Figure 29.11 (Continued ) B: A 16-year-old individual with 46,XY gonadal dysgenesis who presented with primary amenorrhea and markedly elevated FSH levels. Most affected individuals do not present with as much pubic and axillary hair development. The right gonad contained a dysgerminoma, but there was no evidence of metastases. (From Rebar RW. Normal and abnormal sexual differentiation and pubertal development. In: Moore TR, Reiter RC, Rebar RW, et al., eds. Gynecology and obstetrics: a longitudinal approach. New York: Churchill Livingstone, 1993:97–133, with permission.) C: Clitoromegaly noted in the girl with 46,XY gonadal dysgenesis depicted in Figure 29.11B. D: The same individual as depicted in Figure 29.11B and D with 46,XY gonadal dysgenesis 1 year after gonadectomy and replacement with exogenous estrogen.
locus in an X-linked form of the syndrome, and this locus is designated KAL1. Other features of X-linked Kallmann syndrome include unilateral renal agenesis, bimanual synkinesia, and sensorineural hearing loss. In some cases of autosomal dominant Kallmann syndrome, inactivating mutations of the gene encoding the fibroblast growth factor receptor-1 (FGFR1 or KAL2) were reported. The disorder is so heterogeneous that it appears likely that it forms a structural continuum with other midline defects. Septo-optic dysplasia represents the most severe form of the disorder.
Clinically, affected individuals typically present with sexual infantilism and an eunuchoid habitus, but some degree of breast development may occur (Fig. 29.12). Primary amenorrhea is the rule. The ovaries are usually small, with follicles seldom developing beyond the primordial stage. Circulating gonadotropin levels are usually very low but almost invariably measurable. Affected individuals respond readily to pulsatile administration of exogenous GnRH, and this is the most physiologic approach to ovulation induction (48). For women not seeking pregnancy, therapy with exogenous estrogen and progestin is indicated.
Isolated gonadotropin deficiency can occur in association with the Prader-Labhart-Willi syndrome, which is characterized by obesity, short stature, hypogonadism, small hands and feet (acromicria), mental retardation, and infantile hypotonia. When the syndrome occurs in association with the Laurence-Moon-Bardet-Biedl syndrome, retinitis pigmentosa, postaxial polydactyly, obesity, and hypogonadism may be present. Prader-Labhart-Willi syndrome apparently results from rearrangements of chromosome 15q11 to q13, an imprinted region of the human genome (55). Laurence-Moon-Bardet-Biedl syndrome, inherited in an autosomal recessive manner, is apparently heterogeneous, with at least four involved gene loci having been mapped to date (56).
Multiple pituitary hormone deficiencies, which are usually hypothalamic in origin, may be congenital and either part of an inherited constellation of findings or sporadic. IfGH or thyroid-stimulating hormone (TSH) concentrations are subnormal, growth and pubertal development will be affected. Thus, the condition should be diagnosed before the age of puberty. Because individuals with hypopituitarism have a high mortality rate, predominantly caused by vascular and respiratory disease, it is important to identify affected individuals. Later age at diagnosis, female sex, and above all craniopharyngioma are identified as significant independent risk factors (57). Untreated gonadotropin deficiency is an important risk factor for early mortality.