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Hyperinsulinemic hypoglycemia, familial, 4(HHF4)

MedGen UID:
400646
Concept ID:
C1864948
Disease or Syndrome
Synonyms: HADH-Related Hyperinsulinism; HHF4; Hyperinsulinism due to short chain 3-hydroxylacyl-CoA dehydrogenase deficiency
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: 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 individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): HADH (4q25)
 
Monarch Initiative: MONDO:0012382
OMIM®: 609975
Orphanet: ORPHA71212

Definition

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.

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. [from MedlinePlus Genetics]

Clinical features

From HPO
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
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.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
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

Maiorana A, Caviglia S, Greco B, Alfieri P, Cumbo F, Campana C, Bernabei SM, Cusmai R, Mosca A, Dionisi-Vici C
Orphanet J Rare Dis 2021 Oct 11;16(1):424. doi: 10.1186/s13023-021-02045-3. PMID: 34635134Free PMC Article
Ohkubo K, Nagashima M, Naito Y, Taguchi T, Suita S, Okamoto N, Fujinaga H, Tsumura K, Kikuchi K, Ono J
Clin Endocrinol (Oxf) 2005 Apr;62(4):458-65. doi: 10.1111/j.1365-2265.2005.02242.x. PMID: 15807877

Recent clinical studies

Etiology

Sivasubramanian M, Avari P, Gilbert C, Doodson L, Morgan K, Oliver N, Shah P
Front Endocrinol (Lausanne) 2023;14:1265076. Epub 2023 Sep 26 doi: 10.3389/fendo.2023.1265076. PMID: 37822600Free PMC Article
Christ E, Iacovazzo D, Korbonits M, Perren A
Endocr Relat Cancer 2023 Jun 1;30(6) Epub 2023 May 16 doi: 10.1530/ERC-22-0327. PMID: 36952647
Louvigne M, Rouleau S, Caldagues E, Souto I, Montcho Y, Bouvagnet AM, Baud O, Carel JC, Gascoin G, Coutant R
PLoS One 2018;13(5):e0195383. Epub 2018 May 3 doi: 10.1371/journal.pone.0195383. PMID: 29723237Free PMC Article
Kleinberger JW, Maloney KA, Pollin TI
Am J Perinatol 2016 Nov;33(13):1319-1326. Epub 2016 Aug 29 doi: 10.1055/s-0036-1592078. PMID: 27571483Free PMC Article
Gilis-Januszewska A, Piątkowski J, Skalniak A, Piwońska-Solska B, Nazim J, Pach D, Przybylik-Mazurek E, Sowa-Staszczak A, Starzyk J, Hubalewska-Dydejczyk A
Endokrynol Pol 2015;66(4):344-54. doi: 10.5603/EP.2015.0044. PMID: 26323472

Diagnosis

Safran A, Proskorovski-Ohayon R, Eskin-Schwartz M, Yogev Y, Drabkin M, Eremenko E, Aharoni S, Freund O, Jean MM, Agam N, Hadar N, Loewenthal N, Staretz-Chacham O, Birk OS
J Inherit Metab Dis 2023 Jul;46(4):744-755. Epub 2023 Feb 9 doi: 10.1002/jimd.12594. PMID: 36695547
Kleinberger JW, Maloney KA, Pollin TI
Am J Perinatol 2016 Nov;33(13):1319-1326. Epub 2016 Aug 29 doi: 10.1055/s-0036-1592078. PMID: 27571483Free PMC Article
Gilis-Januszewska A, Piątkowski J, Skalniak A, Piwońska-Solska B, Nazim J, Pach D, Przybylik-Mazurek E, Sowa-Staszczak A, Starzyk J, Hubalewska-Dydejczyk A
Endokrynol Pol 2015;66(4):344-54. doi: 10.5603/EP.2015.0044. PMID: 26323472
Colclough K, Bellanne-Chantelot C, Saint-Martin C, Flanagan SE, Ellard S
Hum Mutat 2013 May;34(5):669-85. Epub 2013 Apr 2 doi: 10.1002/humu.22279. PMID: 23348805
Glaser B
Semin Perinatol 2000 Apr;24(2):150-63. doi: 10.1053/sp.2000.6365. PMID: 10805170

