U.S. flag

An official website of the United States government


Send to:

Choose Destination

Hypogonadotropic hypogonadism 22 with or without anosmia(HH22)

MedGen UID:
Concept ID:
Disease or Syndrome
Synonym: HH22
Gene (location): FEZF1 (7q31.32)
Monarch Initiative: MONDO:0014461
OMIM®: 616030

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]
Ravikumar Balasubramanian  |  William F Crowley   view full author information

Additional description

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 is 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 as well as a discussion of oligogenicity of this disorder, see 147950.  http://www.omim.org/entry/616030

Clinical features

From HPO
MedGen UID:
Concept ID:
Congenital Abnormality
Cryptorchidism, or failure of testicular descent, is a common human congenital abnormality with a multifactorial etiology that likely reflects the involvement of endocrine, environmental, and hereditary factors. Cryptorchidism can result in infertility and increases risk for testicular tumors. Testicular descent from abdomen to scrotum occurs in 2 distinct phases: the transabdominal phase and the inguinoscrotal phase (summary by Gorlov et al., 2002).
Primary amenorrhea
MedGen UID:
Concept ID:
Disease or Syndrome
Abnormally late or absent menarche in a female with normal secondary sexual characteristics.
Decreased testicular size
MedGen UID:
Concept ID:
Reduced volume of the testicle (the male gonad).
MedGen UID:
Concept ID:
Congenital Abnormality
Abnormally small penis. At birth, the normal penis is about 3 cm (stretched length from pubic tubercle to tip of penis) with micropenis less than 2.0-2.5 cm.
MedGen UID:
Concept ID:
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.
MedGen UID:
Concept ID:
Disease or Syndrome
A decreased functionality of the gonad.
Decreased serum estradiol
MedGen UID:
Concept ID:
A reduction below normal concentration of estradiol in the circulation.
Decreased circulating follicle stimulating hormone concentration
MedGen UID:
Concept ID:
A reduction of the circulating level of follicle-stimulating hormone (FSH).
Decreased circulating luteinizing hormone level
MedGen UID:
Concept ID:
A reduction in the circulating level of luteinizing hormone (LH).
Decreased serum testosterone concentration
MedGen UID:
Concept ID:
Reduced response to gonadotropin-releasing hormone stimulation test
MedGen UID:
Concept ID:
Failure of the gonadotropin-releasing hormone (GnRH) stimulation test to induce an appropriate increased in luteinizing hormone (LH), follicle-stimulating hormone (FSH) levels.

Professional guidelines


Patel ZM, Holbrook EH, Turner JH, Adappa ND, Albers MW, Altundag A, Appenzeller S, Costanzo RM, Croy I, Davis GE, Dehgani-Mobaraki P, Doty RL, Duffy VB, Goldstein BJ, Gudis DA, Haehner A, Higgins TS, Hopkins C, Huart C, Hummel T, Jitaroon K, Kern RC, Khanwalkar AR, Kobayashi M, Kondo K, Lane AP, Lechner M, Leopold DA, Levy JM, Marmura MJ, Mclelland L, Miwa T, Moberg PJ, Mueller CA, Nigwekar SU, O'Brien EK, Paunescu TG, Pellegrino R, Philpott C, Pinto JM, Reiter ER, Roalf DR, Rowan NR, Schlosser RJ, Schwob J, Seiden AM, Smith TL, Soler ZM, Sowerby L, Tan BK, Thamboo A, Wrobel B, Yan CH
Int Forum Allergy Rhinol 2022 Apr;12(4):327-680. doi: 10.1002/alr.22929. PMID: 35373533
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
Stamou MI, Georgopoulos NA
Metabolism 2018 Sep;86:124-134. Epub 2017 Nov 3 doi: 10.1016/j.metabol.2017.10.012. PMID: 29108899Free PMC Article

Recent clinical studies


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
Schrag A, Bohlken J, Dammertz L, Teipel S, Hermann W, Akmatov MK, Bätzing J, Holstiege J
JAMA Neurol 2023 Feb 1;80(2):161-171. doi: 10.1001/jamaneurol.2022.3902. PMID: 36342675Free PMC Article
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
Burges Watson DL, Campbell M, Hopkins C, Smith B, Kelly C, Deary V
PLoS One 2021;16(9):e0256998. Epub 2021 Sep 24 doi: 10.1371/journal.pone.0256998. PMID: 34559820Free PMC Article
Ide V, Vanderschueren D, Antonio L
Int J Mol Sci 2020 Dec 22;22(1) doi: 10.3390/ijms22010021. PMID: 33375030Free PMC Article


