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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:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: HPO
Autosomal dominant inheritance refers to genetic conditions that occur when a mutation is present in one copy of a given gene (i.e., the person is heterozygous).
 
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 pathgoenic 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.  http://ghr.nlm.nih.gov/condition/congenital-hyperinsulinism

Clinical features

Diabetes Mellitus
MedGen UID:
8350
Concept ID:
C0011849
Disease or Syndrome
Diabetes is a disease in which your blood glucose, or blood sugar, levels are too high. Glucose comes from the foods you eat. Insulin is a hormone that helps the glucose get into your cells to give them energy. With type 1 diabetes, your body does not make insulin. With type 2 diabetes, the more common type, your body does not make or use insulin well. Without enough insulin, the glucose stays in your blood. You can also have prediabetes. This means that your blood sugar is higher than normal but not high enough to be called diabetes. Having prediabetes puts you at a higher risk of getting type 2 diabetes. Over time, having too much glucose in your blood can cause serious problems. It can damage your eyes, kidneys, and nerves. Diabetes can also cause heart disease, stroke and even the need to remove a limb. Pregnant women can also get diabetes, called gestational diabetes. A blood test can show if you have diabetes. Exercise, weight control and sticking to your meal plan can help control your diabetes. You should also monitor your glucose level and take medicine if prescribed. . NIH: National Institute of Diabetes and Digestive and Kidney Diseases.
Hyperinsulinemic hypoglycemia
MedGen UID:
351247
Concept ID:
C1864903
Finding
An increased concentration of insulin combined with a decreased concentration of glucose in the blood.
Hypoglycemic coma
MedGen UID:
5710
Concept ID:
C0020617
Disease or Syndrome
Intellectual functioning disability
MedGen UID:
7544
Concept ID:
C0025362
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.
Hypoglycemic seizures
MedGen UID:
164079
Concept ID:
C0877056
Disease or Syndrome
Diabetes Mellitus
MedGen UID:
8350
Concept ID:
C0011849
Disease or Syndrome
Diabetes is a disease in which your blood glucose, or blood sugar, levels are too high. Glucose comes from the foods you eat. Insulin is a hormone that helps the glucose get into your cells to give them energy. With type 1 diabetes, your body does not make insulin. With type 2 diabetes, the more common type, your body does not make or use insulin well. Without enough insulin, the glucose stays in your blood. You can also have prediabetes. This means that your blood sugar is higher than normal but not high enough to be called diabetes. Having prediabetes puts you at a higher risk of getting type 2 diabetes. Over time, having too much glucose in your blood can cause serious problems. It can damage your eyes, kidneys, and nerves. Diabetes can also cause heart disease, stroke and even the need to remove a limb. Pregnant women can also get diabetes, called gestational diabetes. A blood test can show if you have diabetes. Exercise, weight control and sticking to your meal plan can help control your diabetes. You should also monitor your glucose level and take medicine if prescribed. . NIH: National Institute of Diabetes and Digestive and Kidney Diseases.
Hypoglycemic seizures
MedGen UID:
164079
Concept ID:
C0877056
Disease or Syndrome
Hyperinsulinemic hypoglycemia
MedGen UID:
351247
Concept ID:
C1864903
Finding
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

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
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. [Epub ahead of print] PMID: 20164212Free PMC Article
Anlauf M, Bauersfeld J, Raffel A, Koch CA, Henopp T, Alkatout I, Schmitt A, Weber A, Kruse ML, Braunstein S, Kaserer K, Brauckhoff M, Dralle H, Moch H, Heitz PU, Komminoth P, Knoefel WT, Perren A, Klöppel G
Am J Surg Pathol 2009 Mar;33(3):339-46. doi: 10.1097/PAS.0b013e3181874eca. PMID: 19011561
Desai MP, Khatri JV
Indian Pediatr 1998 Apr;35(4):317-28. PMID: 9770886
Dacou-Voutetakis C, Psychou F, Maniati-Christidis M
J Pediatr Endocrinol Metab 1998 Mar;11 Suppl 1:131-41. PMID: 9642651

Diagnosis

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
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
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. [Epub ahead of print] PMID: 20164212Free PMC Article
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

Therapy

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
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. [Epub ahead of print] PMID: 20164212Free PMC Article
Zaffanello M, Zamboni G, Maffeis C, Antoniazzi F, Tatò L
Minerva Pediatr 2002 Aug;54(4):325-33. PMID: 12131869
Desai MP, Khatri JV
Indian Pediatr 1998 Apr;35(4):317-28. PMID: 9770886
Dacou-Voutetakis C, Psychou F, Maniati-Christidis M
J Pediatr Endocrinol Metab 1998 Mar;11 Suppl 1:131-41. PMID: 9642651

Prognosis

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
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
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
Desai MP, Khatri JV
Indian Pediatr 1998 Apr;35(4):317-28. PMID: 9770886
Thomas PM, Wohllk N, Huang E, Kuhnle U, Rabl W, Gagel RF, Cote GJ
Am J Hum Genet 1996 Sep;59(3):510-8. PMID: 8751851Free PMC Article

Clinical prediction guides

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
Aguilar-Bryan L, Bryan J, Nakazaki M
Recent Prog Horm Res 2001;56:47-68. PMID: 11237225
Thomas PM, Wohllk N, Huang E, Kuhnle U, Rabl W, Gagel RF, Cote GJ
Am J Hum Genet 1996 Sep;59(3):510-8. PMID: 8751851Free PMC Article

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