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Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency

Synonyms: Idiopathic Hypogonadotropic Hypogonadism, Isolated Hypogonadotropic Hypogonadism

, MS, CGC, , MD, PhD, and , MD.

Author Information

Initial Posting: ; Last Update: July 18, 2013.


Clinical characteristics.

Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is characterized by inappropriately low serum concentrations of the gonadotropins LH (luteinizing hormone) and FSH (follicle-stimulating hormone) in the setting of hypogonadism. IGD is associated with a normal sense of smell (normosmic IGD) in approximately 40% of affected individuals and an impaired sense of smell (Kallmann syndrome [KS]) in approximately 60%. IGD can first be apparent in infancy, adolescence, or adulthood. Infant boys with congenital (i.e., present at birth) IGD often have micropenis and cryptorchidism. Adolescents and adults with IGD have clinical evidence of hypogonadism and incomplete sexual maturation on physical examination. Adult males with IGD tend to have prepubertal testicular volume (i.e., <4 mL), absence of secondary sexual features (e.g., facial and axillary hair growth, deepening of the voice), decreased muscle mass, diminished libido, erectile dysfunction, and infertility. Adult females have little or no breast development and primary amenorrhea. Although skeletal maturation is delayed, the rate of linear growth is usually normal except for the absence of a distinct pubertal growth spurt.


IGD is diagnosed by complete or partial absence of GnRH-mediated release of LH and FSH in the setting of otherwise normal anterior pituitary anatomy and function and in the absence of secondary causes of hypogonadotropic hypogonadism (HH). Pathogenic variants in more than 15 genes account for about half of all IGD; the gene(s) in which mutation accounts for the remaining cases of IGD are unknown and unmapped.


Treatment of manifestations: To induce and maintain secondary sex characteristics, gradually increasing doses of gonadal steroids (testosterone or human chorionic gonadotropin [hCG] injections in males; estrogen and progestin in females); to stimulate spermatogenesis or folliculogenesis, either combined gonadotropin therapy (hCG and human menopausal gonadotropins [hMG] or recombinant FSH [rFSH]) or pulsatile GnRH therapy. If conception fails despite spermatogenesis in a male or ovulation induction in a female, in vitro fertilization (IVF) may be an option.

Prevention of secondary complications: Treatment for decreased bone mass as needed.

Surveillance: For children of both sexes with findings suggestive of IGD, monitor at regular intervals after age 11 years: sexual maturation (by Tanner staging on physical examination); gonadotropin and sex hormone levels; bone age. In individuals with confirmed IGD, monitor at regular intervals: bone mineral density.

Evaluation of relatives at risk: If the pathogenic variant(s) in a family are known, testing of prepubertal at-risk relatives may be indicated to clarify their genetic status. Because of variable expressivity, a prepubertal child with a known pathogenic variant may progress through puberty in a normal or delayed fashion, or not at all; therefore, reevaluation over time is necessary.

Genetic counseling.

IGD can be inherited in an X-linked (XL), autosomal dominant (AD), or autosomal recessive (AR) manner. Recurrence risk counseling is based on family history and the results of molecular genetic testing when available. Carrier testing for at-risk relatives in families with XL IGD or AR IGD is possible if the pathogenic variant(s) in the family are known. Prenatal testing for pregnancies at increased risk is possible for all modes of inheritance if the pathogenic variant(s) in the family are known.


Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) can be associated with a normal sense of smell (normosmic IGD) or an impaired sense of smell (Kallmann syndrome [KS]).

The diagnosis of IGD is established by the findings of incomplete sexual maturation on physical examination and laboratory and imaging findings consistent with IGD, in the absence of any of the secondary causes of IGD. Sense of smell is determined by olfactory function testing.

Findings of incomplete sexual maturation on physical examination as determined by Tanner staging (see Table 1):

  • Men with IGD typically have Tanner stage I-II genitalia (prepubertal testicular volumes i.e. <4 mL); however, some males show evidence of partial pubertal maturation (e.g., fertile eunuch variant) [Pitteloud et al 2001].
  • Women with IGD typically have Tanner stage I breast development and amenorrhea; however, some have spontaneous breast development and occasional menses [Shaw et al 2011].

Both men and women with IGD typically have Tanner stage II-III pubic hair, since pubic hair is controlled in part by adrenal androgens.

When IGD occurs in adulthood (i.e., adult-onset IGD), sexual maturation is complete and secondary sexual characteristics may be fully developed.

Table 1.

Tanner Staging

StageNormal Findings
Pubic HairMale GenitaliaFemale Breast Development
INoneChildhood appearance of testes, scrotum, and penis (testicular volume <4 mL)No breast bud, small areola, slight elevation of papilla
IISparse hair that is long and slightly pigmentedEnlargement of testes; reddish discoloration of scrotumFormation of the breast bud; areolar enlargement
IIIDarker, coarser, curly hairContinued growth of testes and elongation of penisContinued growth of the breast bud and areola; areola confluent with breast
IVAdult 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 contour
VLaterally distributed adult-type hairMature adult genitalia (testicular volume >15 mL)Mature (areola again confluent with breast contour; only papilla projects)

Laboratory findings of IGD

  • Total testosterone (T) <100 ng/dL in males and estradiol (E2) <50 pg/mL in females
  • Inappropriately low or normal serum concentration of LH (luteinizing hormone) and FSH (follicle stimulating hormone) in the presence of low circulating concentrations of sex steroids. Levels of other anterior pituitary hormones are typically normal.

Imaging findings of IGD

  • In persons with IGD: typically, normal-appearing hypothalamus and pituitary on MRI exam
  • In persons with KS: typically, aplasia or hypoplasia of the olfactory bulbs/sulci/tracts

Prior to making a diagnosis of IGD, other causes of hypogonadotropic hypogonadism should be excluded (see Differential Diagnosis, Other causes of hypogonadotropic hypogonadism).

Smell testing. Olfactory function is evaluated by history and by formal diagnostic smell tests, such as the University of Pennsylvania smell identification test (UPSIT), a "scratch and sniff" test that evaluates an individual's ability to identify 40 microencapsulated odorants and can be easily performed in most clinical settings [Doty 2007]. Anosmia, hyposmia, or normosmia is identified using the UPSIT manual normogram, which incorporates an individual’s score, age at testing, and gender.

Individuals with IGD with either self-reported complete anosmia or a score of hyposmia/anosmia on UPSIT testing are diagnosed with KS, while those with normal olfactory function are diagnosed with normosmic IGD (nIGD) [Lewkowitz-Shpuntoff et al 2012].

Molecular Genetic Testing

Genes. IGD is caused by pathogenic variants in more than 15 genes [Layman 2013]. Together, pathogenic variants in all IGD-associated genes account for about half of IGD. The gene(s) in which mutation accounts for the remaining cases of IGD are unknown and unmapped.

  • Pathogenic variants in ANOS1 (KAL1), FGFR1, PROKR2, PROK2, CHD7, and FGF8 cause both Kallmann syndrome (KS) and normosmic IGD (nIGD).
  • Pathogenic variants in ANOS1 (KAL1) cause KS.
  • Pathogenic variants in KISS1, KISS1R (GPR54), TAC3, TACR3, GNRHR, and GNRH1 cause nIGD.

