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Hyperinsulinemic hypoglycemia, familial, 1(HHF1)

MedGen UID:
419505
Concept ID:
C2931832
Disease or Syndrome
Synonyms: ABCC8-Related Hyperinsulinism; HHF1; HYPERINSULINISM, FAMILIAL, WITH PANCREATIC NESIDIOBLASTOSIS; HYPOGLYCEMIA, HYPERINSULINEMIC, OF INFANCY; NESIDIOBLASTOSIS OF PANCREAS; Persistent Hyperinsulinemia Hypoglycemia of Infancy; Persistent hyperinsulinemic hypoglycemia of infancy
 
Gene (location): ABCC8 (11p15.1)
 
Monarch Initiative: MONDO:0009734
OMIM®: 256450

Definition

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. HHF3 (602485) is caused by mutation in the glucokinase gene (GCK; 138079) on chromosome 7p13. HHF4 (609975) is caused by mutation in the HADH gene (601609) on chromosome 4q25. HHF5 (609968) is caused by mutation in the insulin receptor gene (INSR; 147670) on chromosome 19p13. HHF6 (606762) is caused by mutation in the GLUD1 gene (138130) on chromosome 10q23. HHF7 (610021) is caused by mutation in the SLC16A1 (600682) on chromosome 1p13. There is evidence of further genetic heterogeneity of HHF. [from OMIM]

Additional description

From MedlinePlus Genetics
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.

Congenital hyperinsulinism is a condition that causes individuals to have abnormally high levels of insulin. Insulin is a hormone that helps control levels of blood glucose, also called blood sugar. People with this condition have frequent episodes of low blood glucose (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 glucose increase the risk for serious complications such as breathing difficulties, seizures, intellectual disability, vision loss, brain damage, and coma.  https://medlineplus.gov/genetics/condition/congenital-hyperinsulinism

Clinical features

From HPO
Large for gestational age
MedGen UID:
341215
Concept ID:
C1848395
Finding
The term large for gestational age applies to babies whose birth weight lies above the 90th percentile for that gestational age.
Pancreatic islet-cell hyperplasia
MedGen UID:
108598
Concept ID:
C0597167
Finding
Hyperplasia of the islets of Langerhans, i.e., of the regions of the pancreas that contain its endocrine cells.
Hypoglycemic coma
MedGen UID:
5710
Concept ID:
C0020617
Disease or Syndrome
Coma induced by low blood sugar.
Hypoglycemic seizures
MedGen UID:
164079
Concept ID:
C0877056
Disease or Syndrome
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
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.

Professional guidelines

PubMed

De Leon DD, Arnoux JB, Banerjee I, Bergada I, Bhatti T, Conwell LS, Fu J, Flanagan SE, Gillis D, Meissner T, Mohnike K, Pasquini TLS, Shah P, Stanley CA, Vella A, Yorifuji T, Thornton PS
Horm Res Paediatr 2024;97(3):279-298. Epub 2023 Jul 14 doi: 10.1159/000531766. PMID: 37454648Free PMC Article
Roeper M, Hoermann H, Kummer S, Meissner T
Front Endocrinol (Lausanne) 2023;14:1179102. Epub 2023 Jun 8 doi: 10.3389/fendo.2023.1179102. PMID: 37361517Free PMC Article
Demirbilek H, Hussain K
J Clin Res Pediatr Endocrinol 2017 Dec 30;9(Suppl 2):69-87. Epub 2017 Dec 27 doi: 10.4274/jcrpe.2017.S007. PMID: 29280746Free PMC Article

