Kallmann Syndrome

Synonyms of Kallmann Syndrome

  • idiopathic hypogonadotropic hypogonadism with anosmia

General Discussion

Kallmann syndrome (KS) is a rare genetic disorder in humans that is defined by a delay/absence of signs of puberty along with an absent/impaired sense of smell. A closely related disorder, normosmic idiopathic hypogonadotropic hypogonadism (nIHH), refers to patients with pubertal failure but with a normal sense of smell. Both KS and nIHH are due to an isolated deficiency of a key reproductive hormone called gonadotropin-releasing hormone (GnRH). KS and nIHH occurs in both sexes but males are more commonly diagnosed with this condition. Patients with KS/nIHH typically present at adolescence due to the delay in the onset of physical changes associated with puberty. KS patients are often aware of their lack of sense of smell but most may not have sought medical advice for this symptom. While these reproductive symptoms predominate in their presentation, non-reproductive features that may be present in KS/nIHH subjects include: facial abnormalities (eg. cleft lip/palate), absence of one kidney, shortened digits, deafness, eye movement abnormality etc. Typically, the diagnosis of KS/nIHH is made by a pediatric/adult endocrinologist. Following clinical examination, biochemical blood testing and various imaging tests are undertaken to confirm the diagnosis. As this is a genetic condition, testing for the various different genetic forms of this disease may also assist in making the diagnosis. For therapy, initially, hormone replacement therapy (testosterone in males; estrogen and progesterone in females) is used to induce secondary sexual characteristics. Once pubertal maturation is achieved, if KS and nIHH subjects wish to be fertile, either injections of pituitary hormones (the gonadotropins, LH and FSH) or in some instances, therapy with the synthetic peptide, GnRH, whose deficiency causes these syndromes, are required to induce the sex organs (testes or ovaries) to make sperm (males) or eggs (females). While both KS and nIHH are usually life-long in their nature, about 10-15% of patients may experience a recovery of their hormonal system, the reasons for which currently remain unclear.


Normal reproductive axis in humans The hypothalamus is a special area in the brain that is responsible for control of several hormones in the body. Reproductive function in humans is under the control of a group of ~ 1,200-1,500 cells (neurons) called GnRH (Gonadotropin-Releasing Hormone) neurons. At the time of puberty, these neurons coordinately secrete GnRH, a peptide hormone, in a series of discrete series of bursts or pulses. This pulsatile pattern of secretion of GnRH is the key to stimulating the production of two other glycoprotein hormones from the pituitary which is downstream from the hypothalamus, namely luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In turn, LH and FSH act on the sex organs or gonads in both sexes (testicles in men; ovaries in women) to do two things that are essential for human reproduction. The first is to stimulate the gonads to secrete sex steroids like testosterone in men and estrogen in women. The second is to produce the germ cells in the gonads (sperm in men and eggs in women). Pathophysiology of Kallmann syndrome (KS) and normosmic idiopathic hypogonadotropic hypogonadism (nIHH) GnRH is the master controller or ‘pilot light’ of reproduction. GnRH neurons are active in stimulating the reproductive axis at birth; become quiet during childhood; and initiate the awakening of the dormant reproductive axis of children at puberty. The GnRH neurons for these processes are unique amongst other hypothalamic neurons in the fact that they have a very complex developmental pattern. During the fetal period, these GnRH neurons originate in the olfactory placode (i.e. the early developing nose); then migrate along the fetal olfactory (smell-related) neurons that also originate in the nose; and eventually enter the brain ultimately wending their way to the hypothalamus, their ultimate residence during early gestation. In both sexes, these GnRH neurons are fully active and functional secreting GnRH soon after birth (neonatal period) and begin to secrete GnRH in a characteristic pulse pattern. However, this GnRH secretory activity, for reasons not entirely clear, becomes quiescent in childhood and mysteriously, reawakens again during adolescence marking the onset of puberty. Defects in either the development of GnRH neurons or their secretory function result in disruption of normal puberty. The condition of KS results when there is failure of the early development and/or migration of the GnRH neurons in the fetus. Therefore, when this migratory journey is interrupted due to various genetic defects, patients develop this unique combination of GnRH deficiency and anosmia (due to loss of olfactory neurons), that define this clinical syndrome. When GnRH deficiency results from either from defective GnRH secretion/action without any developmental migratory deficits, patients present with just GnRH deficiency without any smell defects. This group of patients is labeled as nIHH subjects, the nomosmic counterpart to KS. In both KS and nIHH patients, the rest of the hypothalamic and pituitary hormones are completely normal and the radiographic appearance of the hypothalamic-pituitary region is typically normal. Taken together, both KS and nIHH represent patients with “isolated GnRH deficiency” (IGD), which is the most precise pathophysiologic definition of this disorder. Historically, it was the KS form of IGD that was recognized first. As early as in the 19th century, the clinical association of anosmia and hypogonadism was recognized by a Spanish pathoglogist, Maestre de San Juan. However, it was Kallmann and Schoenfeld in 1944 who redefined this syndrome in the modern era. They showed the co-segregation of anosmia and hypogonadism in affected individuals from three families and therefore established the hereditary nature of this syndrome (i.e. passing from parents to offspring). Since then, this combination of hypogonadotropic hypogonadim and anosmia is described with the eponymous name, “Kallmann syndrome”. However, even in Kallmann’s first report, the presence of nIHH individuals was also recognized in some of these families as well as the presence of various non-reproductive clinical features. Since these early reports, both these clinical entities have been well studied and this report summarizes the clinical symptoms, causes, their associated non-reproductive phenotypes, the correct diagnostic work up, and the various treatment options for both KS and nIHH forms of IGD.

