HH3
MCID: HYP565
MIFTS: 29

Hypogonadotropic Hypogonadism 3 with or Without Anosmia (HH3)

Categories: Cardiovascular diseases, Ear diseases, Endocrine diseases, Fetal diseases, Genetic diseases, Rare diseases, Reproductive diseases

Aliases & Classifications for Hypogonadotropic Hypogonadism 3 with or Without Anosmia

MalaCards integrated aliases for Hypogonadotropic Hypogonadism 3 with or Without Anosmia:

Name: Hypogonadotropic Hypogonadism 3 with or Without Anosmia 57 12 72 13
Hh3 57 72
Hypogonadotropic Hypogonadism, Type 3 with/without Anosmia 39
Hypogonadotropic Hypogonadism 3 Without Anosmia 6
Kallmann Syndrome, Type 3, Recessive 70
Kallmann Syndrome 3 72
Kal3 72

Characteristics:

OMIM®:

57 (Updated 05-Apr-2021)
Miscellaneous:
incomplete penetrance
some patients experience later reversal of hypogonadotropic hypogonadism
phenotype may be oligogenic in some patients who carry mutations in more than one hh-associated gene

Inheritance:
autosomal dominant


HPO:

31
hypogonadotropic hypogonadism 3 with or without anosmia:
Inheritance autosomal dominant inheritance
Onset and clinical course incomplete penetrance


Classifications:



Summaries for Hypogonadotropic Hypogonadism 3 with or Without Anosmia

OMIM® : 57 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. (244200) (Updated 05-Apr-2021)

MalaCards based summary : Hypogonadotropic Hypogonadism 3 with or Without Anosmia, also known as hh3, is related to kallmann syndrome 3 and smith-mccort dysplasia 2. An important gene associated with Hypogonadotropic Hypogonadism 3 with or Without Anosmia is PROKR2 (Prokineticin Receptor 2). Affiliated tissues include pituitary and breast, and related phenotypes are hearing impairment and seizure

Disease Ontology : 12 A hypogonadotropic hypogonadism that has material basis in heterozygous mutation in the PROKR2 gene on chromosome 20p12, sometimes in association with mutation in another gene.

UniProtKB/Swiss-Prot : 72 Hypogonadotropic hypogonadism 3 with or without anosmia: 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. In some cases, it is associated with non- reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin- releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH).

Related Diseases for Hypogonadotropic Hypogonadism 3 with or Without Anosmia

Diseases in the Hypogonadotropic Hypogonadism 7 with or Without Anosmia family:

Hypogonadotropic Hypogonadism 2 with or Without Anosmia Hypogonadotropic Hypogonadism 23 Without Anosmia
Hypogonadotropic Hypogonadism 24 Without Anosmia Hypogonadotropic Hypogonadism 3 with or Without Anosmia
Hypogonadotropic Hypogonadism 1 with or Without Anosmia Hypogonadotropic Hypogonadism 4 with or Without Anosmia
Hypogonadotropic Hypogonadism 5 with or Without Anosmia Hypogonadotropic Hypogonadism 6 with or Without Anosmia
Hypogonadotropic Hypogonadism 8 with or Without Anosmia Hypogonadotropic Hypogonadism 9 with or Without Anosmia
Hypogonadotropic Hypogonadism 10 with or Without Anosmia Hypogonadotropic Hypogonadism 11 with or Without Anosmia
Hypogonadotropic Hypogonadism 12 with or Without Anosmia Hypogonadotropic Hypogonadism 13 with or Without Anosmia
Hypogonadotropic Hypogonadism 14 with or Without Anosmia Hypogonadotropic Hypogonadism 15 with or Without Anosmia
Hypogonadotropic Hypogonadism 16 with or Without Anosmia Hypogonadotropic Hypogonadism 17 with or Without Anosmia
Hypogonadotropic Hypogonadism 18 with or Without Anosmia Hypogonadotropic Hypogonadism 19 with or Without Anosmia
Hypogonadotropic Hypogonadism 20 with or Without Anosmia Hypogonadotropic Hypogonadism 21 with or Without Anosmia
Hypogonadotropic Hypogonadism 22 with or Without Anosmia

Diseases related to Hypogonadotropic Hypogonadism 3 with or Without Anosmia via text searches within MalaCards or GeneCards Suite gene sharing:

