HHF4
MCID: HYP271
MIFTS: 39

Hyperinsulinemic Hypoglycemia, Familial, 4 (HHF4)

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

Aliases & Classifications for Hyperinsulinemic Hypoglycemia, Familial, 4

MalaCards integrated aliases for Hyperinsulinemic Hypoglycemia, Familial, 4:

Name: Hyperinsulinemic Hypoglycemia, Familial, 4 58 30 13 6 41 74
Hyperinsulinism Due to Glutamodehydrogenase Deficiency 12 54 60
Hhf4 58 12 76
Hyperinsulinemic Hypoglycemia Due to Short Chain 3-Hydroxylacyl-Coa Dehydrogenase Deficiency 12 60
Hyperinsulinism Due to Short Chain 3-Hydroxylacyl-Coa Dehydrogenase Deficiency 12 60
Familial Hyperinsulinemic Hypoglycemia 4 12 76
Hyperinsulinism Due to Schad Deficiency 12 60
Congenital Hyperinsulinism 76 74
Persistent Hyperinsulinemic Hypoglycemia of Infancy 76
Schad Deficiency 60
Phhi 76

Characteristics:

Orphanet epidemiological data:

60
hyperinsulinism due to short chain 3-hydroxylacyl-coa dehydrogenase deficiency
Inheritance: Autosomal recessive; Age of onset: Infancy,Neonatal; Age of death: early childhood;

OMIM:

58
Inheritance:
autosomal recessive

Miscellaneous:
genetic heterogeneity (see hhf1 )


HPO:

33
hyperinsulinemic hypoglycemia, familial, 4:
Inheritance heterogeneous autosomal recessive inheritance


Classifications:



Summaries for Hyperinsulinemic Hypoglycemia, Familial, 4

UniProtKB/Swiss-Prot : 76 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 hyperinsulinism due to glutamodehydrogenase deficiency, is related to hyperinsulinemic hypoglycemia, familial, 1 and hyperinsulinemic hypoglycemia, familial, 5. An important gene associated with Hyperinsulinemic Hypoglycemia, Familial, 4 is HADH (Hydroxyacyl-CoA Dehydrogenase). Affiliated tissues include brain, testes and pancreas, and related phenotypes are decreased activity of 3-hydroxyacyl-coa dehydrogenase and neonatal hypotonia

Disease Ontology : 12 A hyperinsulinemic hypoglycemia characterized by autosomal recessive inheritance of hyperinsulinemic hypoglycemia with seizures that has material basis in mutation in the HADH gene on chromosome 4q25.

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 47)
# Related Disease Score Top Affiliating Genes
1 hyperinsulinemic hypoglycemia, familial, 1 12.6
2 hyperinsulinemic hypoglycemia, familial, 5 12.1
3 3-hydroxyacyl-coa dehydrogenase deficiency 12.0
4 hyperinsulinemic hypoglycemia, familial, 2 11.9
5 hyperinsulinemic hypoglycemia, familial, 3 11.6
6 hyperinsulinemic hypoglycemia, familial, 6 11.4
7 3-alpha hydroxyacyl-coa dehydrogenase deficiency 11.2
8 hyperinsulinemic hypoglycemia 11.1
9 hypoglycemia 11.1
10 beckwith-wiedemann syndrome 10.2
11 smith-magenis syndrome 10.1
12 ocular motor apraxia 10.1
13 insulinoma 10.1
14 glucose intolerance 10.1
15 patulous eustachian tube 10.1
16 hyperinsulinism 10.1
17 diabetes mellitus 10.1
18 hepatitis 10.1
19 hypertrophic cardiomyopathy 10.1
20 kabuki syndrome 1 10.0
21 hemihyperplasia, isolated 10.0
22 acute insulin response 10.0
23 maturity-onset diabetes of the young 10.0
24 hepatoblastoma 10.0
25 poland syndrome 9.8
26 septooptic dysplasia 9.8
27 costello syndrome 9.8
28 enterocolitis 9.8
29 galactokinase deficiency 9.8
30 retinitis pigmentosa 9.8
31 insulin-like growth factor i 9.8
32 leber congenital amaurosis 4 9.8
33 fanconi renotubular syndrome 4 with maturity-onset diabetes of the young 9.8
34 ataxia, combined cerebellar and peripheral, with hearing loss and diabetes mellitus 9.8
35 drug-induced hepatitis 9.8
36 glycogen storage disease 9.8
37 neonatal diabetes mellitus 9.8
38 cholestasis 9.8
39 turner syndrome 9.8
40 retinitis 9.8
41 hyperglycemia 9.8
42 perinatal necrotizing enterocolitis 9.8
43 hypopituitarism 9.8
44 degos 'en cocarde' erythrokeratoderma 9.8
45 heparin-induced thrombocytopenia 9.8
46 monogenic diabetes 9.8
47 mosaic genome-wide paternal uniparental disomy 9.8

