At least 17 different single-gene mutations are identified as being associated with delayed or absent puberty in humans (51). They are estimated to account for about 30% of individuals with disorders of puberty. These genes include KAL1 (X-linked Kallmann syndrome), FGFR1 (autosomal Kallmann syndrome), DAX1 (the gene for X-linked congenital adrenal hypoplasia), GNRHR (the gene for the GnRH receptor), PC1 (the gene for prohormone convertase 1), and GPR54 (encoding a G-protein coupled receptor). Delayed puberty may result from mutations in genes affecting gonadotrophs specifically (GnRHR, LHβ, FSHβ) or in genes involved more generally in the development and functioning of the pituitary gland (LHX3, PROP1, HESX1).
Constitutional Delay It is important to remember that low levels of LH and FSH are normally present in the prepubertal years; thus, girls with constitutionally delayed puberty may mistakenly be presumed to have hypogonadotropic hypogonadism. Constitutional delay is the most common cause of delayed puberty. In a normal population, 2% to 3% of normal children will be classified as having pubertal delay, and this finding may be considered a normal variant. Constitutional delayed growth and adolescence can be diagnosed only after careful evaluation excludes other causes of delayed puberty and normal sexual development is documented by longitudinal follow-up. The farther below the third percentile for height that the young girl is, the less likely it is that the cause is constitutional. Because some children are severely handicapped socially by constitutional pubertal delay, some physicians occasionally provide exogenous estrogen in low doses for 3 to 4 months to stimulate some pubertal development. However, the benefits of treatment are not well documented, and there is little evidence to support the idea that treatment improves psychosocial function.
Kallmann Syndrome As originally described in 1944, Kallmann syndrome consisted of the triad of anosmia, hypogonadism, and color blindness in men (52). Women may be affected, and other associated defects may include cleft lip and palate, cerebellar ataxia, nerve deafness, and abnormalities of thirst and vasopressin release. The frequency approximates
Figure 29.11 A: A 16-year-old individual with 46,XX gonadal dysgenesis and primary amenorrhea. Circulating follicle-stimulating hormone (FSH) levels were markedly elevated. The small amount of breast development (Tanner stage 2) is unusual, but some pubertal development may occur in such patients.
1 in 10,000 men and 1 in 50,000 women. Sporadic cases are more common than inherited forms. Inheritance is described as being X-linked recessive, autosomal dominant, and autosomal recessive. Because autopsy studies show partial or complete agenesis of the olfactory bulb, the term olfactogenital dysplasia is used to describe the disorder. These anatomic findings coincide with embryologic studies documenting that GnRH neurons originally develop in the epithelium of the olfactory placode and normally migrate into the hypothalamus (53). In some affected individuals, gene defects were found in one protein, anosmin-1, that facilitates this neuronal migration, thus leading to an absence of GnRH neurons in the hypothalamus and olfactory bulbs and consequent hypogonadotropic hypogonadism and anosmia (Kallmann syndrome) (54). The gene defect resulting in loss of this adhesion protein is localized to the Xp22.3