Signs & Symptoms

The clinical hallmark of IGD is the failure of onset of puberty. This lack of pubertal maturation, i.e. hypogonadism, occurs in both sexes and is characterized by reduced blood levels of the sex hormone levels (testosterone and estrogen) as well as gonadotropins (LH and FSH) and infertility. In boys, the onset of normal pubertal development is heralded by testicular enlargement that is then followed by penile growth and the appearance of pubic hair. Affected men complain of absence of secondary sexual characteristics (facial hair growth, body hair growth, decreased pubic hair growth and genital enlargement) and a delayed growth spurt in comparison to their peers. In addition, an absence of sexual interest (libido) and poor sexual function (inability to attain or sustain an erection) may also be present. Unusual growth of breasts may also be rarely seen in these subjects although this more typically occurs during treatment of this condition and is often transient (see below).

Clinical examinations in these subjects usually confirms the incomplete sexual maturation (e.g. prepubertal testicular volume [< 4ml]), a eunuchoid body habitus (disproportionally long arms when compared to height) and decreased muscle mass. The degree of pubertal maturation can vary considerably with some individuals lacking any sign of puberty whereas others may have partial pubertal features that do not progress normally. Although IGD in males is typically diagnosed at puberty, this diagnosis can be made in infancy due to a small genital size (micropenis/microphallus) and/or lack of descent of testes (undescended testes or referred to as cryptorchidism). As mentioned earlier, pulsatile GnRH secretion and evidence of a normal reproductive axis occurs during the neonatal period. Hence, timely biochemical testing during the first 6 months or so of life may also confirm the presence of hypogonadism with low gonadotropin levels, i.e. the biochemical hallmarks of this condition during this critical window of normal development. However, if this brief developmental window of diagnostic testing is missed, a definite diagnostic confirmation may have to wait until the expected time of puberty although the increasing knowledge of the genetic basis of this condition may enable confirmation by specific genetic testing (see below).