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

Human phenotypes related to Hyperinsulinemic Hypoglycemia, Familial, 4:

60 33 (show all 40)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 decreased activity of 3-hydroxyacyl-coa dehydrogenase 60 33 obligate (100%) Obligate (100%) HP:0100950
2 neonatal hypotonia 60 33 hallmark (90%) Very frequent (99-80%) HP:0001319
3 vomiting 60 33 hallmark (90%) Very frequent (99-80%) HP:0002013
4 intrauterine growth retardation 60 33 hallmark (90%) Very frequent (99-80%) HP:0001511
5 hepatic steatosis 60 33 hallmark (90%) Very frequent (99-80%) HP:0001397
6 elevated hepatic transaminase 60 33 hallmark (90%) Very frequent (99-80%) HP:0002910
7 confusion 60 33 hallmark (90%) Very frequent (99-80%) HP:0001289
8 hyperinsulinemic hypoglycemia 60 33 hallmark (90%) Very frequent (99-80%) HP:0000825
9 diarrhea 60 33 hallmark (90%) Very frequent (99-80%) HP:0002014
10 fasting hyperinsulinemia 60 33 hallmark (90%) Very frequent (99-80%) HP:0008283
11 lethargy 60 33 hallmark (90%) Very frequent (99-80%) HP:0001254
12 neonatal hypoglycemia 60 33 hallmark (90%) Very frequent (99-80%) HP:0001998
13 hypoglycemic seizures 60 33 hallmark (90%) Very frequent (99-80%) HP:0002173
14 proportionate short stature 60 33 hallmark (90%) Very frequent (99-80%) HP:0003508
15 increased circulating free fatty acid level 60 33 hallmark (90%) Very frequent (99-80%) HP:0030781
16 hypoketotic hypoglycemia 60 33 hallmark (90%) Very frequent (99-80%) HP:0001985
17 dicarboxylic aciduria 60 33 hallmark (90%) Very frequent (99-80%) HP:0003215
18 hypoglycemic encephalopathy 60 33 hallmark (90%) Very frequent (99-80%) HP:0006929
19 increased c-peptide level 60 33 hallmark (90%) Very frequent (99-80%) HP:0030796
20 abnormal circulating acetylcarnitine concentration 33 hallmark (90%) HP:0012071
21 failure to thrive 60 33 occasional (7.5%) Occasional (29-5%) HP:0001508
22 feeding difficulties in infancy 60 33 occasional (7.5%) Occasional (29-5%) HP:0008872
23 peripheral neuropathy 60 33 occasional (7.5%) Occasional (29-5%) HP:0009830
24 lactic acidosis 60 33 occasional (7.5%) Occasional (29-5%) HP:0003128
25 motor delay 60 33 occasional (7.5%) Occasional (29-5%) HP:0001270
26 hyperammonemia 60 33 occasional (7.5%) Occasional (29-5%) HP:0001987
27 prolonged prothrombin time 60 33 occasional (7.5%) Occasional (29-5%) HP:0008151
28 pigmentary retinopathy 60 33 occasional (7.5%) Occasional (29-5%) HP:0000580
29 decreased plasma carnitine 60 33 occasional (7.5%) Occasional (29-5%) HP:0003234
30 mildly elevated creatine kinase 33 occasional (7.5%) HP:0008180
31 hypertrophic cardiomyopathy 60 33 very rare (1%) Very rare (<4-1%) HP:0001639
32 prolonged qt interval 60 33 very rare (1%) Very rare (<4-1%) HP:0001657
33 dilated cardiomyopathy 60 33 very rare (1%) Very rare (<4-1%) HP:0001644
34 acute hepatic failure 60 33 very rare (1%) Very rare (<4-1%) HP:0006554
35 myoglobinuria 60 33 very rare (1%) Very rare (<4-1%) HP:0002913
36 hepatic necrosis 60 33 very rare (1%) Very rare (<4-1%) HP:0002605
37 intellectual disability 33 HP:0001249
38 mildly elevated creatine phosphokinase 60 Occasional (29-5%)
39 abnormality of acetylcarnitine metabolism 60 Very frequent (99-80%)
40 hypoglycemic coma 33 HP:0001325

