steroid replacement, in contrast to its absence prior to their administration demonstrates that the hypothalamic GnRH neurons must be in place but merely not functioning at the appropriate time during adolescence.

Anosmia. Individuals with impaired sense of smell may or may not be aware of their olfactory defect which can range from severe to mild. Formal testing is thus 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 thus the impairment may be down-played by the affected individual.

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

• Synkinesia of the digits is 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 is 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 [Dodé 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

The non-reproductive phenotypes caused by PROK2 and PROKR2 mutations include the following [Dodé et al 2006, Pitteloud et al 2007a, Abreu et al 2008, Cole et al 2008, Sarfati et al 2010, Martin et al 2011]:

• Obesity
• Pectus excavatum
• Seizures
• Synkinesia
• High-arched palate
• Pes planus
• Sleep disorders
• Hearing loss

The non-reproductive phenotypes in individuals with IGD/KS caused by CHD7 mutations include the following [Kim et al 2008, Jongmans et al 2009]:

• High-arched or cleft palate
• Dental agenesis
• Auricular dysplasia
• Perceptive deafness and hypoplasia of semicircular canals
• Coloboma
• Short stature

The non-reproductive phenotypes caused by FGF8 mutations include the following [Falardeau et al 2008]:

• Cleft lip and/or palate
• Hyperlaxity of the digits
• Hearing loss
• Ocular hypertelorism
• Camplodactyly

Genotype-Phenotype Correlations

KAL1 (KS1). 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 IGD [Oliveira et al 2001, Pitteloud et al 2002a].

FGFR1 (KS2). The IGD 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. The reproductive defect occurs in both anosmic and normosmic individuals. 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 et al 2006b]. The IGD phenotype is more predominant in males with FGFR1 mutations than in females.

PROKR2 (KS3). PROKR2 mutations give rise to both anosmic and normosmic IGD. Heterozygous, compound heterozygous, and homozygous mutations have been described in IGD families with some showing incomplete penetrance of the reproductive defect. Currently, all individuals with the full reproductive phenotype as a result of homozygous or compound heterozygous PROKR2 mutations are anosmic [Dodé et al 2006, Abreu et al 2008, Cole et al 2008, Sarfati et al 2010, Martin et al 2011].

PROK2 (KS4). PROK2 mutations give rise to both anosmic and normosmic IGD. Heterozygous, compound heterozygous, and homozygous mutations have all been described in IGD families, with some showing incomplete penetrance of the reproductive defect [Dodé et al 2006, Pitteloud et al 2007b, Abreu et al 2008, Cole et al 2008, Sarfati et al 2010, Martin et al 2011].

CHD7 (KS5). CHD7 mutations give rise to both anosmic and normosmic IGD as well as to CHARGE syndrome. An intronic transversion resulting in abnormal splicing has been reported in both KS and CHARGE syndrome and a missense mutation in exon 8 has been found in both normosmic IGD and CHARGE syndrome. Other missense and splice mutations have been reported in individuals with IGD who have no clinical features of CHARGE syndrome [Kim et al 2008, Jongmans et al 2009].

FGF8 (KS6). Heterozygous FGF8 mutations can result in both anosmic and normosmic IGD in family members who have the same mutation. In addition, family members with the same FGF8 mutation can have either a normal reproductive phenotype or a fully penetrant reproductive defect [Falardeau et al 2008, Trarbach et al 2010a].

Penetrance

Penetrance for the IGD phenotype is generally complete in males with KAL1 mutations although discordant identical twins have been documented. Though both brothers presented with hypogonadotropic hypogonadism and hyposmia, one had ventricular septal defect and a much greater LH and FSH response to a serial LH-RH stimulation test, while the other had exotropia and a lower response [Matsuo et al 2000].

Penetrance is incomplete in individuals with FGFR1, PROKR2, PROK2, CHD7, or FGF8 mutations: individuals with mutations and normal gonadal function have been documented.

Penetrance for anosmia in men with mutations in KAL1 is generally complete. In contrast, individuals with IGD and FGFR1, PROKR2, PROK2, CHD7, or FGF8 mutations may be normosmic, hyposmic, or anosmic [Pitteloud et al 2006a, Cole et al 2008, Falardeau et al 2008].

Nomenclature

KS is a subset of isolated GnRH deficiency (IGD) and is sometimes referred to as anosmic IGD, 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 in this group was 1:86,000 [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 IGD, 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 IGD have anosmia/hyposmia (Kallmann syndrome) and one third have normosmic IGD [Authors, unpublished observation].