In girls, the first sign of normal puberty is the onset of breast budding (thelarche), followed by a growth spurt, the appearance of pubic hair growth, and then only later, the onset of menstrual flow, i.e. menarche. IGD females typically report absence of breast development, an attenuated growth spurt, decreased pubic hair growth, and lack of initiation of menses (primary amenorrhea). However, some females may exhibit some evidence of a partial puberty with thelarche that fails to progress. Very occasionally, some IGD females may report onset of menses at the appropriate time period in adolescence that ceases after a few cycles. Clinical exam in IGD females usually confirms their immature sexual characteristics and enuchoid habitus. It is important to note that development of pubic hair can be normal in both sexes as it is controlled by secretion of androgens from the adrenal glands, i.e. adrenarche, which is unaffected in IGD subjects.

As mentioned earlier, ~50% IGD subjects have KS and exhibit either anosmia (complete lack of smell) or hyposmia (reduced ability to smell). Many IGD subjects also exhibit a spectrum of other non-reproductive features and these features may offer clues to the underlying genetic etiology of IGD (see below). Commonly recognized non-reproductive features that may be present in IGD subjects include:

·Midline facial defects such as cleft lip and/ or palate

·Renal agenesis (One kidney does not develop)

·Short metacarpals (short fingers, especially the 4th finger)


·Mirror movements (synkinesia)

·Eye movement abnormalities

·Poor balance due to cerebellar ataxia

·Scoliosis (bent spine)


IGD is caused by mutations in a number of different genes and to-date, ~50% of patients have a demonstrable genetic mutation that is identifiable. While some genes primarily cause the KS form of IGD, others cause nIHH only, and some can cause both forms of this disorder. Mutations in genes that are thought to disrupt the development and migration of GnRH neurons from the olfactory epithelium to hypothalamus result in the KS phenotype. These include: KAL1, NELF, FGFR1, FGF8, PROK2, PROKR2, HS6ST1, CHD7, WDR11 and SEMA3A. Genes that primarily interfere with the normal secretion of GnRH (GNRH1, KISS1, KISS1R (GPR54), TAC3, TACR3) or its action on the pituitary (GNRHR) cause nIHH. The “overlap genes” ie. the ones that cause both KS and nIHH include FGFR1, FGF8, PROK2, PROKR2, HS6ST1, CHD7, WDR11 and SEMA3A. Presumably, these genes may have multiple roles in GnRH biology including both migration and their normal secretory function.

Each of these genes have varied pattern of affecting families, i.e. inheritance (the way that the disorder passes from parents to offspring). All forms of Mendelian inheritance (autosomal dominant, autosomal recessive, and X-lined recessive) as well more complex oligogenic inheritance patterns are now recognized. Understanding the genetic basis of the disorder is crucial not only for genetic counseling for determine the risk of transmission to the next generation, but also for fostering new gene discovery as well as bench-to-bedside research.

General notes on inheritance of genetic diseases:

Genes for any particular trait are located on chromosomes (rod-shaped organelles consisting of DNA in the nucleus of each cell) and each individual receives 23 chromosomes (22 autosomes and one sex-chromosome like the X and Y chromosomes), each from the father and the mother. Knowing which gene is located on which chromosome allows a prediction of the inheritance pattern of each gene and based on this pattern of inheritance, the probability of passing the disease from parents to their children. A brief summary of the common modes of inheritance are discussed below:

Autosomal dominant inheritance: Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary and sufficient to cause a particular disease. Thus the risk of transmitting a dominant gene is the same for males and females and hence can be inherited from either parent. The risk of passing the abnormal gene from an affected parent to offspring is 50% for each pregnancy.

Autosomal recessive inheritance: Recessive genetic disorders also affect both sexes equally but differ from dominant inheritance in that a disease only occurs when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms of that condition. Marriages within close relatives (consanguineous marriages) thus have a higher risk of having children with a recessive genetic disorder than unrelated parents, as they are more likely to carry the same abnormal gene. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. Although consanguineous families with intermarriage are much more likely to experience these recessive diseases, these disorders can also arise in non-consanguineous (i.e. non-related) parents who happen to carry mutations in the same gene.

