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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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Familial Hyperinsulinism

Synonyms: FHI, Persistent Hyperinsulinemic Hypoglycemia of Infancy (PHHI). Includes: ABCC8-Related Hyperinsulinism, GCK-Related Hyperinsulinism, GLUD1-Related Hyperinsulinism, HADH-Related Hyperinsulinism, HNF4A-Related Hyperinsulinism, KCNJ11-Related Hyperinsulinism, UCP2-Related Hyperinsulinism
, MD
Endocrinology and Metabolism
Hadassah-Hebrew University Medical Center
Jerusalem, Israel

Initial Posting: ; Last Update: January 24, 2013.

Summary

Disease characteristics. 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.

Diagnosis/testing. Approximately 45% of affected individuals have mutations in either ABCC8, which encodes the protein SUR1, or KCNJ11, which encodes the protein Kir6.2. In the Ashkenazi Jewish population, two ABCC8 founder mutations are responsible for approximately 97% of FHI. Other ABCC8 founder mutations are present in the Finnish population (p.Val187Asp and p.Asp1506Lys). Mutations in GLUD1 and HNF4A each account for approximately 5% of individuals with FHI. Activating mutations in GCK or inactivating mutations in HADH occur in fewer than 1% of individuals with FHI. Mutations in UCP2 have been reported in only two families to date. Approximately 40% of individuals with FHI do not have an identifiable mutation in any of the genes known to be associated with FHI.

Management. Treatment of manifestations: At initial diagnosis, hypoglycemia is corrected with intravenous glucose to normalize plasma glucose concentration and prevent brain damage. Long-term medical management includes the use of diazoxide, somatostatin analogs, nifedipine, glucagon, recombinant IGF-I, glucocorticoids, human growth hormone, dietary intervention, or combinations of these therapies. In individuals in whom aggressive medical management fails to maintain plasma glucose concentration within safe limits, or in whom such therapy cannot be safely maintained over time, pancreatic resection is considered.

Prevention of secondary complications: Aggressive treatment to prevent hypoglycemia helps avoid irreversible brain damage.

Surveillance: Monitoring of plasma glucose concentrations, especially during intercurrent illness.

Agents/circumstances to avoid: Prolonged fasting of any sort.

Evaluation of relatives at risk: If the family-specific mutation(s) are known, early identification of at-risk relatives by molecular genetic testing ensures initiation of treatment before hypoglycemia occurs.

Pregnancy management: Affected pregnant women who have diabetes due to prior pancreatectomy should receive the same treatment as any pregnant woman who has pre-existing diabetes from any cause.

Genetic counseling. FHI-KATP, caused by mutations in either ABCC8 or KCNJ11, is most commonly inherited in an autosomal recessive manner and less commonly in an autosomal dominant manner, although de novo mutations have been reported. FHI-GCK, caused by mutations in GCK, and HA/HI, caused by mutations in GLUD1, are inherited in an autosomal dominant manner; de novo mutations are not rare. FHI-HADH, caused by mutations in HADH, is inherited in an autosomal recessive manner. The focal form of FHI (pancreatic adenomatous hyperplasia that involves a limited region of the pancreas), caused by biallelic mutations of ABCC8 or KCNJ11, is inherited in an autosomal dominant manner, but only manifests when the mutation occurs on the paternally derived allele and a somatic event results in the loss of the maternal allele in a beta cell precursor. Risk to sibs of a proband depends on the underlying genetic mechanism. Carrier testing for relatives at risk for the autosomal recessive forms of FHI and prenatal diagnosis for pregnancies at increased risk for the diffuse form of FHI (involvement of beta cells throughout the pancreas) are possible if the family-specific mutation(s) are known. Prenatal or preimplantation genetic diagnosis for focal FHI is not possible, as a somatic mutation in the pancreas is required for clinical disease.

Diagnosis

Clinical Diagnosis

Familial hyperinsulinism (FHI) is defined as hypoglycemia in the newborn or infant, associated with inappropriately elevated serum concentration of insulin and metabolic evidence of increased insulin action. The latter may include inappropriately low serum ketone bodies, increased glucose response to glucagon administration, and a glucose requirement to prevent hypoglycemia that is greater than the obligate glucose needs of the appropriate age group.

