HHC3
MCID: HYP608
MIFTS: 42

Hypocalciuric Hypercalcemia, Familial, Type Iii (HHC3)

Categories: Bone diseases, Cardiovascular diseases, Endocrine diseases, Fetal diseases, Genetic diseases, Immune diseases, Metabolic diseases, Nephrological diseases, Rare diseases, Respiratory diseases

Aliases & Classifications for Hypocalciuric Hypercalcemia, Familial, Type Iii

MalaCards integrated aliases for Hypocalciuric Hypercalcemia, Familial, Type Iii:

Name: Hypocalciuric Hypercalcemia, Familial, Type Iii 57 29 13 6 70
Hhc3 57 12 20 72
Familial Hypocalciuric Hypercalcemia Type 3 12 20 58
Fbh3 57 20 72
Hypercalcemia, Familial Benign, Oklahoma Type 57 20
Hypocalciuric Hypercalcemia, Familial, Type 3 20 39
Familial Hypocalciuric Hypercalcemia 3 12 15
Hypocalciuric Hypercalcemia, Type Iii 57 29
Hypocalciuric Hypercalcemia Type Iii 12 72
Fhh Type 3 12 58
Familial Benign Hypercalcemia, Oklahoma Variant 20
Familial Benign Hypercalcemia, Type Iii; Fbh3 57
Familial Benign Hypocalciuric Hypercalcemia 3 72
Familial Benign Hypercalcemia Oklahoma Type 72
Hypercalcemia, Familial Benign, Type Iii 57
Familial Benign Hypercalcemia, Type Iii 57
Hypocalciuric Hypercalcemia, Familial 3 72
Hypercalcemia, Familial Benign, Type 3 20
Familial Benign Hypercalcemia, Type 3 20
Familial Benign Hypercalcemia 3 72
Fbhok 20
Fbhh3 72
Fhh3 72

Characteristics:

OMIM®:

57 (Updated 05-Apr-2021)
Inheritance:
autosomal dominant

Miscellaneous:
variable skeletal features may be present
hypercalcemia appears as early as 1.5 years of age
serum pth increases with age and is above the normal range by age 30 years


HPO:

31
hypocalciuric hypercalcemia, familial, type iii:
Inheritance autosomal dominant inheritance


Classifications:

Orphanet: 58  
Rare respiratory diseases
Rare bone diseases
Rare endocrine diseases
Developmental anomalies during embryogenesis


External Ids:

Disease Ontology 12 DOID:0060702
OMIM® 57 600740
OMIM Phenotypic Series 57 PS145980
MeSH 44 D006934
ICD10 32 E83.5
MESH via Orphanet 45 C537147
ICD10 via Orphanet 33 E83.5
UMLS via Orphanet 71 C1833372
Orphanet 58 ORPHA101050
MedGen 41 C1833372
UMLS 70 C1833372

Summaries for Hypocalciuric Hypercalcemia, Familial, Type Iii

GARD : 20 Familial hypocalciuric hypercalcemia (FHH) type 3 is one of three recognized types of FHH, an inherited condition that causes abnormally high levels of calcium in the blood ( hypercalcemia ). FHH also causes high levels of parathyroid hormone (PTH) and low levels of calcium in the urine (hypocalciuria). In most cases, FHH does not cause signs or symptoms. However, some people with FHH do report symptoms. Signs and symptoms that may occur in some people with FHH type 3 include high magnesium in addition to calcium, general symptoms of hypercalcemia (such as weakness, fatigue, muscle pain, constipation, depression, confusion, and excessive thirst), lower bone mineral density, behavioral disorders, and learning disabilities. FHH type 3 is caused by a mutation in the AP2S1 gene and inheritance is autosomal dominant. Treatment is generally not necessary in people with no signs or symptoms of FHH. In severe cases however, removal of the parathyroid gland ( parathyroidectomy ) may be recommended.

