MCID: HYP776
MIFTS: 40

Hyperparathyroidism, Neonatal Severe

Categories: Genetic diseases, Rare diseases, Bone diseases, Endocrine diseases, Fetal diseases

Aliases & Classifications for Hyperparathyroidism, Neonatal Severe

MalaCards integrated aliases for Hyperparathyroidism, Neonatal Severe:

Name: Hyperparathyroidism, Neonatal Severe 57 75 73
Nshpt 57 59 75 55
Neonatal Severe Hyperparathyroidism 53 29 6
Hyperparathyroidism, Neonatal 57 13 40
Neonatal Severe Primary Hyperparathyroidism 59 75
Neonatal Hyperparathyroidism 37 73
Nsph 57 75
Nhpt 57 75
Hyperparathyroidism, Neonatal Severe Primary 57
Nsph; Nhpt 57

Characteristics:

Orphanet epidemiological data:

59
neonatal severe primary hyperparathyroidism
Inheritance: Autosomal recessive,Not applicable; Age of onset: Neonatal; Age of death: early childhood;

OMIM:

57
Inheritance:
autosomal recessive
autosomal dominant (de novo in some patients)


HPO:

32
hyperparathyroidism, neonatal severe:
Inheritance autosomal recessive inheritance autosomal dominant inheritance


Classifications:



Summaries for Hyperparathyroidism, Neonatal Severe

NIH Rare Diseases : 53 The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.Orpha Number: 417Disease definitionNeonatal severe primary hyperparathyroidism (NSHPT) is characterized by severe hypercalcemia (> 3.5 mM) from birth and associated with major hyperparathyroidism.EpidemiologyThe prevalence is unknown.Clinical descriptionThe clinical manifestations are early (with onset occurring during the first days of life) and severe, including respiratory distress due to hypotonia and rib cage deformities, bone under mineralization, and multiple fractures, all of which influence the immediate vital prognosis.EtiologyNSHPT is associated in most cases with homozygous inactivating mutations in the CASR gene, localized to 3q21.1. This gene encodes the calcium-sensing receptor (CaSR), a member of the subfamily of G protein-coupled transmembrane receptors. CaSR plays a key role in the regulation of phosphocalcic metabolism by controlling parathyroid hormone (PTH) secretion and calcium urinary excretion in response to variations in serum calcium levels.Diagnostic methodsBiologically, children present with extremely high serum calcium and serum PTH levels and a relative hypocalciuria, but in some cases they present with a markedly elevated calciuria.Differential diagnosis'Familial hypocalciuric hypercalcemia (FHH; see this term) is a differential diagnosis. Hypercalcemia is usually milder and PTH levels are lower in FHH than in NSHPT and FHH is asymptomatic in most cases.'Antenatal diagnosisPrenatal diagnosis might be proposed to parents if they are both suffering from FHH.Genetic counselingNSHPT represents the homozygous form of FHH and is transmitted as an autosomal recessivetrait. However, sporadic forms of NSHPT occur and are associated with a heterozygousde novo mutation in the CASR gene. To date, there have been no reports of severe neonatal hyperparathyroidism with homozygous mutations in those with FHH type 2 or 3 (see these terms) but their molecular identification is still too recent to make any definite conclusions.Management and treatmentThe control of hypercalcemia is often obtained through progressive therapeutic intervention involving the use of bisphosphonates, dialysis or even calcimimetics. If this is unsuccessful, a total parathyroidectomy is required. After parathyroidectomy, life-long treatment with 1-alpha hydoxylated vitamin D is required.PrognosisPatients can die from complications of hypercalcemia during the neonatal period from respiratory distress and dramatic hypercalcemia.Visit the Orphanet disease page for more resources.