# Related Disease Score Top Affiliating Genes
1 kallmann syndrome 3 11.4
2 smith-mccort dysplasia 2 10.1

Symptoms & Phenotypes for Hypogonadotropic Hypogonadism 3 with or Without Anosmia

Human phenotypes related to Hypogonadotropic Hypogonadism 3 with or Without Anosmia:

31 (show all 13)
# Description HPO Frequency HPO Source Accession
1 hearing impairment 31 occasional (7.5%) HP:0000365
2 seizure 31 occasional (7.5%) HP:0001250
3 pes planus 31 HP:0001763
4 cleft palate 31 HP:0000175
5 cryptorchidism 31 HP:0000028
6 primary amenorrhea 31 HP:0000786
7 pectus excavatum 31 HP:0000767
8 micropenis 31 HP:0000054
9 anosmia 31 HP:0000458
10 cleft upper lip 31 HP:0000204
11 hypotelorism 31 HP:0000601
12 unilateral renal agenesis 31 HP:0000122
13 hypogonadotropic hypogonadism 31 HP:0000044

Symptoms via clinical synopsis from OMIM®:

57 (Updated 05-Apr-2021)
Skeletal Feet:
pes planus

Genitourinary Internal Genitalia Female:
primary amenorrhea

Endocrine Features:
hypogonadotropic hypogonadism
delayed or absent puberty
low to undetectable gonadotropin levels
low testosterone level
low estradiol level

Chest Breasts:
delayed or absent thelarche

Head And Neck Ears:
hearing loss (rare)

Muscle Soft Tissue:
fibrous dysplasia (rare)

Genitourinary External Genitalia Male:
cryptorchidism
micropenis

Chest External Features:
pectus excavatum

Neurologic Central Nervous System:
seizures (rare)
synkinesia

Head And Neck Nose:
hyposmia/anosmia (in some patients)

Skeletal Hands:
hyperlaxity of digits (rare)

Clinical features from OMIM®:

244200 (Updated 05-Apr-2021)

Drugs & Therapeutics for Hypogonadotropic Hypogonadism 3 with or Without Anosmia

Search Clinical Trials , NIH Clinical Center for Hypogonadotropic Hypogonadism 3 with or Without Anosmia

Genetic Tests for Hypogonadotropic Hypogonadism 3 with or Without Anosmia

Anatomical Context for Hypogonadotropic Hypogonadism 3 with or Without Anosmia

MalaCards organs/tissues related to Hypogonadotropic Hypogonadism 3 with or Without Anosmia:

40
Pituitary, Breast

Publications for Hypogonadotropic Hypogonadism 3 with or Without Anosmia

Articles related to Hypogonadotropic Hypogonadism 3 with or Without Anosmia:

# Title Authors PMID Year
1
Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum. 57 6
18559922 2008
2
Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2. 57 6
17054399 2006
3
A genetic basis for functional hypothalamic amenorrhea. 57
21247312 2011
4
PROKR2 missense mutations associated with Kallmann syndrome impair receptor signalling activity. 6
18826963 2009
5
Reversal of idiopathic hypogonadotropic hypogonadism. 57
17761590 2007
6
Breast Cancer and Major Deviations of Genetic and Gender-related Structures and Function. 61
32594127 2020
7
[Clinical diagnosis and treatment of male Kallmann syndrome]. 61
24432625 2013

Variations for Hypogonadotropic Hypogonadism 3 with or Without Anosmia

ClinVar genetic disease variations for Hypogonadotropic Hypogonadism 3 with or Without Anosmia:

