FIHPT
MCID: PRM005
MIFTS: 68

Primary Hyperparathyroidism (FIHPT) malady

Genetic diseases, Rare diseases, Endocrine diseases, Cancer diseases categories
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Summaries for Primary Hyperparathyroidism

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43NIH Rare Diseases, 65Wikipedia, 47OMIM, 33MalaCards
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NIH Rare Diseases:43 Hyperparathyroidism is an endocrine disorder in which the parathyroid glands in the neck produce too much parathyroid hormone (pth). signs and symptoms are often mild and nonspecific, such as a feeling of weakness and fatigue, depression, or aches and pains. with more severe disease, a person may have a loss of appetite, nausea, vomiting, constipation, confusion or impaired thinking and memory, and increased thirst and urination. patients may have thinning of the bones without symptoms, but with risk of fractures. there are two main types of hyperparathyroidism: primary hyperparathyroidism and secondary hyperparathyroidism. surgery to remove the parathyroid gland(s) is the main treatment for the disorder. some patients with mild disease do not require treatment. last updated: 4/2/2012

MalaCards: Primary Hyperparathyroidism, also known as familial benign hypercalcemia, is related to hyperparathyroidism and parathyroid adenoma. An important gene associated with Primary Hyperparathyroidism is MEN1 (multiple endocrine neoplasia I), and among its related pathways are Development Hedgehog and PTH signaling pathways in bone and cartilage development and Osteoblast Signaling. The compounds gadolinium and 22-oxacalcitriol have been mentioned in the context of this disorder. Affiliated tissues include bone, thyroid and testes, and related mouse phenotypes are immune system and endocrine/exocrine gland.

Wikipedia:65 Primary hyperparathyroidism causes hypercalcemia (elevated blood calcium levels) through the excessive... more...

Description from OMIM:47 145000,610071

Aliases & Classifications for Primary Hyperparathyroidism

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8Disease Ontology, 22GTR, 62UMLS, 9diseasecard, 49Orphanet, 43NIH Rare Diseases, 45Novoseek, 58SNOMED-CT, 40NCIt, 35MeSH, 27ICD9CM, 59SNOMED-CT via Orphanet, 47OMIM, 26ICD10 via Orphanet, 63UMLS via Orphanet, 36MESH via Orphanet, 25ICD10
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Classifications:

Malacards categories (disease lists): (See all malacards categories)
Global: Genetic diseases, Rare diseases, Cancer diseases
Anatomical: Endocrine diseases


Aliases & Descriptions:

primary hyperparathyroidism 8
familial benign hypercalcemia 8 22 62
hyperparathyroidism, primary 43 62
hyperparathyroidism, familial primary 9
familial isolated hyperparathyroidism 49
familial primary hyperparathyroidism 8
hypercalcemia, familial benign 45
parathyroid adenoma, familial 62
familial parathyroid adenoma 49
hyperparathyroidism primary 45
primary hyperthyroidism 43
fihpt 49


External Ids:

Disease Ontology8 DOID:11202
NCIt40 C48280
MeSH35 D049950
ICD9CM27 252.01
SNOMED-CT via Orphanet59 237653008
ICD10 via Orphanet26 E21.0
UMLS via Orphanet63 C1840403
MESH via Orphanet36 C564166
ICD1025 E21.0, E21.3

Related Diseases for Primary Hyperparathyroidism

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Sources:
17GeneCards, 18GeneDecks
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Diseases in the Primary Hyperparathyroidism family:

Hyperparathyroidism Hyperparathyroidism 3

Diseases related to Primary Hyperparathyroidism via text searches within MalaCards or GeneCards/GeneDecks gene sharing:

(show top 50)    (show all 195)
idRelated DiseaseScoreTop Affiliating Genes
1hyperparathyroidism31.9BGLAP, PTH, MEN1, FGF23, CDC73, NR1I3
2parathyroid adenoma31.3CDC73, CALCA, CASR, MEN1, PTH
3adenoma31.2SPINK1, PTH, MEN1, CASR, CALCA, NR1I3
4multiple endocrine neoplasia31.1MEN1, CALCA, CDC73
5osteitis fibrosa31.0CASR, PTH, BGLAP
6parathyroid carcinoma30.9PTH, MEN1, CASR, CDC73
7hypercalcemia30.9FGF23, SPINK1, BGLAP, PTH, MEN1, CASR
8pancreatitis30.8SPINK1, PRSS2, CASR, CTRC
9goiter30.8BGLAP, PTH, CALCA
10hyperparathyroidism-jaw tumor syndrome30.6CDC73
11osteomalacia30.6BGLAP, PTH, CASR, CALCA, FGF23
12thyroid cancer30.6CALCA, PTH, BGLAP
13osteosclerosis30.6SOST, PTH
14hyperthyroidism30.5BGLAP, PTH, FGF23
15hyperparathyroidism, neonatal30.5CASR, NR1I3
16familial isolated hyperparathyroidism30.5MEN1, CDC73
17nephrocalcinosis30.5CASR, NR1I3
18fibrous dysplasia30.4FGF23, BGLAP
19multiple endocrine neoplasia type 2a30.4PTH, MEN1, CALCA, CDC73
20osteoporosis30.4BGLAP, PTH, SOST, CASR, CALCA, NR1I3
21paget's disease of bone30.3CALCA
22acromegaly30.3BGLAP, MEN1
23rickets30.3FGF23, PTH, BGLAP
24graves' disease30.2BGLAP, CASR, FGF23
25pseudohypoparathyroidism30.2BGLAP, PTH, CALCA
26breast cancer30.2PTH, MEN1, CASR, CALCA, NR1I3
27insulinoma30.2CALCA, CASR, MEN1
28giant cell tumor30.2BGLAP, CALCA, FGF23
29nephrolithiasis30.2PTH, CASR, NR1I3, SLC26A6, FGF23
30ossifying fibroma30.1CDC73
31uremia30.1NR1I3, CASR, MEN1, PTH
32hypoparathyroidism30.0BGLAP, PTH, CASR, CALCA, NR1I3, GCM2
33hypophosphatemia29.9FGF23, CALCA, PTH, BGLAP
34renal osteodystrophy29.9BGLAP, PTH, CASR, CALCA, FGF23
35thyroiditis10.7
36familial hypocalciuric hypercalcemia10.6
37hypertension10.4
38papillary thyroid carcinoma10.4
39pheochromocytoma10.4
40acute pancreatitis10.3
41multinodular goiter10.3
42calciphylaxis10.3
43endotheliitis10.3
44neurofibromatosis10.3
45hyperaldosteronism10.3
46sarcoidosis10.3
47hyperparathyroidism, neonatal severe primary10.3
48familial hypocalciuric hypercalcemia type 110.3
49familial hypocalciuric hypercalcemia type 310.3
50hypocalciuric hypercalcemia, type i10.3

Graphical network of the top 20 diseases related to Primary Hyperparathyroidism:



Diseases related to primary hyperparathyroidism

Symptoms for Primary Hyperparathyroidism

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Sources:
47OMIM
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Clinical features from OMIM:

145000,610071

Drugs & Therapeutics for Primary Hyperparathyroidism

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Sources:
42NIH Clinical Center, 6ClinicalTrials, 62UMLS, 41NDF-RT
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Drug clinical trials:

Search ClinicalTrials for Primary Hyperparathyroidism

Search NIH Clinical Center for Primary Hyperparathyroidism

Genetic Tests for Primary Hyperparathyroidism

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Sources:
22GTR
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Genetic tests related to Primary Hyperparathyroidism:

id Genetic test Affiliating Genes
1 Familial Benign Hypercalcemia22

Anatomical Context for Primary Hyperparathyroidism

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33MalaCards
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MalaCards organs/tissues related to Primary Hyperparathyroidism:

33
Bone, Thyroid, Testes, Kidney, Endothelial, Breast, Pituitary, Colon, Lung, Thymus, Pancreatic islet

Animal Models for Primary Hyperparathyroidism or affiliated genes

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37MGI
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MGI Mouse Phenotypes related to Primary Hyperparathyroidism:

37
idDescriptionMGI Source AccessionScoreTop Affiliating Genes
1MP:00053878.3FGF23, CDC73, CASR, MEN1, PTH, SPINK1
2MP:00053798.2SPINK1, PTH, MEN1, CASR, GCM2, CDC73
3MP:00053818.1SPINK1, MEN1, CASR, CDC73, SLC26A6, FGF23
4MP:00053677.8CASR, CALCA, GCM2, CDC73, SLC26A6, FGF23
5MP:00107717.7SPINK1, CASR, CALCA, CDC73, FGF23
6MP:00053907.7PTH, SOST, CASR, CALCA, GCM2, FGF23
7MP:00053787.6SPINK1, PTH, SOST, MEN1, CASR, NR1I3
8MP:00107687.0SPINK1, PTH, MEN1, CASR, CALCA, NR1I3
9MP:00053766.1FGF23, SPINK1, PTH, SOST, MEN1, CASR

Publications for Primary Hyperparathyroidism

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Sources:
52PubMed
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Articles related to Primary Hyperparathyroidism:

(show top 50)    (show all 860)
idTitleAuthorsYear
1
Differentiating familial hypocalciuric hypercalcemia from primary hyperparathyroidism. (23425644)
2013
2
Is there a link between Hashimoto's thyroiditis and primary hyperparathyroidism? A study of serum parathormone and anti-TPO antibodies in 2267 patients. (23865082)
2013
3
The prevalence of undiagnosed and unrecognized primary hyperparathyroidism: a population-based analysis from the electronic medical record. (24383100)
2013
4
Radiographical appearance of osteitis fibrosa cystica in primary hyperparathyroidism before and after parathyroidectomy. (23365170)
2013
5
Epidemiology of Primary Hyperparathyroidism and its Non-classical Manifestations in the City of Recife, Brazil. (24348080)
2013
6
Safety of vitamin D replacement in patients with primary hyperparathyroidism and concomitant vitamin D deficiency. (23337136)
2013
7
Increasing incidence of primary hyperparathyroidism in Denmark. (23461985)
2013
8
Does the pre-operative serum phosphate level predict early hypocalcaemia following parathyroidectomy for primary hyperparathyroidism? (23312554)
2013
9
Vitamin D status in normocalcaemic primary hyperparathyroidism. (23260223)
2013
10
Incidence and prevalence of primary hyperparathyroidism in a racially mixed population. (23418315)
2013
11
Aggressive pulmonary calcification developed after living donor kidney transplantation in a patient with primary hyperparathyroidism. (24034059)
2013
12
Focused parathyroidectomy with intraoperative parathyroid hormone monitoring in patients with lithium-associated primary hyperparathyroidism. (23352236)
2013
13
Bone mineral density evolution after successful parathyroidectomy in patients with normocalcemic primary hyperparathyroidism. (23783096)
2013
14
Arterial Hypertension, Metabolic Syndrome and Subclinical Cardiovascular Organ Damage in Patients with Asymptomatic Primary Hyperparathyroidism before and after Parathyroidectomy: Preliminary Results. (22719761)
2012
15
A comparison of outcomes for younger and older adult patients undergoing surgery for primary hyperparathyroidism. (22207049)
2012
16
Preoperative a8^a8^mTc-sestamibi scintigraphy in patients with primary hyperparathyroidism and concomitant nodular goiter: comparison of SPECT-CT, SPECT, and planar imaging. (22825041)
2012
17
Primary hyperparathyroidism and familial hypocalciuric hypercalcemia: relationships and clinical implications. (22232026)
2012
18
The association of primary hyperparathyroidism with pancreatitis. (22874807)
2012
19
Functioning glucagonoma associated with primary hyperparathyroidism: multiple endocrine neoplasia type 1 or incidental association? (23259638)
2012
20
Forearm bone mineral density in familial hypocalciuric hypercalcemia and primary hyperparathyroidism: a comparative study. (21785908)
2011
21
Primary hyperparathyroidism patients with positive preoperative sestamibi scan and negative ultrasound are more likely to have posteriorly located upper gland adenomas (PLUGs). (21207169)