MalaCards based summary : Hypocalciuric Hypercalcemia, Familial, Type Iii, also known as hhc3, is related to hypercalcemia, infantile, 1 and hyperparathyroidism, and has symptoms including bone pain An important gene associated with Hypocalciuric Hypercalcemia, Familial, Type Iii is AP2S1 (Adaptor Related Protein Complex 2 Subunit Sigma 1), and among its related pathways/superpathways are Signaling by GPCR and Signaling by Retinoic Acid. Affiliated tissues include bone, and related phenotypes are depressivity and muscle weakness

Disease Ontology : 12 A familial hypocalciuric hypercalcemia that has material basis in heterozygous mutation in the AP2S1 gene on chromosome 19q13.

UniProtKB/Swiss-Prot : 72 Hypocalciuric hypercalcemia, familial 3: A form of hypocalciuric hypercalcemia, a disorder of mineral homeostasis that is transmitted as an autosomal dominant trait with a high degree of penetrance. It is characterized biochemically by lifelong elevation of serum calcium concentrations and is associated with inappropriately low urinary calcium excretion and a normal or mildly elevated circulating parathyroid hormone level. Hypermagnesemia is typically present. Affected individuals are usually asymptomatic and the disorder is considered benign. However, chondrocalcinosis and pancreatitis occur in some adults.

More information from OMIM: 600740 PS145980

Related Diseases for Hypocalciuric Hypercalcemia, Familial, Type Iii

Diseases in the Familial Hypocalciuric Hypercalcemia family:

Hypocalciuric Hypercalcemia, Familial, Type I Hypocalciuric Hypercalcemia, Familial, Type Ii
Hypocalciuric Hypercalcemia, Familial, Type Iii

Diseases related to Hypocalciuric Hypercalcemia, Familial, Type Iii via text searches within MalaCards or GeneCards Suite gene sharing:

(show top 50) (show all 53)
# Related Disease Score Top Affiliating Genes
1 hypercalcemia, infantile, 1 30.4 PTH CASR
2 hyperparathyroidism 30.3 PTH CDC73 CASR
3 primary hyperparathyroidism 30.3 PTH CDC73 CASR
4 adenoma 30.1 PTH CDC73 CASR
5 hypoparathyroidism 29.9 PTH GNA11 CASR AP2S1
6 familial hypocalciuric hypercalcemia 29.5 PTH GNA11 CDC73 CASR AP2S1 ADH4
7 hypocalciuric hypercalcemia, familial, type i 28.3 PTH GNA11 CDC73 CASR AP2S1 ADH4
8 nephrolithiasis, calcium oxalate 10.2
9 digeorge syndrome 10.2
10 hypophosphatemia 10.2
11 neuroendocrine tumor 10.2
12 constipation 10.2
13 multiple endocrine neoplasia 10.2
14 nephrolithiasis 10.2
15 hypercalciuria, absorptive, 2 10.2
16 water-clear cell adenoma 10.2 PTH AP2S1
17 calciphylaxis 10.1 PTH CASR
18 hypoparathyroidism-retardation-dysmorphism syndrome 10.1 PTH CASR
19 metaphyseal chondrodysplasia, jansen type 10.1 PTH CASR
20 hypoparathyroidism, sensorineural deafness, and renal disease 10.1 PTH CASR
21 chondrodysplasia, blomstrand type 10.1 PTH CASR
22 multiple endocrine neoplasia, type iv 10.1 CDC73 AP2S1
23 hyperparathyroidism 2 with jaw tumors 10.1 CDC73 CASR
24 pseudopseudohypoparathyroidism 10.1 PTH GNA11
25 phosphorus metabolism disease 10.1 PTH CASR
26 pseudohypoparathyroidism, type ia 10.1 PTH GNA11
27 renal tubular transport disease 10.1 PTH CASR
28 renal osteodystrophy 10.0 PTH CASR
29 clear cell adenoma 10.0 PTH CDC73
30 chondrocalcinosis 10.0 GNA11 CASR AP2S1
31 char syndrome 10.0 TFAP2A AP2B1
32 osseous heteroplasia, progressive 10.0 PTH GNA11
33 bone benign neoplasm 10.0 PTH CDC73
34 ossifying fibroma 10.0 PTH CDC73
35 hyperphosphatemia 10.0 PTH CASR
36 metal metabolism disorder 10.0 PTH GNA11 CASR
37 familial isolated hypoparathyroidism 9.9 PTH GNA11 CASR
38 connective tissue benign neoplasm 9.9 PTH CDC73
39 branchiooculofacial syndrome 9.9 TFAP2A AP2B1
40 secondary hyperparathyroidism 9.9 PTH CASR
41 osteitis fibrosa 9.9 PTH CDC73 CASR
42 osteomalacia 9.9 PTH CASR
43 parathyroid carcinoma 9.9 PTH CDC73 CASR
44 multiple endocrine neoplasia, type i 9.9 PTH CDC73 CASR
45 multiple endocrine neoplasia, type iia 9.9 PTH CDC73 CASR
46 parathyroid adenoma 9.9 PTH CDC73 CASR
47 diabetes insipidus, nephrogenic, autosomal 9.8 PTH CASR
48 parathyroid gland disease 9.7 PTH CDC73 CASR AP2S1
49 mineral metabolism disease 9.7 PTH CDC73 CASR AP2S1
50 bartter disease 9.7 PTH CASR ADH1A