Therapy

Clemente M, Cobo P, Antolín M, Campos A, Yeste D, Tomasini R, Caimari M, Masas M, García-Arumí E, Fernández-Cancio M, Baz-Redón N, Camats-Tarruella N
J Clin Endocrinol Metab 2023 Oct 18;108(11):e1316-e1328. doi: 10.1210/clinem/dgad280. PMID: 37216904
McGlacken-Byrne SM, Mohammad JK, Conlon N, Gubaeva D, Siersbæk J, Schou AJ, Demirbilek H, Dastamani A, Houghton JAL, Brusgaard K, Melikyan M, Christesen H, Flanagan SE, Murphy NP, Shah P
Eur J Endocrinol 2022 Feb 22;186(4):417-427. doi: 10.1530/EJE-21-0897. PMID: 35089870
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
Desai MP, Khatri JV
Indian Pediatr 1998 Apr;35(4):317-28. PMID: 9770886
al-Rabeeah A, al-Ashwal A, al-Herbish A, al-Jurayyan N, Sakati N, Abobakr A
J Pediatr Surg 1995 Aug;30(8):1119-21. doi: 10.1016/0022-3468(95)90001-2. PMID: 7472962

Prognosis

Maiorana A, Caviglia S, Greco B, Alfieri P, Cumbo F, Campana C, Bernabei SM, Cusmai R, Mosca A, Dionisi-Vici C
Orphanet J Rare Dis 2021 Oct 11;16(1):424. doi: 10.1186/s13023-021-02045-3. PMID: 34635134Free PMC Article
Sethi A, Foulds N, Ehtisham S, Ahmed SH, Houghton J, Colclough K, Didi M, Flanagan SE, Senniappan S
J Clin Res Pediatr Endocrinol 2020 Nov 25;12(4):420-426. Epub 2020 Jan 28 doi: 10.4274/jcrpe.galenos.2019.2019.0106. PMID: 31989990Free PMC Article
Pearson ER, Boj SF, Steele AM, Barrett T, Stals K, Shield JP, Ellard S, Ferrer J, Hattersley AT
PLoS Med 2007 Apr;4(4):e118. doi: 10.1371/journal.pmed.0040118. PMID: 17407387Free PMC Article
Desai MP, Khatri JV
Indian Pediatr 1998 Apr;35(4):317-28. PMID: 9770886
al-Rabeeah A, al-Ashwal A, al-Herbish A, al-Jurayyan N, Sakati N, Abobakr A
J Pediatr Surg 1995 Aug;30(8):1119-21. doi: 10.1016/0022-3468(95)90001-2. PMID: 7472962

Clinical prediction guides

Clemente M, Cobo P, Antolín M, Campos A, Yeste D, Tomasini R, Caimari M, Masas M, García-Arumí E, Fernández-Cancio M, Baz-Redón N, Camats-Tarruella N
J Clin Endocrinol Metab 2023 Oct 18;108(11):e1316-e1328. doi: 10.1210/clinem/dgad280. PMID: 37216904
Louvigne M, Rouleau S, Caldagues E, Souto I, Montcho Y, Bouvagnet AM, Baud O, Carel JC, Gascoin G, Coutant R
PLoS One 2018;13(5):e0195383. Epub 2018 May 3 doi: 10.1371/journal.pone.0195383. PMID: 29723237Free PMC Article
Pearson ER, Boj SF, Steele AM, Barrett T, Stals K, Shield JP, Ellard S, Ferrer J, Hattersley AT
PLoS Med 2007 Apr;4(4):e118. doi: 10.1371/journal.pmed.0040118. PMID: 17407387Free 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. doi: 10.2337/diabetes.53.1.221. PMID: 14693719
Kukuvitis A, Deal C, Arbour L, Polychronakos C
J Clin Endocrinol Metab 1997 Apr;82(4):1192-4. doi: 10.1210/jcem.82.4.3904. PMID: 9100595

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