MCID: HYP271
MIFTS: 37

Hyperinsulinemic Hypoglycemia, Familial, 4

Categories: Genetic diseases, Metabolic diseases, Rare diseases, Endocrine diseases

Aliases & Classifications for Hyperinsulinemic Hypoglycemia, Familial, 4

MalaCards integrated aliases for Hyperinsulinemic Hypoglycemia, Familial, 4:

Name: Hyperinsulinemic Hypoglycemia, Familial, 4 53 28 13 69
Congenital Hyperinsulinism 71 69
Hhf4 53 71
Persistent Hyperinsulinemic Hypoglycemia of Infancy 71
Familial Hyperinsulinemic Hypoglycemia 4 71
Phhi 71

Characteristics:

OMIM:

53
Inheritance:
autosomal recessive

Miscellaneous:
genetic heterogeneity (see hhf1 )


HPO:

31
hyperinsulinemic hypoglycemia, familial, 4:
Inheritance autosomal recessive inheritance heterogeneous


Classifications:



External Ids:

OMIM 53 609975
MedGen 39 C1864948

Summaries for Hyperinsulinemic Hypoglycemia, Familial, 4

UniProtKB/Swiss-Prot : 71 Familial hyperinsulinemic hypoglycemia 4: Most common cause of persistent hypoglycemia in infancy. Unless early and aggressive intervention is undertaken, brain damage from recurrent episodes of hypoglycemia may occur. HHF4 should be easily recognizable by analysis of acylcarnitine species and that this disorder responds well to treatment with diazoxide. It provides the first 'experiment of nature' that links impaired fatty acid oxidation to hyperinsulinism and that provides support for the concept that a lipid signaling pathway is implicated in the control of insulin secretion.

MalaCards based summary : Hyperinsulinemic Hypoglycemia, Familial, 4, also known as congenital hyperinsulinism, is related to hyperinsulinism and hypoglycemia, and has symptoms including intellectual disability, hyperinsulinemic hypoglycemia and hypoglycemic seizures. An important gene associated with Hyperinsulinemic Hypoglycemia, Familial, 4 is HADH (Hydroxyacyl-CoA Dehydrogenase), and among its related pathways/superpathways is FOXA2 and FOXA3 transcription factor networks. Affiliated tissues include brain.

Description from OMIM: 609975

Related Diseases for Hyperinsulinemic Hypoglycemia, Familial, 4

Diseases in the Hyperinsulinemic Hypoglycemia family:

Hyperinsulinemic Hypoglycemia, Familial, 1 Hyperinsulinemic Hypoglycemia, Familial, 2
Hyperinsulinemic Hypoglycemia, Familial, 3 Hyperinsulinemic Hypoglycemia, Familial, 6
Hyperinsulinemic Hypoglycemia, Familial, 5 Hyperinsulinemic Hypoglycemia, Familial, 4
Hyperinsulinemic Hypoglycemia, Familial, 7

Diseases related to Hyperinsulinemic Hypoglycemia, Familial, 4 via text searches within MalaCards or GeneCards Suite gene sharing:

(show all 39)
# Related Disease Score Top Affiliating Genes
1 hyperinsulinism 30.6 ABCC8 HADH
2 hypoglycemia 29.3 ABCC8 HADH
3 hyperinsulinemic hypoglycemia 28.9 ABCC8 HADH
4 hyperinsulinemic hypoglycemia, familial, 5 11.9
5 hyperinsulinemic hypoglycemia, familial, 1 11.9
6 hyperinsulinemic hypoglycemia, familial, 3 11.6
7 hyperinsulinemic hypoglycemia, familial, 6 11.3
8 hyperinsulinemic hypoglycemia, familial, 2 11.2
9 pancreatitis 10.3
10 carbonic anhydrase va deficiency, hyperammonemia due to 10.1
11 hepatitis 10.0
12 beckwith-wiedemann syndrome 9.9
13 acute insulin response 9.9
14 hypertrophic cardiomyopathy 9.9
15 hemihyperplasia, isolated 9.8
16 diabetes mellitus 9.8
17 poland syndrome 9.7
18 septooptic dysplasia 9.7
19 costello syndrome 9.7
20 enterocolitis 9.7
21 galactokinase deficiency 9.7
22 retinitis pigmentosa 9.7
23 insulin-like growth factor i 9.7
24 leber congenital amaurosis 4 9.7
25 maturity-onset diabetes of the young 9.7
26 autoinflammation with infantile enterocolitis 9.7
27 ataxia, combined cerebellar and peripheral, with hearing loss and diabetes mellitus 9.7
28 metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration 9.7
29 drug-induced hepatitis 9.7
30 neonatal diabetes mellitus 9.7
31 allergic hypersensitivity disease 9.7
32 cholestasis 9.7
33 retinitis 9.7
34 hyperglycemia 9.7
35 hepatoblastoma 9.7
36 perinatal necrotizing enterocolitis 9.7
37 hypopituitarism 9.7
38 monogenic diabetes 9.7
39 streptococcal group a invasive disease 9.7

