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Hypogonadotropic hypogonadism 25 with anosmia(HH25)

MedGen UID:
1717461
•Concept ID:
C5394246
•
Disease or Syndrome
Synonyms: HH25; HYPOGONADOTROPIC HYPOGONADISM 25 WITH ANOSMIA
 
Gene (location): NDNF (4q27)
 
Monarch Initiative: MONDO:0030010
OMIM®: 618841

Definition

Hypogonadotropic hypogonadism-25 with anosmia (HH25) is characterized by delayed or absent puberty with low gonadotropic hormones in the setting of low testosterone or estradiol. Affected individuals also exhibit hyposmia or anosmia, with hypoplastic olfactory bulbs on MRI. Intrafamilial variable expressivity and incomplete penetrance has been observed (Messina et al., 2020). For a discussion of genetic heterogeneity of hypogonadotropic hypogonadism with or without anosmia, see 147950. [from OMIM]

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).
See: Feature record | Search on this feature
Primary amenorrhea
MedGen UID:
115918
•Concept ID:
C0232939
•
Disease or Syndrome
Abnormally late or absent menarche in a female with normal secondary sexual characteristics.
See: Feature record | Search on this feature
Hypoplasia of the ovary
MedGen UID:
672766
•Concept ID:
C0685840
•
Congenital Abnormality
Developmental hypoplasia of the ovary.
See: Feature record | Search on this feature
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.
See: Feature record | Search on this feature
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.
See: Feature record | Search on this feature
Decreased serum estradiol
MedGen UID:
69129
•Concept ID:
C0241011
•
Finding
A reduction below normal concentration of estradiol in the circulation.
See: Feature record | Search on this feature
Hypothalamic gonadotropin-releasing hormone deficiency
MedGen UID:
871170
•Concept ID:
C4025644
•
Finding
See: Feature record | Search on this feature
Decreased serum testosterone concentration
MedGen UID:
892974
•Concept ID:
C4073137
•
Finding
See: Feature record | Search on this feature
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Professional guidelines

PubMed

Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism--pathogenesis, diagnosis and treatment.
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 clinical studies

Etiology

Spectral signatures of mirror movements in the sensori-motor connectivity in kallmann syndrome.
Manara R, Di Nardo F, Salvalaggio A, Sinisi AA, Bonanni G, Palumbo V, Cantone E, Brunetti A, Di Salle F, D'errico A, Elefante A, Esposito F
Hum Brain Mapp 2018 Jan;39(1):42-53. Epub 2017 Sep 30 doi: 10.1002/hbm.23806. PMID: 28963812Free PMC Article
Bone involvement in males with Kallmann disease.
Iolascon G, Frizzi L, Bianco M, Gimigliano F, Palumbo V, Sinisi AM, Sinisi AA
Aging Clin Exp Res 2015 Oct;27 Suppl 1:S31-6. Epub 2015 Jul 23 doi: 10.1007/s40520-015-0421-5. PMID: 26201943
An objective olfactory evaluation and its correlation with magnetic resonance imaging findings in Asian Indian patients with idiopathic hypogonadotropic hypogonadism.
Jagtap VS, Sarathi V, Lila AR, Nair S, Bukan A, Sankhe SS, Shivane V, Bandgar T, Menon P, Shah NS
Endocr Pract 2013 Jul-Aug;19(4):669-74. doi: 10.4158/EP13008.OR. PMID: 23512393
Reversal of idiopathic hypogonadotropic hypogonadism.
Raivio T, Falardeau J, Dwyer A, Quinton R, Hayes FJ, Hughes VA, Cole LW, Pearce SH, Lee H, Boepple P, Crowley WF Jr, Pitteloud N
N Engl J Med 2007 Aug 30;357(9):863-73. doi: 10.1056/NEJMoa066494. PMID: 17761590
Predictors of outcome of long-term GnRH therapy in men with idiopathic hypogonadotropic hypogonadism.
Pitteloud N, Hayes FJ, Dwyer A, Boepple PA, Lee H, Crowley WF Jr
J Clin Endocrinol Metab 2002 Sep;87(9):4128-36. doi: 10.1210/jc.2002-020518. PMID: 12213860

Diagnosis

Kallmann Syndrome: Functional Analysis of a CHD7 Missense Variant Shows Aberrant RNA Splicing.
Carriço JN, Gonçalves CI, Aragüés JM, Lemos MC
Int J Mol Sci 2024 Nov 10;25(22) doi: 10.3390/ijms252212061. PMID: 39596130Free PMC Article
GNRHR-related central hypogonadism with spontaneous recovery - case report.
Šmigoc Schweiger D, Davidović Povše M, Trebušak Podkrajšek K, Battelino T, Avbelj Stefanija M
Ital J Pediatr 2022 Nov 12;48(1):184. doi: 10.1186/s13052-022-01377-5. PMID: 36371229Free PMC Article
Bone involvement in males with Kallmann disease.
Iolascon G, Frizzi L, Bianco M, Gimigliano F, Palumbo V, Sinisi AM, Sinisi AA
Aging Clin Exp Res 2015 Oct;27 Suppl 1:S31-6. Epub 2015 Jul 23 doi: 10.1007/s40520-015-0421-5. PMID: 26201943
Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism--pathogenesis, diagnosis and treatment.
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
Estimating frequency of Kallmann syndrome among hypogonadic and among anosmic patients.
Pawlowitzki IH, Diekstall P, Schadel A, Miny P
Am J Med Genet 1987 Feb;26(2):473-9. doi: 10.1002/ajmg.1320260226. PMID: 3101500