X-linked inheritance: In X-linked recessive inheritance, females with a mutation in a gene on the X chromosome usually do not display symptoms of the disease linked to the genetic mutation since females have two X chromosomes and the normal gene on the second X chromosome can compensate for the mutated one. However, since males have only one X chromosome that is inherited from their mother (i.e. they are hemizygous), if they inherit an X chromosome that contains a defective gene, they will develop the disease.

Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder is able to reproduce, he will pass the defective gene to all of his daughters who will then be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Hence any condition in which a father passes a disease on to his son is, by definition, not an X-linked condition.

Oligogenic inheritance: Oligogenic inheritance refers to a newly recognized inheritance pattern in which mutations in more than one gene synergistically interact and function in an additive manner to cause a disease phenotype. Both genes may have mutations (i.e. this is a digenic condition) in only one copy (i.e. it is a bi-allelic condition) or occasionally, one gene may have two mutations, each in a different allele they carry and the other may harbor a single mutation giving triallelic-digenic inheritance. Approximately, 10-15% of IGD patients have been shown to display this form of inheritance.

The genes linked to IGD include:


The first gene found responsible for KS was initially localized to the distal portion of X chromosome (Xp22.3) by studying patients with a “contiguous gene syndrome” (i.e. multiple genes lost due to large deletion of a portion of a chromosome resulting in multiple clinical phenotypes). This cluster of phenotypes included: short stature, chondrodysplasia punctata, intellectual disability, icthyosis and KS. By mapping the genes within this large deletion, the KAL1 gene was identified as the cause of KS. KAL1 is an X-linked gene and IGD is inherited in an X-linked recessive manner. KAL1 is comprised by 14 exons and encodes a secreted extracellular matrix protein called anosmin-1. Anosmin-1 plays an important role in the neuronal migration of both the GnRH neurons as well as the olfactory structures. This dual defect results in the characteristic combination of GnRH deficiency and anosmia, respectively. In addition, patients with KAL1 mutations may have additional non-reproductive phenotypes such as unilateral renal agenesis (absence of one kidney) and mirror movements. It is known that anosmin is also involved in kidney development, thus explaining why some patients with KS have renal agenesis. In addition, anosmin is also important for the crossing of the neurons in the developing brain across the midline, and this accounts for the mirror movements. Although KAL1 is a prototypical X-linked recessive gene, it is now known that some female carriers of KAL1 gene may also manifest IGD, suggesting other genetic mechanisms in these female carriers.


In 2003, two independent groups indentified autosomal recessive mutations in KISS1R (formerly called GPR54) as a cause of nIHH form of IGD. The KISS1R encodes the kisspeptin receptor, a cognate G-protein-couple receptor for the ligand, kisspeptin. Kisspeptin is a secreted neuropeptide and it is now well-established the kisspeptin signaling system is an upstream regulator of the GnRH neurons. Recently, mutations in the gene KISS1 encoding kisspeptin itself, was also found to underlie autosomal recessive nIHH. Both KISS1 and KISS1R mutations affect the secretion of GnRH rather than the migration of GnRH neurons, thus resulting in nIHH exclusively. These human genetic observations and other supportive data from both humans and other species, now confirm that kisspeptin signaling is the most robust stimulator of GnRH secretion known currently.