Graphical network of the top 20 diseases related to Hyperinsulinemic Hypoglycemia, Familial, 4:



Diseases related to Hyperinsulinemic Hypoglycemia, Familial, 4

Symptoms & Phenotypes for Hyperinsulinemic Hypoglycemia, Familial, 4

Symptoms via clinical synopsis from OMIM:

53
Neurologic Central Nervous System:
seizures, hypoglycemic
coma, hypoglycemic
mental retardation due to repeated episodes of hypoglycemia

Laboratory Abnormalities:
hypoglycemia
hyperinsulinemia
elevated blood spot hydroxybutyryl carnitine

Endocrine Features:
hyperinsulinemic hypoglycemia


Clinical features from OMIM:

609975

Human phenotypes related to Hyperinsulinemic Hypoglycemia, Familial, 4:

31
# Description HPO Frequency HPO Source Accession
1 intellectual disability 31 HP:0001249
2 hyperinsulinemic hypoglycemia 31 HP:0000825
3 hypoglycemic seizures 31 HP:0002173
4 hypoglycemic coma 31 HP:0001325

Drugs & Therapeutics for Hyperinsulinemic Hypoglycemia, Familial, 4

Search Clinical Trials , NIH Clinical Center for Hyperinsulinemic Hypoglycemia, Familial, 4

Genetic Tests for Hyperinsulinemic Hypoglycemia, Familial, 4

Genetic tests related to Hyperinsulinemic Hypoglycemia, Familial, 4:

# Genetic test Affiliating Genes
1 Hyperinsulinemic Hypoglycemia, Familial, 4 28 HADH

Anatomical Context for Hyperinsulinemic Hypoglycemia, Familial, 4

MalaCards organs/tissues related to Hyperinsulinemic Hypoglycemia, Familial, 4:

38
Brain

Publications for Hyperinsulinemic Hypoglycemia, Familial, 4

Articles related to Hyperinsulinemic Hypoglycemia, Familial, 4:

(show top 50) (show all 273)
# Title Authors Year
1
18F-DOPA PET/CT and 68Ga-DOTANOC PET/CT scans as diagnostic tools in focal congenital hyperinsulinism: a blinded evaluation. ( 29116340 )
2018
2
Formal Neurocognitive Testing in 60 Patients with Congenital Hyperinsulinism. ( 29151084 )
2018
3
Population pharmacokinetics of exendin-(9-39) and clinical dose selection in patients with congenital hyperinsulinism. ( 29077992 )
2018
4
Congenital Hyperinsulinism and Hypopituitarism Attributable to a Novel Mutation in FOXA2. ( 29329447 )
2018
5
Sirolimus therapy for congenital hyperinsulinism in an infant with a novel homozygous KCNJ11 mutation. ( 29176012 )
2018
6
Nutrient sensing in pancreatic islets: lessons from congenital hyperinsulinism and monogenic diabetes. ( 29044608 )
2018
7
Whole-exome sequencing for mutation detection in pediatric disorders of insulin secretion: Maturity onset diabetes of the young and congenital hyperinsulinism. ( 29417725 )
2018
8
Mechanistic Origins of Enzyme Activation in Human Glucokinase Variants Associated with Congenital Hyperinsulinism. ( 29425029 )
2018
9
Morphoproteomics and biomedical analytics coincide with clinical outcomes in supporting a constant but variable role for the mTOR pathway in the biology of congenital hyperinsulinism of infancy. ( 29246172 )
2017
10
Glycolate oxidase deficiency in a patient with congenital hyperinsulinism and unexplained hyperoxaluria. ( 28752386 )
2017
11
Clinical presentation and treatment response to diazoxide in two siblings with congenital hyperinsulinism as a result of a novel compound heterozygous ABCC8 missense mutation. ( 28328534 )
2017
12
Congenital Hyperinsulinism Caused by a De Novo Mutation in the ABCC8 Gene - A Case Report. ( 28439221 )
2017
13
Could a combination of heterozygous ABCC8 and KCNJ11 mutations cause congenital hyperinsulinism? ( 29127764 )
2017
14
A Novel Intragenic SLC16A1 Mutation Associated With Congenital Hyperinsulinism. ( 28491926 )
2017
15
Congenital hyperinsulinism: diagnostic and management challenges in a developing country - case report. ( 29301189 )
2017
16
Atypical Forms of Congenital Hyperinsulinism in Infancy Are Associated With Mosaic Patterns of Immature Islet Cells. ( 28605545 )
2017
17
Congenital hyperinsulinism and Poland syndrome in association with 10p13-14 duplication. ( 28458900 )
2017
18
Modeling Congenital Hyperinsulinism with ABCC8-Deficient Human Embryonic Stem Cells Generated by CRISPR/Cas9. ( 28600547 )
2017
19
A Multicenter Experience with Long-Acting Somatostatin Analogues in Patients with Congenital Hyperinsulinism. ( 29241206 )
2017
20
Clinical practice guidelines for congenital hyperinsulinism. ( 28804205 )
2017
21
Congenital Hyperinsulinism. ( 29131920 )
2017
22
Efficacy and safety of octreotide for the treatment of congenital hyperinsulinism: a prospective, open-label clinical trial and an observational study in Japan using a nationwide registry. ( 28701683 )
2017
23
Congenital Hyperinsulinism: Diagnosis and Treatment Update. ( 29280746 )
2017
24
Images from<sup>18</sup>F-DOPA Scan in Congenital Hyperinsulinism: Not Always a Clue for Diagnosis. ( 29242734 )
2017
25
Vineland adaptive behavior scales to identify neurodevelopmental problems in children with Congenital Hyperinsulinism (CHI). ( 28532504 )
2017
26
Pancreatic uptake and radiation dosimetry of 6-[18F]fluoro-L-DOPA from PET imaging studies in infants with congenital hyperinsulinism. ( 29117181 )
