HHF4
MCID: HYP271
MIFTS: 46

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 57 29 13 6 40 73
Hyperinsulinism Due to Glutamodehydrogenase Deficiency 12 53 59
Hhf4 57 12 75
Hyperinsulinemic Hypoglycemia Due to Short Chain 3-Hydroxylacyl-Coa Dehydrogenase Deficiency 12 59
Hyperinsulinism Due to Short Chain 3-Hydroxylacyl-Coa Dehydrogenase Deficiency 12 59
Familial Hyperinsulinemic Hypoglycemia 4 12 75
Hyperinsulinism Due to Schad Deficiency 12 59
Congenital Hyperinsulinism 75 73
Persistent Hyperinsulinemic Hypoglycemia of Infancy 75
Schad Deficiency 59
Phhi 75

Characteristics:

Orphanet epidemiological data:

59
hyperinsulinism due to short chain 3-hydroxylacyl-coa dehydrogenase deficiency
Inheritance: Autosomal recessive; Age of onset: Infancy,Neonatal; Age of death: early childhood;

OMIM:

57
Inheritance:
autosomal recessive

Miscellaneous:
genetic heterogeneity (see hhf1 )


HPO:

32
hyperinsulinemic hypoglycemia, familial, 4:
Inheritance heterogeneous autosomal recessive inheritance


Classifications:



Summaries for Hyperinsulinemic Hypoglycemia, Familial, 4

UniProtKB/Swiss-Prot : 75 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, 2. An important gene associated with Hyperinsulinemic Hypoglycemia, Familial, 4 is HADH (Hydroxyacyl-CoA Dehydrogenase). Affiliated tissues include brain, pancreas and kidney, and related phenotypes are failure to thrive 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 40)
# Related Disease Score Top Affiliating Genes
1 hyperinsulinemic hypoglycemia, familial, 1 12.6
2 hyperinsulinemic hypoglycemia, familial, 2 12.2
3 hyperinsulinemic hypoglycemia, familial, 5 12.1
4 3-hydroxyacyl-coa dehydrogenase deficiency 11.9
5 hyperinsulinemic hypoglycemia, familial, 3 11.5
6 hyperinsulinemic hypoglycemia, familial, 6 11.3
7 3-alpha hydroxyacyl-coa dehydrogenase deficiency 11.2
8 hyperinsulinism 11.1
9 hyperinsulinemic hypoglycemia 11.1
10 hypoglycemia 11.1
11 neuroblastoma 10.1
12 insulinoma 10.1
13 glucose intolerance 10.1
14 beckwith-wiedemann syndrome 10.1
15 hepatitis 10.1
16 hypertrophic cardiomyopathy 10.1
17 kabuki syndrome 1 10.0
18 acute insulin response 10.0
19 diabetes mellitus 10.0
20 poland syndrome 9.8
21 septooptic dysplasia 9.8
22 costello syndrome 9.8
23 enterocolitis 9.8
24 galactokinase deficiency 9.8
25 retinitis pigmentosa 9.8
26 insulin-like growth factor i 9.8
27 leber congenital amaurosis 4 9.8
28 maturity-onset diabetes of the young 9.8
29 ataxia, combined cerebellar and peripheral, with hearing loss and diabetes mellitus 9.8
30 drug-induced hepatitis 9.8
31 neonatal diabetes mellitus 9.8
32 cholestasis 9.8
33 turner syndrome 9.8
34 retinitis 9.8
35 hyperglycemia 9.8
36 hepatoblastoma 9.8
37 perinatal necrotizing enterocolitis 9.8
38 hypopituitarism 9.8
39 degos 'en cocarde' erythrokeratoderma 9.8
40 monogenic diabetes 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

Symptoms via clinical synopsis from OMIM:

57
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

Human phenotypes related to Hyperinsulinemic Hypoglycemia, Familial, 4:

59 32 (show all 39)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 failure to thrive 59 32 occasional (7.5%) Occasional (29-5%) HP:0001508
2 neonatal hypotonia 59 32 hallmark (90%) Very frequent (99-80%) HP:0001319
3 feeding difficulties in infancy 59 32 occasional (7.5%) Occasional (29-5%) HP:0008872
4 vomiting 59 32 hallmark (90%) Very frequent (99-80%) HP:0002013
5 hypertrophic cardiomyopathy 59 32 very rare (1%) Very rare (<4-1%) HP:0001639
6 peripheral neuropathy 59 32 occasional (7.5%) Occasional (29-5%) HP:0009830
7 intrauterine growth retardation 59 32 hallmark (90%) Very frequent (99-80%) HP:0001511
8 hepatic steatosis 59 32 hallmark (90%) Very frequent (99-80%) HP:0001397
9 prolonged qt interval 59 32 very rare (1%) Very rare (<4-1%) HP:0001657
10 dilated cardiomyopathy 59 32 very rare (1%) Very rare (<4-1%) HP:0001644
11 lactic acidosis 59 32 occasional (7.5%) Occasional (29-5%) HP:0003128
12 motor delay 59 32 occasional (7.5%) Occasional (29-5%) HP:0001270
13 hyperinsulinemic hypoglycemia 59 32 hallmark (90%) Very frequent (99-80%) HP:0000825
14 diarrhea 59 32 hallmark (90%) Very frequent (99-80%) HP:0002014
15 fasting hyperinsulinemia 59 32 hallmark (90%) Very frequent (99-80%) HP:0008283
16 acute hepatic failure 59 32 very rare (1%) Very rare (<4-1%) HP:0006554
17 hyperammonemia 59 32 occasional (7.5%) Occasional (29-5%) HP:0001987
18 lethargy 59 32 hallmark (90%) Very frequent (99-80%) HP:0001254
19 mildly elevated creatine phosphokinase 59 32 occasional (7.5%) Occasional (29-5%) HP:0008180
20 neonatal hypoglycemia 59 32 hallmark (90%) Very frequent (99-80%) HP:0001998
21 confusion 59 32 hallmark (90%) Very frequent (99-80%) HP:0001289
22 myoglobinuria 59 32 very rare (1%) Very rare (<4-1%) HP:0002913
23 prolonged prothrombin time 59 32 occasional (7.5%) Occasional (29-5%) HP:0008151
24 hypoglycemic seizures 59 32 hallmark (90%) Very frequent (99-80%) HP:0002173
25 abnormality of acetylcarnitine metabolism 59 32 hallmark (90%) Very frequent (99-80%) HP:0012071
26 pigmentary retinopathy 59 32 occasional (7.5%) Occasional (29-5%) HP:0000580
27 proportionate short stature 59 32 hallmark (90%) Very frequent (99-80%) HP:0003508
28 increased circulating free fatty acid level 59 32 hallmark (90%) Very frequent (99-80%) HP:0030781
29 hypoketotic hypoglycemia 59 32 hallmark (90%) Very frequent (99-80%) HP:0001985
30 dicarboxylic aciduria 59 32 hallmark (90%) Very frequent (99-80%) HP:0003215
31 decreased plasma carnitine 59 32 occasional (7.5%) Occasional (29-5%) HP:0003234
32 decreased activity of 3-hydroxyacyl-coa dehydrogenase 59 32 obligate (100%) Obligate (100%) HP:0100950
33 hypoglycemic encephalopathy 59 32 hallmark (90%) Very frequent (99-80%) HP:0006929
34 increased c-peptide level 59 32 hallmark (90%) Very frequent (99-80%) HP:0030796
35 hepatic necrosis 59 32 very rare (1%) Very rare (<4-1%) HP:0002605
36 intellectual disability 32 HP:0001249
37 elevated hepatic transaminases 59 Very frequent (99-80%)
38 hypoglycemic coma 32 HP:0001325
39 elevated hepatic transaminase 32 hallmark (90%) HP:0002910

