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Hypogonadotropic hypogonadism 5 with or without anosmia(KAL5)

MedGen UID:
765467
Concept ID:
C3552553
Disease or Syndrome
Synonyms: HYPOGONADOTROPHIC HYPOGONADISM 5 WITHOUT ANOSMIA; HYPOGONADOTROPIC HYPOGONADISM 5 WITH ANOSMIA; KAL5; Kallmann syndrome 5
 
Gene (location): CHD7 (8q12.2)
 
Monarch Initiative: MONDO:0012880
OMIM®: 612370

Definition

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]

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 hypogonadotropic hypogonadism with or without anosmia, see 147950.  http://www.omim.org/entry/612370
From MedlinePlus Genetics
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.

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.

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).
Sensorineural hearing loss disorder
MedGen UID:
9164
Concept ID:
C0018784
Disease or Syndrome
A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.
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.
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).
Cleft lip
MedGen UID:
1370297
Concept ID:
C4321245
Anatomical Abnormality
A gap in the lip or lips.
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

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
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J Clin Endocrinol Metab 2018 May 1;103(5):1715-1744. doi: 10.1210/jc.2018-00229. PMID: 29562364
Rahnema CD, Lipshultz LI, Crosnoe LE, Kovac JR, Kim ED
Fertil Steril 2014 May;101(5):1271-9. Epub 2014 Mar 14 doi: 10.1016/j.fertnstert.2014.02.002. PMID: 24636400

Recent clinical studies

Therapy

Indirli R, Lanzi V, Arosio M, Mantovani G, Ferrante E
Front Endocrinol (Lausanne) 2023;14:1198437. Epub 2023 Aug 10 doi: 10.3389/fendo.2023.1198437. PMID: 37635965Free PMC Article
Bhasin S, Lincoff AM, Basaria S, Bauer DC, Boden WE, Cunningham GR, Davey D, Dubcenco E, Fukumoto S, Garcia M, Granger CB, Kalahasti V, Khera M, Miller MG, Mitchell LM, O'Leary MP, Pencina KM, Snyder PJ, Thompson IM Jr, Travison TG, Wolski K, Nissen SE; TRAVERSE Study Investigators
Am Heart J 2022 Mar;245:41-50. Epub 2021 Dec 4 doi: 10.1016/j.ahj.2021.11.016. PMID: 34871580
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Endocr Rev 2022 Sep 26;43(5):824-851. doi: 10.1210/endrev/bnab043. PMID: 34864951
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Andrology 2020 Sep;8(5):970-987. Epub 2020 Mar 20 doi: 10.1111/andr.12770. PMID: 32026626
Rahnema CD, Lipshultz LI, Crosnoe LE, Kovac JR, Kim ED
Fertil Steril 2014 May;101(5):1271-9. Epub 2014 Mar 14 doi: 10.1016/j.fertnstert.2014.02.002. PMID: 24636400

Prognosis

Papazian EJ, Pinto JM
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Rouadi PW, Idriss SA, Bousquet J
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J Urol 2019 Nov;202(5):1029-1035. Epub 2019 Oct 9 doi: 10.1097/JU.0000000000000396. PMID: 31216250
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Binkley N
Arq Bras Endocrinol Metabol 2006 Aug;50(4):764-74. doi: 10.1590/s0004-27302006000400021. PMID: 17117301

Clinical prediction guides

Rabijewski M
Endokrynol Pol 2023;74(5):480-489. Epub 2023 Oct 2 doi: 10.5603/ep.95626. PMID: 37779374
Blinc A, Schernthaner GH, Poredoš P, Anagnostis P, Jensterle M, Studen KB, Antignani PL, Mikhailidis DP, Šabović M
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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
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

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Int J Impot Res 2024 Jun;36(4):348-364. Epub 2023 Sep 11 doi: 10.1038/s41443-023-00763-9. PMID: 37697053
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Lopez-Leon S, Wegman-Ostrosky T, Ayuzo Del Valle NC, Perelman C, Sepulveda R, Rebolledo PA, Cuapio A, Villapol S
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J Med Virol 2022 Jan;94(1):253-262. Epub 2021 Sep 7 doi: 10.1002/jmv.27309. PMID: 34463956Free PMC Article
Christou MA, Christou PA, Markozannes G, Tsatsoulis A, Mastorakos G, Tigas S
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