DiagnosisClinical DiagnosisKallmann 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 androgensPre-pubertal testicular volume (stage I; <4mL) in malesTable 1. Tanner StagingView in own windowStagePubic HairMale GenitaliaFemale Breast DevelopmentINoneChildhood appearance of testes, scrotum, and penis (testicular volume <4 mL)No breast bud, small areola, slight elevation of papillaIISparse hair that is long and slightly pigmentedEnlargement of testes; reddish discoloration of scrotumFormation of the breast bud; areolar enlargementIIIDarker, coarser, curly hairContinued growth of testes and elongation of penisContinued growth of the breast bud and areola; areola confluent with breastIVAdult hair covering pubisContinued growth of testes, widening of the penis with growth of the glans penis; scrotal darkeningContinued growth; areola and papilla form secondary mound projecting above breast contourVLaterally distributed adult-type hairMature adult genitalia (testicular volume >15mL)Mature (areola again confluent with breast contour; only papilla projects)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.FigureFigure 1. Genes associated with isolated GnRH deficiency (IGD) by sense of smell and mode of inheritance Molecular Genetic TestingGenes. 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 SyndromeView in own windowGene SymbolProportion of KS Attributed to Mutations in This GeneTest MethodMutations DetectedMutation Detection Frequency by Gene and Test Method ^{1Test AvailabilityKAL1RareDeletion / duplication analysis 2, including FISHPartial- or whole-gene deletion>95% 4Clinical 5%-10%Sequence analysis Sequence variants 3>95%FGFR1~10%Sequence analysisSequence variants 3>95%Clinical Deletion / duplication analysis 2DeletionRare 4PROKR2~5%Sequence analysisSequence variants 3>95%ClinicalPROK2<5%Sequence analysisSequence variants 3>95%ClinicalCHD75%-10%Sequence analysisSequence variants 3>95%ClinicalFGF8<5%Sequence analysisSequence variants 3>95%Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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.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 StrategyEstablishing 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 FGF8Females. Sequence analysis of FGFR1, PROKR2, PROK2, CHD7, and FGF8Carrier 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. Genetically Related (Allelic) DisordersKAL1. 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 HistoryGonadal 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 SeizuresSynkinesiaHigh-arched palatePes planus Sleep disordersHearing lossThe 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 palateDental agenesisAuricular dysplasiaPerceptive deafness and hypoplasia of semicircular canalsColobomaShort statureThe non-reproductive phenotypes caused by FGF8 mutations include the following [Falardeau et al 2008]:Cleft lip and/or palate Hyperlaxity of the digitsHearing lossOcular hypertelorismCamplodactyly

Genotype-Phenotype CorrelationsKAL1 (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].

Differential DiagnosisSee Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency Overview.Note testing algorithm to establish the diagnosis of isolated GnRH deficiency (Figure 2). FigureFigure 2. Testing algorithm to establish the diagnosis of isolated GnRH deficiency (IGD) Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisIn 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 planusTreatment of ManifestationsTreatment 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.Sex Steroid ReplacementAs the majority of individuals with HH have not progressed through puberty, one of the initial challenges is initiation of the process of sexual maturation. When fertility is not immediately desired, replacement with gonadal steroids is the most practical option. Initial therapy should be started at low doses and gradually increased with the development of secondary characteristics.For males with IGD/KS Testosterone replacement. In boys or men with prepubertal features, normal virilization can be effectively achieved with testosterone replacement. Usual starting doses are 25-50 mg of a