Using an IGD patient with a chromosomal breakpoint on 8p11.2-p11.1, FGFR1 (KAL2), a gene encoding the tyrosine kinase receptor, fibroblast growth factor receptor 1, was identified as a cause of KS. Subsequently, this was confirmed and in addition, mutations in FGFR1 were also identified in nIHH subjects, thus implicating this gene as an “overlap” gene causing both forms of IGD. Since then a large number of mutations of this gene have been uncovered as a cause of IGD. In mice that lack FGFR1, although the connection between the olfactory axons and the forebrain does occur, the olfactory bulb that is responsible for the sense of smell cannot evaginate from the epithelial wall. This observation could explain GnRH neuronal and olfactory migrational defect in patients with mutations in the FGFR1. Although there are 23 known FGF ligands, using the crystallographic modeling information of these ligands and by studying a single FGFR1 mutation, FGF8 was then identified as the ligand responsible for GnRH neuronal migration and mutations in FGF8 have now indentified in IGD patients. Typically, although both FGF8 and FGFR1 mutations are inherited in an autosomal dominant manner considerable variable penterance/expressivity characterizes pedigrees with these mutations. Amongst their clinical characteristics, patients with mutations in this pathway exhibit unique non-reproductive features such as dental agenesis, midline facial defects (cleft lip/palate) and digital bony abnormalities.

PROK2/PROKR2 (Prokineticin 2/Prokineticin 2 receptor)

Following the demonstration of deletions of Prok2 and Prokr2 as genetic causes of KS in mice, mutations in their respective human homologs, PROK2 and PROKR2 have been identified to cause both KS and nIHH. Both these genes are critical regulators of both GnRH neuronal development as well as the GnRH release. It is important to recognize that the majority of those mutations in these two genes have been found in the heterozygous states in humans, whereas heterozygous mice for these mutations don’t present with a similar phenotype. In addition, human harboring mutations in PROK2 and PROKR2 also present with variable clinical characteristics, ranging from severe IGD to seemingly unaffected healthy subjects. This fact indicates that a combination of mutations in different genes may be required for the eventual expression the IGD phenotype and argues strongly for oligogenicity as the inheritance mode for the PROK2 pathway.


Both GNRH1 and GNRHR are obvious candidate genes to cause IGD. IGD patients with mutations in GNRHR were the first to be described. GNRHR mutations are relatively common and cause the nIHH form of IGD. Studies in patients with GNRHR mutations reveal a heterogeneous clinical presentation, with both autosomal recessive and oligogenic inheritance patterns. After several years of investigation, GNRH1 mutations were eventually shown to be a cause of GnRH deficiency in 2009. While GNRHR mutations are fairly common, mutations in GNRH1 are extremely rare and mutations were only identified after genetic studies were done in over 400 patients with IGD. No specific non-reproductive feature is seen in this group of patients.

TAC3 and TACR3

Using homozygosity mapping in consanguineous pedigrees (families where couples marry with closely related individuals), two novel genes involved in tachykinin signaling, TAC3 (encoding neurokinin B) and its receptor (TACR3) were identified as causes of nIHH. Subsequently, mutations in these two genes were also identified in non-endogamous IGD patients and show the neurokinin pathway plays an important role both in ‘mini-puberty’ as well as the GnRH activation in puberty. However, longitudinal studies have revealed that several subjects with TAC3/TACR3 mutations eventually reverse their GnRH deficiency in adulthood, suggesting that this pathway may be dispensable for adult reproductive function. No specific non-reproductive feature is seen in this group of patients.


Mutations in gene CHD7 cause a severe CHARGE syndrome (eye coloboma, heart anomalies, choanal atresia, growth and developmental retardation, genitourinary anomalies and ear abnormalities) (OMIM #214800). The “G” in CHARGE related to hypogonadism occurring secondary to IGD. Recently, milder allelic variants in CHD7 have been linked to a non-syndromic presentation of IGD (both KS and nIHH), and surprisingly accounts for ~7% of IGD patients. These mutations are typically inherited milder missense mutations vs. CHARGE syndrome mutations which are de novo truncating/frameshift mutations, suggesting a genotype-phenotype correlation (unpublished data from the author’s clinical center). IGD patients with CHD7 mutations may also have additional CHARGE related features and ~30% of patients may display hearing loss (unpublished data from the author’s clinical center). Therefore, physicians as well as genetic counselors should perform extensive clinical evaluation to exclude these features.