2011
22
Can biochemical abnormalities predict symptomatology in patients with primary hyperparathyroidism? (21723154)
2011
23
Breast cancer associated with primary hyperparathyroidism: a nested case control study. (21487450)
2011
24
Lithium use and primary hyperparathyroidism. (21247849)
2011
25
Endothelial activation markers soluble E-selectin and von Willebrand factor in primary hyperparathyroidism. (21471547)
2011
26
Unusual case of calciphylaxis associated with primary hyperparathyroidism without coexistent renal failure. (18463046)
2008
27
Tc-99m sestamibi uptake mimicking parathyroid adenoma in a patient with primary hyperparathyroidism and occult multiple myeloma. (18287846)
2008
28
Normocalcemic, subclinical, asymptomatic primary hyperparathyroidism in patients with goiter or papillary thyroid cancer--preliminary report. Normocalcemic primary hyperparathyroidism and thyroid pathology. (17966885)
2007
29
Primary hyperparathyroidism due to parathyroid adenoma. (17268723)
2007
30
Primary hyperparathyroidism--what the nephrologist should know--an update. (17138574)
2007
31
Water-clear cell parathyroid adenoma causing primary hyperparathyroidism in a patient with neurofibromatosis type 1: report of a case. (17879040)
2007
32
Regulation of plasma fibroblast growth factor 23 by calcium in primary hyperparathyroidism. (16381997)
2006
33
Utilisation of a cryptic non-canonical donor splice site of the gene encoding PARAFIBROMIN is associated with familial isolated primary hyperparathyroidism. (16061557)
2005
34
Inhibition of growth hormone secretion in mild primary hyperparathyroidism. (15249740)
2004
35
Multiple endocrine neoplasia type 1 (MEN1) germline mutations in familial isolated primary hyperparathyroidism. (12699448)
2003
36
Recovery pattern of patients with osteitis fibrosa cystica in primary hyperparathyroidism after successful parathyroidectomy. (12490858)
2002
37
An unusual presentation of calciphylaxis due to primary hyperparathyroidism. (11570914)
2001
38
Molecular mechanisms of primary hyperparathyroidism. (11706744)
2000
39
Lack of relationship between BsmI vitamin D receptor polymorphism and primary hyperparathyroidism in a Spanish female population. (10441653)
1999
40
Increased biochemical markers of bone formation and resorption in primary hyperparathyroidism with special reference to patients with mild disease. (9566639)
1998
41
Plasma chromogranin A in pheochromocytoma, primary hyperparathyroidism and pituitary adenoma in comparison with catecholamine, parathyroid hormone and pituitary hormones. (9228469)
1997
42
Primary hyperparathyroidism due to parathyroid carcinoma. (9204627)
1997
43
Increased plasma levels of islet amyloid polypeptide in patients with primary hyperparathyroidism. (8616529)
1996
44
Coexisting hyperthyroidism and primary hyperparathyroidism with vitamin D-deficient osteomalacia in a Vietnamese immigrant. (15251523)
1996
45
Vitamin D receptor genotypes in primary hyperparathyroidism. (7489414)
1995
46
Plasma intact parathyroid hormone (PTH) and PTH-related peptide in familial benign hypercalcemia: greater responsiveness to endogenous PTH than in primary hyperparathyroidism. (1997510)
1991
47
Chromogranin A and B in parathyroid tissue of cases of primary hyperparathyroidism: an immunohistochemical study. (2024450)
1991
48
Nephrocalcinosis, hypercalcemia, sarcoidosis or primary hyperparathyroidism? (3983783)
1985
49
Primary hyperparathyroidism in infancy associated with familial hypocalciuric hypercalcemia. (6312730)
1983
50
Primary hyperparathyroidism: possible cause of primary hyperaldosteronism in a 60-year-old woman. (6991517)
1980