2017
27
Sirolimus in the treatment of three infants with diffuse congenital hyperinsulinism. ( 28787272 )
2017
28
Diagnosis of congenital hyperinsulinism: Biochemical profiles during hypoglycemia. ( 28597971 )
2017
29
Both Low Blood Glucose and Insufficient Treatment Confer Risk of Neurodevelopmental Impairment in Congenital Hyperinsulinism: A Multinational Cohort Study. ( 28740482 )
2017
30
Conservatively treated Congenital Hyperinsulinism (CHI) due to K-ATP channel gene mutations: reducing severity over time. ( 27908292 )
2016
31
Iatrogenic Necrolytic Migratory Erythema in an Infant with Congenital Hyperinsulinism. ( 26648573 )
2016
32
Diagnosis of ABCC8 congenital hyperinsulinism of infancy in a 20 year-old man evaluated for factitious hypoglycemia. ( 27754802 )
2016
33
Successful treatment of a newborn with congenital hyperinsulinism having a novel heterozygous mutation in the ABCC8 gene using subtotal pancreatectomy. ( 28757749 )
2016
34
Genetic characteristics and long-term follow-up of 11 patients with congenital hyperinsulinism followed in a single center. ( 27682711 )
2016
35
Novel Hypoglycemia Phenotype in Congenital Hyperinsulinism Due to Dominant Mutations of Uncoupling Protein 2 (UCP2). ( 27967291 )
2016
36
mTOR Inhibitors for the Treatment of Severe Congenital Hyperinsulinism: Perspectives on Limited Therapeutic Success. ( 27691052 )
2016
37
Surgery in Focal Congenital Hyperinsulinism (CHI) - The "Hyperinsulinism Germany International" Experience in 30 Children. ( 28508606 )
2016
38
Clinical and genetic characterization of congenital hyperinsulinism in Spain. ( 27188453 )
2016
39
Feeding Problems Are Persistent in Children with Severe Congenital Hyperinsulinism. ( 26903946 )
2016
40
Coexistence of Mosaic Uniparental Isodisomy and a KCNJ11 Mutation Presenting as Diffuse Congenital Hyperinsulinism and Hemihypertrophy. ( 27174046 )
2016
41
A novel mutation of ABCC8 gene in a patient with diazoxide-unresponsive congenital hyperinsulinism. ( 28018462 )
2016
42
A novel mutation in the glutamate dehydrogenase (GLUD1) of a patient with congenital hyperinsulinism-hyperammonemia (HI/HA). ( 26656609 )
2016
43
Coexistence of Mosaic Uniparental Isodisomy and a KCNJ11 Mutation Presenting as Diffuse Congenital Hyperinsulinism and Hemihypertrophy. ( 27173951 )
2016
44
Enhanced Islet Cell Nucleomegaly Defines Diffuse Congenital Hyperinsulinism in Infancy but Not Other Forms of the Disease. ( 27334808 )
2016
45
Perspective on the Genetics and Diagnosis of Congenital Hyperinsulinism Disorders. ( 26908106 )
2016
46
A NOVEL HOMOZYGOUS MUTATION IN THE KCNJ11 GENE p.F315I OF A NEONATE WITH CONGENITAL HYPERINSULINISM AND SUCCESFUL MANAGEMENT BY SIROLIMUS. ( 27181099 )
2016
47
Fluoxetine induced Hypoglycaemia in a patient with persistent form of Congenital Hyperinsulinism (CHI) on Lanreotide Therapy. ( 27087264 )
2016
48
Long-term medical treatment in congenital hyperinsulinism: a descriptive analysis in a large cohort of patients from different clinical centers. ( 26608306 )
2015
49
Fatal congenital hypertrophic cardiomyopathy and a pancreatic nodule morphologically identical to focal lesion of congenital hyperinsulinism in an infant with Costello syndrome: Case report and review of the literature. ( 25668678 )
2015
50
High incidence of heterozygous ABCC8 and HNF1A mutations in Czech patients with congenital hyperinsulinism. ( 26431509 )
2015

