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Hypogonadotropic hypogonadism 10 with or without anosmia(HH10)

MedGen UID:
766757
Concept ID:
C3553843
Disease or Syndrome
Synonym: HH10
 
Gene (location): TAC3 (12q13.3)
 
Monarch Initiative: MONDO:0013912
OMIM®: 614839

Disease characteristics

Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is characterized by inappropriately low serum concentrations of the gonadotropins LH (luteinizing hormone) and FSH (follicle-stimulating hormone) in the presence of low circulating concentrations of sex steroids. IGD is associated with a normal sense of smell (normosmic IGD) in approximately 40% of affected individuals and an impaired sense of smell (Kallmann syndrome) in approximately 60%. IGD can first become apparent in infancy, adolescence, or adulthood. Infant boys with congenital IGD often have micropenis and cryptorchidism. Adolescents and adults with IGD have clinical evidence of hypogonadism and incomplete sexual maturation on physical examination. Adult males with IGD tend to have prepubertal testicular volume (i.e., <4 mL), absence of secondary sexual features (e.g., facial and axillary hair growth, deepening of the voice), decreased muscle mass, diminished libido, erectile dysfunction, and infertility. Adult females have little or no breast development and primary amenorrhea. Although skeletal maturation is delayed, the rate of linear growth is usually normal except for the absence of a distinct pubertal growth spurt. [from GeneReviews]
Authors:
Ravikumar Balasubramanian  |  William F Crowley   view full author information

Additional description

From OMIM
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.  http://www.omim.org/entry/614839

Clinical features

From HPO
Primary amenorrhea
MedGen UID:
115918
Concept ID:
C0232939
Disease or Syndrome
Abnormally late or absent menarche in a female with normal secondary sexual characteristics.
Anosmia
MedGen UID:
1950
Concept ID:
C0003126
Finding
An inability to perceive odors. This is a general term describing inability to smell arising in any part of the process of smelling from absorption of odorants into the nasal mucous overlying the olfactory epithelium, diffusion to the cilia, binding to olfactory receptor sites, generation of action potentials in olfactory neurons, and perception of a smell.
Intellectual disability, mild
MedGen UID:
10044
Concept ID:
C0026106
Mental or Behavioral Dysfunction
Mild intellectual disability is defined as an intelligence quotient (IQ) in the range of 50-69.
Hypogonadotropic hypogonadism
MedGen UID:
82883
Concept ID:
C0271623
Disease or Syndrome
Hypogonadotropic hypogonadism is characterized by reduced function of the gonads (testes in males or ovaries in females) and results from the absence of the gonadal stimulating pituitary hormones
Decreased circulating follicle stimulating hormone concentration
MedGen UID:
892977
Concept ID:
C4072889
Finding
A reduction of the circulating level of follicle-stimulating hormone (FSH).
Decreased circulating luteinizing hormone level
MedGen UID:
893008
Concept ID:
C4072890
Finding
A reduction in the circulating level of luteinizing hormone (LH).
Decreased serum testosterone concentration
MedGen UID:
892974
Concept ID:
C4073137
Finding

Professional guidelines

PubMed

Tritos NA, Miller KK
JAMA 2023 Apr 25;329(16):1386-1398. doi: 10.1001/jama.2023.5444. PMID: 37097352
Jankovic J, Tan EK
J Neurol Neurosurg Psychiatry 2020 Aug;91(8):795-808. Epub 2020 Jun 23 doi: 10.1136/jnnp-2019-322338. PMID: 32576618
Gravholt CH, Viuff MH, Brun S, Stochholm K, Andersen NH
Nat Rev Endocrinol 2019 Oct;15(10):601-614. Epub 2019 Jun 18 doi: 10.1038/s41574-019-0224-4. PMID: 31213699