Recent clinical studies

Etiology

Roeper M, Hoermann H, Kummer S, Meissner T
Front Endocrinol (Lausanne) 2023;14:1179102. Epub 2023 Jun 8 doi: 10.3389/fendo.2023.1179102. PMID: 37361517Free PMC Article
Sims K
Neoreviews 2021 Apr;22(4):e230-e240. doi: 10.1542/neo.22-4-e230. PMID: 33795398
Gϋemes M, Rahman SA, Kapoor RR, Flanagan S, Houghton JAL, Misra S, Oliver N, Dattani MT, Shah P
Rev Endocr Metab Disord 2020 Dec;21(4):577-597. doi: 10.1007/s11154-020-09548-7. PMID: 32185602Free PMC Article
Rosenfeld E, Ganguly A, De Leon DD
Am J Med Genet C Semin Med Genet 2019 Dec;181(4):682-692. Epub 2019 Aug 14 doi: 10.1002/ajmg.c.31737. PMID: 31414570Free PMC Article
Demirbilek H, Hussain K
J Clin Res Pediatr Endocrinol 2017 Dec 30;9(Suppl 2):69-87. Epub 2017 Dec 27 doi: 10.4274/jcrpe.2017.S007. PMID: 29280746Free PMC Article

Diagnosis

De Leon DD, Arnoux JB, Banerjee I, Bergada I, Bhatti T, Conwell LS, Fu J, Flanagan SE, Gillis D, Meissner T, Mohnike K, Pasquini TLS, Shah P, Stanley CA, Vella A, Yorifuji T, Thornton PS
Horm Res Paediatr 2024;97(3):279-298. Epub 2023 Jul 14 doi: 10.1159/000531766. PMID: 37454648Free PMC Article
Velde CD, Reigstad H, Tjora E, Guthe HJT, Hansen EV, Molven A, Njølstad PR
Tidsskr Nor Laegeforen 2023 Dec 12;143(18) Epub 2023 Dec 11 doi: 10.4045/tidsskr.23.0425. PMID: 38088279
Casertano A, Rossi A, Fecarotta S, Rosanio FM, Moracas C, Di Candia F, Parenti G, Franzese A, Mozzillo E
Front Endocrinol (Lausanne) 2021;12:684011. Epub 2021 Aug 2 doi: 10.3389/fendo.2021.684011. PMID: 34408725Free PMC Article
Rosenfeld E, Ganguly A, De Leon DD
Am J Med Genet C Semin Med Genet 2019 Dec;181(4):682-692. Epub 2019 Aug 14 doi: 10.1002/ajmg.c.31737. PMID: 31414570Free PMC Article
Demirbilek H, Hussain K
J Clin Res Pediatr Endocrinol 2017 Dec 30;9(Suppl 2):69-87. Epub 2017 Dec 27 doi: 10.4274/jcrpe.2017.S007. PMID: 29280746Free PMC Article

Therapy

De Leon DD, Arnoux JB, Banerjee I, Bergada I, Bhatti T, Conwell LS, Fu J, Flanagan SE, Gillis D, Meissner T, Mohnike K, Pasquini TLS, Shah P, Stanley CA, Vella A, Yorifuji T, Thornton PS
Horm Res Paediatr 2024;97(3):279-298. Epub 2023 Jul 14 doi: 10.1159/000531766. PMID: 37454648Free PMC Article
Giri D, Hawton K, Senniappan S
J Pediatr Endocrinol Metab 2022 Mar 28;35(3):279-296. Epub 2021 Sep 21 doi: 10.1515/jpem-2021-0369. PMID: 34547194
Brar PC, Heksch R, Cossen K, De Leon DD, Kamboj MK, Marks SD, Marshall BA, Miller R, Page L, Stanley T, Mitchell D, Thornton P
J Clin Endocrinol Metab 2020 Dec 1;105(12) doi: 10.1210/clinem/dgaa543. PMID: 32810255
Gomes-Porras M, Cárdenas-Salas J, Álvarez-Escolá C
Int J Mol Sci 2020 Feb 29;21(5) doi: 10.3390/ijms21051682. PMID: 32121432Free PMC Article
Güemes M, Hussain K
Pediatr Clin North Am 2015 Aug;62(4):1017-36. Epub 2015 May 13 doi: 10.1016/j.pcl.2015.04.010. PMID: 26210630