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 29 HADH

Anatomical Context for Hyperinsulinemic Hypoglycemia, Familial, 4

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

41
Brain, Pancreas, Kidney, Testes, Spleen, Pituitary, Pancreatic Islet

Publications for Hyperinsulinemic Hypoglycemia, Familial, 4

Articles related to Hyperinsulinemic Hypoglycemia, Familial, 4:

(show top 50) (show all 307)
# Title Authors Year
1
Formal Neurocognitive Testing in 60 Patients with Congenital Hyperinsulinism. ( 29151084 )
2018
2
CORRIGENDUM FOR &amp;quot;Novel Hypoglycemia Phenotype in Congenital Hyperinsulinism Due to Dominant Mutations of Uncoupling Protein 2&amp;quot;. ( 29538671 )
2018
3
Nutrient sensing in pancreatic islets: lessons from congenital hyperinsulinism and monogenic diabetes. ( 29044608 )
2018
4
Congenital hyperinsulinism as the presenting feature of Kabuki syndrome: clinical and molecular characterization of 10 affected individuals. ( 29907798 )
2018
5
Population pharmacokinetics of exendin-(9-39) and clinical dose selection in patients with congenital hyperinsulinism. ( 29077992 )
2018
6
Mechanistic Origins of Enzyme Activation in Human Glucokinase Variants Associated with Congenital Hyperinsulinism. ( 29425029 )
2018
7
Congenital Hyperinsulinism and Hypopituitarism Attributable to a Novel Mutation in FOXA2. ( 29329447 )
2018
8
Genetic characteristics of patients with congenital hyperinsulinism. ( 29750770 )
2018
9
Ketotic Hypoglycemia in Children with Previous Transient Congenital Hyperinsulinism. ( 29503277 )
2018
10
Whole-exome sequencing for mutation detection in pediatric disorders of insulin secretion: Maturity onset diabetes of the young and congenital hyperinsulinism. ( 29417725 )
2018
11
Focal Congenital Hyperinsulinism as a Cause for Sudden Infant Death. ( 29558846 )
2018
12
Continuous Flash Glucose Monitoring in children with Congenital Hyperinsulinism; first report on accuracy and patient experience. ( 29599801 )
2018
13
Congenital Hyperinsulinism in Infants with Turner Syndrome: Possible Association with Monosomy X and KDM6A Haploinsufficiency. ( 29902804 )
2018
14
18F-DOPA PET/CT and 68Ga-DOTANOC PET/CT scans as diagnostic tools in focal congenital hyperinsulinism: a blinded evaluation. ( 29116340 )
2018
15
Sirolimus therapy for congenital hyperinsulinism in an infant with a novel homozygous KCNJ11 mutation. ( 29176012 )
2018
16
Congenital hyperinsulinism and evolution to sulfonylurea-responsive diabetes later in life due to a novel homozygous p.L171F <i> <i>ABCC8</i> </i> mutation. ( 29739729 )
2018
17
Challenging diagnosis of congenital hyperinsulinism in two infants of diabetic mothers with rare pathogenic KCNJ11 and HNF4A gene variants. ( 30026763 )
2018
18
The burden of congenital hyperinsulinism in the United Kingdom: a cost of illness study. ( 30029695 )
2018
19
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
20
Continuous Intragastric Dextrose: A Therapeutic Option for Refractory Hypoglycemia in Congenital Hyperinsulinism. ( 30086540 )
2018
21
Correction: "Congenital hyperinsulinism as the presenting feature of Kabuki syndrome: clinical and molecular characterization of 10 affected individuals". ( 30097611 )
2018
22
Intraoperative Ultrasound: A Tool to Support Tissue-Sparing Curative Pancreatic Resection in Focal Congenital Hyperinsulinism. ( 30186238 )
2018
23
Therapies and outcomes of congenital hyperinsulinism-induced hypoglycaemia. ( 30246418 )
2018
24