Variations for Hyperinsulinemic Hypoglycemia, Familial, 4

UniProtKB/Swiss-Prot genetic disease variations for Hyperinsulinemic Hypoglycemia, Familial, 4:

71
# Symbol AA change Variation ID SNP ID
1 HADH p.Pro258Leu VAR_024081 rs137853103

ClinVar genetic disease variations for Hyperinsulinemic Hypoglycemia, Familial, 4:

6 (show all 44)
# Gene Variation Type Significance SNP ID Assembly Location
1 HADH NM_005327.4(HADH): c.773C> T (p.Pro258Leu) single nucleotide variant Pathogenic rs137853103 GRCh37 Chromosome 4, 108954395: 108954395
2 HADH HADH, 6-BP DEL deletion Pathogenic
3 ABCC8 NM_001287174.1(ABCC8): c.4310G> A (p.Arg1437Gln) single nucleotide variant Pathogenic rs387906407 GRCh37 Chromosome 11, 17417157: 17417157
4 ABCC8 NM_001287174.1(ABCC8): c.3992-9G> A single nucleotide variant Pathogenic rs151344623 GRCh37 Chromosome 11, 17418602: 17418602
5 ABCC8 ABCC8, IVS, G-A, -1 single nucleotide variant Pathogenic
6 ABCC8 ABCC8, BRANCH POINT, A-G, -20 single nucleotide variant Pathogenic
7 ABCC8 ABCC8, EX35, G-A single nucleotide variant Pathogenic
8 ABCC8 NM_001287174.1(ABCC8): c.4058G> C (p.Arg1353Pro) single nucleotide variant Pathogenic rs28936370 GRCh37 Chromosome 11, 17418527: 17418527
9 ABCC8 NM_001287174.1(ABCC8): c.4261C> T (p.Arg1421Cys) single nucleotide variant Pathogenic rs28938469 GRCh37 Chromosome 11, 17417206: 17417206
10 ABCC8 NM_000352.4(ABCC8): c.4477C> T (p.Arg1493Trp) single nucleotide variant Pathogenic/Likely pathogenic rs28936371 GRCh37 Chromosome 11, 17415881: 17415881
11 ABCC8 NM_001287174.1(ABCC8): c.4519G> A (p.Glu1507Lys) single nucleotide variant Pathogenic rs137852671 GRCh37 Chromosome 11, 17415842: 17415842
12 ABCC8 NM_000352.4(ABCC8): c.560T> A (p.Val187Asp) single nucleotide variant Pathogenic rs137852672 GRCh37 Chromosome 11, 17485004: 17485004
13 ABCC8 NM_000352.4(ABCC8): c.4157_4159delCCT (p.Ser1386del) deletion Pathogenic rs387906408 GRCh37 Chromosome 11, 17417438: 17417440
14 ABCC8 ABCC8, -64C-G single nucleotide variant Pathogenic
15 ABCC8 NM_001287174.1(ABCC8): c.2147G> T (p.Gly716Val) single nucleotide variant Pathogenic rs72559723 GRCh37 Chromosome 11, 17448671: 17448671
16 ABCC8 NM_000352.4(ABCC8): c.4198G> A (p.Gly1400Arg) single nucleotide variant Pathogenic/Likely pathogenic rs137852676 GRCh37 Chromosome 11, 17417399: 17417399
17 ABCC8 NM_000352.4(ABCC8): c.4306C> T (p.Arg1436Ter) single nucleotide variant Pathogenic/Likely pathogenic rs193922402 GRCh37 Chromosome 11, 17417158: 17417158
18 HADH HADH, EX1DEL deletion Pathogenic
19 ABCC8 ABCC8, EX13DEL deletion Pathogenic
20 ABCC8 ABCC8, 1-BP DUP, 512T duplication Pathogenic
21 ABCC8 ABCC8, IVS8, A-G, -1013 single nucleotide variant Pathogenic
22 HADH NM_005327.4(HADH): c.706C> T (p.Arg236Ter) single nucleotide variant Pathogenic rs375717077 GRCh37 Chromosome 4, 108948913: 108948913
23 HADH NM_005327.4(HADH): c.636+471G> T single nucleotide variant Pathogenic rs786200932 GRCh38 Chromosome 4, 108024034: 108024034
24 ABCC8 NM_000352.4(ABCC8): c.3509delT (p.Leu1170Argfs) deletion Pathogenic rs587783169 GRCh37 Chromosome 11, 17426107: 17426107
25 ABCC8 NM_000352.4(ABCC8): c.2857C> T (p.Gln953Ter) single nucleotide variant Pathogenic/Likely pathogenic rs541269678 GRCh38 Chromosome 11, 17407417: 17407417
26 ABCC8 NM_001287174.1(ABCC8): c.2800C> T (p.Arg934Ter) single nucleotide variant Pathogenic/Likely pathogenic rs570388861 GRCh38 Chromosome 11, 17408415: 17408415