Symptoms via clinical synopsis from OMIM:

58
Laboratory Abnormalities:
hypoglycemia
hyperinsulinemia
elevated blood spot hydroxybutyryl carnitine

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

Endocrine Features:
hyperinsulinemic hypoglycemia

Clinical features from OMIM:

609975

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 30 HADH

Anatomical Context for Hyperinsulinemic Hypoglycemia, Familial, 4

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

42
Brain, Testes, Pancreas, Spleen, Pituitary, Pancreatic Islet

Publications for Hyperinsulinemic Hypoglycemia, Familial, 4

Articles related to Hyperinsulinemic Hypoglycemia, Familial, 4:

(show top 50) (show all 322)
# Title Authors Year
1
Hepatoblastoma and Wilms' tumour in an infant with Beckwith-Wiedemann syndrome and diazoxide resistant congenital hyperinsulinism. ( 30817313 )
2019
2
Focal Congenital Hyperinsulinism as a Cause for Sudden Infant Death. ( 29558846 )
2019
3
Congenital Hyperinsulinism and Evolution to Sulfonylurearesponsive Diabetes Later in Life due to a Novel Homozygous p.L171F ABCC8 Mutation ( 29739729 )
2019
4
Congenital hyperinsulinism as the presenting feature of Kabuki syndrome: clinical and molecular characterization of 10 affected individuals. ( 29907798 )
2019
5
Continuous Intragastric Dextrose: A Therapeutic Option for Refractory Hypoglycemia in Congenital Hyperinsulinism. ( 30086540 )
2019
6
Correction: "Congenital hyperinsulinism as the presenting feature of Kabuki syndrome: clinical and molecular characterization of 10 affected individuals". ( 30097611 )
2019
7
Therapies and outcomes of congenital hyperinsulinism-induced hypoglycaemia. ( 30246418 )
2019
8
The effect of hypoglycaemia on neurocognitive outcome in children and adolescents with transient or persistent congenital hyperinsulinism. ( 30246438 )
2019
9
The Effect of Continuous Intravenous Glucagon on Glucose Requirements in Infants with Congenital Hyperinsulinism. ( 30311139 )
2019
10
Surgical treatment of congenital hyperinsulinism: Results from 500 pancreatectomies in neonates and children. ( 30343978 )
2019
11
A rare case of congenital hyperinsulinism (CHI) due to dual genetic aetiology involving HNF4A and ABCC8. ( 30730840 )
2019
12
Tissue variations of mosaic genome-wide paternal uniparental disomy and phenotype of multi-syndromal congenital hyperinsulinism. ( 30797057 )
2019
13
News: FDA Reviews NDA for 18F-FDOPA in Congenital Hyperinsulinism. ( 30824673 )
2019
14
The Genetic and Molecular Mechanisms of Congenital Hyperinsulinism. ( 30873120 )
2019
15
A Newborn with Congenital Hyperinsulinism. ( 31002010 )
2019
16
First Report of Diabetes Phenotype due to a Loss-of-Function ABCC8 Mutation Previously Known to Cause Congenital Hyperinsulinism. ( 31110826 )
2019
17
Diagnosis of congenital hyperinsulinism: Biochemical profiles during hypoglycemia. ( 28597971 )
2018
18
Nutrient sensing in pancreatic islets: lessons from congenital hyperinsulinism and monogenic diabetes. ( 29044608 )
2018
19
Population pharmacokinetics of exendin-(9-39) and clinical dose selection in patients with congenital hyperinsulinism. ( 29077992 )
2018
20
18F-DOPA PET/CT and 68Ga-DOTANOC PET/CT scans as diagnostic tools in focal congenital hyperinsulinism: a blinded evaluation. ( 29116340 )
2018
21
Formal Neurocognitive Testing in 60 Patients with Congenital Hyperinsulinism. ( 29151084 )
2018
22
Sirolimus therapy for congenital hyperinsulinism in an infant with a novel homozygous KCNJ11 mutation. ( 29176012 )
2018
23