The effect of hypoglycaemia on neurocognitive outcome in children and adolescents with transient or persistent congenital hyperinsulinism. ( 30246438 )
2018
25
Prevalence of Adverse Events in Children With Congenital Hyperinsulinism Treated With Diazoxide. ( 30247666 )
2018
26
The Effect of Continuous Intravenous Glucagon on Glucose Requirements in Infants with Congenital Hyperinsulinism. ( 30311139 )
2018
27
Surgical treatment of congenital hyperinsulinism: Results from 500 pancreatectomies in neonates and children. ( 30343978 )
2018
28
Clinical Diversity in Focal Congenital Hyperinsulinism in Infancy Correlates With Histological Heterogeneity of Islet Cell Lesions. ( 30386300 )
2018
29
Congenital hyperinsulinism in two siblings with ABCC8 mutation: same genotype, different phenotypes. ( 30462810 )
2018
30
Could a combination of heterozygous ABCC8 and KCNJ11 mutations cause congenital hyperinsulinism? ( 29127764 )
2017
31
Both Low Blood Glucose and Insufficient Treatment Confer Risk of Neurodevelopmental Impairment in Congenital Hyperinsulinism: A Multinational Cohort Study. ( 28740482 )
2017
32
Congenital Hyperinsulinism. ( 29131920 )
2017
33
Congenital hyperinsulinism and glycogenosis-like phenotype due to a novel HNF4A mutation. ( 28242437 )
2017
34
Sirolimus in the treatment of three infants with diffuse congenital hyperinsulinism. ( 28787272 )
2017
35
Pancreatic uptake and radiation dosimetry of 6-[18F]fluoro-L-DOPA from PET imaging studies in infants with congenital hyperinsulinism. ( 29117181 )
2017
36
Glycolate oxidase deficiency in a patient with congenital hyperinsulinism and unexplained hyperoxaluria. ( 28752386 )
2017
37
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
38
Clinical practice guidelines for congenital hyperinsulinism. ( 28804205 )
2017
39
A Novel Intragenic SLC16A1 Mutation Associated With Congenital Hyperinsulinism. ( 28491926 )
2017
40
Atypical Forms of Congenital Hyperinsulinism in Infancy Are Associated With Mosaic Patterns of Immature Islet Cells. ( 28605545 )
2017
41
Images from<sup>18</sup>F-DOPA Scan in Congenital Hyperinsulinism: Not Always a Clue for Diagnosis. ( 29242734 )
2017
42
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
43
Congenital hyperinsulinism and Poland syndrome in association with 10p13-14 duplication. ( 28458900 )
2017
44
A Multicenter Experience with Long-Acting Somatostatin Analogues in Patients with Congenital Hyperinsulinism. ( 29241206 )
2017
45
Diagnosis of congenital hyperinsulinism: Biochemical profiles during hypoglycemia. ( 28597971 )
2017
46
Modeling Congenital Hyperinsulinism with ABCC8-Deficient Human Embryonic Stem Cells Generated by CRISPR/Cas9. ( 28600547 )
2017
47
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
48
Congenital Hyperinsulinism Caused by a De Novo Mutation in the ABCC8 Gene - A Case Report. ( 28439221 )
2017
49
Congenital Hyperinsulinism: Diagnosis and Treatment Update. ( 29280746 )
2017
50
Asymptomatic Congenital Hyperinsulinism due to a Glucokinase-Activating Mutation, Treated as Adrenal Insufficiency for Twelve Years. ( 28163940 )
2017

Variations for Hyperinsulinemic Hypoglycemia, Familial, 4

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

75
# Symbol AA change Variation ID SNP ID
1 HADH p.Pro258Leu VAR_024081 rs137853103

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

6
# 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

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

Sources for Hyperinsulinemic Hypoglycemia, Familial, 4

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