Graphical network of the top 20 diseases related to Hypocalciuric Hypercalcemia, Familial, Type Iii:



Diseases related to Hypocalciuric Hypercalcemia, Familial, Type Iii

Symptoms & Phenotypes for Hypocalciuric Hypercalcemia, Familial, Type Iii

Human phenotypes related to Hypocalciuric Hypercalcemia, Familial, Type Iii:

31 (show all 19)
# Description HPO Frequency HPO Source Accession
1 depressivity 31 occasional (7.5%) HP:0000716
2 muscle weakness 31 occasional (7.5%) HP:0001324
3 fatigue 31 occasional (7.5%) HP:0012378
4 renal insufficiency 31 occasional (7.5%) HP:0000083
5 nephrolithiasis 31 occasional (7.5%) HP:0000787
6 peptic ulcer 31 occasional (7.5%) HP:0004398
7 headache 31 occasional (7.5%) HP:0002315
8 multiple small medullary renal cysts 31 occasional (7.5%) HP:0008659
9 hypophosphatemia 31 HP:0002148
10 multiple lipomas 31 HP:0001012
11 osteomalacia 31 HP:0002749
12 hypercalcemia 31 HP:0003072
13 bone pain 31 HP:0002653
14 chondrocalcinosis 31 HP:0000934
15 pancreatitis 31 HP:0001733
16 hypocalciuria 31 HP:0003127
17 primary hyperparathyroidism 31 HP:0008200
18 parathormone-independent increased renal tubular calcium reabsorption 31 HP:0003529
19 hypermagnesemia 31 HP:0002918

Symptoms via clinical synopsis from OMIM®:

57 (Updated 05-Apr-2021)
Skeletal:
osteomalacia
bone pain
chondrocalcinosis
pseudofracture

Genitourinary Kidneys:
renal failure (rare)
medullary cystic disease (rare)

Neurologic Central Nervous System:
headaches (in some patients)

Endocrine Features:
elevated serum parathyroid hormone (pth) levels
parathyroid gland unremarkable on ultrasound
parathyroid tissue unremarkable on biopsy

Laboratory Abnormalities:
hypercalcemia
hypocalciuria
hypophosphatemia, mild
hypermagnesemia, mild

Muscle Soft Tissue:
muscle weakness (in some patients)
periarticular calcifications (in some patients)

Neurologic Behavioral Psychiatric Manifestations:
depression (in some patients)
fatigue (in some patients)