Siderowf A, Concha-Marambio L, Lafontant DE, Farris CM, Ma Y, Urenia PA, Nguyen H, Alcalay RN, Chahine LM, Foroud T, Galasko D, Kieburtz K, Merchant K, Mollenhauer B, Poston KL, Seibyl J, Simuni T, Tanner CM, Weintraub D, Videnovic A, Choi SH, Kurth R, Caspell-Garcia C, Coffey CS, Frasier M, Oliveira LMA, Hutten SJ, Sherer T, Marek K, Soto C; Parkinson's Progression Markers Initiative
Lancet Neurol 2023 May;22(5):407-417. doi: 10.1016/S1474-4422(23)00109-6. PMID: 37059509Free PMC Article
Dong Y, Li Y, Liu K, Han X, Liu R, Ren Y, Cong L, Zhang Q, Hou T, Song L, Tang S, Shi L, Luo Y, Kalpouzos G, Laukka EJ, Winblad B, Wang Y, Du Y, Qiu C
Alzheimers Dement 2023 Feb;19(2):589-601. Epub 2022 Sep 15 doi: 10.1002/alz.12777. PMID: 36341691
Cioppi F, Rosta V, Krausz C
Int J Mol Sci 2021 Mar 23;22(6) doi: 10.3390/ijms22063264. PMID: 33806855Free PMC Article
Butowt R, von Bartheld CS
Neuroscientist 2021 Dec;27(6):582-603. Epub 2020 Sep 11 doi: 10.1177/1073858420956905. PMID: 32914699Free PMC Article
Roy D, Ghosh R, Dubey S, Dubey MJ, Benito-León J, Kanti Ray B
Can J Neurol Sci 2021 Jan;48(1):9-24. Epub 2020 Aug 5 doi: 10.1017/cjn.2020.173. PMID: 32753076Free PMC Article


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
Wittert G, Bracken K, Robledo KP, Grossmann M, Yeap BB, Handelsman DJ, Stuckey B, Conway A, Inder W, McLachlan R, Allan C, Jesudason D, Fui MNT, Hague W, Jenkins A, Daniel M, Gebski V, Keech A
Lancet Diabetes Endocrinol 2021 Jan;9(1):32-45. doi: 10.1016/S2213-8587(20)30367-3. PMID: 33338415
Ide V, Vanderschueren D, Antonio L
Int J Mol Sci 2020 Dec 22;22(1) doi: 10.3390/ijms22010021. PMID: 33375030Free PMC Article
Calogero AE, Burgio G, Condorelli RA, Cannarella R, La Vignera S
Aging Male 2019 Mar;22(1):12-19. Epub 2018 Feb 2 doi: 10.1080/13685538.2018.1434772. PMID: 29392976
Els C, Jackson TD, Kunyk D, Lappi VG, Sonnenberg B, Hagtvedt R, Sharma S, Kolahdooz F, Straube S
Cochrane Database Syst Rev 2017 Oct 30;10(10):CD012509. doi: 10.1002/14651858.CD012509.pub2. PMID: 29084357Free PMC Article


Ladani AP, Loganathan M, Kolikonda MK, Lippmann S
South Med J 2021 Dec;114(12):751-759. doi: 10.14423/SMJ.0000000000001337. PMID: 34853850Free PMC Article
Papazian EJ, Pinto JM
Chem Senses 2021 Jan 1;46 doi: 10.1093/chemse/bjab045. PMID: 34673938
Kaye R, Chang CWD, Kazahaya K, Brereton J, Denneny JC 3rd
Otolaryngol Head Neck Surg 2020 Jul;163(1):132-134. Epub 2020 Apr 28 doi: 10.1177/0194599820922992. PMID: 32340555
Boesveldt S, Postma EM, Boak D, Welge-Luessen A, Schöpf V, Mainland JD, Martens J, Ngai J, Duffy VB
Chem Senses 2017 Sep 1;42(7):513-523. doi: 10.1093/chemse/bjx025. PMID: 28531300Free PMC Article
Fenichel P
Endocr Dev 2012;22:138-159. Epub 2012 Jul 25 doi: 10.1159/000326686. PMID: 22846526

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
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
Lechien JR, Michel J, Radulesco T, Chiesa-Estomba CM, Vaira LA, De Riu G, Sowerby L, Hopkins C, Saussez S
Laryngoscope 2020 Nov;130(11):2526-2531. Epub 2020 Aug 11 doi: 10.1002/lary.28993. PMID: 32678494Free PMC Article
Yassin A, AlRumaihi K, Alzubaidi R, Alkadhi S, Al Ansari A
Aging Male 2019 Dec;22(4):219-227. Epub 2019 Jan 7 doi: 10.1080/13685538.2018.1524456. PMID: 30614347

Recent systematic reviews

Vance DE, Del Bene VA, Kamath V, Frank JS, Billings R, Cho DY, Byun JY, Jacob A, Anderson JN, Visscher K, Triebel K, Martin KM, Li W, Puga F, Fazeli PL
Neuropsychol Rev 2024 Mar;34(1):155-191. Epub 2023 Feb 2 doi: 10.1007/s11065-022-09573-0. PMID: 36725781Free PMC Article
Lu Z, Sun Y, Zhang Y, Chen Y, Guo L, Liao Y, Kang Z, Feng X, Yue W
Transl Psychiatry 2022 Jul 5;12(1):267. doi: 10.1038/s41398-022-02027-4. PMID: 35790713Free PMC Article
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
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
Gómez-Ochoa SA, Franco OH, Rojas LZ, Raguindin PF, Roa-Díaz ZM, Wyssmann BM, Guevara SLR, Echeverría LE, Glisic M, Muka T
Am J Epidemiol 2021 Jan 4;190(1):161-175. doi: 10.1093/aje/kwaa191. PMID: 32870978Free PMC Article

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Recent activity

    Your browsing activity is empty.

    Activity recording is turned off.

    Turn recording back on

    See more...