Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary ... Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. Idiopathic hypogonadotropic hypogonadism can be caused by an isolated defect in gonadotropin-releasing hormone (GNRH; 152760) release, action, or both. Other associated nonreproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss, occur with variable frequency. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism has been called 'Kallmann syndrome (KS),' whereas in the presence of a normal sense of smell, it has been termed 'normosmic idiopathic hypogonadotropic hypogonadism (nIHH)' (summary by Raivio et al., 2007). Because families have been found to segregate both KS and nIHH, the disorder is here referred to as 'hypogonadotropic hypogonadism with or without anosmia (HH).' For a discussion of genetic heterogeneity of hypogonadotropic hypogonadism with or without anosmia, see 147950.
Dean et al. (1990) suggested autosomal dominant inheritance with variable expression as the basis for aggregation of isolated hypogonadotropic hypogonadism in the family they studied. A brother and sister had been most fully studied. Limited examination was performed ... Dean et al. (1990) suggested autosomal dominant inheritance with variable expression as the basis for aggregation of isolated hypogonadotropic hypogonadism in the family they studied. A brother and sister had been most fully studied. Limited examination was performed on 2 aunts and the son of one of the aunts. The sister presented at age 17 with primary amenorrhea. She did not have anosmia. Ovulation was subsequently induced by pulsatile infusion of gonadotropin-releasing hormone (GNRH1; 152760). The brother presented at age 21 with delayed puberty. He likewise denied anosmia. Both testes were small but were in the scrotum. One paternal aunt had primary amenorrhea and an adopted son, whereas another paternal aunt had menarche at age 23, following which she had 5 or 6 menstrual periods. Six years after her last period she became pregnant and delivered an apparently normal male infant. In the subsequent 21 years she did not menstruate. The son had immature genitalia and an unbroken voice at age 16 but refused examinations. The father of the brother and sister had died from thromboembolism and was not available for study. De Roux et al. (1997) studied a brother and sister with normosmic hypogonadotropic hypogonadism. The 22-year-old propositus was referred because of hypogonadism and impaired libido, who had undergone puberty at age 16. His height was 180 cm and his arm span 186 cm. Physical examination revealed absence of facial hair, sparse pubic hair (Tanner stage 3), and a penis of 6 cm. He had scrotal testes, and the volume of each was 8 ml (normal, 15 to 25 ml). There was no gynecomastia. He had a normal sense of smell and no mirror movements of the upper limbs, no abnormal eye movements, no colorblindness, and no renal or craniofacial abnormalities. The karyotype was 46,XY. The patient's 37-year-old sister had a history of primary amenorrhea and infertility. Spontaneous thelarche had occurred at age 14 years. She had a single episode of uterine bleeding at age 18, and afterward received combined oral contraceptive treatment. This treatment was interrupted when she desired children. However, amenorrhea and absence of pregnancy led to ovulation-inducing treatment, which resulted in 2 normal pregnancies and the births of a girl and a boy, 4 and 7 years old at the time of report. After each pregnancy, she had persistent amenorrhea, and oral contraceptive treatment was resumed. Her height was 165 cm. Pubic hair development was at Tanner stage 5, and her breasts and external genitalia were those of a normal woman. Both parents and a sister were clinically and endocrinologically normal. Janovick et al. (2002) showed pharmacologic rescue, assessed by ligand binding and restoration of receptor coupling to effector, of 5 naturally occurring GNRHR mutants identified from patients with hypogonadotropic hypogonadism, as well as rescue of other defective receptors manufactured with internal or terminal deletions or substitutions at sites expected to be involved in establishment of tertiary receptor structure. The pharmacologic agent used was a small, membrane-permeant molecule, originally designed as an orally active, nonpeptide receptor antagonist, but is believed to function as a folding template, capable of correcting the structural defects caused by the mutations and thereby restoring function. The rescued receptor, stabilized in the plasma membrane, coupled ligand binding to activation of the appropriate effector system. Janovick et al. (2002) concluded that mutant GNRHRs frequently have not lost intrinsic functionality and are subject to rescue by techniques that enhance membrane expression, and that the findings demonstrated the efficacy of an approach based on pharmacologic rescue and suggested the basis of new approaches for intervention in this and similar disorders.
