HH4
MCID: HYP531
MIFTS: 27

Hypogonadotropic Hypogonadism 4 with or Without Anosmia (HH4)

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

Aliases & Classifications for Hypogonadotropic Hypogonadism 4 with or Without Anosmia

MalaCards integrated aliases for Hypogonadotropic Hypogonadism 4 with or Without Anosmia:

Name: Hypogonadotropic Hypogonadism 4 with or Without Anosmia 57 12 72 29 13 6
Kallmann Syndrome 4 72 70
Hh4 57 72
Hypogonadotropic Hypogonadism, Type 4 with/without Anosmia 39
Kal4 72

Characteristics:

OMIM®:

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

Inheritance:
autosomal dominant


HPO:

31
hypogonadotropic hypogonadism 4 with or without anosmia:
Inheritance autosomal dominant inheritance
Onset and clinical course incomplete penetrance


Classifications:



External Ids:

Disease Ontology 12 DOID:0090077
OMIM® 57 610628
OMIM Phenotypic Series 57 PS147950
MeSH 44 D017436
ICD10 32 E23.0
UMLS 70 C1857720

Summaries for Hypogonadotropic Hypogonadism 4 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. (610628) (Updated 05-Apr-2021)

MalaCards based summary : Hypogonadotropic Hypogonadism 4 with or Without Anosmia, also known as kallmann syndrome 4, is related to kallmann syndrome 4. An important gene associated with Hypogonadotropic Hypogonadism 4 with or Without Anosmia is PROK2 (Prokineticin 2). Affiliated tissues include pituitary and testes, and related phenotypes are diabetes mellitus and osteoporosis

Disease Ontology : 12 A hypogonadotropic hypogonadism that has material basis in heterozygous mutation in the prokineticin-2 gene (PROK2) on chromosome 3p13, sometimes in association with mutation in another gene.

UniProtKB/Swiss-Prot : 72 Hypogonadotropic hypogonadism 4 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 4 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 4 with or Without Anosmia via text searches within MalaCards or GeneCards Suite gene sharing:

# Related Disease Score Top Affiliating Genes
1 kallmann syndrome 4 11.4

Symptoms & Phenotypes for Hypogonadotropic Hypogonadism 4 with or Without Anosmia

Human phenotypes related to Hypogonadotropic Hypogonadism 4 with or Without Anosmia:

31 (show all 10)
# Description HPO Frequency HPO Source Accession
1 diabetes mellitus 31 occasional (7.5%) HP:0000819
2 osteoporosis 31 occasional (7.5%) HP:0000939
3 obesity 31 occasional (7.5%) HP:0001513
4 anosmia 31 occasional (7.5%) HP:0000458
5 seizure 31 occasional (7.5%) HP:0001250
6 cryptorchidism 31 HP:0000028
7 primary amenorrhea 31 HP:0000786
8 micropenis 31 HP:0000054
9 decreased testicular size 31 HP:0008734
10 hypogonadotropic hypogonadism 31 HP:0000044

Symptoms via clinical synopsis from OMIM®:

57 (Updated 05-Apr-2021)
Genitourinary External Genitalia Male:
cryptorchidism
micropenis
small testes

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

Skeletal:
osteoporosis (in some patients)

Genitourinary Internal Genitalia Female:
primary amenorrhea

Neurologic Central Nervous System:
seizures (rare)
sleep disorder (rare)
synkinesia (rare)

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

Growth Weight:
obesity (rare)

Clinical features from OMIM®:

610628 (Updated 05-Apr-2021)

Drugs & Therapeutics for Hypogonadotropic Hypogonadism 4 with or Without Anosmia

Search Clinical Trials , NIH Clinical Center for Hypogonadotropic Hypogonadism 4 with or Without Anosmia

Genetic Tests for Hypogonadotropic Hypogonadism 4 with or Without Anosmia

Genetic tests related to Hypogonadotropic Hypogonadism 4 with or Without Anosmia:

