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 presence of low circulating concentrations of sex steroids. 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) in approximately 60%. IGD can first become apparent in infancy, adolescence, or adulthood. Infant boys with congenital 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.

Diagnosis/testing.

IGD is typically diagnosed in adolescents presenting with absent or partial puberty using biochemical testing that reveals low serum testosterone or estradiol (hypogonadism) that results from complete or partial absence of GnRH-mediated release of LH and FSH (hypogonadotropic hypogonadism [HH]) in the setting of otherwise normal anterior pituitary anatomy and function and in the absence of secondary causes of HH. Pathogenic variants in more than 25 genes account for about half of all IGD; the genetic cause for the remaining cases of IGD is unknown.

Management.

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

Prevention of secondary complications: Optimal calcium and vitamin D intake should be encouraged and specific 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: serum sex steroid levels (to guide optimal hormone replacement); bone mineral density.

Evaluation of relatives at risk: If the pathogenic variant(s) in a family are known, genetic 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, clinical reevaluation over time is necessary.

Genetic counseling.

IGD can be inherited in an X-linked, autosomal dominant, or autosomal recessive manner. Almost all IGD-related genes have also been associated with indeterminate or oligogenic inheritance. 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 X-linked IGD or autosomal recessive IGD is possible if the pathogenic variant(s) in the family are known. Prenatal testing for a pregnancy at increased risk is possible if the pathogenic variant(s) in the family are known.

Suggestive Findings

Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) should be suspected in individuals with the following:

• Absent or partial puberty at presentation in adolescents; low serum testosterone or estradiol on biochemical 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 [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.
  In rare males, IGD may present later in adulthood (i.e., adult-onset IGD). However, in these patients, as puberty was not disrupted, sexual maturation is complete and secondary sexual characteristics may be fully developed. Diagnosis of adult-onset IGD relies on documentation of hypogonadotropic hypogonadism (HH) and absence of other secondary causes of HH.
• Laboratory findings of IGD (See Figure 1 and Figure 2 for algorithm.)
  • 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.
• Olfactory findings. 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 sex.
  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].

Figure 1.

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

Figure 2.

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

Establishing the Diagnosis

The diagnosis of IGD is established in a proband based on clinical and biochemical investigations above; a genetic diagnosis can be made with identification of pathogenic (or likely pathogenic) variant(s) in one of the genes listed in Table 2a and Table 2b.

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis.

See Table 2a for the most common genetic causes (i.e., pathogenic variants of any one of the genes included in this table account for >2% of IGD) and Table 2b for less common genetic causes (i.e., pathogenic variants of any one of the genes included in this table are reported in only a few families).

Molecular testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

Serial single-gene testing can be considered based on mode of inheritance and clinical findings, especially non-reproductive phenotypic features that indicate that pathogenic variation of a particular gene is most likely. Sequence analysis of the gene of interest is performed first, followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.

To help prioritize the order of serial single-gene testing, the following can be considered (see Figure 3 and Figure 4):

Figure 3.

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

Figure 4.

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

• Sense of smell
  • Pathogenic variants in CHD7, FGF8, FGF17, FGFR1, HS6ST1, NSMF (NELF), PROK2, PROKR2, and WDR11 cause both Kallmann syndrome (KS) and normosmic IGD (nIGD).
  • Pathogenic variants in ANOS1 (KAL1), CCDC141, FEZF1, IL17RD, SEMA3A, SEMA3E, and SOX10 cause KS.
  • Pathogenic variants in GNRH1, GNRHR, KISS1, KISS1R (GPR54), TAC3, and TACR3 cause nIGD.
• Mode of inheritance
  • X-linked. Sequence analysis of ANOS1 (KAL1) is the highest-yield molecular genetic test.
  • Autosomal dominant. In families with clear autosomal dominant inheritance, testing of CHD7, FGFR1, FGF8 and SOX10 can be considered.
  • Autosomal recessive. Testing of GNRH1, GNRHR, KISS1, KISS1R, TAC3, and TACR3 can be considered in families with autosomal recessive normosmic IGD; testing of FEZF1, PROK2 and PROKR2 can be considered in families with autosomal recessive KS.
• Associated phenotypic features. The presence of some associated clinical phenotypic features may also help prioritize genetic testing in IGD [Costa-Barbosa et al 2013]. See Figure 4.

A multigene panel that includes the genes listed in Table 2a and Table 2b and other genes of interest (see Differential Diagnosis) may be considered. This should be the first step when the proband has no clearly affected family members and/or no associated phenotypic features. Note: The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

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 – in infancy, adolescence, or (rarely) adulthood. Most individuals with IGD are identified at puberty; however, suggestive clinical features may be present in infancy.

