Alternative titles; symbols
SNOMEDCT: 123953004; ORPHA: 432; DO: 0090078;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 4q13.2 | Hypogonadotropic hypogonadism 7 without anosmia | 146110 | Autosomal recessive | 3 | GNRHR | 138850 |
A number sign (#) is used with this entry because hypogonadotropic hypogonadism-7 with or without anosmia (HH7) is caused by homozygous or compound heterozygous mutation in the GNRHR gene (138850) on chromosome 4q13, sometimes in association with mutation in another gene, e.g., FGFR1 (136350).
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.
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.
Caron et al. (1999) studied 3 sibs with mutations in GNRHR from a kindred with isolated hypogonadotropic hypogonadism. The 2 brothers, who were referred for lack of puberty, had microphallus and bilateral cryptorchidism; 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 instead be treated with gonadotropins to induce spermatogenesis or ovulation.
Pitteloud et al. (2001) reported a 26-year-old male with a mild form of hypogonadotropic hypogonadism, which they called a 'fertile eunuch variant' of HH. The proband had hypogonadal testosterone levels, detectable but apulsatile gonadotropin secretion, and a normal adult male testicular size of 17 mL at baseline. After only 4 months of treatment with chorionic gonadotropin (CG; see 118860) alone, he developed sperm in his ejaculate, and his wife conceived. Following cessation of CG therapy, the patient demonstrated reversal of his hypogonadotropism as evidenced by normal adult male testosterone levels and the appearance of pulsatile luteinizing hormone (LH; see 152780) secretion. The authors concluded that this case expanded the clinical spectrum of GNRHR mutations, providing the first genetic basis for the fertile eunuch variant of hypogonadotropic hypogonadism and documenting the occurrence of reversible hypogonadotropic hypogonadism in a patient with a GNRHR mutation.
Clinical Variability
De Roux et al. (1999) performed detailed endocrinologic studies in 3 affected members of a family with hypogonadotropic hypogonadism who had mutations in GNRHR (see MOLECULAR GENETICS). The proband, a 30-year-old male, had complete HH with extremely low plasma levels of gonadotropins, absence of pulsatility of endogenous LH and alpha subunit (see 152780), absence of response to GNRH (152760) and GNRH agonist (triptorelin), and absence of effect of pulsatile administration of GNRH. His affected 18- and 24-year-old sisters had only partial hypogonadotropic hypogonadism. They both had primary amenorrhea and normal breast development, but the younger sister had retarded bone maturation and uterus development. Gonadotropin concentrations were normal or low, but in both cases were restored to normal levels by a single injection of GNRH. In both sisters, there were no spontaneous pulses of LH, but pulsatile administration of GNRH provoked pulsatile secretion of LH in the younger one. The authors concluded that the same GNRHR mutations may exhibit varying degrees of alteration of gonadotropin function in affected members of the same family.
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.
The transmission pattern of hypogonadotropic hypogonadism in the family reported by de Roux et al. (1997) was consistent with autosomal recessive inheritance.
In a brother and sister with normosmic hypogonadotropic hypogonadism, de Roux et al. (1997) identified compound heterozygosity for 2 missense mutations in the GNRHR gene (Q106R, 138850.0001 and R262Q, 138850.0002).
Layman et al. (1998) screened 46 unrelated patients with normosmic idiopathic HH for GNRHR mutations, including 32 males at least 18 years of age and 14 females at least 17 years of age, and identified compound heterozygosity for the R262Q mutation and another missense mutation (Y284C; 138850.0003) in 1 family with 4 affected sibs. At least 1 of the affected females ovulated in response to exogenous gonadotropins.
In 3 sibs from a kindred with isolated HH, Caron et al. (1999) identified compound heterozygosity for the R262Q mutation and another missense mutation in GNRHR (A129D; 138850.0004).
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 and R262Q 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 (S168R; 138850.0006).
In a woman with complete HH, Kottler et al. (2000) identified compound heterozygosity for Q106R and a nonsense mutation (L314X; 138850.0007) in the GNRHR gene.
In a 26-year-old male with a mild form of hypogonadotropic hypogonadism, Pitteloud et al. (2001) identified homozygosity for the R262Q mutation in the GNRHR gene.
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 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 (R139H; 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 the Q106R mutation and another missense mutation in GNRHR (N10K; 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).
In 2 brothers with HH, Lin et al. (2006) reported homozygosity for the R262Q mutation in GNRHR. 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.
Oligogenic Inheritance
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 the Q106R and R262Q mutations in the GNRHR gene. 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.
