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.