Therapy

GNRHR-related central hypogonadism with spontaneous recovery - case report.
Šmigoc Schweiger D, Davidović Povše M, Trebušak Podkrajšek K, Battelino T, Avbelj Stefanija M
Ital J Pediatr 2022 Nov 12;48(1):184. doi: 10.1186/s13052-022-01377-5. PMID: 36371229Free PMC Article
Bone involvement in males with Kallmann disease.
Iolascon G, Frizzi L, Bianco M, Gimigliano F, Palumbo V, Sinisi AM, Sinisi AA
Aging Clin Exp Res 2015 Oct;27 Suppl 1:S31-6. Epub 2015 Jul 23 doi: 10.1007/s40520-015-0421-5. PMID: 26201943
Reversal of idiopathic hypogonadotropic hypogonadism.
Raivio T, Falardeau J, Dwyer A, Quinton R, Hayes FJ, Hughes VA, Cole LW, Pearce SH, Lee H, Boepple P, Crowley WF Jr, Pitteloud N
N Engl J Med 2007 Aug 30;357(9):863-73. doi: 10.1056/NEJMoa066494. PMID: 17761590
Predictors of outcome of long-term GnRH therapy in men with idiopathic hypogonadotropic hypogonadism.
Pitteloud N, Hayes FJ, Dwyer A, Boepple PA, Lee H, Crowley WF Jr
J Clin Endocrinol Metab 2002 Sep;87(9):4128-36. doi: 10.1210/jc.2002-020518. PMID: 12213860
Gonadotropin responses to low dose pulsatile administration of GnRH in a case of anosmia with hypogonadotropic hypogonadism associated with gonadal dysgenesis 47 XXY.
Hazard J, Rozenberg I, Perlemuter L, Kestenbaum S, Vendrely E, Raoul O, Fiet J, Villete JM
Acta Endocrinol (Copenh) 1986 Dec;113(4):593-7. doi: 10.1530/acta.0.1130593. PMID: 3098018

Prognosis

Spectral signatures of mirror movements in the sensori-motor connectivity in kallmann syndrome.
Manara R, Di Nardo F, Salvalaggio A, Sinisi AA, Bonanni G, Palumbo V, Cantone E, Brunetti A, Di Salle F, D'errico A, Elefante A, Esposito F
Hum Brain Mapp 2018 Jan;39(1):42-53. Epub 2017 Sep 30 doi: 10.1002/hbm.23806. PMID: 28963812Free PMC Article
Next-generation sequencing of patients with congenital anosmia.
Alkelai A, Olender T, Dode C, Shushan S, Tatarskyy P, Furman-Haran E, Boyko V, Gross-Isseroff R, Halvorsen M, Greenbaum L, Milgrom R, Yamada K, Haneishi A, Blau I, Lancet D
Eur J Hum Genet 2017 Dec;25(12):1377-1387. Epub 2017 Nov 13 doi: 10.1038/s41431-017-0014-1. PMID: 29255181Free PMC Article
Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism--pathogenesis, diagnosis and treatment.
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
Incidence, phenotypic features and molecular genetics of Kallmann syndrome in Finland.
Laitinen EM, Vaaralahti K, Tommiska J, Eklund E, Tervaniemi M, Valanne L, Raivio T
Orphanet J Rare Dis 2011 Jun 17;6:41. doi: 10.1186/1750-1172-6-41. PMID: 21682876Free PMC Article
Reversal of idiopathic hypogonadotropic hypogonadism.
Raivio T, Falardeau J, Dwyer A, Quinton R, Hayes FJ, Hughes VA, Cole LW, Pearce SH, Lee H, Boepple P, Crowley WF Jr, Pitteloud N
N Engl J Med 2007 Aug 30;357(9):863-73. doi: 10.1056/NEJMoa066494. PMID: 17761590

Clinical prediction guides

Spectral signatures of mirror movements in the sensori-motor connectivity in kallmann syndrome.
Manara R, Di Nardo F, Salvalaggio A, Sinisi AA, Bonanni G, Palumbo V, Cantone E, Brunetti A, Di Salle F, D'errico A, Elefante A, Esposito F
Hum Brain Mapp 2018 Jan;39(1):42-53. Epub 2017 Sep 30 doi: 10.1002/hbm.23806. PMID: 28963812Free PMC Article
Next-generation sequencing of patients with congenital anosmia.
Alkelai A, Olender T, Dode C, Shushan S, Tatarskyy P, Furman-Haran E, Boyko V, Gross-Isseroff R, Halvorsen M, Greenbaum L, Milgrom R, Yamada K, Haneishi A, Blau I, Lancet D
Eur J Hum Genet 2017 Dec;25(12):1377-1387. Epub 2017 Nov 13 doi: 10.1038/s41431-017-0014-1. PMID: 29255181Free PMC Article
Bone involvement in males with Kallmann disease.
Iolascon G, Frizzi L, Bianco M, Gimigliano F, Palumbo V, Sinisi AM, Sinisi AA
Aging Clin Exp Res 2015 Oct;27 Suppl 1:S31-6. Epub 2015 Jul 23 doi: 10.1007/s40520-015-0421-5. PMID: 26201943
Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism--pathogenesis, diagnosis and treatment.
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
An objective olfactory evaluation and its correlation with magnetic resonance imaging findings in Asian Indian patients with idiopathic hypogonadotropic hypogonadism.
Jagtap VS, Sarathi V, Lila AR, Nair S, Bukan A, Sankhe SS, Shivane V, Bandgar T, Menon P, Shah NS
Endocr Pract 2013 Jul-Aug;19(4):669-74. doi: 10.4158/EP13008.OR. PMID: 23512393

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