Possible Association with Functional Hypothalamic Amenorrhea in Carrier Females
Caronia et al. (2011) studied 55 women with functional hypothalamic amenorrhea, who had all completed puberty spontaneously and had a history of secondary amenorrhea for 6 months or more, with low or normal gonadotropin levels and low serum estradiol levels. All had 1 or more predisposing factors, including excessive exercise, loss of more than 15% of body weight, and/or a subclinical eating disorder, and all had normal results on neuroimaging. The authors screened 7 HH-associated genes in the 55 affected women and identified 7 patients from 6 families who carried heterozygous mutations, including 1 in KAL1, 2 in FGFR1, 2 in PROKR2 (607123), and 1 in the GNRHR gene. Since these women with mutations resumed regular menses after discontinuing hormone-replacement therapy, Caronia et al. (2011) concluded that the genetic component of hypothalamic amenorrhea predisposes patients to, but is not sufficient to cause, 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 gene. 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.
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.
Beranova, M., Oliveira, L. M. B., Bedecarrats, G. Y., Schipani, E., Vallejo, M., Ammini, A. C., Quintos, J. B., Hall, J. E., Martin, K. A., Hayes, F. J., Pitteloud, N., Kaiser, U. B., Crowley, W. F., Jr., Seminara, S. B. Prevalence, phenotypic spectrum, and modes of inheritance of gonadotropin-releasing hormone receptor mutations in idiopathic hypogonadotropic hypogonadism. J. Clin. Endocr. Metab. 86: 1580-1588, 2001. [PubMed: 11297587] [Full Text: https://doi.org/10.1210/jcem.86.4.7395]
Bhagavath, B., Ozata, M., Ozdemir, I. C., Bolu, E., Bick, D. P., Sherins, R. J., Layman, L. C. The prevalence of gonadotropin-releasing hormone receptor mutations in a large cohort of patients with hypogonadotropic hypogonadism. Fertil. Steril. 84: 951-957, 2005. [PubMed: 16213849] [Full Text: https://doi.org/10.1016/j.fertnstert.2005.04.029]
Caron, P., Chauvin, S., Christin-Maitre, S., Bennet, A., Lahlou, N., Counis, R., Bouchard, P., Kottler, M.-L. Resistance of hypogonadic patients with mutated GnRH receptor genes to pulsatile GnRH administration. J. Clin. Endocr. Metab. 84: 990-996, 1999. [PubMed: 10084584] [Full Text: https://doi.org/10.1210/jcem.84.3.5518]
Caronia, L. M., Martin, C., Welt, C. K., Sykiotis, G. P., Quinton, R., Thambundit, A., Avbelj, M., Dhruvakumar, S., Plummer, L., Hughes, V. A., Seminara, S. B., Boepple, P. A., Sidis, Y., Crowley, W. F., Jr., Martin, K. A., Hall, J. E., Pitteloud, N. A genetic basis for functional hypothalamic amenorrhea. New Eng. J. Med. 364: 215-225, 2011. [PubMed: 21247312] [Full Text: https://doi.org/10.1056/NEJMoa0911064]
Costa, E. M. F., Bedecarrats, G. Y., Mendonca, B. B., Arnhold, I. J. P., Kaiser, U. B., Latronico, A. C. Two novel mutations in the gonadotropin- releasing hormone receptor gene in Brazilian patients with hypogonadotropic hypogonadism and normal olfaction. J. Clin. Endocr. Metab. 86: 2680-2686, 2001. [PubMed: 11397871] [Full Text: https://doi.org/10.1210/jcem.86.6.7551]
de Roux, N., Young, J., Brailly-Tabard, S., Misrahi, M., Milgrom, E., Schaison, G. The same molecular defects of the gonadotropin-releasing hormone receptor determine a variable degree of hypogonadism in affected kindred. J. Clin. Endocr. Metab. 84: 567-572, 1999. [PubMed: 10022417] [Full Text: https://doi.org/10.1210/jcem.84.2.5449]
de Roux, N., Young, J., Misrahi, M., Genet, R., Chanson, P., Schaison, G., Milgrom, E. A family with hypogonadotropic hypogonadism and mutations in the gonadotropin-releasing hormone receptor. New Eng. J. Med. 337: 1597-1602, 1997. [PubMed: 9371856] [Full Text: https://doi.org/10.1056/NEJM199711273372205]
Janovick, J. A., Maya-Nunez, G., Conn, P. M. Rescue of hypogonadotropic hypogonadism-causing and manufactured GnRH receptor mutants by a specific protein-folding template: misrouted proteins as a novel disease etiology and therapeutic target. J. Clin. Endocr. Metab. 87: 3255-3262, 2002. [PubMed: 12107234] [Full Text: https://doi.org/10.1210/jcem.87.7.8582]