Additionally, pathogenic variants in NSMF (NELF), WDR11, HS6ST1, and SEMA3A – in conjunction with mutation of other genes – have been associated with IGD, suggesting that they could be modifier genes that are not sufficient to cause IGD on their own.

Table 2.

Summary of Molecular Genetic Testing Used in Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency

Gene 1 / LocusProportion of IGD Attributed to Mutation of This GeneTest MethodVariants Detected 2
ANOS1 (KAL1) / KS1RareDeletion/duplication analysis 3, 4, including FISHExon or whole-gene deletions 5
5%-10% 6 of KSSequence analysis 7Sequence variants
FGFR1 / KS2~10% 6Sequence analysis 7Sequence variants
Deletion/duplication analysis 3Exon or whole-gene deletions 5, 8
PROKR2 / KS3~5% 6Sequence analysis 7Sequence variants
Deletion/duplication analysis 3Unknown, none reported 9
PROK2 / KS4<5% 6Sequence analysis 7Sequence variants
Deletion/duplication analysis 3Unknown, none reported 9
CHD7 / KS55%-10% 6Sequence analysis 7Sequence variants
Deletion/duplication analysis 3Unknown, none reported 9
FGF8 / KS6<2% 6Sequence analysis 7Sequence variants
GNRHR / HH75%-10% 6 of nIGDSequence analysis 7Sequence variants
KISS1R / HH8<5% 6 of nIGDSequence analysis 7Sequence variants
Deletion/duplication analysis 3Unknown, none reported 9
NELF (NSMF) / HH9Unknown 10Sequence analysis 7Sequence variants
TAC3 / HH10<2% 6 of nIGDSequence analysis 7Sequence variants
TACR3 / HH11~5% 6 of nIGDSequence analysis 7Sequence variants
GNRH1 / HH12<2% 6 of nIGDSequence analysis 7Sequence variants
KISS1 / HH13<2% 6 of nIGDSequence analysis 7Sequence variants
Deletion/duplication analysis 3Unknown, none reported 9
WDR11 / HH14Unknown 10Sequence analysis 7Sequence variants
HS6ST1 / HH15Unknown 10Sequence analysis 7Sequence variants
SEMA3A / HH16Unknown 10Sequence analysis 7Sequence variants

See Molecular Genetics for information on allelic variants.


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.


Detection of deletion of ANOS1 (KAL1) by FISH or CMA (chromosome microarray analysis) is possible [Hou et al 1999]. Most deletions include an exon or multiple exons. Whole-gene deletions of ANOS1 (KAL1) are a rare cause of KS.


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


Proportion of IGD attributed to these genes is determined from the author’s cohort of 950 probands with IGD who were screened for rare sequence variants (<1% of control cohort).


Examples of pathogenic variants detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


FGFR1 deletions are rare [Trarbach et al 2010b].


No exon or whole-gene deletions or duplications of PROKR2, PROK2, CHD7, KISS1R, or KISS1 have been reported to cause IGD.


Pathogenic variants in NELF (NSMF), WDR11, HS6ST1, and SEMA3A are not thought to cause IGD without contributions from other IGD-related genes, so the proportion of IGD caused by mutation of these genes is unknown.

Testing Strategy

To confirm/establish the diagnosis in a proband suspected of having isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD)

  • Evaluate sense of smell to distinguish between those with IGD and anosmia (i.e., Kallmann syndrome) and those with normosmic IGD (Figure 1).
  • Establish the clinical diagnosis of IGD (see Figure 2).
  • Molecular genetic testing can be undertaken to establish the underlying genetic mechanism in a person with IGD (Table 2). Two options are single gene testing or a multi-gene panel.
Figure 1.

Figure 1.

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

Figure 2.

Figure 2.

Testing algorithm to establish the diagnosis of isolated GnRH deficiency (IGD)

Option 1: Single gene testing. To help prioritize the order of testing the following can be considered:

  • Mode of inheritance:
    • X-linked. Sequence analysis of the coding regions of ANOS1 (KAL1) is the highest-yield molecular genetic test. In those with no ANOS1 (KAL1) pathogenic variant identified on sequence analysis and if clinical suspicion of a potential ANOS1 (KAL1) defect is high (inheritance pattern, presence of associated clinical phenotypes [Figure 3]), deletion/duplication analysis of ANOS1 (KAL1) should be considered.
    • Autosomal dominant. In families with clear autosomal dominant inheritance, testing of FGFR1, CHD7, and FGF8 can be considered. In families with suspected autosomal dominant inheritance, with variable expressivity and reduced penetrance, a multi-gene panel (see Option 2: Multi-gene panel) should be considered.
    • Autosomal recessive. Testing of GNRHR, KISS1R, TAC3, TACR3, KISS1 and GNRH1 can be considered in families with autosomal recessive normosmic IGD; testing of PROK2 and PROKR2 can be considered in families with autosomal recessive KS.
  • Presence of associated phenotypic features (Figure 3). In addition to mode of inheritance, the presence of some associated clinical phenotypic features may also help prioritize genetic testing in IGD [Costa-Barbosa et al 2013].
Figure 3.

Figure 3.

Suggested guidelines for prioritization of genetic testing for patients with IGD based on phenotype [Au et al 2011]

Option 2: Multi-gene panel. As an alternative to the sequential molecular genetic testing described above, a multi-gene panel can be used for the simultaneous analysis of some or all of the genes associated with IGD. Multi-gene panels have the benefit of being able to screen for digenic causes of IGD and may be useful for simplex cases (i.e., a single occurrence in a family) when mode of inheritance is uncertain or when no phenotypic findings characteristic of specific genes are present. Multi-gene panels vary by methods used and genes included; thus, the ability of a panel to detect a causative variant or variants in any given individual with IGD also varies.

Clinical Characteristics

Clinical Description

The clinical manifestations of isolated GnRH deficiency (IGD) depend on the stage of development at which the deficiency in the reproductive axis first occurred (infancy or adolescence). Most individuals with IGD are identified at puberty; however, suggestive clinical features may be present in infancy.

Reproductive phenotype

Infancy. Microphallus (stretched penile length <1.9 cm in a full-term newborn male) and cryptorchidism (undescended testes) represent two early clinical findings that may be present in male infants with IGD, although the significance of these findings is usually not recognized until puberty. Both clinical features reflect congenital GnRH deficiency and, if measured, concentrations of testosterone, LH (luteinizing hormone), and FSH (follicle stimulating hormone) are low in the first months of life in these infants [Grumbach 2005].

Although microphallus and cryptorchidism can occur in both forms of IGD (KS and normosmic IGD), these features are more common in males with KS than in those with normosmic IGD [Pitteloud et al 2002a].

Adolescence. At puberty, most individuals with IGD have abnormal sexual maturation, usually with incomplete development of secondary sexual characteristics. However, the degree to which sexual maturation is affected can vary (see Fertile eunuch variant).

Males with IGD typically have prepubertal testicular volume (i.e., <4 mL), absence of secondary sexual features (e.g., facial and axillary hair growth and deepening of the voice), and decreased muscle mass.