6 (show all 48)
# Gene Name Type Significance ClinVarId dbSNP ID Position
1 PROKR2 NM_144773.3(PROKR2):c.629A>G (p.Gln210Arg) SNV Pathogenic 3450 rs74315417 GRCh37: 20:5283212-5283212
GRCh38: 20:5302566-5302566
2 PROKR2 NM_144773.3(PROKR2):c.969G>A (p.Met323Ile) SNV Pathogenic 3453 rs74315419 GRCh37: 20:5282872-5282872
GRCh38: 20:5302226-5302226
3 PROKR2 NM_144773.3(PROKR2):c.343G>A (p.Val115Met) SNV Pathogenic 156563 rs138672528 GRCh37: 20:5294673-5294673
GRCh38: 20:5314027-5314027
4 PROKR2 NM_144773.3(PROKR2):c.743G>A (p.Arg248Gln) SNV Pathogenic 156565 rs376142095 GRCh37: 20:5283098-5283098
GRCh38: 20:5302452-5302452
5 PROKR2 NM_144773.3(PROKR2):c.253C>T (p.Arg85Cys) SNV Pathogenic 156562 rs141090506 GRCh37: 20:5294763-5294763
GRCh38: 20:5314117-5314117
6 PROKR2 NM_144773.3(PROKR2):c.97T>C (p.Tyr33His) SNV Likely pathogenic 267202 rs886037916 GRCh37: 20:5294919-5294919
GRCh38: 20:5314273-5314273
7 PROKR2 NM_144773.3(PROKR2):c.533G>C (p.Trp178Ser) SNV Likely pathogenic 156564 rs201835496 GRCh37: 20:5283308-5283308
GRCh38: 20:5302662-5302662
8 PROKR2 NM_144773.3(PROKR2):c.685G>C (p.Gly229Arg) SNV Likely pathogenic 816917 rs1600577387 GRCh37: 20:5283156-5283156
GRCh38: 20:5302510-5302510
9 PROKR2 NM_144773.3(PROKR2):c.889G>A (p.Val297Ile) SNV Conflicting interpretations of pathogenicity 803597 rs139399061 GRCh37: 20:5282952-5282952
GRCh38: 20:5302306-5302306
10 PROKR2 NM_144773.3(PROKR2):c.518T>G (p.Leu173Arg) SNV Conflicting interpretations of pathogenicity 3449 rs74315416 GRCh37: 20:5283323-5283323
GRCh38: 20:5302677-5302677
11 PROKR2 NM_144773.3(PROKR2):c.254G>A (p.Arg85His) SNV Uncertain significance 3451 rs74315418 GRCh37: 20:5294762-5294762
GRCh38: 20:5314116-5314116
12 PROKR2 NM_144773.3(PROKR2):c.328G>A (p.Glu110Lys) SNV Uncertain significance 898721 GRCh37: 20:5294688-5294688
GRCh38: 20:5314042-5314042
13 PROKR2 NM_144773.3(PROKR2):c.273C>T (p.Leu91=) SNV Uncertain significance 898722 GRCh37: 20:5294743-5294743
GRCh38: 20:5314097-5314097
14 PROKR2 NM_144773.3(PROKR2):c.58del (p.His20fs) Deletion Uncertain significance 3452 rs587777834 GRCh37: 20:5294958-5294958
GRCh38: 20:5314312-5314312
15 PROKR2 NM_144773.3(PROKR2):c.889G>T (p.Val297Phe) SNV Uncertain significance 638189 rs139399061 GRCh37: 20:5282952-5282952
GRCh38: 20:5302306-5302306
16 PROKR2 NM_144773.3(PROKR2):c.930C>G (p.His310Gln) SNV Uncertain significance 338856 rs775755881 GRCh37: 20:5282911-5282911
GRCh38: 20:5302265-5302265
17 PROKR2 NM_144773.3(PROKR2):c.819G>A (p.Thr273=) SNV Uncertain significance 338857 rs755527948 GRCh37: 20:5283022-5283022
GRCh38: 20:5302376-5302376
18 PROKR2 NM_144773.3(PROKR2):c.955G>A (p.Glu319Lys) SNV Uncertain significance 338855 rs754796297 GRCh37: 20:5282886-5282886
GRCh38: 20:5302240-5302240
19 PROKR2 NM_144773.3(PROKR2):c.376G>A (p.Val126Met) SNV Uncertain significance 338861 rs200048973 GRCh37: 20:5294640-5294640
GRCh38: 20:5313994-5313994
20 PROKR2 NM_144773.3(PROKR2):c.403C>T (p.Arg135Cys) SNV Uncertain significance 818210 rs149396342 GRCh37: 20:5294613-5294613
GRCh38: 20:5313967-5313967
21 PROKR2 NM_144773.3(PROKR2):c.728A>G (p.Tyr243Cys) SNV Uncertain significance 818211 rs921084722 GRCh37: 20:5283113-5283113
GRCh38: 20:5302467-5302467
22 PROKR2 NM_144773.3(PROKR2):c.1111G>A (p.Gly371Arg) SNV Uncertain significance 895677 GRCh37: 20:5282730-5282730
GRCh38: 20:5302084-5302084
23 PROKR2 NM_144773.3(PROKR2):c.1052A>C (p.His351Pro) SNV Uncertain significance 895678 GRCh37: 20:5282789-5282789