Pathophysiology

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 points in the reproductive life cycle.

In individuals with IGD, 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 IGD.

Genotype-Phenotype Correlations

Gene-specific phenotypes have been noted; see Table 3 and Figure 4.

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

Penetrance

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 an 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 IGD is also fairly high when pathogenic variants occur in the biallelic state (i.e., recessive variants) (FEZF1, GNRH1, GNRHR, IL17RD, KISS1, KISS1R, TAC3, TACR3). However, penetrance for the reproductive phenotype in those with pathogenic heterozygous variants in almost all known IGD-related genes is incomplete as individuals with normal gonadal function who are heterozygous for pathogenic variants in these genes have been documented. 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 an ANOS1 (KAL1) pathogenic variant is generally complete, whereas penetrance for abnormal olfactory function in individuals with IGD and heterozygous pathogenic variants in several genes (CHD7, FGFR1, FGF8, FGF17, HS6ST1, NSMF, PROK2, PROKR2) is incomplete as normosmia, hyposmia, or anosmia can be seen [Pitteloud et al 2006a, Cole et al 2008, Falardeau et al 2008, Miraoui et al 2013, Balasubramanian et al 2014].

Nomenclature

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

The term “hypogonadism” refers to impaired sexual development based on findings from the individual’s clinical history (e.g., amenorrhea, hot flashes, erectile dysfunction) as well as 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.

Prevalence

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).

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 sarcoidosis and histiocytosis

Syndromes listed in Table 4 can be associated with hypogonadotropic hypogonadism along with other significant clinical findings and/or other pituitary hormone deficits.

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 later 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 1 and Figure 2 provide testing algorithms for establishing the diagnosis of isolated GnRH deficiency in males and females, respectively.

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).
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

An expert European consensus statement on the management of IGD has recently been published [Boehm et al 2015] (full text).

Typically, a definitive diagnosis of IGD is made around age 18 years. Occasionally, however, 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.

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).

Surveillance

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, serum sex steroid levels (to guide optimal hormone replacement) and bone mineral density should be monitored at regular intervals.

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from surveillance and prompt initiation of treatment. Evaluations can include:

• Molecular genetic testing if the pathogenic variant(s) in the family are known. However, a prepubertal child with a known pathogenic variant may progress through puberty in a normal fashion, 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.
• If the pathogenic variant(s) in the family are not known, clinical review of at-risk relatives of pubertal age to assess clinical onset of signs of puberty and if delayed, to initiate appropriate therapy for pubertal induction.

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

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.

Mode of Inheritance

Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) can be inherited in an X-linked, autosomal dominant, or autosomal recessive manner (see Figure 3).

Almost all IGD-related genes have also been associated with indeterminate or oligogenic inheritance (especially when an IGD-related pathogenic variant occurs in the heterozygous state [Sykiotis et al 2010b, Hanchate et al 2012, Miraoui et al 2013]).

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 for 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.

X-Linked Inheritance – Risk to Family Members

Parents of a male proband

• The father of an affected male will not have the disease nor will he be hemizygous for the ANOS1 (KAL1) pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected son and no other affected relatives and if the pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism (maternal germline mosaicism has not been reported to date for ANOS1).
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier) or the affected male may have a de novo ANOS1 pathogenic variant, in which case the mother is not a carrier. About 70% of affected males represent simplex cases.

Sibs of a male proband. The risk to sibs depends on the genetic status of the mother:

• If the mother of the proband has a ANOS1 pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Male sibs who inherit the pathogenic variant will be affected; female sibs who inherit the pathogenic variant will be heterozygous and may display some clinical features.
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the theoretic possibility of maternal germline mosaicism.

Offspring of a male proband

• With treatment, males with IGD can be fertile.
• Affected males transmit the ANOS1 pathogenic variant to:
  • All of their daughters, who will be heterozygous and may display some clinical features.
  • None of their sons.

Other family members. The proband's maternal uncles may be at risk of being affected and the maternal aunts may be at risk of being carriers for the ANOS1 pathogenic variant. The aunts' offspring, depending on their sex, may be at risk of being carriers or of being affected.

Heterozygote detection. Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the ANOS1 pathogenic variant has been identified in the proband.