MalaCards based summary : Hyperparathyroidism, Neonatal Severe, also known as nshpt, is related to hyperparathyroidism and primary hyperparathyroidism, and has symptoms including constipation, dyspnea and polyuria. An important gene associated with Hyperparathyroidism, Neonatal Severe is CASR (Calcium Sensing Receptor), and among its related pathways/superpathways is Ca, cAMP and Lipid Signaling. Affiliated tissues include bone and thyroid, and related phenotypes are muscular hypotonia and splenomegaly

OMIM : 57 Neonatal severe hyperparathyroidism usually manifests in the first 6 months of life with severe hypercalcemia, bone demineralization, and failure to thrive. Early diagnosis is critical because untreated NSHPT can be a devastating neurodevelopmental disorder, which in some cases is lethal without parathyroidectomy. Some infants have milder hyperparathyroidism and a substantially milder clinical presentation and natural history (summary by Egbuna and Brown, 2008). (239200)

UniProtKB/Swiss-Prot : 75 Hyperparathyroidism, neonatal severe: A disorder characterized by severe hypercalcemia, bone demineralization, and failure to thrive usually manifesting in the first 6 months of life. If untreated, NSHPT can be a devastating neurodevelopmental disorder, which in some cases is lethal without parathyroidectomy.

Related Diseases for Hyperparathyroidism, Neonatal Severe

Graphical network of the top 20 diseases related to Hyperparathyroidism, Neonatal Severe:



Diseases related to Hyperparathyroidism, Neonatal Severe

Symptoms & Phenotypes for Hyperparathyroidism, Neonatal Severe

Symptoms via clinical synopsis from OMIM:

57
Growth Other:
failure to thrive

AbdomenSpleen:
splenomegaly

Laboratory Abnormalities:
hypophosphatemia
aminoaciduria
hypercalciuria
hypercalcemia
hyperphosphaturia
more
Hematology:
anemia

Neurologic Central Nervous System:
hypotonia

Skeletal:
multiple fractures
irregular metaphyses
demineralization

Abdomen Gastrointestinal:
constipation
polydipsia
poor feeding

Abdomen Liver:
hepatomegaly

Respiratory:
dyspnea
tachypnea

Chest External Features:
narrow chest

Genitourinary Kidneys:
polyuria
renal calcinosis

Endocrine Features:
neonatal primary hyperparathyroidism


Clinical features from OMIM:

239200

Human phenotypes related to Hyperparathyroidism, Neonatal Severe:

59 32 (show all 27)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 muscular hypotonia 59 32 hallmark (90%) Very frequent (99-80%) HP:0001252
2 splenomegaly 59 32 hallmark (90%) Very frequent (99-80%) HP:0001744
3 hepatomegaly 59 32 hallmark (90%) Very frequent (99-80%) HP:0002240
4 short stature 59 32 hallmark (90%) Very frequent (99-80%) HP:0004322
5 aminoaciduria 59 32 hallmark (90%) Very frequent (99-80%) HP:0003355
6 abnormality of the metaphysis 59 32 hallmark (90%) Very frequent (99-80%) HP:0000944
7 narrow chest 59 32 hallmark (90%) Very frequent (99-80%) HP:0000774
8 recurrent fractures 59 32 hallmark (90%) Very frequent (99-80%) HP:0002757
9 abnormality of calcium-phosphate metabolism 59 32 hallmark (90%) Very frequent (99-80%) HP:0100530
10 abnormality of the thyroid gland 59 32 hallmark (90%) Very frequent (99-80%) HP:0000820
11 failure to thrive 32 HP:0001508
12 constipation 32 HP:0002019
13 feeding difficulties in infancy 32 HP:0008872
14 polydipsia 32 HP:0001959
15 hypophosphatemia 32 HP:0002148
16 dyspnea 32 HP:0002094
17 anemia 32 HP:0001903
18 hypercalciuria 32 HP:0002150
19 hypercalcemia 32 HP:0003072
20 elevated circulating parathyroid hormone level 32 HP:0003165
21 tachypnea 32 HP:0002789
22 generalized hypotonia 32 HP:0001290
23 metaphyseal irregularity 32 HP:0003025
24 hyperphosphaturia 32 HP:0003109
25 primary hyperparathyroidism 32 HP:0008200
26 calcinosis 32 HP:0003761
27 polyuria 32 HP:0000103