In a brother and sister with normosmic hypogonadotropic hypogonadism, de Roux et al. (1997) identified compound heterozygosity for mutations in the GNRHR gene (138850.0001-138850.0002).
Layman et al. (1998) screened 46 unrelated patients with hypogonadotropic hypogonadism without ... In a brother and sister with normosmic hypogonadotropic hypogonadism, de Roux et al. (1997) identified compound heterozygosity for mutations in the GNRHR gene (138850.0001-138850.0002). Layman et al. (1998) screened 46 unrelated patients with hypogonadotropic hypogonadism without anosmia, including 32 males at least 18 years of age and 14 females at least 17 years of age, and identified compound heterozygosity for 2 missense mutations in the GNRHR gene in each of 4 affected sibs of a family (138850.0002-138850.0003). At least 1 of the affected females ovulated with exogenous gonadotropins. Caron et al. (1999) studied a kindred in which 3 sibs with isolated HH were compound heterozygous for 2 missense mutations in the GNRHR gene (138850.0002 and 138850.0004), resulting in a complete loss of function. The 2 brothers had microphallus and bilateral cryptorchidism and were referred for lack of puberty; their sister had primary amenorrhea and a complete lack of puberty. The authors concluded that these hypogonadal patients were partially resistant to pulsatile GNRH administration, suggesting that they should be treated with gonadotropins to induce spermatogenesis or ovulation rather than with pulsatile GNRH. Kottler et al. (1999) analyzed in detail the GNRHR mutations in 7 independent familial and sporadic cases of idiopathic hypogonadotropic hypogonadism reported to that time. The Q106R (138850.0001) and R262Q (138850.0002) mutations were frequent in patients from all geographic areas (North and South America, and Europe). In a brother and 2 sisters with HH, De Roux et al. (1999) identified compound heterozygosity for 3 missense mutations in the GNRHR gene, with R262Q on 1 allele, and Q106R and S217R (138850.0005) on the other allele. Endocrinologic analysis demonstrated varying degrees of alteration of gonadotropin function in the 3 sibs, although they all carried the same mutations. In a male patient with complete HH, who presented with primary failure of pulsatile GNRH (152760) therapy, but responded to exogenous gonadotropin administration, Pralong et al. (1999) identified homozygosity for a missense mutation in the GNRHR gene (138850.0006). In 2 sisters with primary amenorrhea and no breast development at 25 and 18 years of age, respectively, Seminara et al. (2000) identified compound heterozygosity for missense mutations in the GNRNR gene (138850.0001 and 138850.0002). The apparently unaffected parents were heterozygous for the mutations. Pitteloud et al. (2007) reexamined the family studied by Seminara et al. (2000) and identified heterozygosity for an additional missense mutation in the FGFR1 gene (136350.0016) in the 2 sisters and in their father, who had a history of delayed puberty. Mutation analysis of the children of the younger sister revealed that her unaffected daughter, who had undergone normal puberty, was heterozygous for the mutation in FGFR1 but had no mutations in the GNRHR gene, and that her prepubertal 10-year-old twin sons, born without cryptorchidism or microphallus, were each heterozygous for 1 of the mutations in GNRHR but did not have any mutations in the FGFR1 gene. Pitteloud et al. (2007) concluded that defects in 2 different genes can synergize to produce a more severe phenotype in families with hypogonadotropic hypogonadism than either alone, and that this digenic model may account for some of the phenotypic heterogeneity seen in GnRH deficiency. To determine the frequency and distribution of GNRHR mutations in a heterogeneous population of patients with idiopathic hypogonadotropic hypogonadism, Beranova et al. (2001) screened 108 probands with idiopathic hypogonadotropic hypogonadism for mutations in the coding sequence of GNRHR. Forty-eight of the 108 patients had a normal sense of smell, whereas the remaining 60 had