Females with IGD typically have little or no breast development and primary amenorrhea, but milder presentations with spontaneous menses are recognized [Shaw et al 2011].

Since adrenal maturation proceeds normally, the low levels of androgens produced in the adrenal glands may be sufficient for normal onset of pubic hair growth (adrenarche) in both sexes.

Because of the failure of growth plates in the bone to fuse in the absence of sex hormones, most individuals with IGD have a eunuchoid body habitus (i.e., arm span exceeds height by ≥5 cm). Whereas skeletal maturation is delayed, the rate of linear growth is usually normal (save for the absence of a distinct pubertal growth spurt) [Van Dop et al 1987].

Fertile eunuch variant. Some degree of pubertal development can occur in some individuals with IGD. The relatively mildest form of abnormal pubertal development is the "fertile eunuch" variant in males who have clinical evidence of hypogonadism with low serum concentration of testosterone but evidence of partial pubertal development with normal or near-normal testicular volumes, normal levels of inhibin B (the seminiferous tubular secretory protein), and, often, sperm in their ejaculate.

Reversal. Reversal of IGD, defined as restoration of normal serum testosterone concentrations after cessation of even brief treatment with sex steroid, gonadotropin, or GnRH, occurs in about 10% of all men with IGD, including those with KS [Raivio et al 2007]. This post-treatment “awakening” of the hypothalamo-pituitary-gonadal (HPG) axis suggests the presence of hypothalamic GnRH neurons that do not function during adolescence and possibly require hitherto undefined stimuli (potentially environmental/sex steroid exposure) to initiate normal activity.

Olfactory phenotype

Anosmia. The impaired olfactory function in Kallmann syndrome can be either hyposmia or complete anosmia) [Bianco & Kaiser 2009]. The difference between hyposmia and anosmia is quantitative and not qualitative (i.e., odorants can be variably affected in persons with hyposmia). Most individuals with impaired smell do not have any physical or social impairment and the finding often goes unnoticed until IGD is diagnosed.

Reproductive and non-reproductive phenotypes by gene

Table 3 summarizes by gene the scope of the reproductive defect, olfactory function, and non-reproductive issues.

Table 3.

IGD Phenotype by Gene

Gene / LocusPhenotypic FeaturesReferences
ReproductiveOlfactoryOther Non-Reproductive
ANOS1 (KAL11, 2 / KS1 (males)Complete IGD
Small testes
↑ Cryptorchidism (compared to normosmic IGD)
Anosmia or hyposmiaDigital synkinesia (in ~80% males)
Unilateral renal agenesis (in ~30% males) 3
High-arched palate
Oliveira et al [2001], Quinton et al [2001], Pitteloud et al [2002a], Massin et al [2003], Costa-Barbosa et al [2013]
FGFR1 1, 2 / KS2Complete IGD to normal puberty
IGD in males > females
Anosmia or normosmia 4Synkinesia (in ~10%)
Cleft lip and/or palate
Agenesis of 1+ teeth
Digit malformations (brachydactyly, syndactyly)
Dodé et al [2003], Pitteloud et al [2006b], Costa-Barbosa et al [2013]
PROKR2 1, 2 / KS3 and PROK2 1, 2 / KS4IGDAnosmia or normosmia 4NoneCosta-Barbosa et al [2013]
CHD7 1, 2 / KS5IGDAnosmia or normosmia 4High-arched or cleft palate
Dental agenesis
Auricular dysplasia
Perceptive deafness and hypoplasia of semicircular canals
Short stature
Intellectual disability
Kim et al [2008], Jongmans et al [2009], Costa-Barbosa et al [2013]
FGF8 1, 2 / KS6Complete IGD to normal pubertyAnosmia or normosmia 4Cleft lip and/or palate
Hearing loss
Ocular hypertelorism
Hyperlaxity of the digits
Falardeau et al [2008], Trarbach et al [2010a]
GnRHR 1, 2 / HH7IGDNormosmiaNonede Roux et al [1997], Cerrato et al [2006], Bédécarrats & Kaiser [2007]
KISS1R 1, 2 / HH8IGDNormosmiaNonede Roux et al [2003], Seminara et al [2003], Semple et al [2005]
NELF 2 / HH9IGDAnosmia or normosmia 4NoneXu et al [2011]
TAC3 1, 2 / HH10IGDNormosmiaNoneTopaloglu et al [2009]
TACR3 1, 2 / HH11IGDNormosmiaNoneGuran et al [2009], Topaloglu et al [2009], Gianetti et al [2010]
GNRH1 1, 2 / HH12IGDNormosmiaNoneBouligand et al [2009], Chan et al [2009]
KISS1 1, 2 / HH13IGDNormosmiaNoneTopaloglu et al [2012]
WDR11 2 / HH14IGDAnosmia or normosmia 4NoneKim et al [2010]
HS6ST 2 / HH15IGDAnosmia or normosmia 4NoneTornberg et al [2011]
SEMA3A 2 / HH16IGDAnosmia or hyposmiaNoneCariboni et al [2011], Hanchate et al [2012]

Monogenic inheritance


Digenic/oligogenic inheritance


Often asymptomatic; also reported in KS of unknown cause


Depending on penetrance


Pulsatile secretion of GnRH into the hypophyseal portal circulation represents the initial neuroendocrine step in the regulation of the hypothalamo-pituitary-gonadal (HPG) axis in both sexes. Thus, this specialized GnRH neuronal network plays a commanding role in this biologic hierarchy and controls episodic gonadotropin secretion, modulates gonadal steroid feedback, and ultimately determines the initiation or suppression of pubertal development and fertility across the life cycle [Hoffman & Crowley 1982, Crowley et al 1985].

Under normal conditions, the GnRH neuronal network undergoes a series of dynamic changes from fetal life to adulthood. The initiation of GnRH secretion is initiated in early fetal life and remains active until the first several months of infancy (representing the “mini-puberty”), and then becomes remarkably dampened during the years of the childhood “quiescence” [Waldhauser et al 1981]. At puberty, unknown biologic triggers re-ignite GnRH secretion, resulting in full sexual maturation. Therefore, the controls of the reproductive axis are in dynamic flux, turning on and turning off in response to as-yet-unknown biologic signals at various time points in the reproductive life cycle.

In individuals with KS analyses of the pulsatile pattern of gonadotropins have demonstrated a rather broad spectrum of abnormal developmental patterns varying from completely absent GnRH-induced LH pulses to sleep-entrained GnRH release that is indistinguishable from that of early puberty [Spratt et al 1987, Nachtigall et al 1997, Raivio et al 2007]. This broad spectrum of neuroendocrine activity accounts for the variable reproductive phenotypes observed in persons with KS.

Genotype-Phenotype Correlations

Gene-specific phenotypes have been noted; see Table 3 and Figure 3.

No reproductive and non-reproductive phenotype is specific to a single pathogenic variant or particular type of pathogenic variant in any of the IGD-related genes.


The underlying genetic etiology typically determines the penetrance of both reproductive and non-reproductive phenotypes.

