DISEASE 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.
DIAGNOSIS/TESTING: 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). Mutations 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.
MANAGEMENT: 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 disease-causing mutation(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 mutation 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 disease-causing mutation(s) in the family are known. Prenatal testing for pregnancies at increased risk is possible for all modes of inheritance if the disease causing mutation(s) in the family are known.
Pagon, RA; Adam, MP; Bird, TD; Dolan, CR; Fong, CT; Smith, RJH; Stephens, K