27 ABCC8 NM_001287174.1(ABCC8): c.2509C> T (p.Arg837Ter) single nucleotide variant Pathogenic/Likely pathogenic rs72559722 GRCh38 Chromosome 11, 17412716: 17412716
28 ABCC8 NM_001287174.1(ABCC8): c.4163_4165delTCT (p.Phe1388del) deletion Pathogenic rs151344624 GRCh37 Chromosome 11, 17417435: 17417437
29 ABCC8 NM_000352.4(ABCC8): c.4119+1G> A single nucleotide variant Pathogenic rs797045211 GRCh38 Chromosome 11, 17396915: 17396915
30 ABCC8 NM_000352.4(ABCC8): c.2117-1G> A single nucleotide variant Pathogenic rs797045207 GRCh37 Chromosome 11, 17448702: 17448702
31 ABCC8 NM_000352.4(ABCC8): c.563A> G (p.Asn188Ser) single nucleotide variant Pathogenic/Likely pathogenic rs797045213 GRCh38 Chromosome 11, 17463454: 17463454
32 ABCC8 NM_000352.4(ABCC8): c.331G> A (p.Gly111Arg) single nucleotide variant Pathogenic/Likely pathogenic rs761749884 GRCh37 Chromosome 11, 17491729: 17491729
33 ABCC8 NM_000352.4(ABCC8): c.3748C> T (p.Arg1250Ter) single nucleotide variant Pathogenic rs1057516281 GRCh37 Chromosome 11, 17419891: 17419891
34 ABCC8 NM_000352.4(ABCC8): c.1879delC (p.His627Metfs) deletion Pathogenic/Likely pathogenic rs1057516860 GRCh37 Chromosome 11, 17450156: 17450156
35 ABCC8 NM_000352.4(ABCC8): c.1630+1G> T single nucleotide variant Pathogenic rs773306994 GRCh38 Chromosome 11, 17442719: 17442719
36 ABCC8 NM_000352.4(ABCC8): c.584dupA (p.Tyr195Terfs) duplication Pathogenic rs1057517199 GRCh38 Chromosome 11, 17461821: 17461821
37 ABCC8 NM_000352.4(ABCC8): c.4450G> A (p.Gly1484Arg) single nucleotide variant Pathogenic GRCh37 Chromosome 11, 17415908: 17415908
38 ABCC8 NM_000352.4(ABCC8): c.4432G> A (p.Gly1478Arg) single nucleotide variant Pathogenic rs72559715 GRCh38 Chromosome 11, 17394379: 17394379
39 ABCC8 NM_000352.4(ABCC8): c.4376T> G (p.Leu1459Arg) single nucleotide variant Pathogenic rs971604271 GRCh37 Chromosome 11, 17416754: 17416754
40 ABCC8 NM_000352.4(ABCC8): c.2992C> T (p.Arg998Ter) single nucleotide variant Pathogenic rs769518471 GRCh37 Chromosome 11, 17428605: 17428605
41 ABCC8 NM_000352.4(ABCC8): c.2295_2307delGAGAGGCCCCGTGinsAA (p.Arg766Serfs) indel Pathogenic GRCh38 Chromosome 11, 17414595: 17414607
42 ABCC8 NM_000352.4(ABCC8): c.1792C> T (p.Arg598Ter) single nucleotide variant Pathogenic rs139328569 GRCh37 Chromosome 11, 17452386: 17452386
43 ABCC8 NM_000352.4(ABCC8): c.1752delT (p.His584Glnfs) deletion Pathogenic GRCh37 Chromosome 11, 17452426: 17452426
44 ABCC8 NM_000352.4(ABCC8): c.1254_1284dup (p.Met429Terfs) duplication Pathogenic rs768951263 GRCh38 Chromosome 11, 17448564: 17448594

Expression for Hyperinsulinemic Hypoglycemia, Familial, 4

Search GEO for disease gene expression data for Hyperinsulinemic Hypoglycemia, Familial, 4.

Pathways for Hyperinsulinemic Hypoglycemia, Familial, 4

Pathways related to Hyperinsulinemic Hypoglycemia, Familial, 4 according to GeneCards Suite gene sharing:

# Super pathways Score Top Affiliating Genes
1 10.27 ABCC8 HADH

GO Terms for Hyperinsulinemic Hypoglycemia, Familial, 4

Biological processes related to Hyperinsulinemic Hypoglycemia, Familial, 4 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 response to drug GO:0042493 9.16 ABCC8 HADH
2 response to insulin GO:0032868 8.96 ABCC8 HADH
3 negative regulation of insulin secretion GO:0046676 8.62 ABCC8 HADH

Sources for Hyperinsulinemic Hypoglycemia, Familial, 4

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