The penetrance for the KS phenotype (both IGD and anosmia) is generally complete in males with a ANOS1 (KAL1) pathogenic variant. However, other non-reproductive phenotypes may have variable penetrance even in the setting of the same ANOS1 (KAL1) defect. One set of identical twin males with a small deletion in ANOS1 (KAL1) with discordant neuroendocrine and non-reproductive phenotypes has been documented: one twin had a ventricular septal defect and a much greater LH and FSH response to a serial LH-RH stimulation test, whereas the other had exotropia and a lower response to the serial LH-RH stimulation test [Matsuo et al 2000].

Penetrance for the reproductive phenotype in those with a pathogenic variant in FGFR1, PROKR2, PROK2, CHD7, or FGF8 is incomplete as individuals with normal gonadal function have been documented despite being heterozygous for pathogenic variants in these genes. Discordance for KS has also been demonstrated in identical twins, suggesting that additional modifiers may play a role in phenotypic expression [Hipkin et al 1990].

Penetrance for anosmia in men with a ANOS1 (KAL1) pathogenic variant is generally complete, whereas penetrance for abnormal olfactory function in individuals with IGD and a FGFR1, PROKR2, PROK2, CHD7, or FGF8 pathogenic variant is incomplete, as normosmia, hyposmia, or anosmia can be seen [Pitteloud et al 2006a, Cole et al 2008, Falardeau et al 2008].


The biochemical term “hypogonadotropic hypogonadism” has evolved with the increased understanding of reproductive physiology.

The term “hypogonadism” refers to individuals with impaired sexual development based on findings from both clinical history (e.g., amenorrhea, hot flashes, erectile dysfunction) and physical examination (e.g., small testes, vaginal pallor).

With greater understanding of the hypothalamo-pituitary-gonadal (HPG) axis (see Pathophysiology) and the introduction of urinary gonadotropin measurements, the term “hypergonadotropic” hypogonadism was used to identify those with a primary gonadal defect, while “hypogonadotropic” hypogonadism identified those with a central (i.e., pituitary or hypothalamic) defect.

When anatomic (and later functional) causes of central hypogonadism were identified, “idiopathic” or “isolated” hypogonadotropic hypogonadism (IHH) came into use to indicate those individuals in whom secondary causes of hypogonadotropic hypogonadism had been excluded.

Subsequently the ability to measure the effect of exogenous GnRH administration demonstrated that the vast majority of individuals with “idiopathic” HH had a functional deficiency of GnRH resulting from a defect in GnRH biosynthesis, secretion, and/or action (hence “isolated GnRH deficiency” [IGD]). Aside from hypothalamic GnRH deficiency, individuals with IGD typically have normal pituitary function tests and their hypogonadism typically responds to a physiologic regimen of exogenous GnRH [Hoffman & Crowley 1982].

At this point, the term “isolated GnRH deficiency” (IGD) more properly reflects the current understanding of the clinical entity rather than the previous biochemical description of IHH and, thus, is the better term for what was previously called IHH.


A recent epidemiologic study in Finland showed a minimal incidence of KS of 1:30,000 in males and 1:125,000 in females [Laitinen et al 2011].

In the authors’ cohort of 250 individuals with IGD, males predominate with a male-to-female ratio of nearly 4:1 [Seminara et al 1998].

KS accounts for nearly two thirds of individuals with isolated GnRH deficiency (IGD).

Differential Diagnosis

Other Causes of Hypogonadotropic Hypogonadism

Hypogonadotropic hypogonadism refers to a diverse group of clinical conditions with characteristic biochemical findings of inappropriately low serum concentrations of LH (luteinizing hormone) and FSH (follicle stimulating hormone) occurring in the setting of hypogonadism.

Distinguishing between isolated GnRH deficiency (IGD) and secondary causes of hypogonadotropic hypogonadism and syndromic/genetic causes of hypogonadotropic hypogonadism often requires additional clinical, laboratory, and radiologic evaluations. These may include physical examination for other systemic findings, family history, and measurement of serum concentration of other pituitary hormones, serum iron studies, and hypothalamic/pituitary imaging. Of note, despite a thorough evaluation, IGD can sometimes be difficult to distinguish from other causes of decreased gonadotropin secretion. Hence, molecular genetic testing of the known IGD-related genes (Table 2) may help make the diagnosis of IGD

Acquired causes. Multiple disease processes ranging from systemic diseases to brain and pituitary tumors can result in impaired gonadotropin secretion. These conditions, which can be relatively common and frequently give rise to defects in other pituitary hormones, include the following:

  • CNS or pituitary tumors
  • Pituitary apoplexy
  • Brain/pituitary radiation
  • Head trauma
  • Drugs: GnRH agonists/antagonists, glucocorticoids, narcotics, chemotherapy, drugs causing hyperprolactinemia
  • Functional deficiency resulting from hyperprolactinemia, chronic systemic illness, eating disorders, malnutrition, hypothyroidism, diabetes mellitus, Cushing’s disease
  • Systemic diseases such as hemochromatosis (see HFE-Associated Hereditary Hemochromatosis), sarcoidosis, and histiocytosis

Syndromes such as CHARGE syndrome, Prader-Willi syndrome, combined pituitary hormone deficiency, Bardet-Biedl syndrome, and leptin deficiency/ resistance syndromes can be associated with hypogonadotropic hypogonadism along with other significant clinical findings and/or other pituitary hormone deficits. See Table 4.

Table 4.

Syndromes Associated with Hypogonadotropic Hypogonadism

SyndromeGenetic MechanismPhenotypeReference
Prader-Willi syndromeLoss of paternal 15q11.2Hypotonia in infancy, developmental delay, cryptorchidism/microphallus in males, abnormal satiety, intellectual disability
Combined pituitary hormone deficiencyMutation of PROP1Various degrees of hypopituitarism
Mutation of HESX1Cohen & Radovick [2002]
Mutation of LHX3
Obesity syndromesMutation of PCSK1 (PC1)Morbid obesity, hypocortisolism, hypoinsulinemiaJackson et al [1997], Jackson et al [2003]
Mutation of LEPMorbid obesityStrobel et al [1998]
Mutation of LEPRClément et al [1998]
Bardet-Biedl syndromeMutation of one of 16 genes 1Developmental delay, visual impairment, postaxial polydactyly, obesity, renal impairment
CHARGE syndromeMutation of CHD7Coloboma, heart defect, choanal atresia, growth retardation, ear abnormalitiesPinto et al [2005], Lalani & Belmont [2009]
HFE-related hereditary hemochromatosisMutation of HFECirrhosis, diabetes, cardiomyopathy, arthritis, skin hyperpigmentation
X-linked adrenal hypoplasia congenitaMutation of DAX1Adrenal failure
Xp22.3 contiguous gene deletion syndromeXp22.3 microdeletionKS, icthyosis, short stature, intellectual disability, chondrodysplasia punctata, digital synkinesiaBick et al [1989], Hou [2005]

The 16 genes associated with BBS: BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, BBS9, BBS10, TRIM32, BBS12, CEP290, MKS1, SDCCAG8, WDPCP

Differential Diagnosis of IGD at Specific Developmental Stages

Infancy. Although males with IGD may have cryptorchidism and/or microphallus at birth, these features are not specific for IGD. Numerous disorders can give rise to these genital defects, ranging from isolated findings to syndromes such as Prader-Willi syndrome or abnormal pituitary development (see PROP1-Related Combined Pituitary Hormone Deficiency). This is particularly true for cryptorchidism, the most common birth defect of the male genitalia.