Clinical features from OMIM®:

600740 (Updated 05-Apr-2021)

UMLS symptoms related to Hypocalciuric Hypercalcemia, Familial, Type Iii:


bone pain

MGI Mouse Phenotypes related to Hypocalciuric Hypercalcemia, Familial, Type Iii:

46
# Description MGI Source Accession Score Top Affiliating Genes
1 craniofacial MP:0005382 9.02 CASR CDC73 GNA11 PTH TFAP2A

Drugs & Therapeutics for Hypocalciuric Hypercalcemia, Familial, Type Iii

Search Clinical Trials , NIH Clinical Center for Hypocalciuric Hypercalcemia, Familial, Type Iii

Genetic Tests for Hypocalciuric Hypercalcemia, Familial, Type Iii

Genetic tests related to Hypocalciuric Hypercalcemia, Familial, Type Iii:

# Genetic test Affiliating Genes
1 Hypocalciuric Hypercalcemia, Familial, Type Iii 29 AP2S1
2 Hypocalciuric Hypercalcemia, Type Iii 29

Anatomical Context for Hypocalciuric Hypercalcemia, Familial, Type Iii

MalaCards organs/tissues related to Hypocalciuric Hypercalcemia, Familial, Type Iii:

40
Bone

Publications for Hypocalciuric Hypercalcemia, Familial, Type Iii

Articles related to Hypocalciuric Hypercalcemia, Familial, Type Iii:

(show all 13)
# Title Authors PMID Year
1
Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3. 57 6
23222959 2013
2
Identification of a second kindred with familial hypocalciuric hypercalcemia type 3 (FHH3) narrows localization to a <3.5 megabase pair region on chromosome 19q13.3. 57 6
20133464 2010
3
Significant developmental elevation in serum parathyroid hormone levels in a large kindred with familial benign (hypocalciuric) hypercalcemia. 57 6
1524075 1992
4
Cinacalcet for Symptomatic Hypercalcemia Caused by AP2S1 Mutations. 57
27050234 2016
5
Comparison of human chromosome 19q13 and syntenic region on mouse chromosome 7 reveals absence, in man, of 11.6 Mb containing four mouse calcium-sensing receptor-related sequences: relevance to familial benign hypocalciuric hypercalcaemia type 3. 57
19809483 2010
6
Localization of familial benign hypercalcemia, Oklahoma variant (FBHOk), to chromosome 19q13. 57
9915958 1999
7
Linkage studies in a kindred from Oklahoma, with familial benign (hypocalciuric) hypercalcaemia (FBH) and developmental elevations in serum parathyroid hormone levels, indicate a third locus for FBH. 57
7635467 1995
8
Stepwise CaSR, AP2S1, and GNA11 sequencing in patients with suspected familial hypocalciuric hypercalcemia. 20
28176280 2017
9
The Arabidopsis histone demethylase JMJ28 regulates CONSTANS by interacting with FBH transcription factors. 61
33604650 2021
10
Reconstitution of Abscisic Acid Signaling from the Receptor to DNA via bHLH Transcription Factors. 61
28438792 2017
11
Inhibition of the Arabidopsis bHLH transcription factor by monomerization through abscisic acid-induced phosphorylation. 61
27227462 2016
12
FLOWERING BHLH transcriptional activators control expression of the photoperiodic flowering regulator CONSTANS in Arabidopsis. 61
22334645 2012
13
Theoretical studies of carbocations in ion pairs. 8. Search for anchimeric assistance in the ionization of 2-butyl cation precursors. 61
18327922 2008

Variations for Hypocalciuric Hypercalcemia, Familial, Type Iii

ClinVar genetic disease variations for Hypocalciuric Hypercalcemia, Familial, Type Iii:

6
# Gene Name Type Significance ClinVarId dbSNP ID Position
1 AP2S1 NM_004069.5(AP2S1):c.44G>A (p.Arg15His) SNV Pathogenic 39426 rs397514499 GRCh37: 19:47349359-47349359
GRCh38: 19:46846102-46846102
2 AP2S1 NM_004069.5(AP2S1):c.43C>T (p.Arg15Cys) SNV Pathogenic 39424 rs397514498 GRCh37: 19:47349360-47349360
GRCh38: 19:46846103-46846103
3 AP2S1 NM_004069.5(AP2S1):c.44G>T (p.Arg15Leu) SNV Pathogenic 39425 rs397514499 GRCh37: 19:47349359-47349359
GRCh38: 19:46846102-46846102
4 AP2S1 NM_004069.5(AP2S1):c.28C>T (p.Arg10Trp) SNV Uncertain significance 421594 rs1064795235 GRCh37: 19:47349375-47349375
GRCh38: 19:46846118-46846118

UniProtKB/Swiss-Prot genetic disease variations for Hypocalciuric Hypercalcemia, Familial, Type Iii:

72
# Symbol AA change Variation ID SNP ID
1 AP2S1 p.Arg15Cys VAR_069570 rs397514498
2 AP2S1 p.Arg15His VAR_069571 rs397514499
3 AP2S1 p.Arg15Leu VAR_069572 rs397514499

Expression for Hypocalciuric Hypercalcemia, Familial, Type Iii

Search GEO for disease gene expression data for Hypocalciuric Hypercalcemia, Familial, Type Iii.

Pathways for Hypocalciuric Hypercalcemia, Familial, Type Iii

GO Terms for Hypocalciuric Hypercalcemia, Familial, Type Iii

Cellular components related to Hypocalciuric Hypercalcemia, Familial, Type Iii according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 endocytic vesicle membrane GO:0030666 9.4 AP2S1 AP2B1
2 clathrin-coated pit GO:0005905 9.37 AP2S1 AP2B1
3 clathrin-coated endocytic vesicle membrane GO:0030669 9.32 AP2S1 AP2B1
4 membrane coat GO:0030117 9.26 AP2S1 AP2B1
5 clathrin-coated endocytic vesicle GO:0045334 9.16 AP2S1 AP2B1
6 endolysosome membrane GO:0036020 8.96 AP2S1 AP2B1
7 AP-2 adaptor complex GO:0030122 8.62 AP2S1 AP2B1

Biological processes related to Hypocalciuric Hypercalcemia, Familial, Type Iii according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 retinol metabolic process GO:0042572 9.48 ADH4 ADH1A
2 positive regulation of bone mineralization GO:0030501 9.46 TFAP2A PTH
3 regulation of defense response to virus by virus GO:0050690 9.43 AP2S1 AP2B1
4 clathrin-dependent endocytosis GO:0072583 9.4 AP2S1 AP2B1
5 low-density lipoprotein particle clearance GO:0034383 9.37 AP2S1 AP2B1
6 clathrin coat assembly GO:0048268 9.32 AP2S1 AP2B1
7 ethanol oxidation GO:0006069 9.26 ADH4 ADH1A
8 low-density lipoprotein particle receptor catabolic process GO:0032802 9.16 AP2S1 AP2B1
9 response to fibroblast growth factor GO:0071774 8.96 PTH CASR
10 alcohol metabolic process GO:0006066 8.62 ADH4 ADH1A

Molecular functions related to Hypocalciuric Hypercalcemia, Familial, Type Iii according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 retinol dehydrogenase activity GO:0004745 9.26 ADH4 ADH1A
2 clathrin adaptor activity GO:0035615 9.16 AP2S1 AP2B1
3 alcohol dehydrogenase (NAD) activity GO:0004022 8.96 ADH4 ADH1A
4 alcohol dehydrogenase activity, zinc-dependent GO:0004024 8.62 ADH4 ADH1A

Sources for Hypocalciuric Hypercalcemia, Familial, Type Iii

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
Content
Loading form....