UMLS symptoms related to Hyperparathyroidism, Neonatal Severe:


constipation, dyspnea, polyuria, polydipsia

MGI Mouse Phenotypes related to Hyperparathyroidism, Neonatal Severe:

46
# Description MGI Source Accession Score Top Affiliating Genes
1 cellular MP:0005384 9.46 CASR CXADR NR1I3 PRKAR1A
2 digestive/alimentary MP:0005381 9.13 CASR CXADR PRKAR1A
3 muscle MP:0005369 8.8 CASR CXADR PRKAR1A

Drugs & Therapeutics for Hyperparathyroidism, Neonatal Severe

Search Clinical Trials , NIH Clinical Center for Hyperparathyroidism, Neonatal Severe

Genetic Tests for Hyperparathyroidism, Neonatal Severe

Genetic tests related to Hyperparathyroidism, Neonatal Severe:

# Genetic test Affiliating Genes
1 Neonatal Severe Hyperparathyroidism 29 CASR

Anatomical Context for Hyperparathyroidism, Neonatal Severe

MalaCards organs/tissues related to Hyperparathyroidism, Neonatal Severe:

41
Bone, Thyroid

Publications for Hyperparathyroidism, Neonatal Severe

Articles related to Hyperparathyroidism, Neonatal Severe:

(show all 20)
# Title Authors Year
1
Neonatal severe hyperparathyroidism caused by homozygous mutation in CASR: A rare cause of life-threatening hypercalcemia. ( 26855056 )
2016
2
Cinacalcet monotherapy in neonatal severe hyperparathyroidism: a case study and review. ( 24203066 )
2014
3
A novel CASR mutation associated with neonatal severe hyperparathyroidism transmitted as an autosomal recessive disorder. ( 24854525 )
2014
4
Molecular and clinical analysis of a neonatal severe hyperparathyroidism case caused by a stop mutation in the calcium-sensing receptor extracellular domain representing in effect a human 'knockout'. ( 23612447 )
2013
5
New mutation in the CASR gene in a family with familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT). ( 21468522 )
2011
6
Neonatal severe hyperparathyroidism associated with a novel de novo heterozygous R551K inactivating mutation and a heterozygous A986S polymorphism of the calcium-sensing receptor gene. ( 17555508 )
2007
7
A novel homozygous deletion in the calcium-sensing receptor ligand-binding domain associated with neonatal severe hyperparathyroidism. ( 16509534 )
2006
8
Neonatal severe hyperparathyroidism: genotype/phenotype correlation and the use of pamidronate as rescue therapy. ( 15241688 )
2004
9
Functional deletion of the calcium-sensing receptor in a case of neonatal severe hyperparathyroidism. ( 15292296 )
2004
10
CASRdb: calcium-sensing receptor locus-specific database for mutations causing familial (benign) hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. ( 15241791 )
2004
11
[Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism caused by inactivating mutations of calcium-sensing receptor]. ( 11857921 )
2002
12
An acceptor splice site mutation in the calcium-sensing receptor (CASR) gene in familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. ( 11668634 )
2001
13
Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism associated with mutations in the human Ca2+-sensing receptor gene in three Danish families. ( 10885494 )
2000
14
Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. ( 11013439 )
2000
15
Neonatal severe hyperparathyroidism, secondary hyperparathyroidism, and familial hypocalciuric hypercalcemia: multiple different phenotypes associated with an inactivating Alu insertion mutation of the calcium-sensing receptor gene. ( 9217223 )
1997
16
Two novel missense mutations in calcium-sensing receptor gene associated with neonatal severe hyperparathyroidism. ( 9253359 )
1997
17
Markedly reduced activity of mutant calcium-sensing receptor with an inserted Alu element from a kindred with familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. ( 9109436 )
1997
18
A mouse model of human familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. ( 7493018 )
1995
19
Insertion of an Alu sequence in the Ca(2+)-sensing receptor gene in familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. ( 7717399 )
1995
20
Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. ( 7916660 )
1993

Variations for Hyperparathyroidism, Neonatal Severe

UniProtKB/Swiss-Prot genetic disease variations for Hyperparathyroidism, Neonatal Severe:

75
# Symbol AA change Variation ID SNP ID
1 CASR p.Arg227Leu VAR_003594 rs28936684
2 CASR p.Cys582Tyr VAR_003597 rs104893690
3 CASR p.Gly670Glu VAR_058073 rs104893700
4 CASR p.Thr100Ile VAR_065199
5 CASR p.Leu650Pro VAR_065202
6 CASR p.Val689Met VAR_065203
7 CASR p.Arg551Lys VAR_078163

ClinVar genetic disease variations for Hyperparathyroidism, Neonatal Severe:

6
(show top 50) (show all 107)
# Gene Variation Type Significance SNP ID Assembly Location
1 CASR NM_000388.3(CASR): c.889G> A (p.Glu297Lys) single nucleotide variant Pathogenic rs121909259 GRCh37 Chromosome 3, 121980771: 121980771
2 CASR NM_000388.3(CASR): c.889G> A (p.Glu297Lys) single nucleotide variant Pathogenic rs121909259 GRCh38 Chromosome 3, 122261924: 122261924
3 CASR NM_000388.3(CASR): c.554G> A (p.Arg185Gln) single nucleotide variant Pathogenic rs104893689 GRCh37 Chromosome 3, 121980436: 121980436
4 CASR NM_000388.3(CASR): c.554G> A (p.Arg185Gln) single nucleotide variant Pathogenic rs104893689 GRCh38 Chromosome 3, 122261589: 122261589
5 CASR CASR, ALU INS, CODON 877 insertion Pathogenic
6 CASR NM_000388.3(CASR): c.680G> T (p.Arg227Leu) single nucleotide variant Pathogenic rs28936684 GRCh37 Chromosome 3, 121980562: 121980562
7 CASR NM_000388.3(CASR): c.680G> T (p.Arg227Leu) single nucleotide variant Pathogenic rs28936684 GRCh38 Chromosome 3, 122261715: 122261715
8 CASR NM_000388.3(CASR): c.2241_2242delCCinsT (p.Ser749Glnfs) indel Pathogenic rs869320729 GRCh37 Chromosome 3, 122003042: 122003043
9 CASR NM_000388.3(CASR): c.2241_2242delCCinsT (p.Ser749Glnfs) indel Pathogenic rs869320729 GRCh38 Chromosome 3, 122284195: 122284196
10 CASR NM_000388.3(CASR): c.2009G> A (p.Gly670Glu) single nucleotide variant Pathogenic rs104893700 GRCh37 Chromosome 3, 122002810: 122002810
11 CASR NM_000388.3(CASR): c.2009G> A (p.Gly670Glu) single nucleotide variant Pathogenic rs104893700 GRCh38 Chromosome 3, 122283963: 122283963
12 CASR NM_000388.3(CASR): c.1942C> T (p.Arg648Ter) single nucleotide variant Pathogenic rs104893705 GRCh37 Chromosome 3, 122002743: 122002743
13 CASR NM_000388.3(CASR): c.1942C> T (p.Arg648Ter) single nucleotide variant Pathogenic rs104893705 GRCh38 Chromosome 3, 122283896: 122283896
14 CASR NM_000388.3(CASR): c.186-1G> T single nucleotide variant Pathogenic rs797044441 GRCh37 Chromosome 3, 121975927: 121975927
15 CASR NM_000388.3(CASR): c.186-1G> T single nucleotide variant Pathogenic rs797044441 GRCh38 Chromosome 3, 122257080: 122257080
16 CASR NM_000388.3(CASR): c.553C> T (p.Arg185Ter) single nucleotide variant Pathogenic rs104893707 GRCh37 Chromosome 3, 121980435: 121980435
17 CASR NM_000388.3(CASR): c.553C> T (p.Arg185Ter) single nucleotide variant Pathogenic rs104893707 GRCh38 Chromosome 3, 122261588: 122261588
18 CASR NM_000388.3(CASR): c.280G> T (p.Gly94Ter) single nucleotide variant Pathogenic rs104893709 GRCh37 Chromosome 3, 121976022: 121976022
19 CASR NM_000388.3(CASR): c.280G> T (p.Gly94Ter) single nucleotide variant Pathogenic rs104893709 GRCh38 Chromosome 3, 122257175: 122257175
20 CASR NM_000388.3(CASR): c.78C> G (p.Ala26=) single nucleotide variant Benign rs77852524 GRCh37 Chromosome 3, 121973114: 121973114
21 CASR NM_000388.3(CASR): c.78C> G (p.Ala26=) single nucleotide variant Benign rs77852524 GRCh38 Chromosome 3, 122254267: 122254267
22 CASR NM_000388.3(CASR): c.748G> A (p.Glu250Lys) single nucleotide variant Benign/Likely benign rs62269092 GRCh37 Chromosome 3, 121980630: 121980630
23 CASR NM_000388.3(CASR): c.748G> A (p.Glu250Lys) single nucleotide variant Benign/Likely benign rs62269092 GRCh38 Chromosome 3, 122261783: 122261783
24 CASR NM_000388.3(CASR): c.2610G> A (p.Glu870=) single nucleotide variant Benign rs143738711 GRCh37 Chromosome 3, 122003411: 122003411
25 CASR NM_000388.3(CASR): c.2610G> A (p.Glu870=) single nucleotide variant Benign rs143738711 GRCh38 Chromosome 3, 122284564: 122284564