Evaluations Following Initial Diagnosis

In an individual diagnosed with Kallmann syndrome (KS) and identified as having a mutation in KAL1, FGFR1, PROKR2, PROK2, CHD7, or FGF8, 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 including severity of anosmia, presence of unilateral renal agenesis, synkinesia and/or skeletal abnormalities, agenesis of the corpus callosum (as seen on MRI), cleft lip/palate, ear/hearing defects, coloboma, hyperlaxity of joints, pectus excavatum, and pes planus

Treatment of Manifestations

Treatment options for individuals with IGD 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.

Evaluation 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 whether 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 be initiated only when IGD with impaired pubertal development is diagnosed.

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, staffed by genetics professionals, provide 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.

Mode of Inheritance

Kallmann syndrome 1 (KS1) (caused by mutations in KAL1) is inherited in an X-linked manner.

KS2 (caused by mutations in FGFR1), KS3 (PROKR2), KS4 (PROK2), KS5 (CHD7), and KS6 (FGF8) are predominantly inherited in an autosomal dominant manner. Most of these genes (KAL1, FGFR1, PROKR2, PROK2, and FGF8) have also been shown to have digenic interactions with each other in giving rise to several cases of IGD [Sykiotis et al 2010].

KS3 (PROKR2) and KS4 (PROK2) can also be inherited in an autosomal recessive 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, in which case 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 KAL1 and his mother is not a carrier.
  • His mother is a carrier and has a de novo disease-causing mutation in KAL1, 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 on 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 KS can be fertile.
• Males with X-linked KS 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 possible if the mutation has been identified in the family.

Risk to Family Members — Autosomal Dominant Inheritance

Parents of a proband

• Some individuals diagnosed with KS2, KS3, KS4, or KS6 have an affected parent, although the severity of the phenotype can differ.
• A proband with KS2, KS3, KS4, KS5, or KS6 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, PROK2, or FGF8 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 KS2, KS3, KS4, or KS6 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 diagnosis of the disease in an affected relative.

Sibs of a proband. The risk to the sibs of the proband depends on 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. Germline mosaicism has been reported in family with CHARGE syndrome [Jongmans et al 2006]; it has not been reported in families with KS but remains a possibility.

Offspring of a proband. Each child of an individual with KS2, KS3, KS4, KS5, or KS6 can have up to a 50% chance of inheriting the mutation.

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

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

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.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

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. See for a list of laboratories offering DNA banking.

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 approximately ten to 12 weeks' gestation or by amniocentesis usually performed at approximately 15 to 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, 3, 4, 5, or 6 (caused by mutations in FGFR1, PROKR2, PROK2, CHD7, and FGF8 respectively) is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately 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.

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

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

Anosmia. 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.

Literature Cited

1. Abreu AP, Trarbach EB, de Castro M, Frade Costa EM, Versiani B, Matias Baptista MT, Garmes HM, Mendonca BB, Latronico AC. Loss-of-function mutations in the genes encoding prokineticin-2 or prokineticin receptor-2 cause autosomal recessive Kallmann syndrome. J Clin Endocrinol Metab. 2008;93:4113–8. [PubMed: 18682503]
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Suggested Reading

1. Ballabio A, Rugarli EI. Kallmann syndrome. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 225. Available online. 2010. Accessed 12-4-12.
2. Semple RK, Kemal Topaloglu A. The recent genetics of hypogonadotrophic hypogonadism - novel insights and new questions. Clin Endocrinol (Oxf). 2010;72:427–35. [PubMed: 19719764]

Author History

Margaret Au, MBE, MS, CGC (2010-present)
Marissa Caudill; University of Connecticut Health Center (2007-2010)
William F Crowley, Jr, MD (2007-present)
J Carl Pallais, MD, MPH (2007-present)
Nelly Pitteloud, MD (2007-present)
Stephanie Seminara, MD (2007-present)

Revision History

• 18 August 2011 (cd) Revision: sequence analysis and prenatal diagnosis available clinically for mutations in FGF8 causing Kallmann syndrome 6
• 4 January 2011 (cd) Revision: changes in nomenclature, Tanner staging, and test availability; references added
• 8 April 2010 (me) Comprehensive update posted live
• 23 May 2007 (me) Review posted to live Web site
• 1 June 2006 (jcp) Original submission