Testing

For most individuals, the definitive diagnosis of FHI can be made rapidly if the appropriate blood and urine samples are obtained during an episode of spontaneous hypoglycemia [Glaser et al 1999, Kapoor et al 2009] (see Table 1):

1.

At time of hypoglycemia, either spontaneous or during monitored fasting (glucose <40 mg/dL), obtain three to six blood samples for measurements.

2.

Obtain urine samples for measurements.

3.

Perform glucagon stimulation test. A glycemic response of greater than 30 mg/dL following injection of 0.03 mg/kg glucagon excludes a primary hepatic or metabolic defect.

4.

Calculate glucose requirement. A requirement of greater than 15 mg/kg/min is highly suggestive of HI. Normal requirements:

  • Neonate: 5-8 mg/kg/min
  • Older infant or child: 3-5 mg/kg/min

Note: Provocative tests with insulin secretagogues may be dangerous and are contraindicated.

Table 1. Diagnostic Tests for Documentation of HI

FactorExpected Result in HI
Blood samplesInsulinInappropriately elevated
C-peptideElevated
Free fatty acidsInappropriately low
β-hydroxybutyrateInappropriately low
AcetoacetateInappropriately low
Lactic acidNormal
CarnitineNormal
Growth hormoneElevated due to hypoglycemia
CortisolElevated due to hypoglycemia
T4, T3, TSHNormal
AmmoniaElevated in HI/HA syndrome only
Urine samplesKetone bodies (at time of hypoglycemia)Negative
Reducing substancesNegative
C-peptideElevated

Reprinted from Glaser et al [1999] with permission from Elsevier

Severe disease. In a newborn or young infant with severe disease that appears shortly after birth, the diagnosis of FHI can be based on documentation of inappropriately elevated plasma insulin concentration (>14.4 pmol/L [2 μU/mL]) in the presence of symptomatic hypoglycemia (plasma glucose concentration <2.7 mmol/L [50 mg/dL]).

Note: (1) "Inappropriately elevated insulin levels" are difficult to define, largely because of marked differences in specificity and sensitivity of commercial insulin assays. The concentrations mentioned here and in the literature must not be taken as hard cut-offs. (2) Pathologic hypoglycemia levels are not defined in any age group, particularly newborns.

Mild disease. In some cases, particularly those with milder disease appearing after the first few days or weeks of life, fasting plasma insulin concentrations may fluctuate greatly, and the presence of pathologically elevated insulin concentrations may be difficult to demonstrate convincingly. In these individuals, the following surrogate measurements of insulin action can be useful:

  • Inappropriate hypoketonemia (free fatty acid concentration <1.5 mmol/L)
  • Exaggerated glycemic response to glucagon (>1.7 mmol/L [30 mg/dL] at a time of hypoglycemia)
  • A markedly elevated glucose requirement to prevent hypoglycemia (i.e., exogenous glucose requirements that may exceed 15-20 mg/kg/min [normal: 5-8 mg/kg/min])

Hyperammonemia/hyperinsulinism syndrome. Mildly to moderately elevated serum concentration of ammonia (serum ammonia levels 1.5-4.0 times the upper limit of normal for specific assay) suggests the presence of the hyperammonemia/hyperinsulinism syndrome.

Hyperinsulinism caused by mutations in HADH. Elevated urinary 3-hydroxyglutaric acid excretion suggests this diagnosis [Clayton et al 2001, Molven et al 2004], but a normal plasma acylcarnitine profile and urine organic acid analysis does not exclude this diagnosis. Individuals with this form of disease typically develop severe hypoglycemia after leucine administration [Stanley 2011].