A Multicenter Experience with Long-Acting Somatostatin Analogues in Patients with Congenital Hyperinsulinism. ( 29241206 )
2018
24
Congenital Hyperinsulinism and Hypopituitarism Attributable to a Mutation in FOXA2. ( 29329447 )
2018
25
Whole-exome sequencing for mutation detection in pediatric disorders of insulin secretion: Maturity onset diabetes of the young and congenital hyperinsulinism. ( 29417725 )
2018
26
Mechanistic Origins of Enzyme Activation in Human Glucokinase Variants Associated with Congenital Hyperinsulinism. ( 29425029 )
2018
27
Ketotic Hypoglycemia in Children with Previous Transient Congenital Hyperinsulinism. ( 29503277 )
2018
28
CORRIGENDUM FOR "Novel Hypoglycemia Phenotype in Congenital Hyperinsulinism Due to Dominant Mutations of Uncoupling Protein 2". ( 29538671 )
2018
29
Continuous Flash Glucose Monitoring in children with Congenital Hyperinsulinism; first report on accuracy and patient experience. ( 29599801 )
2018
30
Genetic characteristics of patients with congenital hyperinsulinism. ( 29750770 )
2018
31
Congenital Hyperinsulinism in Infants with Turner Syndrome: Possible Association with Monosomy X and KDM6A Haploinsufficiency. ( 29902804 )
2018
32
Challenging diagnosis of congenital hyperinsulinism in two infants of diabetic mothers with rare pathogenic KCNJ11 and HNF4A gene variants. ( 30026763 )
2018
33
The burden of congenital hyperinsulinism in the United Kingdom: a cost of illness study. ( 30029695 )
2018
34
Congenital hyperinsulinism treated by surgical resection of the hyperplastic lesion which had been preoperatively diagnosed by 18F-DOPA PET examination in Japan: a nationwide survey. ( 30076450 )
2018
35
Intraoperative Ultrasound: A Tool to Support Tissue-Sparing Curative Pancreatic Resection in Focal Congenital Hyperinsulinism. ( 30186238 )
2018
36
Prevalence of Adverse Events in Children With Congenital Hyperinsulinism Treated With Diazoxide. ( 30247666 )
2018
37
Clinical Diversity in Focal Congenital Hyperinsulinism in Infancy Correlates With Histological Heterogeneity of Islet Cell Lesions. ( 30386300 )
2018
38
Congenital hyperinsulinism in two siblings with ABCC8 mutation: same genotype, different phenotypes. ( 30462810 )
2018
39
Characterization of diabetes following pancreatic surgery in patients with congenital hyperinsulinism. ( 30577875 )
2018
40
Novel Hypoglycemia Phenotype in Congenital Hyperinsulinism Due to Dominant Mutations of Uncoupling Protein 2. ( 27967291 )
2017
41
Asymptomatic Congenital Hyperinsulinism due to a Glucokinase-Activating Mutation, Treated as Adrenal Insufficiency for Twelve Years. ( 28163940 )
2017
42
Congenital hyperinsulinism and glycogenosis-like phenotype due to a novel HNF4A mutation. ( 28242437 )
2017
43
Congenital Hyperinsulinism in China: A Review of Chinese Literature Over the Past 15 Years. ( 28270372 )
2017
44
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
45
Extreme caution on the use of sirolimus for the congenital hyperinsulinism in infancy patient. ( 28410602 )
2017
46
Congenital Hyperinsulinism Caused by a De Novo Mutation in the ABCC8 Gene - A Case Report. ( 28439221 )
2017
47
Congenital hyperinsulinism and Poland syndrome in association with 10p13-14 duplication. ( 28458900 )
2017
48
A Novel Intragenic SLC16A1 Mutation Associated With Congenital Hyperinsulinism. ( 28491926 )
2017
49
Vineland adaptive behavior scales to identify neurodevelopmental problems in children with Congenital Hyperinsulinism (CHI). ( 28532504 )
2017
50
Modeling Congenital Hyperinsulinism with ABCC8-Deficient Human Embryonic Stem Cells Generated by CRISPR/Cas9. ( 28600547 )
2017