26 CASR NM_001178065.1(CASR): c.2998A> G (p.Arg1000Gly) single nucleotide variant Benign rs1042636 GRCh37 Chromosome 3, 122003769: 122003769
27 CASR NM_001178065.1(CASR): c.2998A> G (p.Arg1000Gly) single nucleotide variant Benign rs1042636 GRCh38 Chromosome 3, 122284922: 122284922
28 CASR NM_000388.3(CASR): c.573G> A (p.Glu191=) single nucleotide variant Benign/Likely benign rs141631116 GRCh37 Chromosome 3, 121980455: 121980455
29 CASR NM_000388.3(CASR): c.573G> A (p.Glu191=) single nucleotide variant Benign/Likely benign rs141631116 GRCh38 Chromosome 3, 122261608: 122261608
30 CASR NM_000388.3(CASR): c.762T> C (p.His254=) single nucleotide variant Likely benign rs76438850 GRCh37 Chromosome 3, 121980644: 121980644
31 CASR NM_000388.3(CASR): c.762T> C (p.His254=) single nucleotide variant Likely benign rs76438850 GRCh38 Chromosome 3, 122261797: 122261797
32 CASR NM_000388.3(CASR): c.1285C> T (p.His429Tyr) single nucleotide variant Benign/Likely benign rs142818334 GRCh37 Chromosome 3, 121981167: 121981167
33 CASR NM_000388.3(CASR): c.1285C> T (p.His429Tyr) single nucleotide variant Benign/Likely benign rs142818334 GRCh38 Chromosome 3, 122262320: 122262320
34 CASR NM_000388.3(CASR): c.1631G> A (p.Arg544Gln) single nucleotide variant Conflicting interpretations of pathogenicity rs115230894 GRCh38 Chromosome 3, 122282135: 122282135
35 CASR NM_000388.3(CASR): c.1631G> A (p.Arg544Gln) single nucleotide variant Conflicting interpretations of pathogenicity rs115230894 GRCh37 Chromosome 3, 122000982: 122000982
36 CASR NM_000388.3(CASR): c.1752G> A (p.Lys584=) single nucleotide variant Likely benign rs138638329 GRCh37 Chromosome 3, 122002553: 122002553
37 CASR NM_000388.3(CASR): c.1752G> A (p.Lys584=) single nucleotide variant Likely benign rs138638329 GRCh38 Chromosome 3, 122283706: 122283706
38 CASR NM_000388.3(CASR): c.1775A> G (p.Asn592Ser) single nucleotide variant Benign/Likely benign rs117375173 GRCh37 Chromosome 3, 122002576: 122002576
39 CASR NM_000388.3(CASR): c.1775A> G (p.Asn592Ser) single nucleotide variant Benign/Likely benign rs117375173 GRCh38 Chromosome 3, 122283729: 122283729
40 CASR NM_000388.3(CASR): c.2064C> T (p.Phe688=) single nucleotide variant Conflicting interpretations of pathogenicity rs150869744 GRCh37 Chromosome 3, 122002865: 122002865
41 CASR NM_000388.3(CASR): c.2064C> T (p.Phe688=) single nucleotide variant Conflicting interpretations of pathogenicity rs150869744 GRCh38 Chromosome 3, 122284018: 122284018
42 CASR NM_001178065.1(CASR): c.1763-9A> G single nucleotide variant Benign/Likely benign rs190731787 GRCh37 Chromosome 3, 122002525: 122002525
43 CASR NM_001178065.1(CASR): c.1763-9A> G single nucleotide variant Benign/Likely benign rs190731787 GRCh38 Chromosome 3, 122283678: 122283678
44 CASR NM_000388.3(CASR): c.1665T> C (p.Ile555=) single nucleotide variant Likely benign rs201955278 GRCh37 Chromosome 3, 122001016: 122001016
45 CASR NM_000388.3(CASR): c.1665T> C (p.Ile555=) single nucleotide variant Likely benign rs201955278 GRCh38 Chromosome 3, 122282169: 122282169
46 CASR NM_000388.3(CASR): c.1923C> T (p.Pro641=) single nucleotide variant Uncertain significance rs368093724 GRCh37 Chromosome 3, 122002724: 122002724
47 CASR NM_000388.3(CASR): c.1923C> T (p.Pro641=) single nucleotide variant Uncertain significance rs368093724 GRCh38 Chromosome 3, 122283877: 122283877
48 CASR NM_000388.3(CASR): c.2824G> A (p.Glu942Lys) single nucleotide variant Benign/Likely benign rs76327999 GRCh37 Chromosome 3, 122003625: 122003625
49 CASR NM_000388.3(CASR): c.2824G> A (p.Glu942Lys) single nucleotide variant Benign/Likely benign rs76327999 GRCh38 Chromosome 3, 122284778: 122284778
50 CASR NM_000388.3(CASR): c.2915C> T (p.Thr972Met) single nucleotide variant Conflicting interpretations of pathogenicity rs200620134 GRCh37 Chromosome 3, 122003716: 122003716