Kottler, M.-L., Chauvin, S., Lahlou, N., Harris, C. E., Johnston, C. J., Lagarde, J.-P., Bouchard, P., Farid, N. R., Counis, R. A new compound heterozygous mutation of the gonadotropin-releasing hormone receptor (L314X, Q106R) in a woman with complete hypogonadotropic hypogonadism: chronic estrogen administration amplifies the gonadotropin defect. J. Clin. Endocr. Metab. 85: 3002-3008, 2000. [PubMed: 10999776] [Full Text: https://doi.org/10.1210/jcem.85.9.6783]
Kottler, M.-L., Counis, R., Bouchard, P. Mutations of the GnRH receptor gene: a new cause of autosomal-recessive hypogonadotropic hypogonadism. Arch. Med. Res. 30: 481-485, 1999. [PubMed: 10714361] [Full Text: https://doi.org/10.1016/s0188-4409(99)00072-7]
Layman, L. C., Cohen, D. P., Jin, M., Xie, J., Li, Z., Reindollar, R. H., Bolbolan, S., Bick, D. P., Sherins, R. R., Duck, L. W., Musgrove, L. C., Sellers, J. C., Neill, J. D. Mutations in gonadotropin-releasing hormone receptor gene cause hypogonadotropic hypogonadism. (Letter) Nature Genet. 18: 14-15, 1998. [PubMed: 9425890] [Full Text: https://doi.org/10.1038/ng0198-14]
Lin, L, Conway, G. S, Hill, N. R, Dattani, M. T, Hindmarsh, P. C, Achermann, J. C. A homozygous R262Q mutation in the gonadotropin-releasing hormone receptor presenting as constitutional delay of growth and puberty with subsequent borderline oligospermia. J. Clin. Endocr. Metab. 91: 5117-5121, 2006. [PubMed: 16968799] [Full Text: https://doi.org/10.1210/jc.2006-0807]
Meysing, A. U., Kanasaki, H., Bedecarrats, G. Y., Acierno, J. S., Jr., Conn, P. M., Martin, K. A., Seminara, S. B., Hall, J. E., Crowley, W. F., Jr., Kaiser, U. B. GNRHR mutations in a woman with idiopathic hypogonadotropic hypogonadism highlight the differential sensitivity of luteinizing hormone and follicle-stimulating hormone to gonadotropin-releasing hormone. J. Clin. Endocr. Metab. 89: 3189-3198, 2004. [PubMed: 15240592] [Full Text: https://doi.org/10.1210/jc.2003-031808]
Pitteloud, N., Boepple, P. A., DeCruz, S., Valkenburgh, S. B., Crowley, W. F., Jr., Hayes, F. J. The fertile eunuch variant of idiopathic hypogonadotropic hypogonadism: spontaneous reversal associated with a homozygous mutation in the gonadotropin-releasing hormone receptor. J. Clin. Endocr. Metab. 86: 2470-2475, 2001. [PubMed: 11397842] [Full Text: https://doi.org/10.1210/jcem.86.6.7542]
Pitteloud, N., Quinton, R., Pearce, S., Raivio, T., Acierno, J., Dwyer, A., Plummer, L., Hughes, V., Seminara, S., Cheng, Y.-Z., Li, W.-P., Maccoll, G., Eliseenkova, A. V., Olsen, S. K., Ibrahimi, O. A., Hayes, F. J., Boepple, P., Hall, J. E., Bouloux, P., Mohammadi, M., Crowley, W., Jr. Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism. J. Clin. Invest. 117: 457-463, 2007. [PubMed: 17235395] [Full Text: https://doi.org/10.1172/JCI29884]
Pralong, F. P., Gomez, F., Castillo, E., Cotecchia, S., Abuin, L., Aubert, M. L., Portmann, L., Gaillard, R. C. Complete hypogonadotropic hypogonadism associated with a novel inactivating mutation of the gonadotropin-releasing hormone receptor. J. Clin. Endocr. Metab. 84: 3811-3816, 1999. [PubMed: 10523035] [Full Text: https://doi.org/10.1210/jcem.84.10.6042]
Raivio, T., Falardeau, J., Dwyer, A., Quinton, R., Hayes, F. J., Hughes, V. A., Cole, L. W., Pearce, S. H., Lee, H., Boepple, P., Crowley, W. F., Jr., Pitteloud, N. Reversal of idiopathic hypogonadotropic hypogonadism. New Eng. J. Med. 357: 863-873, 2007. [PubMed: 17761590] [Full Text: https://doi.org/10.1056/NEJMoa066494]
Seminara, S. B., Beranova, M., Oliveira, L. M. B., Martin, K. A., Crowley, W. F., Jr., Hall, J. E. Successful use of pulsatile gonadotropin-releasing hormone (GnRH) for ovulation induction and pregnancy in a patient with GnRH receptor mutations. J. Clin. Endocr. Metab. 85: 556-562, 2000. [PubMed: 10690855] [Full Text: https://doi.org/10.1210/jcem.85.2.6357]
Silveira, L. F. G., Stewart, P. M., Thomas, M., Clark, D. A., Bouloux, P. M. G., MacColl, G. S. Novel homozygous splice acceptor site GnRH receptor (GnRHR) mutation: human GnRHR 'knockout'. J. Clin. Endocr. Metab. 87: 2973-2977, 2002. [PubMed: 12050282] [Full Text: https://doi.org/10.1210/jcem.87.6.8535]