GRCh38: 20:5302143-5302143
24 PROKR2 NM_144773.3(PROKR2):c.208G>A (p.Gly70Ser) SNV Uncertain significance 895747 GRCh37: 20:5294808-5294808
GRCh38: 20:5314162-5314162
25 PROKR2 NM_144773.3(PROKR2):c.868C>T (p.Pro290Ser) SNV Uncertain significance 897086 GRCh37: 20:5282973-5282973
GRCh38: 20:5302327-5302327
26 PROKR2 NM_144773.3(PROKR2):c.797G>T (p.Arg266Leu) SNV Uncertain significance 897562 GRCh37: 20:5283044-5283044
GRCh38: 20:5302398-5302398
27 PROKR2 NM_144773.3(PROKR2):c.725G>A (p.Cys242Tyr) SNV Uncertain significance 897563 GRCh37: 20:5283116-5283116
GRCh38: 20:5302470-5302470
28 PROKR2 NM_144773.3(PROKR2):c.538G>A (p.Val180Met) SNV Likely benign 897564 GRCh37: 20:5283303-5283303
GRCh38: 20:5302657-5302657
29 PROKR2 NM_144773.3(PROKR2):c.506C>T (p.Thr169Met) SNV Likely benign 898720 GRCh37: 20:5283335-5283335
GRCh38: 20:5302689-5302689
30 PROKR2 NM_144773.3(PROKR2):c.809G>A (p.Arg270His) SNV Likely benign 897087 GRCh37: 20:5283032-5283032
GRCh38: 20:5302386-5302386
31 PROKR2 NM_144773.3(PROKR2):c.169G>T (p.Gly57Cys) SNV Likely benign 895748 GRCh37: 20:5294847-5294847
GRCh38: 20:5314201-5314201
32 PROKR2 NM_144773.3(PROKR2):c.261C>T (p.Leu87=) SNV Likely benign 895746 GRCh37: 20:5294755-5294755
GRCh38: 20:5314109-5314109
33 PROKR2 NM_144773.3(PROKR2):c.1111G>C (p.Gly371Arg) SNV Likely benign 895676 GRCh37: 20:5282730-5282730
GRCh38: 20:5302084-5302084
34 PROKR2 NM_144773.3(PROKR2):c.337T>C (p.Tyr113His) SNV Likely benign 338862 rs202203360 GRCh37: 20:5294679-5294679
GRCh38: 20:5314033-5314033
35 PROKR2 NM_144773.3(PROKR2):c.390C>T (p.Ser130=) SNV Likely benign 338860 rs144778137 GRCh37: 20:5294626-5294626
GRCh38: 20:5313980-5313980
36 PROKR2 NM_144773.3(PROKR2):c.802C>T (p.Arg268Cys) SNV Likely benign 282345 rs78861628 GRCh37: 20:5283039-5283039
GRCh38: 20:5302393-5302393
37 PROKR2 NM_144773.3(PROKR2):c.254G>T (p.Arg85Leu) SNV Likely benign 338863 rs74315418 GRCh37: 20:5294762-5294762
GRCh38: 20:5314116-5314116
38 PROKR2 NM_144773.3(PROKR2):c.253C>G (p.Arg85Gly) SNV Likely benign 338864 rs141090506 GRCh37: 20:5294763-5294763
GRCh38: 20:5314117-5314117
39 PROKR2 NM_144773.3(PROKR2):c.991G>A (p.Val331Met) SNV Benign/Likely benign 338854 rs117106081 GRCh37: 20:5282850-5282850
GRCh38: 20:5302204-5302204
40 PROKR2 NM_144773.3(PROKR2):c.525C>G (p.Ala175=) SNV Benign 138812 rs3746683 GRCh37: 20:5283316-5283316
GRCh38: 20:5302670-5302670
41 PROKR2 NM_144773.3(PROKR2):c.1122C>A (p.Thr374=) SNV Benign 338851 rs76469093 GRCh37: 20:5282719-5282719
GRCh38: 20:5302073-5302073
42 PROKR2 NM_144773.3(PROKR2):c.1110C>T (p.Asn370=) SNV Benign 338852 rs76049287 GRCh37: 20:5282731-5282731
GRCh38: 20:5302085-5302085
43 PROKR2 NM_144773.3(PROKR2):c.151G>A (p.Ala51Thr) SNV Benign 338865 rs144994507 GRCh37: 20:5294865-5294865
GRCh38: 20:5314219-5314219
44 PROKR2 NM_144773.3(PROKR2):c.585G>C (p.Thr195=) SNV Benign 338858 rs3746682 GRCh37: 20:5283256-5283256
GRCh38: 20:5302610-5302610
45 PROKR2 NM_144773.3(PROKR2):c.465C>T (p.Leu155=) SNV Benign 338859 rs3746684 GRCh37: 20:5283376-5283376
GRCh38: 20:5302730-5302730
46 PROKR2 NM_144773.3(PROKR2):c.1005G>A (p.Thr335=) SNV Benign 338853 rs150381386 GRCh37: 20:5282836-5282836
GRCh38: 20:5302190-5302190
47 PROKR2 NM_144773.3(PROKR2):c.743G>A (p.Arg248Gln) SNV Benign 156565 rs376142095 GRCh37: 20:5283098-5283098
GRCh38: 20:5302452-5302452
48 PROKR2 NM_144773.3(PROKR2):c.375C>T (p.His125=) SNV Benign 695243 rs148596437 GRCh37: 20:5294641-5294641
GRCh38: 20:5313995-5313995

