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 pregnancies 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 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].

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 variant(s) in one of the genes listed in Table 2a and Table 2b.

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 at the most reasonable cost 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.