long-acting testosterone ester given intramuscularly every two weeks. The doses can be gradually increased by 25-50 mg every two to three months until full virilization is achieved. Once adult doses (~200 mg every two weeks) are reached, further adjustments are based on serum testosterone concentration. Therapy should be continued indefinitely to ensure normal sexual function and maintenance of proper muscle, bone, and red blood cell mass. Transdermal methods of testosterone administration can also be used; they have the added benefit of offering a more favorable pharmacokinetic profile. Human chorionic gonadotropin (hCG) injections. Although treatment with hCG can also promote testicular growth, this must be weighed against the increased risk of developing gynecomastia. Ultimately, the determination of which formulation to choose is based on the preference of the affected individual. Treatment with hCG is usually initiated at 1,000 IU intramuscularly or subcutaneously every other day to normalize serum testosterone concentration. Depending on the initial testicular volume, some males with IGD can produce sufficient sperm to achieve conception with hCG treatment only [Burris et al 1988] (see Fertility Induction). For females with IGD/KS. Initial treatment should consist of unopposed estrogen to allow optimal breast development. After approximately six months, once breast development has been optimized, a progestin should be added for endometrial protection. Many formulations of estrogens and progestins are available and can be given in either cyclical or continuous fashion. Preference of the individual is important in choosing the right treatment plan, although low estrogen formulations should be considered in women with clotting abnormalities (see Factor V Leiden Thrombophilia and Prothrombin Thrombophilia).Fertility InductionFor males with IGD/KS. Although androgen administration helps maintain normal sexual function, gonadotropins are usually required to realize the fertility potential in males with HH/KS. Gonadotropin therapy. Traditionally, the combination of the gonadotropins (hCG and human menopausal gonadotropins [hMG] or recombinant FSH [rFSH]) is utilized to stimulate spermatogenesis. Treatment with hCG is usually initiated at 1,000 IU intramuscularly or subcutaneously every other day to normalize serum testosterone concentration. FSH is added to the regimen at doses ranging from 37.5 to 75 IU as either hMG or recombinant formulation. Depending on the initial testicular volume, some males with IGD can produce sufficient sperm to achieve conception with hCG treatment alone [Burris et al 1988]. However, if after six to nine months, semen analysis reveals persistent azoospermia or marked oligospermia, FSH is added to the regimen at doses ranging from 37.5 to 75 IU as either hMG or recombinant formulation.
Care must be taken to track testicular volume, as this is one of the primary determinants of successful spermatogenesis. In fact, sperm are rarely seen in the semen analysis until testicular volume reaches 8 mL [Whitcomb & Crowley 1990]. In individuals without a history of cryptorchidism, sperm function is usually normal and conception can occur even with relatively low sperm counts.Pulsatile GnRH stimulation. An alternative method for induction of spermatogenesis is pulsatile GnRH. As the primary defect of IGD/KS is typically localized to the hypothalamus, the pituitary responds appropriately to physiologic doses of GnRH.
Subcutaneous administration of GnRH in a pulsatile manner through a portable pump that delivers a GnRH bolus every two hours is an efficient way of inducing testicular growth and spermatogenesis [Pitteloud et al 2002b]. Although gonadotropin therapy or pulsatile GnRH stimulation can induce spermatogenesis in approximately 90%-95% of men with IGD, some men have a better response to pulsatile GnRH stimulation than to gonadotropin therapy. However, pulsatile GnRH therapy is not currently approved by the Food and Drug Administration (FDA) for the treatment of infertility in men and thus is only available for treatment of infertility in men at specialized research centers.