anosmia or hyposmia (Kallmann syndrome). Five unrelated probands (3 men and 2 women), all normosmic, were documented to have changes in the coding sequence of the GNRHR. Two of these probands were from a subgroup of 5 kindreds consistent with a recessive mode of inheritance, establishing a GNRHR mutation frequency of 2 of 5 (40%) in patients with normosmic autosomal recessive idiopathic hypogonadotropic hypogonadism. The remaining 3 probands with GNRHR mutations were from a subgroup of 18 patients without evidence of familial involvement, indicating a prevalence of 3 of 18 (16.7%) in patients with sporadic idiopathic hypogonadotropic hypogonadism and a normal sense of smell. Among the 5 individuals bearing GNRHR mutations, a broad spectrum of phenotypes was noted, including testicular sizes that varied from prepubertal to the normal adult male range. Costa et al. (2001) investigated 17 Brazilian patients, 10 males and 7 females, from 14 different families with normosmic hypogonadotropic hypogonadism. The diagnosis of HH was based on absent or incomplete sexual development after 17 years of age associated with low or normal levels of LH (152780) in both sexes and low levels of testosterone in males and of estradiol in females. All patients presented with a normal sense of smell in an olfactory-specific test. In 1 female patient with complete HH, who had undetectable serum basal LH and FSH levels that failed to respond to GNRH stimulation, Costa et al. (2001) identified homozygosity for a missense mutation in the GNRHR gene (138850.0008). In 4 sibs with partial HH, who had low serum basal LH levels that were responsive to GNRH stimulation, they identified compound heterozygosity for GNRHR missense mutations (138850.0001 and 138850.0009). In a woman with primary amenorrhea and absent thelarche and pubarche, Silveira et al. (2002) identified homozygosity for a splice site mutation (138850.0011). The patient had no spontaneous gonadotropin pulsatility and did not respond to either exogenous pulsatile or acute GNRH administration, but exogenous gonadotropin administration resulted in a normal pregnancy. Meysing et al. (2004) reported a normosmic female patient with congenital idiopathic HH in whom treatment with pulsatile GNRH resulted in an unusual response: she not only required an increased dose of pulsatile GNRH for ovarian follicular development, but LH secretion did not increase appropriately, estradiol levels remained low, and she did not ovulate spontaneously. Analysis of the GNRHR coding sequence revealed compound heterozygous GNRHR mutations (138850.0013 and 138850.0014). Bhagavath et al. (2005) analyzed DNA from 185 HH patients and identified compound heterozygous GNRHR mutations in 3 (1.6%). All 3 were Caucasian, from a cohort of 85 HH patients with documented normosmia, and both the male patients as well as the female patient had so-called 'complete' HH, in which there is no evidence of steroid production as evidenced by a completely prepubertal phenotype. No mutations were found in the hyposmic or anosmic HH patients. GNRHR mutations were identified in 1 (6.7%) of 15 families with at least 2 affected sibs and in 2 (11.1%) of 18 normosmic HH females. No mutations were found in presumed autosomal dominant families. Bhagavath et al. (2005) concluded that GNRHR mutations account for approximately 3.5% of all normosmic HH and 7 to 11% of presumed autosomal recessive HH, suggesting that additional genes play an important role in normal puberty. Lin et al. (2006) reported a homozygous missense mutation in the GNRH receptor in 2 brothers with HH (R262Q; 138850.0002). The proband presented at 15 years of age with delayed puberty. After a short course of testosterone, he seemed to be progressing through puberty appropriately and was discharged from follow-up. His younger brother was also referred with delayed puberty but showed little progress after treatment. Lin et al. (2006) concluded that homozygous partial loss-of-function mutations in GNRHR such as R262Q can present with variable phenotypes, including apparent delayed puberty.