Adolescence. Perhaps the most difficult distinction to make is between IGD and constitutional delay of puberty (CDP). Time is a critical factor in distinguishing between these two conditions. In CDP, spontaneous and otherwise normal puberty eventually occurs, whereas in IGD spontaneous sexual maturation does not occur at any time. Evidence suggests that CDP and IGD are not discrete clinical entities but rather are part of a phenotypic spectrum. In families with IGD, delayed puberty occurs at a much higher frequency in otherwise "normal" family members than in the general population, suggesting that CDP may represent a milder clinical variant of the IGD phenotype [Waldstreicher et al 1996, Pitteloud et al 2006a].

Although the distinction between CDP and IGD cannot be reliably made at any age, age 18 years has traditionally been suggested as the age at which IGD can be diagnosed; however, the recent description of IGD "reversal" occurring in persons in their 20s and older raises the possibility that such individuals may have a severe form of CDP [Raivio et al 2007]. In contrast, the presence of other clinical features associated with IGD (e.g., anosmia, synkinesia) (Table 3) may result in a diagnosis of IGD being made before age 18 years.

Currently, no clinically available test can reliably differentiate CDP from IGD. Data analyses have suggested that the mean serum concentrations of LH and sex hormones after GnRH or hCG (human chorionic gonadotropin) stimulation vary significantly between individuals with CDP and those with IGD. However, the clinical utility of measuring serum LH and sex hormone concentrations after stimulation with GnRH and hCG is limited by the significant variation in individual LH and sex hormone serum concentrations, resulting in considerable overlap between groups [Degros et al 2003].

A peak-to-basal ratio of free alpha subunit (FAS) after the administration of GnRH has been proposed to help distinguish between CDP and IGD with a sensitivity and specificity in the 95% range and an overlap rate of 10% [Mainieri & Elnecave 2003]. More recently, combining a 19-day hCG test with a conventional GnRH test has also been proposed to improve the differentiation between IGD and CDP [Segal et al 2009]. However, given the relatively small number of individuals studied and limited follow-up in both studies, prospective validation is required to determine the true diagnostic reliability of the above tests.

Figure 2 provides a testing algorithm for establishing the diagnosis of isolated HnRH deficiency.


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with IGD, the following evaluations are recommended:

  • Assessment of clinical manifestations of hypogonadism based on the age and sex of the individual, if not already performed as part of the diagnostic work up (see Diagnosis and Table 1)
  • Assessment of laboratory findings* of hypogonadotropic hypogonadism if not already performed as part of the diagnostic work up

    * Serum concentration of LH (luteinizing hormone) and FSH (follicle-stimulating hormone) and in males total testosterone (T) <100 ng/dL and in females estradiol (E2) <50 pg/mL
  • Assessment for presence of possible non-reproductive features including: renal ultrasound examination (to detect unilateral renal agenesis), hearing tests (to detect sensorineural hearing loss), skeletal survey (to detect limb/spine bony abnormalities), dental exam (to detect dental agenesis), eye exam (to detect iris and/or chorioretinal coloboma) and developmental assessment (if there is evidence of developmental delay)
  • In addition to assessing the degree of hypogonadism/GnRH deficiency, potential deterioration in bone health that may have resulted from periods of low-circulating sex hormones needs to be addressed. Depending on the timing of puberty, duration of GnRH deficiency, and other osteoporotic risk factors (e.g., glucocorticoid excess, smoking), one should consider obtaining a bone mineral density study (see Prevention of Secondary Complications).

Treatment of Manifestations

Typically, a definitive diagnosis of IGD is made around age 18 years. However, occasionally, a high clinical suspicion of IGD may be present in an adolescent presenting with anosmia and delayed puberty or in an infant with microphallus and cryptorchidism.

Males with IGD Age ≥18 Years

Treatment options include sex steroids, gonadotropins, and pulsatile GnRH administration. Choice of therapy in adults is determined by the goal(s) of treatment (i.e., to induce and maintain secondary sex characteristics and/or to induce and maintain fertility). The selection of hormone replacement therapy is also based on the preference of the individual being treated; however, when fertility is not immediately desired, replacement with testosterone therapy is the most practical option. As the majority of individuals with IGD have not progressed through puberty at the time of diagnosis, initial therapy should be started at low doses and gradually increased to adult doses once the development of secondary sexual characteristics is achieved.

Hormone replacement therapy for males not desiring fertility

  • Testosterone therapy
    • Testosterone therapy in the form of injectable or transdermal routes of testosterone administration is typically used to both induce puberty and maintain adult levels of testosterone.

      The injectable testosterone preparations have a “roller-coaster” pharmacokinetics with peak and trough levels that can go to extraphysiologic levels; thus, the transdermal preparations have the added benefit of offering a more favorable pharmacokinetic profile. A typical adult dose of testosterone replacement is 200 mg of testosterone ester injections every two weeks or 5 g of a 1% testosterone gel every day. Doses do vary with newer testosterone preparations and manufacturer’s instructions should be followed for individual testosterone preparations.

      Men using topical androgen replacement must take care to avoid exposing other individuals to treated skin. 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 with undesirable side effects.
    • Once puberty is initiated, testosterone replacement therapy is usually required indefinitely to ensure normal sexual function and maintenance of proper muscle, bone, and red blood cell mass.

      However, in approximately 10% of males, reversal of IGD may occur; thus, if clinical evidence shows endogenous activity of the hypothalamo-pituitary-axis (e.g., testicular growth on testosterone, maintained testosterone levels despite missing/withholding therapy), a brief washout of testosterone therapy should be done with monitoring of testosterone levels. If testosterone levels fall, therapy should be re-initiated. If levels are normal, no further testosterone therapy will be required and serial monitoring of levels should be undertaken, as some individuals may require re-initiation of therapy.
  • Human chorionic gonadotropin (hCG). An alternative to testosterone therapy, hCG injections promote testicular growth, normalize serum concentration of testosterone, and induce development of secondary sexual characteristics.
    • In adults, treatment with hCG is usually initiated at 1,500 IU intramuscularly or subcutaneously every other day to normalize serum testosterone concentrations. Dose should be increased by increments of 250 IU if serum testosterone levels remain low.
    • Treatment with hCG must be weighed against the increased risk of developing gynecomastia (resulting from the estrogen produced by stimulation of the testes with hCG). To some extent the risk of gynecomastia can be minimized by gradually reducing the dose of hCG to the minimum required to sustain a serum testosterone concentration in the mid normal range (~500 ng/dL).

Male Infants/Adolescents with Suspicion of IGD

If IGD is clinically suspected (e.g., low testosterone levels with low/normal gonadotropins) low-dose testosterone or hCG therapy can be given in early infancy to boys with microphallus to increase penile length [Bin-Abbas et al 1999, Young 2012].

