Clinical Guidance

Gene-specific phenotypes have been noted; see and . 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.

Source: GeneReviews — "Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency"

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 .

Source: GeneReviews — "Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency"

Diagnostic Criteria

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]). 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 : • 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 . • Women with IGD typically have Tanner stage I breast development and amenorrhea; however, some have spontaneous breast development and occasional menses . • 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 individuals, 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 and 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 . 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) . Table 1. Tanner Staging Stage | Normal Findings

Source: GeneReviews — "Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency"

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

Management Guidelines

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 and .)

• 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

Source: GeneReviews — "Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency"

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.

Source: GeneReviews — "Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency"

Surveillance Guidelines

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

• 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.

Source: GeneReviews — "Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency"