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Persistent hyperinsulinemic hypoglycemia of infancy(HHF1)

MedGen UID:
226230
Concept ID:
C1257959
Disease or Syndrome
Synonyms: ABCC8-Related Hyperinsulinism; dominant CH; HHF1; HYPERINSULINEMIC HYPOGLYCEMIA DUE TO FOCAL ADENOMATOUS HYPERPLASIA; HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 1; HYPERINSULINISM, CONGENITAL; HYPERINSULINISM, FAMILIAL, WITH PANCREATIC NESIDIOBLASTOSIS; HYPOGLYCEMIA, HYPERINSULINEMIC, OF INFANCY; NESIDIOBLASTOSIS OF PANCREAS; Persistent Hyperinsulinemia Hypoglycemia of Infancy
Modes of inheritance:
Heterogeneous
MedGen UID:
5539
Concept ID:
C0019409
Qualitative Concept
Made up of elements or ingredients that are not alike.
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Autosomal recessive inheritance refers to genetic conditions that occur only when mutations are present in both copies of a given gene (i.e., the person is homozygous for a mutation, or carries two different mutations of the same gene, a state referred to as compound heterozygosity).
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
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: ABCC8
Cytogenetic location: 11p15.1
OMIM: 256450; 601820

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 mutations 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 mutations in GCK, may be much milder than FHI-KATP; however, some persons have severe, diazoxide-unresponsive hypoglycemia. FHI-HADH, caused by mutations in HADH, tends to be relatively mild, although severe cases have been reported. Individuals with FHI-HNF4A, caused by mutations in HNF4A, are typically born large for gestational age and have mild features that respond to diazoxide treatment. FHI-UCP2, caused by mutations 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 mutations in GLUD1. [from GeneReviews]
Full text of GeneReview (by section):
Summary  |  Diagnosis  |  Clinical Description  |  Differential Diagnosis  |  Management  |  Genetic Counseling  |  Resources  |  Molecular Genetics  |  References  |  Chapter Notes
Authors:
Benjamin Glaser   view full author information

Additional descriptions

From OMIM
Familial hyperinsulinism, also referred to as congenital hyperinsulinism, nesidioblastosis, or persistent hyperinsulinemic hypoglycemia of infancy (PPHI), is the most common cause of persistent hypoglycemia in infancy and is due to defective negative feedback regulation of insulin secretion by low glucose levels. Unless early and aggressive intervention is undertaken, brain damage from recurrent episodes of hypoglycemia may occur (Thornton et al., 1998). Genetic Heterogeneity of Hyperinsulinemic Hypoglycemia HHF2 (601820) is caused by mutation in the KCNJ11 gene (600937), on chromosome 11p15.1. HHF3 (602485) is caused by mutation in the glucokinase gene (GCK; 138079) on chromosome 7p15-p13. HHF4 (609975) is caused by mutation in the HADH gene (601609) on chromosome 4q22-q26. HHF5 (609968) is caused by mutation in the insulin receptor gene (INSR; 147670) on chromosome 19p13.2. HHF6 (606762) is caused by mutation in the GLUD1 gene (138130) on chromosome 10q23.3. HHF7 (610021) is caused by mutation in the SLC16A1 (600682) on chromosome 1p13.2-p12. There is evidence of further genetic heterogeneity of HHF.  http://www.omim.org/entry/256450
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

Pancreatic islet-cell hyperplasia
MedGen UID:
786397
Concept ID:
CN004001
Finding
Hyperplasia of the islets of Langerhans, i.e., of the regions of the pancreas that contain its endocrine cells.
Large for gestational age
MedGen UID:
56389
Concept ID:
C0158915
Finding
A fetus or infant who is larger than expected for the age or gender, or who has a birth weight greater than the 90th percentile.
Hypoglycemia
MedGen UID:
505016
Concept ID:
CN001757
Finding
A `decreased concentration` (PATO:0001163) of `glucose` (CHEBI:17234) in the `blood` (FMA:9670).

Recent clinical studies

Etiology

Al-Shanafey S, Alkhudhur H
J Pediatr Surg 2012 May;47(5):895-7. doi: 10.1016/j.jpedsurg.2012.03.002. PMID: 22595568
Al-Shanafey S
J Pediatr Surg 2009 May;44(5):957-61. doi: 10.1016/j.jpedsurg.2009.01.042. PMID: 19433178
Gussinyer M, Clemente M, Cebrián R, Yeste D, Albisu M, Carrascosa A
Diabetes Care 2008 Jun;31(6):1257-9. Epub 2008 Mar 13 doi: 10.2337/dc07-2059. [Epub ahead of print] PMID: 18339976
Bin-Abbas BS, Al-Mulhim AN, Sakati NA, Al-Ashwal AA
Saudi Med J 2003 Aug;24(8):890-4. PMID: 12939679
Sawathiparnich P, Likitmaskul S, Angsusingha K, Nimkarn S, Chaichanwatanakul K, Laohapansang M, Tuchinda C
J Med Assoc Thai 2002 Aug;85 Suppl 2:S506-12. PMID: 12403226

Diagnosis

Yadav D, Dhingra B, Kumar S, Kumar V, Dutta AK
J Pediatr Endocrinol Metab 2012;25(5-6):591-3. PMID: 22876564
Sempoux C, Capito C, Bellanné-Chantelot C, Verkarre V, de Lonlay P, Aigrain Y, Fekete C, Guiot Y, Rahier J
J Clin Endocrinol Metab 2011 Dec;96(12):3785-93. Epub 2011 Sep 28 doi: 10.1210/jc.2010-3032. [Epub ahead of print] PMID: 21956412
Dejkhamron P, Unachak K, Thanarattanakorn P, Charoenkwan P, Tantiprabha W, Chotinaruemol S, Chaiwun B
J Med Assoc Thai 2010 Jun;93(6):745-8. PMID: 20572382
Al-Shanafey S, Habib Z, AlNassar S
J Pediatr Surg 2009 Jan;44(1):134-8; discussion 138. doi: 10.1016/j.jpedsurg.2008.10.120. PMID: 19159730
Bin-Abbas BS, Al-Mulhim AN, Sakati NA, Al-Ashwal AA
Saudi Med J 2003 Aug;24(8):890-4. PMID: 12939679

Therapy

Abdel Khalek M, Kandil E
Eur J Pediatr Surg 2011 May;21(3):188-9. Epub 2011 Jan 31 doi: 10.1055/s-0030-1270455. [Epub ahead of print] PMID: 21283963
Ilamaran V, Venkatesh C, Manish K, Adhisivam B
Indian J Pediatr 2010 Jul;77(7):803-4. Epub 2010 Jun 29 doi: 10.1007/s12098-010-0100-7. [Epub ahead of print] PMID: 20589481
Dejkhamron P, Unachak K, Thanarattanakorn P, Charoenkwan P, Tantiprabha W, Chotinaruemol S, Chaiwun B
J Med Assoc Thai 2010 Jun;93(6):745-8. PMID: 20572382
Alyaarubi S, Ramsay M, Rodd C
Acta Paediatr 2004 Mar;93(3):422-3. PMID: 15124853
Bin-Abbas BS, Al-Mulhim AN, Sakati NA, Al-Ashwal AA
Saudi Med J 2003 Aug;24(8):890-4. PMID: 12939679

Prognosis

Al-Shanafey S, Alkhudhur H
J Pediatr Surg 2012 May;47(5):895-7. doi: 10.1016/j.jpedsurg.2012.03.002. PMID: 22595568
Al-Shanafey S
J Pediatr Surg 2009 May;44(5):957-61. doi: 10.1016/j.jpedsurg.2009.01.042. PMID: 19433178
Gussinyer M, Clemente M, Cebrián R, Yeste D, Albisu M, Carrascosa A
Diabetes Care 2008 Jun;31(6):1257-9. Epub 2008 Mar 13 doi: 10.2337/dc07-2059. [Epub ahead of print] PMID: 18339976
Bin-Abbas BS, Al-Mulhim AN, Sakati NA, Al-Ashwal AA
Saudi Med J 2003 Aug;24(8):890-4. PMID: 12939679
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

Gussinyer M, Clemente M, Cebrián R, Yeste D, Albisu M, Carrascosa A
Diabetes Care 2008 Jun;31(6):1257-9. Epub 2008 Mar 13 doi: 10.2337/dc07-2059. [Epub ahead of print] PMID: 18339976
Webb M, James RF
Endocr Res 2005;31(2):99-109. PMID: 16353670
Matsuo M, Trapp S, Tanizawa Y, Kioka N, Amachi T, Oka Y, Ashcroft FM, Ueda K
J Biol Chem 2000 Dec 29;275(52):41184-91. doi: 10.1074/jbc.M006503200. PMID: 10993895
Otonkoski T, Ammälä C, Huopio H, Cote GJ, Chapman J, Cosgrove K, Ashfield R, Huang E, Komulainen J, Ashcroft FM, Dunne MJ, Kere J, Thomas PM
Diabetes 1999 Feb;48(2):408-15. PMID: 10334322
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

Recent systematic reviews

Al-Shanafey S, Habib Z, AlNassar S
J Pediatr Surg 2009 Jan;44(1):134-8; discussion 138. doi: 10.1016/j.jpedsurg.2008.10.120. PMID: 19159730

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