U.S. flag

An official website of the United States government

Format

Send to:

Choose Destination

Hypogonadotropic hypogonadism 3 with or without anosmia(HH3)

MedGen UID:
763392
Concept ID:
C3550478
Disease or Syndrome
Synonyms: HH3; HYPOGONADOTROPIC HYPOGONADISM 3 WITH ANOSMIA; Kallmann syndrome 3
 
Gene (location): PROKR2 (20p12.3)
 
Monarch Initiative: MONDO:0009482
OMIM®: 244200

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 descriptions

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 autosomal hypogonadotropic hypogonadism with or without anosmia, see 147950.  http://www.omim.org/entry/244200
From MedlinePlus Genetics
Kallmann syndrome can have a wide variety of additional signs and symptoms. These include a failure of one kidney to develop (unilateral renal agenesis), abnormalities of bones in the fingers or toes, a cleft lip with or without an opening in the roof of the mouth (a cleft palate), abnormal eye movements, hearing loss, and abnormalities of tooth development. Some affected individuals have a feature called bimanual synkinesis, in which the movements of one hand are mirrored by the other hand. Bimanual synkinesis can make it difficult to do tasks that require the hands to move separately, such as playing a musical instrument.

In Kallmann syndrome, the sense of smell is either diminished (hyposmia) or completely absent (anosmia). This feature distinguishes Kallmann syndrome from most other forms of hypogonadotropic hypogonadism, which do not affect the sense of smell. Many people with Kallmann syndrome are not aware that they are unable to detect odors until the impairment is discovered through testing.

This disorder is a form of hypogonadotropic hypogonadism, which is a condition resulting from a lack of production of certain hormones that direct sexual development. These hormones are normally made in a part of the brain called the hypothalamus. Males born with hypogonadotropic hypogonadism often have an unusually small penis (micropenis) and undescended testes (cryptorchidism). At puberty, most affected individuals do not develop secondary sex characteristics, such as the growth of facial hair and deepening of the voice in males, the start of monthly periods (menstruation) and breast development in females, and a growth spurt in both sexes. Without treatment, most affected men and women are unable to have biological children (infertile).

Kallmann syndrome is a condition characterized by delayed or absent puberty and an impaired sense of smell.  https://medlineplus.gov/genetics/condition/kallmann-syndrome

Clinical features

From HPO
Cryptorchidism
MedGen UID:
8192
Concept ID:
C0010417
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:
115918
Concept ID:
C0232939
Disease or Syndrome
Abnormally late or absent menarche in a female with normal secondary sexual characteristics.
Unilateral renal agenesis
MedGen UID:
75607
Concept ID:
C0266294
Congenital Abnormality
A unilateral form of agenesis of the kidney.
Micropenis
MedGen UID:
1633603
Concept ID:
C4551492
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.
Pes planus
MedGen UID:
42034
Concept ID:
C0016202
Anatomical Abnormality
A foot where the longitudinal arch of the foot is in contact with the ground or floor when the individual is standing; or, in a patient lying supine, a foot where the arch is in contact with the surface of a flat board pressed against the sole of the foot by the examiner with a pressure similar to that expected from weight bearing; or, the height of the arch is reduced.
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
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.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Bimanual synkinesia
MedGen UID:
473166
Concept ID:
C0454455
Disease or Syndrome
Involuntary movements of one hand that accompany and mirror intentional movements of the opposite hand.
Hyposmia
MedGen UID:
473584
Concept ID:
C2364082
Finding
A decreased sensitivity to odorants (that is, a decreased ability to perceive odors).
Aplasia of the olfactory bulb
MedGen UID:
1696661
Concept ID:
C5139362
Congenital Abnormality
Lack of formation (congenital absence) of the olfactory bulb.
Finger joint hypermobility
MedGen UID:
154359
Concept ID:
C0574974
Finding
Pectus excavatum
MedGen UID:
781174
Concept ID:
C2051831
Finding
A defect of the chest wall characterized by a depression of the sternum, giving the chest ("pectus") a caved-in ("excavatum") appearance.
Cleft upper lip
MedGen UID:
40327
Concept ID:
C0008924
Congenital Abnormality
A gap or groove in the upper lip. This is a congenital defect resulting from nonfusion of tissues of the lip during embryonal development.
Cleft palate
MedGen UID:
756015
Concept ID:
C2981150
Congenital Abnormality
Cleft palate is a developmental defect of the palate resulting from a failure of fusion of the palatine processes and manifesting as a separation of the roof of the mouth (soft and hard palate).
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
Hypotelorism
MedGen UID:
96107
Concept ID:
C0424711
Finding
Interpupillary distance less than 2 SD below the mean (alternatively, the appearance of an decreased interpupillary distance or closely spaced eyes).

Professional guidelines

PubMed

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
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
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