The human nasal embryonic LHRH factor gene, NELF, has been shown to function as a guidance molecule for olfactory axon projections and neurophilic migration of GnRH cells in mice. Mutations in NELF have been identified in IGD patients (both KS and nIHH), primarily in an oligogenic inheritance pattern.


The WDR11 gene encodes for WD Repeat Containing Protein 11. Heterozygous mutations in WDR11 were recently identified as a cause of IGD. While both KS and nIHH subjects harbored variants in WDR11, murine studies show interaction of WDR11 with EMX1, a homeodomain transcription factor in olfactory neuronal development, thus accounting for its implication in KS. The precise biologic role of WDR11 in neuroendocrine regulation of GnRH is yet to be established.


Mutations in HS6ST1 gene, encoding heparan sulfate (HS) 6-O-sulfotransferase, a member if heparan sulfate (HS) polysaccharides were recently identified as an oligogenic cause of IGD (both KS and nIHH). HS6ST1 catalyzes the transfer of sulfate from 3-prime-phosphoadenosine 5-prime-phosphosulfate to position 6 of the N-sulfoglucosamine residue of heparan sulfate and plays a crucial role in cell-cell communication and neuronal development. Genetics experiments in the worm, (C. elegans) also revealed that reveal that HS cell specifically regulates neural branching in vivo in concert with other IHH-associated genes, such as KAL1, FGFR1 and FGF8. These findings are consistent with a model in which anosmin-1 can act as a modulatory coligand with FGF8 to activate the FGFR1 receptor in an HS-dependent manner.


Most recently, mutations as well as partial deletions in SEMA3A, encoding a secreted axonal guidance molecule, semaphorin 3A, were identified in ~6% of KS patients. Semaphorin 3A, a class 3 semaphorin, activates the neuropilin-plexin-A1 holoreceptor complex and acts as an axonal repulsive cue to the axonal growth cone during embryonic development. Supportive data from both murine deletions of Sema3a as well as mice with specific mutation in the semaphorin binding domain of its receptor show abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the basal forebrain.

In conclusion, IGD is caused by a large number of mutations in many different genes, which now explain ~50% of the genetic causes of the disorder. While most are inherited in a strict Mendelian pattern, several of these genes are shown to interact with each other in an oligogenic manner, which means that patients with IGD may carry mutations in more than one gene, contributing to the complexity of the disease as well as its inheritance to the next generations. Thus, IGD patients require formal genetic counseling to both assess the etiology of their condition as well as the risk of transmission to subsequent generations.

Affected Populations

Both KS and nIHH are relatively rare, can affect both males and females, with a clear male predominance (~4:1). According to a recent retrospective study, to identify all diagnosed KS cases throughout Finland born during a defined time period, the minimal incidence of KS in Finland was approximately 1 in 48,000 newborns. There was a clear difference in estimates between boys (1 in 30,000) and girls (1 in 125,000). The reason for this sex ratio relates in part to the genetics and in part due to a bias of ascertainment wherein males with delayed puberty tend to seek care more frequently than do their female counterparts. A precise estimate of prevalence remains a challenge as there may be differences in different populations.


The diagnosis of Kallmann syndrome is based on the clinical evidence of arrested sexual maturation or hypogonadism and the incomplete sexual maturation by Tanner staging on physical examination. Tanner staging is an established way used during the physical examination by endocrinologists and pediatric endocrinologists worldwide to evaluate the maturation of the primary and secondary sexual characteristics:


Pubic Hair. None

Male Genitalia. Childhood appearance of testes, scrotum, and penis (testicular volume <4 mL)

Female Breast Development. No breast bud, small areola, slight elevation of papilla


Pubic Hair. Sparse hair that is long and slightly pigmented

Male Genitalia. Enlargement of testes; reddish discoloration of scrotum

Female Breast Development. Formation of the breast bud; areolar enlargement


Pubic Hair. Darker, coarser, curly hair

Male Genitalia. Continued growth of testes and elongation of penis

Female Breast Development. Continued growth of the breast bud and areola; areola confluent with breast