# Genetic test Affiliating Genes
1 Hypogonadotropic Hypogonadism 4 with or Without Anosmia 29 PROK2

Anatomical Context for Hypogonadotropic Hypogonadism 4 with or Without Anosmia

MalaCards organs/tissues related to Hypogonadotropic Hypogonadism 4 with or Without Anosmia:

40
Pituitary, Testes

Publications for Hypogonadotropic Hypogonadism 4 with or Without Anosmia

Articles related to Hypogonadotropic Hypogonadism 4 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
Biallelic mutations in the prokineticin-2 gene in two sporadic cases of Kallmann syndrome. 57 6
18285834 2008
3
Loss-of-function mutation in the prokineticin 2 gene causes Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism. 57 6
17959774 2007
4
Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2. 57 6
17054399 2006
5
Reversal of idiopathic hypogonadotropic hypogonadism. 57
17761590 2007
6
The induction of ovulation by pulsatile administration of GnRH: an appropriate method in hypothalamic amenorrhea. 61
28277105 2017

Variations for Hypogonadotropic Hypogonadism 4 with or Without Anosmia

ClinVar genetic disease variations for Hypogonadotropic Hypogonadism 4 with or Without Anosmia:

6
# Gene Name Type Significance ClinVarId dbSNP ID Position
1 PROK2 NM_001126128.2(PROK2):c.94G>C (p.Gly32Arg) SNV Pathogenic 3601 rs104893767 GRCh37: 3:71834110-71834110
GRCh38: 3:71784959-71784959
2 PROK2 PROK2, 1-BP INS, 234T Insertion Pathogenic 3602 GRCh37:
GRCh38:
3 PROK2 NM_001126128.2(PROK2):c.163del (p.Ser54_Ile55insTer) Deletion Pathogenic 3603 rs554675432 GRCh37: 3:71830677-71830677
GRCh38: 3:71781526-71781526
4 PROK2 NM_001126128.2(PROK2):c.217C>T (p.Arg73Cys) SNV Pathogenic 3604 rs121434272 GRCh37: 3:71830623-71830623
GRCh38: 3:71781472-71781472
5 PROK2 NM_001126128.2(PROK2):c.70G>C (p.Ala24Pro) SNV Pathogenic 156560 rs587777863 GRCh37: 3:71834134-71834134
GRCh38: 3:71784983-71784983
6 PROK2 NM_001126128.2(PROK2):c.101G>A (p.Cys34Tyr) SNV Pathogenic 156561 rs587777864 GRCh37: 3:71830739-71830739
GRCh38: 3:71781588-71781588
7 PROK2 NM_001126128.2(PROK2):c.223-2A>G SNV Pathogenic 997621 GRCh37: 3:71823660-71823660
GRCh38: 3:71774509-71774509
8 PROK2 NM_001126128.2(PROK2):c.-4C>A SNV Benign 801987 rs552496938 GRCh37: 3:71834207-71834207
GRCh38: 3:71785056-71785056

UniProtKB/Swiss-Prot genetic disease variations for Hypogonadotropic Hypogonadism 4 with or Without Anosmia:

72
# Symbol AA change Variation ID SNP ID
1 PROK2 p.Gly32Arg VAR_030955 rs104893767
2 PROK2 p.Arg73Cys VAR_030956 rs121434272
3 PROK2 p.Ala24Pro VAR_069970 rs587777863
4 PROK2 p.Cys34Tyr VAR_072177 rs587777864
5 PROK2 p.Ile50Met VAR_072178 rs138829087
6 PROK2 p.Cys46Tyr VAR_072991 rs142701726

Expression for Hypogonadotropic Hypogonadism 4 with or Without Anosmia

Search GEO for disease gene expression data for Hypogonadotropic Hypogonadism 4 with or Without Anosmia.

Pathways for Hypogonadotropic Hypogonadism 4 with or Without Anosmia

GO Terms for Hypogonadotropic Hypogonadism 4 with or Without Anosmia

Sources for Hypogonadotropic Hypogonadism 4 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
41 MedGen
44 MeSH
45 MESH via Orphanet
46 MGI
49 NCI
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
70 UMLS
71 UMLS via Orphanet
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