Prognosis

Velde CD, Reigstad H, Tjora E, Guthe HJT, Hansen EV, Molven A, Njølstad PR
Tidsskr Nor Laegeforen 2023 Dec 12;143(18) Epub 2023 Dec 11 doi: 10.4045/tidsskr.23.0425. PMID: 38088279
Sims K
Neoreviews 2021 Apr;22(4):e230-e240. doi: 10.1542/neo.22-4-e230. PMID: 33795398
Rosenfeld E, Ganguly A, De Leon DD
Am J Med Genet C Semin Med Genet 2019 Dec;181(4):682-692. Epub 2019 Aug 14 doi: 10.1002/ajmg.c.31737. PMID: 31414570Free PMC Article
Snider KE, Becker S, Boyajian L, Shyng SL, MacMullen C, Hughes N, Ganapathy K, Bhatti T, Stanley CA, Ganguly A
J Clin Endocrinol Metab 2013 Feb;98(2):E355-63. Epub 2012 Dec 28 doi: 10.1210/jc.2012-2169. PMID: 23275527Free PMC Article
Osbak KK, Colclough K, Saint-Martin C, Beer NL, Bellanné-Chantelot C, Ellard S, Gloyn AL
Hum Mutat 2009 Nov;30(11):1512-26. doi: 10.1002/humu.21110. PMID: 19790256

Clinical prediction guides

Stanley CA, De Leon DD
Adv Pediatr 2024 Aug;71(1):119-134. Epub 2024 Apr 23 doi: 10.1016/j.yapd.2024.03.001. PMID: 38944478
Rosenfeld E, Ganguly A, De Leon DD
Am J Med Genet C Semin Med Genet 2019 Dec;181(4):682-692. Epub 2019 Aug 14 doi: 10.1002/ajmg.c.31737. PMID: 31414570Free PMC Article
Minakova E, Chu A
Pediatr Ann 2017 Nov 1;46(11):e409-e414. doi: 10.3928/19382359-20171020-01. PMID: 29131920
Arya VB, Mohammed Z, Blankenstein O, De Lonlay P, Hussain K
Horm Metab Res 2014 Mar;46(3):157-70. Epub 2014 Feb 20 doi: 10.1055/s-0034-1367063. PMID: 24557504
Snider KE, Becker S, Boyajian L, Shyng SL, MacMullen C, Hughes N, Ganapathy K, Bhatti T, Stanley CA, Ganguly A
J Clin Endocrinol Metab 2013 Feb;98(2):E355-63. Epub 2012 Dec 28 doi: 10.1210/jc.2012-2169. PMID: 23275527Free PMC Article

Recent systematic reviews

Jeffery TC, Chang AB, Conwell LS
Cochrane Database Syst Rev 2023 Jan 10;1(1):CD002010. doi: 10.1002/14651858.CD002010.pub5. PMID: 36625789Free PMC Article
Perge K, Nicolino M
Rev Endocr Metab Disord 2022 Oct;23(5):1063-1078. Epub 2022 Aug 23 doi: 10.1007/s11154-022-09749-2. PMID: 35996042
Kostopoulou E, Dastamani A, Güemes M, Clement E, Caiulo S, Shanmugananda P, Dattani M, Gilbert C, Hurst JA, Shah P
Clin Endocrinol (Oxf) 2021 Mar;94(3):399-412. Epub 2021 Jan 31 doi: 10.1111/cen.14393. PMID: 33345357
Ma D, Chen Z, Wang Y, Yu X, Xin Q, Chen Y
Eur J Clin Nutr 2021 Aug;75(8):1193-1204. Epub 2020 Dec 17 doi: 10.1038/s41430-020-00831-z. PMID: 33328601
Shah R, Harding J, Brown J, McKinlay C
Neonatology 2019;115(2):116-126. Epub 2018 Nov 8 doi: 10.1159/000492859. PMID: 30408811

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