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Hyperinsulinemic hypoglycemia familial 3(HHF3)

MedGen UID:
355435
Concept ID:
C1865290
Disease or Syndrome
Synonyms: GCK-Related Hyperinsulinism; HHF3; Hyperinsulinism due to glucokinase deficiency
Modes of inheritance:
Heterogeneous
MedGen UID:
67020
Concept ID:
C0242960
Organism Attribute
Source: HPO
The presence of apparently similar characters for which the genetic evidence indicates that different genes or different genetic mechanisms are involved in different pedigrees. In clinical settings genetic heterogeneity refers to the presence of a variety of genetic defects which cause the same disease, often due to mutations at different loci on the same gene, a finding common to many human diseases including ALZHEIMER DISEASE; CYSTIC FIBROSIS; LIPOPROTEIN LIPASE DEFICIENCY, FAMILIAL; and POLYCYSTIC KIDNEY DISEASES. (Rieger, et al., Glossary of Genetics: Classical and Molecular, 5th ed; Segen, Dictionary of Modern Medicine, 1992)
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
 
Gene (location): GCK (7p13)
OMIM®: 602485
Orphanet: ORPHA79299

Disease characteristics

Excerpted from the GeneReview: Familial Hyperinsulinism
Familial hyperinsulinism (referred to as FHI in this GeneReview) is characterized by hypoglycemia that ranges from severe neonatal-onset, difficult-to-manage disease to childhood-onset disease with mild symptoms and difficult-to-diagnose hypoglycemia. Neonatal-onset disease manifests within hours to two days after birth. Childhood-onset disease manifests during the first months or years of life. In the newborn period, presenting symptoms may be nonspecific, including seizures, hypotonia, poor feeding, and apnea. In severe cases, serum glucose concentrations are typically extremely low and thus easily recognized, whereas in milder cases, variable and mild hypoglycemia may make the diagnosis more difficult. Even within the same family, disease manifestations can range from mild to severe. Individuals with autosomal recessive familial hyperinsulinism, caused by pathogenic variants in either ABCC8 or KCNJ11 (FHI-KATP), tend to be large for gestational age and usually present with severe refractory hypoglycemia in the first 48 hours of life; affected infants usually respond only partially to diet or medical management (i.e., diazoxide therapy) and thus may require pancreatic resection. Individuals with autosomal dominant FHI-KATP tend to be appropriate for gestational age at birth, to present at approximately age one year (range: 2 days - 30 years), and to respond to diet and diazoxide therapy. Exceptions to both of these generalities have been reported. FHI-GCK, caused by pathogenic variants in GCK, may be much milder than FHI-KATP; however, some persons have severe, diazoxide-unresponsive hypoglycemia. FHI-HADH, caused by pathogenic variants in HADH, tends to be relatively mild, although severe cases have been reported. Individuals with FHI-HNF4A, caused by pathogenic variants in HNF4A, are typically born large for gestational age and have mild features that respond to diazoxide treatment. FHI-UCP2, caused by pathogenic variants in UCP2, is a rare cause of diazoxide-responsive FH1. Hyperammonemia/hyperinsulinism (HA/HI) is associated with mild-to-moderate hyperammonemia and with relatively mild, late-onset hypoglycemia; most but not all affected individuals have pathogenic variants in GLUD1. [from GeneReviews]
Authors:
Benjamin Glaser   view full author information

Additional description

From GHR
Congenital hyperinsulinism is a condition that causes individuals to have abnormally high levels of insulin, which is a hormone that helps control blood sugar levels. People with this condition have frequent episodes of low blood sugar (hypoglycemia). In infants and young children, these episodes are characterized by a lack of energy (lethargy), irritability, or difficulty feeding. Repeated episodes of low blood sugar increase the risk for serious complications such as breathing difficulties, seizures, intellectual disability, vision loss, brain damage, and coma.The severity of congenital hyperinsulinism varies widely among affected individuals, even among members of the same family. About 60 percent of infants with this condition experience a hypoglycemic episode within the first month of life. Other affected children develop hypoglycemia by early childhood. Unlike typical episodes of hypoglycemia, which occur most often after periods without food (fasting) or after exercising, episodes of hypoglycemia in people with congenital hyperinsulinism can also occur after eating.  https://ghr.nlm.nih.gov/condition/congenital-hyperinsulinism