Note: (1) Females heterozygous for an ANOS1 pathogenic variant may occasionally display clinical features that are diagnostic of IGD [Shaw et al 2011]. (2) Identification of female heterozygotes requires either (a) prior identification of the ANOS1 pathogenic variant in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and if no pathogenic variant is identified, by gene-targeted deletion/duplication analysis.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• Some individuals with autosomal dominant IGD have an affected parent.
• 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 a de novo pathogenic variant is unknown.
• Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include:
  • A detailed pubertal history of both parents; and
  • Molecular genetic testing of both parents for the pathogenic variant identified in the proband.
• If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent (germline mosaicism for an IGD-related pathogenic variant has been reported in one family [Sato & Ogata 2006]).
• Evaluation of parents may determine that a parent has the pathogenic variant identified in the proband but has escaped previous diagnosis because of a milder phenotypic presentation, reduced penetrance, or late onset of the disorder. Therefore, an apparently negative family history cannot be fully confirmed until appropriate evaluations have been performed.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is affected and/or has a pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50% although their actual risk may be lower due to variable expressivity and reduced penetrance.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [Sato & Ogata 2006].

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 may be less than 50% because of variable expressivity and reduced penetrance.

Other family member. The risk to other family members depends on the genetic status of the proband's parents: if a parent is affected or has a known pathogenic variant, members of the parent's family may be at risk.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of a child with autosomal recessive IGD are obligate heterozygotes (i.e., carriers of one pathogenic variant).
• Heterozygotes are typically unaffected.
• Occasionally, heterozygotes display clinical features diagnostic of IGD [Cole et al 2008, Gianetti et al 2010, Sykiotis et al 2010b, Chan et al 2011, Miraoui et al 2013]; this may be due to unknown environmental, epigenetic, or oligogenic factors.

Sibs of a proband

• At conception, each sib of an individual with autosomal recessive IGD has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Occasionally, heterozygotes display clinical features diagnostic of IGD [Cole et al 2008, Gianetti et al 2010, Sykiotis et al 2010b, Chan et al 2011, Miraoui et al 2013]; this may be due to unknown environmental, epigenetic, or oligogenic factors.

Offspring of a proband. The offspring of an affected individual are obligate heterozygotes (carriers) for an IGD-related pathogenic variant.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier of an IGD-related pathogenic variant.

Carrier detection. Identification of heterozygotes requires prior identification of the IGD-related pathogenic variants in the family.

Indeterminate or Oligogenic Inheritance – Risk to Family Members

The exact risk for IGD to the family members of a simplex proband (a single individual with a disorder in a family) with IGD of unknown cause or a proband with an indeterminate or oligogenic inheritance is uncertain but may be up to 50%.

Related Genetic Counseling Issues

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

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

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

Molecular Pathogenesis

Over the last three decades, a combination of clinical investigational strategies and contemporary genetic approaches has revealed more than 25 causal/contributory genes for the nonsyndromic forms of IGD, with varied modes of inheritance. Broadly, two groups of genetic pathways are linked to IGD: (i) Neurodevelopmental genes govern the origin of the GnRH neurons and typically cause the Kallmann syndrome (KS) form of IGD. (ii) A group of neuroendocrine genes that control the secretion or action of GnRH cause the normosmic isolated GnRH deficiency (nIGD) form IGD. A small subset of genes may cause both KS and nIGD forms of IGD and this suggests that they govern both GnRH migration and GnRH secretion/action. (see Table 2a and Table 2b).

In addition to Mendelian modes of inheritance, a complex genetic architecture for IGD (occurring in 10%-15% of cases) has now been documented wherein pathogenic variants in two or more IGD-related genes are present in a single individual. These pathogenic variants are typically heterozygous and by themselves are not sufficient to cause IGD but require the presence of additional pathogenic variants in a second gene to cause IGD [Sykiotis et al 2010b]. Almost all of the known IGD-related genes have been associated with oligogenic inheritance. These oligogenic pathogenic variants presumably act in a synergistic manner, potentially accounting for some of the variable expressivity and incomplete penetrance that is characteristic of IGD.

Author History

Margaret Au, MBE, MS, CGC; Massachusetts General Hospital (2010-2013)
Ravikumar Balasubramanian, MD, PhD (2013-present)
Cassandra Buck, MS, CGC; Massachusetts General Hospital (2013-2017)
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

• 12 May 2022 (aa) Revision: encephalocraniocutaneous lipomatosis added to Genetically Related Disorders
• 2 March 2017 (ha) Comprehensive update posted live
• 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 live
• 1 June 2006 (jcp) Original submission

Published Guidelines / Consensus Statements

• Boehm U, Bouloux PM, Dattani MT, de Roux N, Dodé C, Dunkel L, Dwyer AA, Giacobini P, Hardelin JP, Juul A, Maghnie M, Pitteloud N, Prevot V, Raivio T, Tena-Sempere M, Quinton R, Young J. Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism--pathogenesis, diagnosis and treatment. Available online. 2015. Accessed 11-1-22. [PubMed: 26194704]

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