Pubic Hair. Adult hair covering pubis

Male Genitalia. Continued growth of testes, widening of the penis with growth of the glans penis; scrotal darkening

Female Breast Development. Continued growth; areola and papilla form secondary mound projecting above breast contour


Pubic Hair. Laterally distributed adult- type hair

Male Genitalia. Mature adult genitalia (testicular volume >15mL)

Female Breast Development. Mature (areola again confluent with breast contour; only papilla projects)

Typically, Tanner staging in IGD patients show:

·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

However, the degree of sexual maturation can vary considerably between subjects. Occasionally, males with IGD can present with a partial pubertal phenotype, termed as the ‘fertile eunuch syndrome’, first described in 1950’s by Paqualini and Bur. These patients are hypogonodal with eunuchoid body proportions but their testicular measurements and spermatogenesis are nearly normal, suggesting an element of spontaneous testicular maturation. Similarly, in females, partial phenotypes with variable degree of breast development and in some extreme cases, menses may occur which then ceases. These partial phenotypes may be seen across all genetic forms of the disease and indicate some attenuated activity of their GnRH neuronal secretory activity.

Apart from the physical examination, biochemical testing is also critical for diagnosis of IGD. As GnRH is not measurable, serum concentration of the gonadotropins (LH and FSH (secreted by the pituitary) and sex steroids are used for diagnosis. In patients with IGD, LH and FSH serum concentrations can be either low or normal, which is highly inappropriate in the presence of low testosterone (in males) and estradiol (in females). In addition, radiographic imaging of the hypothalamus-pituitary region using MRI scans is undertaken to rule any anatomical structural abnormalities. In addition the MRI exam may also indicate the absence of the olfactory structures in KS patients.

Sense of smell can be evaluated by history and by formal diagnostic smell tests, such as the University of Pennsylvania smell identification test (UPSIT). 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 and is interpreted using a standard normogram in the UPSIT manual.

As it has been already mentioned, molecular genetic testing for specifying the genes responsible for each affected individual indicates the way that other family members can be affected. Currently, clinical molecular genetic testing for mutations in KAL1,GNRHR, KISS1R, FGFR1, PROKR2, PROK2, CHD7, FGF8, GNRH1 and TACR3 genes are available to confirm the diagnosis.

Standard Therapies


The standard forms of medical treatment involve hormone replacement therapies and this is usually tailored the clinical need of the patients. Typically, once the diagnosis is made, in both sexes, treatment is aimed at inducing puberty and maintaining normal hormonal levels. Subsequently, treatment may also be need for inducing fertility for achieving pregnancy.

In males, puberty is usually initiated using testosterone therapy and various formulations of testosterone are currently available for this purpose. The most commonly used modes of treatment include testosterone injections given intramuscularly every 2 or 3 weeks depending on the particular injection) or topical testosterone formulations (patches, gels, liquids etc). Once puberty is initiated, testosterone therapy is continued to maintain secondary sex characteristics as well as to normalize biochemical testosterone levels in the blood. When fertility is desired, gonadotropin therapy (hCG and human menopausal gonadotropins [hMG] or recombinant FSH [rFSH]) can be administered to stimulate testicular growth and initiate sperm production (spermatogenesis). Typically, sperm is rarely seen in the semen analysis until testicular volume reaches at least 8 mL. In most IGD individuals without a history of cryptorchidism (undescended testes), sperm function is usually normal and conception can occur even with relatively low sperm counts.

In females, estrogen and progestin therapy is used to induce the secondary sex characteristics, whereas gonadotropins or pulsatile GnRH therapy can be utilized to stimulate production of mature egg cells (folliculogenesis). If spontaneous pregnancy fails to occur despite normal folliculogenesis, in vitro fertilization may be considered with conception rates reported to be approximately 30% per ovulatory cycle.

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