Variations for Hyperinsulinemic Hypoglycemia, Familial, 4

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

76
# 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 14)
# 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 NM_005327.4(HADH): c.773C> T (p.Pro258Leu) single nucleotide variant Pathogenic rs137853103 GRCh38 Chromosome 4, 108033239: 108033239
3 HADH HADH, 6-BP DEL deletion Pathogenic
4 HADH NM_005327.4(HADH): c.706C> T (p.Arg236Ter) single nucleotide variant Pathogenic rs375717077 GRCh37 Chromosome 4, 108948913: 108948913
5 HADH NM_005327.4(HADH): c.706C> T (p.Arg236Ter) single nucleotide variant Pathogenic rs375717077 GRCh38 Chromosome 4, 108027757: 108027757
6 HADH HADH, EX1DEL deletion Pathogenic
7 HADH NM_005327.4(HADH): c.636+471G> T single nucleotide variant Pathogenic rs786200932 GRCh38 Chromosome 4, 108024034: 108024034
8 HADH NM_005327.4(HADH): c.636+471G> T single nucleotide variant Pathogenic rs786200932 GRCh37 Chromosome 4, 108945190: 108945190
9 HADH NM_005327.4(HADH): c.456G> T (p.Gln152His) single nucleotide variant Conflicting interpretations of pathogenicity rs1051519 GRCh37 Chromosome 4, 108940732: 108940732
10 HADH NM_005327.4(HADH): c.456G> T (p.Gln152His) single nucleotide variant Conflicting interpretations of pathogenicity rs1051519 GRCh38 Chromosome 4, 108019576: 108019576
11 HADH NM_005327.4(HADH): c.662G> A (p.Arg221His) single nucleotide variant Uncertain significance rs76476980 GRCh37 Chromosome 4, 108948869: 108948869
12 HADH NM_005327.4(HADH): c.662G> A (p.Arg221His) single nucleotide variant Uncertain significance rs76476980 GRCh38 Chromosome 4, 108027713: 108027713
13 HADH NM_005327.4(HADH): c.643C> A (p.Pro215Thr) single nucleotide variant Uncertain significance rs140413151 GRCh37 Chromosome 4, 108948850: 108948850
14 HADH NM_005327.4(HADH): c.643C> A (p.Pro215Thr) single nucleotide variant Uncertain significance rs140413151 GRCh38 Chromosome 4, 108027694: 108027694

Expression for Hyperinsulinemic Hypoglycemia, Familial, 4

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

Pathways for Hyperinsulinemic Hypoglycemia, Familial, 4

GO Terms for Hyperinsulinemic Hypoglycemia, Familial, 4

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