UniProtKB/Swiss-Prot genetic disease variations for Hypogonadotropic Hypogonadism 3 with or Without Anosmia:

72 (show all 16)
# Symbol AA change Variation ID SNP ID
1 PROKR2 p.Arg85Cys VAR_030957 rs141090506
2 PROKR2 p.Arg85His VAR_030958 rs74315418
3 PROKR2 p.Arg164Gln VAR_030959 rs751875578
4 PROKR2 p.Leu173Arg VAR_030960 rs74315416
5 PROKR2 p.Trp178Ser VAR_030961 rs201835496
6 PROKR2 p.Gln210Arg VAR_030962 rs74315417
7 PROKR2 p.Pro290Ser VAR_030964 rs149992595
8 PROKR2 p.Met323Ile VAR_030965 rs74315419
9 PROKR2 p.Val115Met VAR_069964 rs138672528
10 PROKR2 p.Ser202Gly VAR_069965 rs200755554
11 PROKR2 p.Tyr113His VAR_072173 rs202203360
12 PROKR2 p.Ser188Leu VAR_072174 rs376239580
13 PROKR2 p.Arg248Gln VAR_072175 rs376142095
14 PROKR2 p.Arg357Trp VAR_072176 rs375036628
15 PROKR2 p.Val158Ile VAR_072978 rs368732206
16 PROKR2 p.Val334Met VAR_072979 rs371564610

Expression for Hypogonadotropic Hypogonadism 3 with or Without Anosmia

Search GEO for disease gene expression data for Hypogonadotropic Hypogonadism 3 with or Without Anosmia.

Pathways for Hypogonadotropic Hypogonadism 3 with or Without Anosmia

GO Terms for Hypogonadotropic Hypogonadism 3 with or Without Anosmia

Sources for Hypogonadotropic Hypogonadism 3 with or Without Anosmia

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
19 FMA
20 GARD
28 GO
29 GTR
30 HMDB
31 HPO
32 ICD10
33 ICD10 via Orphanet
34 ICD9CM
35 IUPHAR
36 KEGG
37 LifeMap
39 LOVD
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44 MeSH
45 MESH via Orphanet
46 MGI
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50 NCIt
51 NDF-RT
53 NINDS
54 Novoseek
56 OMIM via Orphanet
57 OMIM® (Updated 05-Apr-2021)
61 PubMed
63 QIAGEN
68 SNOMED-CT via HPO
69 Tocris
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71 UMLS via Orphanet
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