Recent clinical studies

Etiology

De Silva NL, Papanikolaou N, Grossmann M, Antonio L, Quinton R, Anawalt BD, Jayasena CN
Lancet Diabetes Endocrinol 2024 Oct;12(10):761-774. Epub 2024 Aug 16 doi: 10.1016/S2213-8587(24)00199-2. PMID: 39159641
Snyder PJ, Bauer DC, Ellenberg SS, Cauley JA, Buhr KA, Bhasin S, Miller MG, Khan NS, Li X, Nissen SE
N Engl J Med 2024 Jan 18;390(3):203-211. doi: 10.1056/NEJMoa2308836. PMID: 38231621
Luther PM, Spillers NJ, Talbot NC, Sinnathamby ES, Ellison D, Kelkar RA, Ahmadzadeh S, Shekoohi S, Kaye AD
Expert Opin Pharmacother 2024 Jan-Apr;25(1):25-35. Epub 2024 Feb 1 doi: 10.1080/14656566.2024.2306832. PMID: 38229462
Ahmad SJ, Feigen CM, Vazquez JP, Kobets AJ, Altschul DJ
J Integr Neurosci 2022 Apr 6;21(3):77. doi: 10.31083/j.jin2103077. PMID: 35633158
Corona G, Goulis DG, Huhtaniemi I, Zitzmann M, Toppari J, Forti G, Vanderschueren D, Wu FC
Andrology 2020 Sep;8(5):970-987. Epub 2020 Mar 20 doi: 10.1111/andr.12770. PMID: 32026626

Diagnosis

Bandeira L, Silva BC, Bilezikian JP
Arch Endocrinol Metab 2022 Nov 11;66(5):739-747. doi: 10.20945/2359-3997000000563. PMID: 36382763Free PMC Article
Corona G, Goulis DG, Huhtaniemi I, Zitzmann M, Toppari J, Forti G, Vanderschueren D, Wu FC
Andrology 2020 Sep;8(5):970-987. Epub 2020 Mar 20 doi: 10.1111/andr.12770. PMID: 32026626
Young J, Xu C, Papadakis GE, Acierno JS, Maione L, Hietamäki J, Raivio T, Pitteloud N
Endocr Rev 2019 Apr 1;40(2):669-710. doi: 10.1210/er.2018-00116. PMID: 30698671
Bhasin S, Brito JP, Cunningham GR, Hayes FJ, Hodis HN, Matsumoto AM, Snyder PJ, Swerdloff RS, Wu FC, Yialamas MA
J Clin Endocrinol Metab 2018 May 1;103(5):1715-1744. doi: 10.1210/jc.2018-00229. PMID: 29562364
Fraietta R, Zylberstejn DS, Esteves SC
Clinics (Sao Paulo) 2013;68 Suppl 1(Suppl 1):81-8. doi: 10.6061/clinics/2013(sup01)09. PMID: 23503957Free PMC Article

Therapy

Snyder PJ, Bauer DC, Ellenberg SS, Cauley JA, Buhr KA, Bhasin S, Miller MG, Khan NS, Li X, Nissen SE
N Engl J Med 2024 Jan 18;390(3):203-211. doi: 10.1056/NEJMoa2308836. PMID: 38231621
García-Arnés JA, García-Casares N
Rev Clin Esp (Barc) 2022 Dec;222(10):612-620. Epub 2022 Nov 15 doi: 10.1016/j.rceng.2022.09.003. PMID: 36400345
Corona G, Goulis DG, Huhtaniemi I, Zitzmann M, Toppari J, Forti G, Vanderschueren D, Wu FC
Andrology 2020 Sep;8(5):970-987. Epub 2020 Mar 20 doi: 10.1111/andr.12770. PMID: 32026626
Young J, Xu C, Papadakis GE, Acierno JS, Maione L, Hietamäki J, Raivio T, Pitteloud N
Endocr Rev 2019 Apr 1;40(2):669-710. doi: 10.1210/er.2018-00116. PMID: 30698671
Bhasin S, Brito JP, Cunningham GR, Hayes FJ, Hodis HN, Matsumoto AM, Snyder PJ, Swerdloff RS, Wu FC, Yialamas MA
J Clin Endocrinol Metab 2018 May 1;103(5):1715-1744. doi: 10.1210/jc.2018-00229. PMID: 29562364