Since a definitive diagnosis of IGD may not be possible until age 18 years, after infancy these boys do not generally need to be treated until around the time of puberty. At this time, if a high suspicion of IGD remains (e.g., associated anosmia and delay in onset puberty), these subjects may benefit from early initiation of hormonal replacement therapy with either testosterone or hCG treatment early in the pubertal period. A suggestive puberty induction regimen in adolescents is to start a long-acting testosterone ester at a dose of 25-50 mg, 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/2 weeks) are reached, further adjustments are based on serum testosterone levels.

Hormone replacement therapy for males desiring fertility (fertility induction in males). As testosterone replacement therapy suppresses spermatogenesis in the testes, gonadotropins or pulsatile GnRH therapy is usually required to realize the fertility potential in males.

  • Gonadotropin therapy
    • In most males with IGD, a combination of gonadotropins (hCG along with either human menopausal gonadotropins [hMG] or recombinant FSH [rFSH]) is used to stimulate spermatogenesis. In males with very low testicular volumes (≤~8 mL) the initiating dose of hCG is usually 1,500 IU intramuscularly or subcutaneously every other day; FSH is added at doses ranging from 37.5 to 75 IU as either hMG or recombinant formulation. Trough serum testosterone concentrations (target: mid-normal range [~500 ng/dL]), trough serum FSH levels (target: mid-normal reference range), and sperm count are monitored to assess response.
    • In males with higher baseline testicular volumes, treatment with hCG alone may be sufficient to achieve spermatogenesis and conception [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 a recombinant formulation.
    • In either treatment, testicular volume must be tracked, 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 most males without a history of cryptorchidism, sperm function is usually normal and conception can occur even with relatively low sperm counts. Note: Liu et al [2009] have noted that previous treatment with gonadotropins may reduce the period of subsequent gonadotropin treatment required for initiation of spermatogenesis.
    • If a pituitary defect exists, gonadotropin therapy becomes the treatment of choice.
  • Pulsatile GnRH stimulation vs. gonadotropin therapy. While either 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.
    • 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]. As the primary defect of IGD is typically localized to the hypothalamus, the pituitary responds appropriately to physiologic doses of GnRH. Pulsatile GnRH therapy, however, is not currently approved by the Food and Drug Administration for the treatment of infertility in men and, thus, is available for treatment of infertility in men only at specialized research centers.

Females with IGD

Hormone replacement therapy for females not desiring fertility. Although a definitive diagnosis of IGD in females is usually made around age 18 years, occasionally, a high clinical suspicion of IGD may be present in an adolescent presenting with anosmia and delayed puberty and therapy may need to be initiated earlier (age ~14 years)

  • To allow optimal breast development, initial treatment should consist of unopposed estrogen replacement via oral or topical preparations. Many formulations of estrogens are available; a suggested oral regimen is using premarin 0.3 mg daily to be increased gradually to an adult replacement dose of 1-1.25 mg daily.
  • Once breast development is optimal, a progestin should be added for endometrial protection (e.g., cyclical Prometrium® 200 mg daily for 10-12 days).
  • Although preference of the individual plays an important role in choice of treatment plan, low-estrogen formulations should be considered in women with clotting abnormalities (see Factor V Leiden Thrombophilia and Prothrombin Thrombophilia).

Hormone replacement therapy for females desiring fertility (fertility induction in females). Pulsatile GnRH stimulation and exogenous gonadotropins are FDA approved for folliculogenesis in women with IGD. Either therapy should be administered with close supervision by physicians specializing in ovulation induction. Intravenous administration of GnRH at various frequencies throughout the menstrual cycle closely mimics the dynamics of normal menstrual cycles resulting in ovulation of a single follicle [Santoro et al 1986]. This therapy offers a clear advantage over the traditional treatment with exogenous gonadotropins, which results in 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].

Fertility Options in Patients with IGD if Fertility Induction is Unsuccessful

In vitro fertilization. Although successful spermatogenesis can be obtained in most males with IGD through pulsatile GnRH therapy or combined gonadotropin therapy, some men with KS resulting from a ANOS1 (KAL1) pathogenic variant may have an atypical response to therapy [Sykiotis et al 2010a]. In those who respond to therapy, low sperm numbers can often result in conception; however, if infertility continues despite successful spermatogenesis or if spermatogenesis fails to occur, in vitro fertilization (IVF) is an option.

Similarly, if spontaneous conception fails to occur in women with IGD who have undergone ovulation induction, IVF may be an option.

Prevention of Secondary Complications

Optimal calcium and vitamin D intake should be encouraged and specific treatment for decreased bone mass with bisphosphonates should be considered depending on the degree of bone mineralization (see Evaluations Following Initial Diagnosis).


Children of both sexes with findings suggestive of IGD (e.g., microphallus, anosmia) should be monitored at regular intervals from age 11 years onwards with the following:

  • Assessment of sexual maturation by Tanner staging (Table 1)
  • Measurement of serum concentrations of LH, FSH, and total testosterone (T) in males and estradiol (E2) in females
  • Bone age determinations

In individuals with a confirmed diagnosis of IGD, bone mineral density should be monitored at regular intervals.

Evaluation of Relatives at Risk

Testing of at-risk relatives may be indicated when a pathogenic variant has been identified in a family (e.g., testing the brother of a proband with a known ANOS1 (KAL1) pathogenic variant whose mother is a known carrier). Because of variable expressivity, however, it is unknown whether a prepubertal child with a known pathogenic variant will progress through puberty in a normal or delayed fashion, or not at all. Therefore, reevaluation of such individuals over time is important, and 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 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

ANOS1 (KAL1)-related isolated gonadotropin-releasing hormone (GnRH) deficiency (Kallmann syndrome 1) is inherited in an X-linked manner.

Isolated GnRH deficiency (IGD) syndromes caused by mutation of FGFR1 (Kallmann syndrome 2), PROKR2 (Kallmann syndrome 3), PROK2 (Kallmann syndrome 4), CHD7 (Kallmann syndrome 5), and FGF8 (Kallmann syndrome 6) are predominantly inherited in an autosomal dominant manner.

IGD syndromes caused by pathogenic variants in GNRHR, KISS1R, TAC3, TACR3, and GNRH1 are primarily inherited in an autosomal recessive manner. PROKR2-related IGD (Kallmann syndrome 3) and PROK2-related IGD (Kallmann syndrome 4) can also be inherited in an autosomal recessive manner.


  • PROKR2 and PROK2, and FGF8 and FGFR1 have also been shown to have digenic interactions with each other in giving rise to several cases of IGD [Sykiotis et al 2010b].
  • Triallelic inheritance (2 pathogenic variants in FGF8 and 1 in FGFR1) has also been described [Sykiotis et al 2010b].