Variations for Primary Hyperparathyroidism

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1 National Center for Biotechnology Information (Clinvar)
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Clinvar genetic disease variations for Primary Hyperparathyroidism:

1 (show all 16)
id Gene Name Type Significance SNP ID Assembly Location
1CASRNM_000388.3(CASR): c.662C> A (p.Pro221Gln)single nucleotide variantPathogenicrs397514728GRCh37Chr 3, 121980544: 121980544
2CASRNM_000388.3(CASR): c.2383C> T (p.Arg795Trp)single nucleotide variantPathogenicrs121909258GRCh37Chr 3, 122003184: 122003184
3CASRNM_000388.3(CASR): c.889G> A (p.Glu297Lys)single nucleotide variantPathogenicrs121909259GRCh37Chr 3, 121980771: 121980771
4CASRNM_000388.3(CASR): c.554G> A (p.Arg185Gln)single nucleotide variantPathogenicrs104893689GRCh37Chr 3, 121980436: 121980436
5CASRNM_000388.3(CASR): c.115C> G (p.Pro39Ala)single nucleotide variantPathogenicrs121909262GRCh37Chr 3, 121973151: 121973151
6CASRNM_000388.3(CASR): c.413C> T (p.Thr138Met)single nucleotide variantPathogenicrs121909263GRCh37Chr 3, 121976155: 121976155
7CASRNM_000388.3(CASR): c.428G> A (p.Gly143Glu)single nucleotide variantPathogenicrs121909264GRCh37Chr 3, 121976170: 121976170
8CASRNM_000388.3(CASR): c.185G> T (p.Arg62Met)single nucleotide variantPathogenicrs121909265GRCh37Chr 3, 121973221: 121973221
9CASRNM_000388.3(CASR): c.196C> T (p.Arg66Cys)single nucleotide variantPathogenicrs121909266GRCh37Chr 3, 121975938: 121975938
10CASRNM_000388.3(CASR): c.1942C> T (p.Arg648Ter)single nucleotide variantPathogenicrs104893705GRCh37Chr 3, 122002743: 122002743
11CASRNM_000388.3(CASR): c.1394G> A (p.Arg465Gln)single nucleotide variantPathogenicrs104893716GRCh37Chr 3, 121994675: 121994675
12CASRNM_000388.3(CASR): c.38T> C (p.Leu13Pro)single nucleotide variantPathogenicrs104893717GRCh37Chr 3, 121973074: 121973074
13CASRNM_000388.3(CASR): c.539T> G (p.Phe180Cys)single nucleotide variantPathogenicrs121909268GRCh37Chr 3, 121980421: 121980421
14CASRNM_000388.3(CASR): c.1745G> T (p.Cys582Phe)single nucleotide variantPathogenicrs104893690GRCh37Chr 3, 122002546: 122002546
15CASRNM_000388.3(CASR): c.1657G> A (p.Gly553Arg)single nucleotide variantPathogenicrs104893719GRCh37Chr 3, 122001008: 122001008
16CASRNM_000388.3(CASR): c.680G> A (p.Arg227Gln)single nucleotide variantPathogenicrs28936684GRCh37Chr 3, 121980562: 121980562

Expression for genes affiliated with Primary Hyperparathyroidism

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2BioGPS, 15Gene Expression Omnibus DataSets
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Expression patterns in normal tissues for genes affiliated with Primary Hyperparathyroidism

Search GEO for disease gene expression data for Primary Hyperparathyroidism.

Pathways for genes affiliated with Primary Hyperparathyroidism

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Sources:
50PathCards, 60Thomson Reuters, 38NCBI BioSystems Database, 55Reactome, 30KEGG
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Compounds for genes affiliated with Primary Hyperparathyroidism

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Sources:
45Novoseek, 61Tocris Bioscience, 29IUPHAR, 11DrugBank, 24HMDB, 51PharmGKB
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Compounds related to Primary Hyperparathyroidism according to GeneCards/GeneDecks:

(show top 50)    (show all 58)
idCompoundScoreTop Affiliating Genes
1gadolinium4510.2CASR, NR1I3
222-oxacalcitriol4510.2CASR, BGLAP
3calcipotriol45 61 29 1112.9NR1I3, BGLAP
4estrone45 29 24 1112.9NR1I3, PTH, BGLAP
5inositol 1,4,5 trisphosphate459.8PTH, CASR, NR1I3
6strontium ranelate459.8CASR, CALCA
7ipriflavone459.7CALCA, BGLAP
8calcium gluconate459.7CALCA, BGLAP
9sevelamer459.7FGF23, CASR, BGLAP
1024,25-dihydroxyvitamin d3459.7BGLAP, CALCA
11teriparatide45 1110.7BGLAP, CALCA
12denosumab45 1110.7SOST, CALCA
13etidronate459.7BGLAP, CALCA
14nandrolone decanoate45 1110.6BGLAP, CALCA
15ibandronate45 1110.6BGLAP, CALCA
16hydroxyapatite459.6FGF23, CASR, BGLAP
17l-tryptophan51 29 45 24 1113.6CASR, NR1I3
18vitamin k2459.6CALCA, BGLAP
19tartrate459.6CALCA, BGLAP
20sodium fluoride459.6BGLAP, CALCA
21cinacalcet45 29 1111.5CASR, CALCA, NR1I3
22risedronate45 51 29 61 1113.5CALCA, BGLAP
23trypsinogen459.5SPINK1, PRSS2, CTRC
24clodronate45 51 1111.5CALCA, BGLAP
25thiazide459.5BGLAP, CASR, CALCA
26calcium carbonate459.4BGLAP, PTH, CALCA
27alfacalcidol45 61 1111.4NR1I3, CALCA, BGLAP
28deoxypyridinoline459.4BGLAP, PTH, CALCA
29alendronate45 51 1111.4CALCA, PTH, BGLAP
30hydroxyproline45 24 1111.4BGLAP, PTH, CALCA
31tibolone459.4CALCA, BGLAP
32pyridinoline459.3BGLAP, CALCA
33phenylalanine459.3FGF23, NR1I3, CASR
34thyroxine45 2410.3CALCA, PTH, BGLAP
35pamidronate45 51 1111.2BGLAP, PTH, CASR, CALCA
36fluoride459.2SPINK1, BGLAP, CALCA
37pge2459.1BGLAP, PTH, CASR, CALCA
38cyclosporin a45 29 6111.0BGLAP, CASR, CALCA, NR1I3
39arginine459.0BGLAP, PTH, CASR, NR1I3, FGF23
40cyclic amp45 2410.0PTH, CASR, CALCA, NR1I3
41testosterone45 61 24 1111.6NR1I3, CALCA, PTH, BGLAP
4225-hydroxyvitamin d458.6BGLAP, PTH, CASR, CALCA, FGF23
43phosphorus458.3FGF23, BGLAP, PTH, CASR, CALCA, NR1I3
441,25 dihydroxy vitamin d3458.3BGLAP, PTH, CASR, CALCA, NR1I3, FGF23
45calcitriol45 61 24 1111.3BGLAP, PTH, CASR, CALCA, NR1I3, FGF23
46estrogen458.3BGLAP, PTH, SOST, MEN1, CASR, CALCA
47creatinine458.0SPINK1, BGLAP, PTH, CASR, CALCA, FGF23
48serine457.7SPINK1, BGLAP, PRSS2, MEN1, CASR, NR1I3
49vitamin d457.7BGLAP, PTH, SOST, MEN1, CASR, CALCA
50calcium45 51 24 119.0PRSS2, SOST, PTH, BGLAP, SPINK1, MEN1

GO Terms for genes affiliated with Primary Hyperparathyroidism

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Sources:
16Gene Ontology
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Cellular components related to Primary Hyperparathyroidism according to GeneCards/GeneDecks:

idNameGO IDScoreTop Affiliating Genes
1membrane-bounded vesicleGO:0319889.6SLC26A6, BGLAP
2extracellular spaceGO:0056157.5FGF23, CALCA, PRSS2, SOST, PTH, BGLAP
3extracellular regionGO:0055767.1SPINK1, BGLAP, PTH, PRSS2, CALCA, FGF23

Biological processes related to Primary Hyperparathyroidism according to GeneCards/GeneDecks:

(show all 9)
idNameGO IDScoreTop Affiliating Genes
1response to vitamin DGO:03328010.0BGLAP, PTH
2osteoblast developmentGO:00207610.0BGLAP, MEN1
3cellular calcium ion homeostasisGO:0068749.8GCM2, CASR, PTH
4response to mechanical stimulusGO:0096129.8SOST, BGLAP
5cellular phosphate ion homeostasisGO:0306439.7FGF23, GCM2
6negative regulation of osteoblast differentiationGO:0456689.6FGF23, MEN1
7negative regulation of ossificationGO:0302799.4SOST, CALCA
8positive regulation of cAMP biosynthetic processGO:0308199.3CALCA, PTH
9adenylate cyclase-activating G-protein coupled receptor signaling pathwayGO:0071899.1CALCA, PTH

Products for genes affiliated with Primary Hyperparathyroidism

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  • Antibodies
  • Proteins
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  • Antibodies

Sources for Primary Hyperparathyroidism

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4CDC
13ExPASy
14FMA
22GTR
23HGMD
24HMDB
25ICD10
26ICD10 via Orphanet
27ICD9CM
29IUPHAR
30KEGG
35MeSH
36MESH via Orphanet
37MGI
40NCIt
41NDF-RT
44NINDS
45Novoseek
47OMIM
48OMIM via Orphanet
52PubMed
53QIAGEN
59SNOMED-CT via Orphanet
62UMLS
63UMLS via Orphanet