Clinical features

Hypoglycemic coma
MedGen UID:
5710
Concept ID:
C0020617
Disease or Syndrome
Hypoglycemic seizures
MedGen UID:
164079
Concept ID:
C0877056
Disease or Syndrome
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Subnormal intellectual functioning which originates during the developmental period. Intellectual disability, previously referred to as mental retardation, has been defined as an IQ score below 70.
Diabetes mellitus
MedGen UID:
8350
Concept ID:
C0011849
Disease or Syndrome
A group of abnormalities characterized by hyperglycemia and glucose intolerance.
Hypoglycemic seizures
MedGen UID:
164079
Concept ID:
C0877056
Disease or Syndrome
Hyperinsulinemic hypoglycemia
MedGen UID:
351247
Concept ID:
C1864903
Disease or Syndrome
An increased concentration of insulin combined with a decreased concentration of glucose in the blood.
Diabetes mellitus
MedGen UID:
8350
Concept ID:
C0011849
Disease or Syndrome
A group of abnormalities characterized by hyperglycemia and glucose intolerance.
Hyperinsulinemic hypoglycemia
MedGen UID:
351247
Concept ID:
C1864903
Disease or Syndrome
An increased concentration of insulin combined with a decreased concentration of glucose in the blood.

Term Hierarchy

Follow this link to review classifications for Hyperinsulinemic hypoglycemia familial 3 in Orphanet.

Recent clinical studies

Etiology

Satapathy AK, Jain V, Ellard S, Flanagan SE
Indian Pediatr 2016 Oct 8;53(10):912-913. PMID: 27771675
Stanley CA
J Clin Endocrinol Metab 2016 Mar;101(3):815-26. Epub 2016 Feb 23 doi: 10.1210/jc.2015-3651. PMID: 26908106Free PMC Article
Sang Y, Xu Z, Liu M, Yan J, Wu Y, Zhu C, Ni G
Endocr J 2014;61(9):901-10. Epub 2014 Jul 8 PMID: 25008049
Kapoor RR, Flanagan SE, Arya VB, Shield JP, Ellard S, Hussain K
Eur J Endocrinol 2013 Apr;168(4):557-64. Epub 2013 Mar 15 doi: 10.1530/EJE-12-0673. PMID: 23345197Free PMC Article
Flanagan SE, Kapoor RR, Mali G, Cody D, Murphy N, Schwahn B, Siahanidou T, Banerjee I, Akcay T, Rubio-Cabezas O, Shield JP, Hussain K, Ellard S
Eur J Endocrinol 2010 May;162(5):987-92. Epub 2010 Feb 17 doi: 10.1530/EJE-09-0861. PMID: 20164212Free PMC Article

Diagnosis

Galcheva S, Iotova V, Ellard S, Flanagan SE, Halvadzhiyan I, Petrova C, Hussain K
J Pediatr Endocrinol Metab 2017 Apr 1;30(4):471-474. doi: 10.1515/jpem-2016-0345. PMID: 28328534
Satapathy AK, Jain V, Ellard S, Flanagan SE
Indian Pediatr 2016 Oct 8;53(10):912-913. PMID: 27771675
Stanley CA
J Clin Endocrinol Metab 2016 Mar;101(3):815-26. Epub 2016 Feb 23 doi: 10.1210/jc.2015-3651. PMID: 26908106Free PMC Article
Fang C, Ding X, Huang Y, Huang J, Zhao P, Hu J
J Pediatr Endocrinol Metab 2016 Mar;29(3):385-8. doi: 10.1515/jpem-2015-0276. PMID: 26656609
Flanagan SE, Kapoor RR, Mali G, Cody D, Murphy N, Schwahn B, Siahanidou T, Banerjee I, Akcay T, Rubio-Cabezas O, Shield JP, Hussain K, Ellard S
Eur J Endocrinol 2010 May;162(5):987-92. Epub 2010 Feb 17 doi: 10.1530/EJE-09-0861. PMID: 20164212Free PMC Article