A three-generation family history should be obtained to understand the mode of inheritance of IGD to aid genetic testing and genetic counseling. Detailed histories including questions regarding consanguinity, reproductive features (e.g., microphallus and cryptorchidism, pubertal development, fertility/infertility), olfactory function (normal sense of smell, hyposmia, anosmia), and non-reproductive features (e.g., craniofacial abnormalities including cleft lip/palate/missing teeth, hearing loss, synkinesia of the digits, and renal agenesis) should be obtained in all family members. If other individuals with IGD or these associated findings are identified in the family, the mode of inheritance may become apparent. In the majority of individuals, however, no such family history is present.

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 pathogenic variant.
  • In a family with more than one affected individual, the mother of an affected male is an obligate carrier. If a woman has more than one affected son and the pathogenic variant cannot be detected in her DNA, she may have germline mosaicism. Germline mosaicism in mothers has not been reported for ANOS1 (KAL1), but the possibility exists.
  • 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 pathogenic variant, in which case the mother is not a carrier. The frequency of de novo mutation is unknown.
  • 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:

Sibs of a proband

  • The risk to sibs depends on the carrier status of the mother.
  • If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Male sibs who inherit the variant will be affected; female sibs who inherit the variant will be carriers and may display some clinical features.
  • If the pathogenic variant 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 pathogenic variant 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 on their gender, may be at risk of being carriers or of being affected.

Risk to Family Members — Autosomal Dominant Inheritance

Parents of a proband

  • Some affected individuals with pathogenic variants in FGFR1, PROK2, PROKR2, CHD7, or FGF8 have an affected parent, although the severity of the phenotype can differ.
  • A proband with autosomal dominant IGD may have the disorder as the result of a de novo pathogenic variant. The proportion of cases caused by de novo mutation is unknown.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include: (1) a detailed pubertal history of both parents and (2) molecular genetic testing of both parents for the family-specific pathogenic variant. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of 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 IGD 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:

Offspring of a proband. Each child of an individual with autosomal dominant IGD has a 50% chance of inheriting the pathogenic variant; however, the actual risk of being affected may be less than 50% because of variable expressivity of the disease.

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 or has a known pathogenic variant, his or her family members may be at risk.

Risk to Family Members — Autosomal Recessive Inheritance

Parents of a proband

Sibs of a proband

Offspring of a proband. The offspring of an individual with biallelic pathogenic variants in an autosomal recessive IGD-related gene are obligate carriers (heterozygotes).

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Risk to Family Members — Unknown/Complex Inheritance

In simplex probands (a single individual with a disorder in a family) with IGD with an unknown cause, or those with complex genetic etiologies such as di-/polygenic inheritance, parents and offspring can have up to a 50% risk of or being affected with IGD though exact risks are uncertain.

Carrier Detection

X-linked inheritance. Carrier testing of at-risk female relatives is possible if the pathogenic variant has been identified in the family. In families with an affected male with a known ANOS1 (KAL1) pathogenic variant, female at risk to be carriers should be tested for the specific variant. If an affected male is not available for testing, carrier testing should include molecular genetic testing first by sequence analysis, and if no pathogenic variant is identified, then by methods to detect deletions in ANOS1 (KAL1). Note: Heterozygous female carriers of a ANOS1 (KAL1) pathogenic variant may occasionally display clinical features that are diagnostic of IGD [Shaw et al 2011].

Autosomal recessive inheritance. Identification of carriers (heterozygotes) requires prior identification of the pathogenic variants in the family.

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.

Digenic and triallelic inheritance. In the rare instance of suspected digenic or triallelic inheritance, referral for genetic counseling is warranted.

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 based on family history.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the pathogenic variant(s) have been identified in an affected family member, prenatal testing and preimplantation genetic diagnosis for a pregnancy at increased risk for IGD are possible options.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Pituitary Network Association
    PO Box 1958
    Thousand Oaks CA 91358
    Phone: 805-499-9973
    Fax: 805-480-0633
  • My46 Trait Profile
  • Pituitary Foundation
    PO Box 1944
    Bristol BS99 2UB
    United Kingdom
    Phone: 0845 450 0375 (Helpline); 0845 450 0376
    Fax: 0117 933 0910
  • The Pituitary Society
    VA Medical Center
    423 East 23rd Street
    Room 16048aW
    New York NY 10010
    Phone: 212-951-7035
    Fax: 212-951-7050

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table B.

OMIM Entries for Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency (View All in OMIM)

300836KAL1 GENE; KAL1


Gene structure. ANOS1 (KAL1) comprises 14 exons and has no alternative spice variants.

Pathogenic allelic variants. Reported pathogenic variants in ANOS1 (KAL1) include deletion of the entire gene, of an exon(s), and of several nucleotides as well as missense, nonsense, and splice variants.

For more information, see Table A.

Normal gene product. The protein encoded by ANOS1 (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.


Gene structure. CHD7 comprises 38 exons.

Pathogenic allelic variants. Pathogenic variants of CHD7 resulting in KS are predominantly missense variants or intronic variants resulting in abnormal splicing. Additional pathogenic variants, 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 pathogenic variants reported in individuals with KS or nIGD result in truncated proteins or amino acid substitutions of conserved residues when compared with CHD7 orthologs [Kim et al 2008].


Gene structure. FGF8 comprises six coding exons which are alternatively spliced into four isoforms.

Pathogenic allelic variants. Pathogenic variants of FGF8 are predominantly missense variants.

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].


Gene structure. FGFR1 comprises 18 exons with a known splice variant at the end of exon 10.

Pathogenic allelic variants. Pathogenic variants in FGFR1 include deletions and missense, nonsense, and splice variants.

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].


Gene structure. GNRH1 comprises three coding exons and one alternative splice variant.

Pathogenic allelic variants. Pathogenic frameshift variants of GNRH1 causing autosomal recessive normosmic IGD have been described.

Normal gene product. GNRH1 encodes a secreted preprohormone that cleaved to a biologically active decapeptide, GnRH, which in turn stimulates the pituitary to secret the two glycoprotein gonadotropin hormones, LH and FSH, which control steroidogenesis and gametogenesis in the gonads.

Abnormal gene product. Abnormal GNRH1 gene product due to pathogenic variants in GNRH1 results in an aberrant peptide lacking biologic activity [Bouligand et al 2009, Chan et al 2009].


Gene structure. GNRHR comprises three coding exons and one alternative splice variant.

Pathogenic allelic variants. GNRHR pathogenic variants, typically missense variants, cause normosmic IGD in an autosomal recessive inheritance pattern. Other pathogenic variants in GNRHR include nonsense and frameshift variants that occasionally cause autosomal recessive IGD. Heterozygous pathogenic variants (missense, frameshift, and nonsense) are also seen in persons with IGD with diverse clinical phenotypes, suggesting an oligogenic inheritance pattern [Gianetti et al 2012].

Normal gene product. GNRHR encodes for the gonadotropin-releasing hormone receptor, GNRHR, a G protein-coupled transmembrane receptor for the decapeptide, GNRH.

Abnormal gene product. Abnormal GNRHR gene products result in diminished or absent GNRH signaling through the receptor resulting in hypogonadotropism.


Gene structure. KISS1 comprises two coding exons and has no alternative splice variants.

Pathogenic allelic variants. Homozygous missense KISS1 variants cause normosmic IGD in an autosomal recessive inheritance pattern, but are exceedingly rare. Rare heterozygous variants have also been associated with IGD suggesting a likely oligogenic inheritance in those individuals.