Prognosis

Papazian EJ, Pinto JM
Chem Senses 2021 Jan 1;46 doi: 10.1093/chemse/bjab045. PMID: 34673938
Krzastek SC, Sharma D, Abdullah N, Sultan M, Machen GL, Wenzel JL, Ells A, Chen X, Kavoussi M, Costabile RA, Smith RP, Kavoussi PK
J Urol 2019 Nov;202(5):1029-1035. Epub 2019 Oct 9 doi: 10.1097/JU.0000000000000396. PMID: 31216250
Rastrelli G, Filippi S, Sforza A, Maggi M, Corona G
Front Horm Res 2018;49:131-155. Epub 2018 May 24 doi: 10.1159/000485999. PMID: 29895018
Boehm U, Bouloux PM, Dattani MT, de Roux N, Dodé C, Dunkel L, Dwyer AA, Giacobini P, Hardelin JP, Juul A, Maghnie M, Pitteloud N, Prevot V, Raivio T, Tena-Sempere M, Quinton R, Young J
Nat Rev Endocrinol 2015 Sep;11(9):547-64. Epub 2015 Jul 21 doi: 10.1038/nrendo.2015.112. PMID: 26194704
Kulkarni ML, Balaji MD, Kulkarni AM, Sushanth S, Kulkarni BM
Indian J Pediatr 2007 Dec;74(12):1113-5. doi: 10.1007/s12098-007-0209-5. PMID: 18174649

Clinical prediction guides

Yan CH, Jang SS, Lin HC, Ma Y, Khanwalkar AR, Thai A, Patel ZM
Int Forum Allergy Rhinol 2023 Jun;13(6):989-997. Epub 2022 Dec 21 doi: 10.1002/alr.23116. PMID: 36507615Free PMC Article
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Arch Endocrinol Metab 2022 Nov 11;66(5):739-747. doi: 10.20945/2359-3997000000563. PMID: 36382763Free PMC Article
Papazian EJ, Pinto JM
Chem Senses 2021 Jan 1;46 doi: 10.1093/chemse/bjab045. PMID: 34673938
Rouadi PW, Idriss SA, Bousquet J
Curr Opin Allergy Clin Immunol 2021 Jun 1;21(3):229-244. doi: 10.1097/ACI.0000000000000735. PMID: 33560742
Boehm U, Bouloux PM, Dattani MT, de Roux N, Dodé C, Dunkel L, Dwyer AA, Giacobini P, Hardelin JP, Juul A, Maghnie M, Pitteloud N, Prevot V, Raivio T, Tena-Sempere M, Quinton R, Young J
Nat Rev Endocrinol 2015 Sep;11(9):547-64. Epub 2015 Jul 21 doi: 10.1038/nrendo.2015.112. PMID: 26194704

Recent systematic reviews

Alexander EC, Faruqi D, Farquhar R, Unadkat A, Ng Yin K, Hoskyns R, Varughese R, Howard SR
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Morgado A, Tsampoukas G, Sokolakis I, Schoentgen N, Urkmez A, Sarikaya S
Int J Impot Res 2024 Jun;36(4):348-364. Epub 2023 Sep 11 doi: 10.1038/s41443-023-00763-9. PMID: 37697053
Lopez-Leon S, Wegman-Ostrosky T, Ayuzo Del Valle NC, Perelman C, Sepulveda R, Rebolledo PA, Cuapio A, Villapol S
Sci Rep 2022 Jun 23;12(1):9950. doi: 10.1038/s41598-022-13495-5. PMID: 35739136Free PMC Article
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Andrology 2022 Mar;10(3):451-469. Epub 2022 Jan 8 doi: 10.1111/andr.13146. PMID: 34933414
Malik P, Patel K, Pinto C, Jaiswal R, Tirupathi R, Pillai S, Patel U
J Med Virol 2022 Jan;94(1):253-262. Epub 2021 Sep 7 doi: 10.1002/jmv.27309. PMID: 34463956Free PMC Article

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