Expression for Hyperparathyroidism, Neonatal Severe

Search GEO for disease gene expression data for Hyperparathyroidism, Neonatal Severe.

Pathways for Hyperparathyroidism, Neonatal Severe

Pathways related to Hyperparathyroidism, Neonatal Severe according to GeneCards Suite gene sharing:

# Super pathways Score Top Affiliating Genes
1 10.73 CASR PRKAR1A

GO Terms for Hyperparathyroidism, Neonatal Severe

Cellular components related to Hyperparathyroidism, Neonatal Severe according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 basolateral plasma membrane GO:0016323 8.62 CASR CXADR

Biological processes related to Hyperparathyroidism, Neonatal Severe according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 heart development GO:0007507 8.62 CXADR PRKAR1A

Molecular functions related to Hyperparathyroidism, Neonatal Severe according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 integrin binding GO:0005178 8.62 CASR CXADR

Sources for Hyperparathyroidism, Neonatal Severe

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 ExPASy
19 FMA
28 GO
29 GTR
30 HGMD
31 HMDB
32 HPO
33 ICD10
34 ICD10 via Orphanet
35 ICD9CM
36 IUPHAR
37 KEGG
38 LifeMap
40 LOVD
42 MedGen
44 MeSH
45 MESH via Orphanet
46 MGI
49 NCI
50 NCIt
51 NDF-RT
54 NINDS
55 Novoseek
57 OMIM
58 OMIM via Orphanet
62 PubMed
64 QIAGEN
69 SNOMED-CT via HPO
70 SNOMED-CT via Orphanet
71 TGDB
72 Tocris
73 UMLS
74 UMLS via Orphanet
Content
Loading form....