Normal gene product. KISS1 encodes for kisspeptin, a secreted peptide that is a potent stimulus for GnRH secretion in all mammalian species through KISS1R, its cognate receptor.

Abnormal gene product. Abnormal KISS1 gene products result in diminished or absent kisspetin signaling through the receptor resulting in secondary GnRH deficiency and consequent hypogonadotropism.


Gene structure. KISS1R comprises five coding exons and one alternative splice variant.

Pathogenic allelic variants. KISS1R pathogenic variants, typically nonsense or missense variants, cause normosmic IGD in an autosomal recessive inheritance pattern. These variants are extremely rare. Occasionally, heterozygous pathogenic variants are also seen in persons with IGD, suggesting an oligogenic inheritance pattern.

Normal gene product. KISS1R encodes for the kisspeptin receptor, KISS1R, a G protein-coupled transmembrane receptor for kisspeptin.

Abnormal gene product. Abnormal KISS1R gene products result in diminished or absent kisspetin signaling through the receptor resulting in secondary GnRH deficiency and consequent hypogonadotropism.


Gene structure. PROK2 comprises four coding exons, including an alternative exon 3.

Pathogenic allelic variants. Pathogenic variants of PROK2 include missense and nonsense variants 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 pathogenic variants resulted in diminished signaling through the PROKR2 receptor [Cole et al 2008, Martin et al 2011].


Gene structure. PROKR2 comprises two exons.

Pathogenic allelic variants. Pathogenic variants of PROKR2 described include missense and nonsense variants.

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 pathogenic variants identified in individuals with KS/nIGD 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 pathogenic variants 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].


Gene structure. TAC3 comprises five coding exons and has two protein-coding alternative splice variants.

Pathogenic allelic variants. Homozygous missense, nonsense, and frameshift TAC3 variants cause normosmic IGD in an autosomal recessive inheritance pattern. Rare heterozygous TAC3 variants have also been associated with IGD suggesting a likely oligogenic inheritance in these patients.

Normal gene product. TAC3 encodes for neurokinin B, a neuropeptide that is secreted by neurons, a subset of which also coexpress kisspeptin. While the precise role of TAC3 in regaultion of GNRH secretion is still unclear.

Abnormal gene product. Abnormal TAC3 gene products result in diminished or absent neurokinin B signaling through its cognate receptor, TACR3, and results in secondary GnRH deficiency and consequent hypogonadotropism.


Gene structure. TACR3 comprises five coding exons and no alternative splice variants.

Pathogenic allelic variants. TACR3 nonsense, frameshift, or missense variants cause normosmic IGD in an autosomal recessive inheritance pattern. Occasionally, heterozygous pathogenic variants are also seen in persons with IGD, suggesting an oligogenic inheritance pattern

Normal gene product. TACR3 encodes for TACR3, a G protein-coupled transmembrane receptor for neurokinin B.

Abnormal gene product. Abnormal TACR3 gene products result in diminished or absent neurokinin B signaling through the receptor resulting in secondary GnRH deficiency and consequent hypogonadotropism.


Gene structure. HS6ST1 comprises two coding exons and has no alternative splice variants.

Pathogenic allelic variants. HS6ST1 pathogenic variants include missense variants either in the heterozygous or homozygous state and cause IGD in an oligogenic inheritance pattern.

Normal gene product. HS6ST1 encodes for a type II integral membrane protein that functions as a heparin sulfate biosynthetic enzyme and is responsible for 6-O-sulfation of heparan sulfate. Heparan sulfate, an extracellular glycosaminoglycan, has been shown to be crucial for neural development and heparin 6-O sulfation is required for function of both anosmin-1 and FGFR1 signaling, both of which are critical for GnRH neuronal migration.

Abnormal gene product. Abnormal HS6ST1 protein function disrupts GnRH neuronal migration by compromising anosmin-1 and FGF signaling during neural development.


Gene structure. NELF comprises 16 coding exons and has ten protein-coding alternative splice variants.

Pathogenic allelic variants. NELF pathogenic variants include missense variants and splice variants, either in the heterozygous or compound heterozygous state and cause IGD in an oligogenic inheritance pattern.

Normal gene product. NELF encodes for nasal embryonic LHRH factor, a protein involved in guidance of olfactory axon projections and migration of GnRH neurons.

Abnormal gene product. The precise pathophysiologic role of NELF pathogenic variants is not clear, but abnormal NELF gene products are postulated to result in disruption of embryonic migration of GnRH neurons [Xu et al 2011].


Gene structure. SEMA3A comprises 17 coding exons and has five alternative protein-coding splice variants.

Pathogenic allelic variants. SEMA3A pathogenic variants implicated in IGD include heterozygous deletions and missense/frameshift variants, and cause IGD in an oligogenic inheritance pattern.

Normal gene product. SEMA3A is a member of the semaphorin family and encodes a protein with an Ig-like C2-type (immunoglobulin-like) domain, a PSI domain and a Sema domain. This secreted protein can function as either a chemorepulsive agent, inhibiting axonal outgrowth, or as a chemoattractive agent, stimulating the growth of apical dendrites.

Abnormal gene product. Abnormal SEMA3A protein results in impaired embryonic migration of the GnRH neurons due to dysfunctional axonal guidance.


Gene structure. WDR11 comprises 29 coding exons and has no alternative protein-coding splice variants.

Pathogenic allelic variants. WDR11 pathogenic variants implicated in IGD include heterozygous missense variants and cause IGD in an oligogenic inheritance pattern.

Normal gene product. WDR11 interacts with EMX1, a homeodomain transcription factor involved in the development of olfactory neurons and hence governs GnRH neuronal migration.

Abnormal gene product. Abnormal WDR11 protein abolishes the interaction of WDR11 with EMX1 and disrupts GnRH neuronal migration.


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Suggested Reading

  1. Ballabio A, Rugarli EI. Kallmann syndrome. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 225. McGraw-Hill. Available online. Accessed 5-12-16.
  2. Crowley WF, Balasubramanian R, eds. Special Issue: Genetics of GnRH Deficiency. Mol Cell Endocrinol. 2011;346.
  3. Semple RK, Kemal Topaloglu A. The recent genetics of hypogonadotropic hypogonadism - novel insights and new questions. Clin Endocrinol (Oxf) 2010;72:427–35. [PubMed: 19719764]

Chapter Notes

Author History

Margaret Au, MBE, MS, CGC; Massachusetts General Hospital (2010-2013)
Ravikumar Balasubramanian, MD, PhD (2013-present)
Cassandra Buck, MS, CGC (2013-present)
Marissa Caudill; University of Connecticut Health Center (2007-2010)
William F Crowley Jr, MD (2007-present)
J Carl Pallais, MD, MPH; Massachusetts General Hospital (2007-2013)
Nelly Pitteloud, MD; Massachusetts General Hospital (2007-2013)
Stephanie Seminara, MD; Massachusetts General Hospital (2007-2013)

Revision History

  • 18 July 2013 (me) Comprehensive update posted live
  • 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
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