Etiology

Huijben M, Lock MTWT, de Kemp VF, Beck JJH, De Kort LMO, van Breda HMK
Endocrinol Diabetes Metab 2023 May;6(3):e416. Epub 2023 Mar 30 doi: 10.1002/edm2.416. PMID: 36998229Free PMC Article
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
Corona G, Rastrelli G, Dicuio M, Concetti S, Minnetti M, Pivonello R, Isidori A, Sforza A, Maggi M
Minerva Endocrinol (Torino) 2021 Sep;46(3):252-261. Epub 2020 Sep 24 doi: 10.23736/S2724-6507.20.03208-3. PMID: 32969626
Guerri G, Maniscalchi T, Barati S, Dhuli K, Busetto GM, Del Giudice F, De Berardinis E, De Antoni L, Miertus J, Bertelli M
Acta Biomed 2019 Sep 30;90(10-S):75-82. doi: 10.23750/abm.v90i10-S.8764. PMID: 31577259Free PMC Article
Miraoui H, Dwyer AA, Sykiotis GP, Plummer L, Chung W, Feng B, Beenken A, Clarke J, Pers TH, Dworzynski P, Keefe K, Niedziela M, Raivio T, Crowley WF Jr, Seminara SB, Quinton R, Hughes VA, Kumanov P, Young J, Yialamas MA, Hall JE, Van Vliet G, Chanoine JP, Rubenstein J, Mohammadi M, Tsai PS, Sidis Y, Lage K, Pitteloud N
Am J Hum Genet 2013 May 2;92(5):725-43. doi: 10.1016/j.ajhg.2013.04.008. PMID: 23643382Free PMC Article

Diagnosis

Harrington J, Palmert MR
J Clin Endocrinol Metab 2022 May 17;107(6):1739-1750. doi: 10.1210/clinem/dgac054. PMID: 35100608
Butler G, Purushothaman P
Minerva Pediatr 2020 Dec;72(6):484-490. Epub 2020 Aug 4 doi: 10.23736/S0026-4946.20.05968-X. PMID: 32748610
Raivio T, Miettinen PJ
Best Pract Res Clin Endocrinol Metab 2019 Jun;33(3):101316. Epub 2019 Sep 5 doi: 10.1016/j.beem.2019.101316. PMID: 31522908
Richard-Eaglin A
Nurs Clin North Am 2018 Sep;53(3):395-405. doi: 10.1016/j.cnur.2018.04.006. PMID: 30100005
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
Huijben M, Lock MTWT, de Kemp VF, Beck JJH, De Kort LMO, van Breda HMK
Endocrinol Diabetes Metab 2023 May;6(3):e416. Epub 2023 Mar 30 doi: 10.1002/edm2.416. PMID: 36998229Free PMC Article
Koyama S, Kondo K, Ueha R, Kashiwadani H, Heinbockel T
Int J Mol Sci 2021 Aug 18;22(16) doi: 10.3390/ijms22168912. PMID: 34445619Free PMC Article
Corona G, Rastrelli G, Dicuio M, Concetti S, Minnetti M, Pivonello R, Isidori A, Sforza A, Maggi M
Minerva Endocrinol (Torino) 2021 Sep;46(3):252-261. Epub 2020 Sep 24 doi: 10.23736/S2724-6507.20.03208-3. PMID: 32969626
Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM; Task Force, Endocrine Society
J Clin Endocrinol Metab 2010 Jun;95(6):2536-59. doi: 10.1210/jc.2009-2354. PMID: 20525905

Prognosis

Mohanraj S, Prasad HK
Indian J Pediatr 2023 Jun;90(6):590-597. Epub 2023 May 2 doi: 10.1007/s12098-023-04577-x. PMID: 37127825
Huijben M, Lock MTWT, de Kemp VF, Beck JJH, De Kort LMO, van Breda HMK
Endocrinol Diabetes Metab 2023 May;6(3):e416. Epub 2023 Mar 30 doi: 10.1002/edm2.416. PMID: 36998229Free PMC Article
Figueiredo MG, Gagliano-Jucá T, Basaria S
J Clin Endocrinol Metab 2022 Feb 17;107(3):614-626. doi: 10.1210/clinem/dgab772. PMID: 34698352Free PMC Article
Butler G, Purushothaman P
Minerva Pediatr 2020 Dec;72(6):484-490. Epub 2020 Aug 4 doi: 10.23736/S0026-4946.20.05968-X. PMID: 32748610
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

Clinical prediction guides

Huijben M, Lock MTWT, de Kemp VF, Beck JJH, De Kort LMO, van Breda HMK
Endocrinol Diabetes Metab 2023 May;6(3):e416. Epub 2023 Mar 30 doi: 10.1002/edm2.416. PMID: 36998229Free 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
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
Butler G, Purushothaman P
Minerva Pediatr 2020 Dec;72(6):484-490. Epub 2020 Aug 4 doi: 10.23736/S0026-4946.20.05968-X. PMID: 32748610
Miraoui H, Dwyer AA, Sykiotis GP, Plummer L, Chung W, Feng B, Beenken A, Clarke J, Pers TH, Dworzynski P, Keefe K, Niedziela M, Raivio T, Crowley WF Jr, Seminara SB, Quinton R, Hughes VA, Kumanov P, Young J, Yialamas MA, Hall JE, Van Vliet G, Chanoine JP, Rubenstein J, Mohammadi M, Tsai PS, Sidis Y, Lage K, Pitteloud N
Am J Hum Genet 2013 May 2;92(5):725-43. doi: 10.1016/j.ajhg.2013.04.008. PMID: 23643382Free PMC Article

Recent systematic reviews

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
Huijben M, Lock MTWT, de Kemp VF, de Kort LMO, van Breda HMK
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
Salonia A, Bettocchi C, Boeri L, Capogrosso P, Carvalho J, Cilesiz NC, Cocci A, Corona G, Dimitropoulos K, Gül M, Hatzichristodoulou G, Jones TH, Kadioglu A, Martínez Salamanca JI, Milenkovic U, Modgil V, Russo GI, Serefoglu EC, Tharakan T, Verze P, Minhas S; EAU Working Group on Male Sexual and Reproductive Health
Eur Urol 2021 Sep;80(3):333-357. Epub 2021 Jun 26 doi: 10.1016/j.eururo.2021.06.007. PMID: 34183196
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...