Therapy

Galcheva S, Iotova V, Ellard S, Flanagan SE, Halvadzhiyan I, Petrova C, Hussain K
J Pediatr Endocrinol Metab 2017 Apr 1;30(4):471-474. doi: 10.1515/jpem-2016-0345. PMID: 28328534
Ağladıoğlu SY, Savaş Erdeve S, Cetinkaya S, Baş VN, Peltek Kendirci HN, Onder A, Aycan Z
J Clin Res Pediatr Endocrinol 2013 Sep 10;5(3):150-5. doi: 10.4274/Jcrpe.991. PMID: 24072082Free PMC Article
Kapoor RR, Flanagan SE, Arya VB, Shield JP, Ellard S, Hussain K
Eur J Endocrinol 2013 Apr;168(4):557-64. Epub 2013 Mar 15 doi: 10.1530/EJE-12-0673. PMID: 23345197Free PMC Article
Flanagan SE, Kapoor RR, Mali G, Cody D, Murphy N, Schwahn B, Siahanidou T, Banerjee I, Akcay T, Rubio-Cabezas O, Shield JP, Hussain K, Ellard S
Eur J Endocrinol 2010 May;162(5):987-92. Epub 2010 Feb 17 doi: 10.1530/EJE-09-0861. PMID: 20164212Free PMC Article
Zaffanello M, Zamboni G, Maffeis C, Antoniazzi F, Tatò L
Minerva Pediatr 2002 Aug;54(4):325-33. PMID: 12131869

Prognosis

Galcheva S, Iotova V, Ellard S, Flanagan SE, Halvadzhiyan I, Petrova C, Hussain K
J Pediatr Endocrinol Metab 2017 Apr 1;30(4):471-474. doi: 10.1515/jpem-2016-0345. PMID: 28328534
Stanley CA
J Clin Endocrinol Metab 2016 Mar;101(3):815-26. Epub 2016 Feb 23 doi: 10.1210/jc.2015-3651. PMID: 26908106Free PMC Article
Fang C, Ding X, Huang Y, Huang J, Zhao P, Hu J
J Pediatr Endocrinol Metab 2016 Mar;29(3):385-8. doi: 10.1515/jpem-2015-0276. PMID: 26656609
Tran C, Konstantopoulou V, Mecjia M, Perlman K, Mercimek-Mahmutoglu S, Kronick JB
J Pediatr Endocrinol Metab 2015 Jul;28(7-8):873-6. doi: 10.1515/jpem-2014-0441. PMID: 25781533
Molven A, Matre GE, Duran M, Wanders RJ, Rishaug U, Njølstad PR, Jellum E, Søvik O
Diabetes 2004 Jan;53(1):221-7. PMID: 14693719

Clinical prediction guides

Satapathy AK, Jain V, Ellard S, Flanagan SE
Indian Pediatr 2016 Oct 8;53(10):912-913. PMID: 27771675
Sang Y, Xu Z, Liu M, Yan J, Wu Y, Zhu C, Ni G
Endocr J 2014;61(9):901-10. Epub 2014 Jul 8 PMID: 25008049
Højlund K, Hansen T, Lajer M, Henriksen JE, Levin K, Lindholm J, Pedersen O, Beck-Nielsen H
Diabetes 2004 Jun;53(6):1592-8. PMID: 15161766
Molven A, Matre GE, Duran M, Wanders RJ, Rishaug U, Njølstad PR, Jellum E, Søvik O
Diabetes 2004 Jan;53(1):221-7. PMID: 14693719
Zaffanello M, Zamboni G, Maffeis C, Antoniazzi F, Tatò L
Minerva Pediatr 2002 Aug;54(4):325-33. PMID: 12131869

Recent systematic reviews

Stanley CA
J Clin Endocrinol Metab 2016 Mar;101(3):815-26. Epub 2016 Feb 23 doi: 10.1210/jc.2015-3651. PMID: 26908106Free PMC Article
Marx SJ
J Clin Endocrinol Metab 2014 Nov;99(11):4051-9. Epub 2014 Jul 8 doi: 10.1210/jc.2014-2113. PMID: 25004249Free PMC Article

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