CIHH is characterized by an isolated defect in GnRH secretion or function. Criteria for the diagnosis of CIHH include: (1) decreased T levels in the hypogonadal range (e.g., <3.5 nmol/L), (2) low/normal gonadotropin levels representing absent or reduced GnRH secretion, (3) otherwise normal hormonal testing of the anterior pituitary, (4) a normal ferritin level, and, (5) normal radiographic imaging of the hypothalamic-pitu-itary region.
Familial CIHH was reported in 1944, in association with anosmia and was termed Kallmann syndrome (29,30). However, some hypogonadal patients do not present with an abnormal sense of smell but instead have the normosmic form of CIHH (nIHH). In our retrospective series of 78 men with CIHH, we found approx 60% with Kallmann syndrome and 40% with nIHH (31). Several phenotypic abnormalities are described in CIHH, but it is not clear if they represent true associations. Synkinesia has been reported in patients with Kallmann syndrome (29,32,33). Abnormal fast-conducting ipsilateral corticospinal tract projections were found in these patients (34). Abnormalities in spatial perception have been found specifically in patients with Kallmann syndrome with synkinesia (35). The association of renal agenesis is also reported in association with Kallmann syndrome (32,36). Craniofacial and palate abnormalities have been described in Kallmann syndrome (37). Finally, cardiovascular defects (38,39) have been associated with Kallmann syndrome. Because it is a rare disease, data on CIHH prevalence are limited and are estimated to be approx 1/10,000 to 1/86,000 (40). Isolated GnRH deficiency is predominantly a male disease, with a 4:1 ratio based on analysis of more than 300 cases at the Massachusetts General Hospital.
Although the classification of CIHH based on the presence or absence of smell is frequently used in the literature, clinical phenotypic overlap is seen between Kallmann syndrome and nIHH (31). Moreover, families have been documented with individuals having full Kallmann syndrome, nIHH, and isolated ansomia within a single sibship (41). We have found recently that stratifying patients according to the time of onset and severity of GnRH deficiency provides greater insight into the clinical spectrum of CIHH (31). In the absence of other congenital abnormalities, the clinical features of GnRH deficiency are first manifested at puberty; however, subjects may present at any age.
During the neonatal period, the presence of cryptorchidism or/and microphallus in a male fetus may indicate GnRH deficiency. Typically, gonadotropin, sex steroid, and inhibin levels are inappropriately low in such infants, because they are unable to normally activate the hypothalamic-pituitary-gonadal axis during the neonatal window (42). Notably, these neonates have otherwise normal sexual differentiation. Indeed, the growth and differentiation of the male genitalia, which develop from the Wolffian ducts and the urogenital sinus, are stimulated by T production from fetal Leydig cells (see Chapter 2). After an initial gonadotropin-independent phase, steroidogenesis activation, as well as Leydig cell development and differentiation, are completely dependent on placental human chorionic gonadotropin (hCG) (43). However, cryptorchidism and microphallus in patients with CHH indicates that in the late fetal/early neonatal period, endogenous GnRH secretion is necessary for inguinoscrotal descent of the testes and full growth of the external genitalia (15).
Most often, however, the diagnosis of CIHH is delayed until adolescence. At that time, considerable clinical heterogeneity is observed with variable spontaneous puber-tal development. The most common phenotype is represented by patients who fail to undergo puberty (see Fig. 4). Their clinical features include a lack of secondary sex characteristics, eunuchoidal body proportions (upper/lower body ratio <1 with an arm span >6 cm standing height) (44,45), a high-pitched voice, slight anemia, delayed bone age, and prepubertal sized testes (1-3 mL). A large proportion of these subjects report a history of cryptorchidism (40%) or microphallus (20%) (46). These latter two clinical signs provide evidence for the lack of activity of the hypothalamic-pituitary-gonadal axis during the feto-neonatal window and, thus, represent clinical surrogate markers of the failure to activate GnRH secretion at that stage of development. However, both of these markers lack sensitivity, because other factors may compensate for the lack of feto-neonatal T production. In addition, the incidence of microphallus in the men with CIHH with no prior puberty might be underestimated, given the reported successful induction of phallus growth with androgen therapy during childhood (47). Although most men with CIHH (75%) fail to go through puberty, the remainder display some degree of spontaneous puberty as assessed by at least two of these criteria: (1) some testicular growth, (2) a growth spurt, (3) an increase in the number of erections, and (4) the initiation of shaving. At the milder end of the spectrum, lies the fertile eunuch variant (see following discussion). Gynecomastia is seen in approx 20-30% of men with CIHH and most often is not related to prior therapy with gonadotropins (31,48).
Variant Forms of Congenital Hypogonadotropic Hypergonadism. Fertile Eunuch Syndrome. The first report of a man with the fertile eunuch variant of CIHH was in 1950 by McCullagh. These subjects harbor eunuchoidal proportions and
* Good general health
* Absence of puberty
* Decreased/absent sense of smell
• Little or/no axillary or pubic hair
Fig. 4. Typical presentation of a man with idiopathic hypogonadotropic hypogonadism (IHH) with the most severe phenotype, including absence of puberty, eunuchoidal proportions, prepubertal testis, microphallus, and cryptorchidism.
undervirilization but have normal gonadal size and preserved spermatogenesis (49). In this disorder, endogenous GnRH secretion, although decreased and insufficient to stimulate full virilization, produces adequate intragonadal T levels to support spermatogenesis and testicular growth. Indeed, these patients can be fertile either spontaneously or with T or human chorionic gonadotropin (hCG) therapy without the addition of FSH (50,51). The clinical picture of the fertile eunuch thus resembles that of normal midpubertal boys; indeed, a nocturnal rise of LH and T secretion synchronous with sleep, as seen normally in midpuberty, was demonstrated in two men with the fertile eunuch syndrome (52). These two cases of fertile eunuch syndrome may have resulted from defects in GnRH regulation. In contrast, we recently described a patient with the fertile eunuch variant who had detectable, but apulsatile, LH secretion associated with a partially inactivating mutation of the GnRH receptor (GnRH-R)
(53). These data underscore the clinical, genetic, and pathophysiological heterogeneity that exists in this syndrome.
Delayed Puberty. Delayed puberty is frequently reported in the family members of patients with CIHH (41). In our series of 106 patients with CIHH, 12% had relatives with a history of delayed puberty (41), as compared to 1% in the general population
(54). These data suggest that delayed puberty may represent the mildest end of the phe-notypic spectrum of CIHH.
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