Successful spermatogenesis can be obtained in most males with IGD through pulsatile GnRH therapy or combined gonadotropin therapy. Men with IGD usually do not have a defect in sperm function; thus, low sperm numbers can often result in conception. However, if infertility remains a problem despite successful spermatogenesis, in vitro fertilization is an option.For females with IGD Pulsatile GnRH stimulation and exogenous gonadotropins. Pulsatile GnRH stimulation is an FDA-approved therapy for folliculogenesis in women with IGD. Intravenous administration of GnRH at various frequencies throughout the menstrual cycle closely mimics normal cycle dynamics with the resulting ovulation of a single follicle. This therapy offers a clear advantage over the traditional treatment with exogenous gonadotropins, which involves higher rates of both multiple gestation and ovarian hyperstimulation syndrome. For either approach, however, the rate of conception is approximately 30% per ovulatory cycle [Martin et al 1990]. SurveillanceGonadal 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 AvoidWhen 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 RiskTesting 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 InvestigationSearch 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.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Kallmann Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDFGFR18p11​.23-p11.22Fibroblast growth factor receptor 1Catalogue of Somatic Mutations in Cancer (COSMIC)
FGFR1 homepage - Mendelian genesFGFR1KAL1Xp22​.31Anosmin-1KAL1 @ LOVDKAL1CHD78q12​.1-q12.2Chromodomain-helicase-DNA-binding protein 7 CHD7PROKR220p12​.3Prokineticin receptor 2PROKR2 homepage - Mendelian genesPROKR2PROK23p13Prokineticin-2PROK2 homepage - Mendelian genesPROK2FGF810q24​.32Fibroblast growth factor 8FGF8 homepage - Mendelian genesFGF8Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Kallmann Syndrome (View All in OMIM) View in own window 136350FIBROBLAST GROWTH FACTOR RECEPTOR 1; FGFR1 147950HYPOGONADOTROPIC HYPOGONADISM 2 WITH OR WITHOUT ANOSMIA; HH2 244200HYPOGONADOTROPIC HYPOGONADISM 3 WITH OR WITHOUT ANOSMIA; HH3 300836KAL1 GENE; KAL1 308700HYPOGONADOTROPIC HYPOGONADISM 1 WITH OR WITHOUT ANOSMIA; HH1 600483FIBROBLAST GROWTH FACTOR 8; FGF8 607002PROKINETICIN 2; PROK2 607123PROKINETICIN RECEPTOR 2; PROKR2 608892CHROMODOMAIN HELICASE DNA-BINDING PROTEIN 7; CHD7 610628HYPOGONADOTROPIC HYPOGONADISM 4 WITH OR WITHOUT ANOSMIA; HH4 612370HYPOGONADOTROPIC HYPOGONADISM 5 WITH OR WITHOUT ANOSMIA; HH5 612702HYPOGONADOTROPIC HYPOGONADISM 6 WITH OR WITHOUT ANOSMIA; HH6Molecular Genetic PathogenesisAnosmia. 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 an exon(s), deletion of several nucleotides, missense mutations, nonsense mutations, and mutations predicted to cause splice variants. For more information, see Table A.Normal gene product. The protein encoded by KAL1, anosmin 1, has 680 amino acids with functional similarities to 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 signs of Kallmann syndrome (KS), IGD, 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 Table A.Normal gene product. FGFR1 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 IGD phenotype in males than females [Dodé 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. The PROKR2 mutations identified in individuals with KS/normosmic IGD result in diminished receptor function and impaired signaling [Cole et al 2008, Monnier et al 2009, Martin et al 2011]. Functional studies of selected PROKR2 mutations have failed to demonstrate a dominant negative effect. Knockout mice lack olfactory bulbs and have severe atrophy of the reproductive system related to the absence of gonadotropin-releasing hormone (Gnrh)-synthesizing neurons in the hypothalamus [Matsumoto et al 2006, Martin et al 2011]. 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. PROK2 mutations resulted in diminished signaling through the PROKR2 receptor [Cole et al 2008, Martin et al 2011]. CHD7Normal allelic variants. CHD7 has 38 exons. Pathologic allelic variants. Pathologic variants of CHD7 resulting in KS are predominantly missense mutations or intronic mutations resulting in abnormal splicing. Additional mutations, including microdeletions, have been reported in individuals with CHARGE syndrome. Normal gene product. The normal gene product is chromodomain helicase DNA-binding protein 7. It belongs to a family of proteins that are thought to alter nucleosome structures and mediate chromatin interactions. Abnormal gene product. CHD7 mutations reported in individuals with KS or normosmic IGD result in truncated proteins or amino acid substitutions of conserved residues when compared with CHD7 orthologs [Kim et al 2008]. FGF8Normal allelic variants. FGF8 has six coding exons which are alternatively spliced into four isoforms. Pathologic allelic variants. Pathologic variants of FGF8 are predominantly missense mutations. Normal gene product. The normal gene product is FGF8, one of the main ligands for FGFR1 which is involved in neuronal patterning, survival of neural cells, and GnRH neuron development. Abnormal gene product. Abnormal FGF8 gene product results in impaired activation of the FGFR1 receptor. Fgf8 hypomorphic mice have olfactory bulb dysgenesis and reduced number of Gnrh neurons in the hypothalamus [Falardeau et al 2008].