Histology. Pancreatic beta cells (comprising <2% of all pancreatic cells) synthesize, store, and secrete insulin. Beta cells are located within the islets of Langerhans. Two major pancreatic histologic types (‘diffuse’ and ‘focal’) are recognized in familial hyperinsulinism. A third histologic form (‘atypical’ or ‘mosaic’) has recently been described, although the genetic etiology of this form of FHI has not yet been discovered [Sempoux et al 2011]:

  • Diffuse involvement of beta cells throughout the pancreas. Seen in approximately 60%-70% of individuals, diffuse disease is characterized by essentially normal neonatal pancreatic architecture. All beta cells are affected and many have large nuclei, abundant cytoplasm and histologic evidence of increased metabolic activity.
  • Focal pancreatic adenomatous hyperplasia. Seen in approximately 30%-40% of individuals, focal changes involve a limited region of the pancreas, with the remainder of the tissue being both histologically and functionally normal. A focal lesion is the confluence of apparently normal islets. Focal lesions typically are not macroscopically visible; they differ from true adenomas, which can be identified on gross inspection of the pancreas. Beta cells outside the focal lesion have small nuclei and sparse cytoplasm-histologic evidence that they are suppressed and not actively producing and secreting insulin.
  • Mosaic involvement of the pancreatic islets. Pancreatic histology reveals the coexistence of two types of islet: large islets with cytoplasm-rich beta cells and occasional enlarged nuclei alongside shrunken islets with beta cells exhibiting little cytoplasm and small nuclei. Large islets are mostly confined to a few lobules suggesting that removal of these particular lobules by partial pancreatectomy could result in a cure [Sempoux et al 2011]. The genetic etiology of this form of FHI is not known.

Transhepatic percutaneous pancreatic venous sampling (TPPVS) was used in the past to differentiate between diffuse and focal FHI; however, it has largely been supplanted by F-Dopa PET, which is safer and easier. TPPVS is discussed here because it is still mentioned in the medical literature.

TPPVS must be performed by an experienced radiologist, supported by a pediatric endocrinologist. A catheter is placed through the liver into the portal vein. Insulin concentration is determined from blood samples taken from veins draining different regions of the pancreas. Simultaneous peripheral venous or arterial insulin concentrations are obtained. Prior to and throughout the test, the individual's serum glucose concentrations must be maintained at less than 50 mg/dL to prevent insulin secretion from normal beta cells:

  • A positive gradient across all regions of the pancreas is diagnostic of diffuse disease.
  • A positive gradient only in veins draining a discrete region of the pancreas is diagnostic of a focal lesion within that region.

Note: The test can be interpreted accurately only if samples are taken from the small veins directly draining regions of the pancreas. Spurious results are likely if blood is sampled only from the major veins, such as the splenic, portal, and superior mesenteric veins.

Fluorodopa positron emission tomography (F-DOPA-PET) scanning has been used successfully for the preoperative localization of focal lesions [Otonkoski et al 2006, Mohnike et al 2008a]. DOPA is concentrated in secretory granules, where it is transformed to dopamine by the enzyme DOPA decarboxylase. Dopamine is thus trapped within the granule until secreted. Immunohistologic studies have shown that DOPA decarboxylase is normally present in both islet and exocrine cells of the pancreas. Furthermore, zymogen granules in the ascinar cells also appear to contain dopamine. Thus, the diffuse uptake and trapping of F-DOPA that is seen throughout the entire pancreas on F-DOPA-PET may be due primarily to the exocrine tissue. While distribution of the enzyme is similar in control individuals and in affected individuals with diffuse FHI, in those with focal HI the enzyme distribution appears to be lower in the exocrine tissue, except in the immediate vicinity of the lesion. Also, beta cell expression of DOPA decarboxylase appears to be increased in the focal lesion. Thus, most affected individuals with focal HI demonstrate focal uptake of the tracer, whereas individuals with diffuse disease have diffuse tracer uptake [de Lonlay et al 2006]. In approximately 70%-80% of histologically proven focal HI, the uptake will be sufficiently concentrated in the region of the lesion to allow detection and localization on preoperative scan. This test does not require the technical expertise needed to perform TPPVS, and more importantly, it does not require that the affected individual be maintained with mild hypoglycemia prior to and during the test; however, it does require access to 18F-DOPA (which is not readily available in all centers) and extensive experience in interpreting the scans.

Molecular Genetic Testing

Genes. There are seven genes in which mutations are known to cause FHI (Table 2, Molecular Genetics):

  • ABCC8 encodes the ATP-binding cassette transporter subfamily C member 8.
  • KCNJ11 encodes the ATP-sensitive inward rectifier potassium channel 11.
  • GLUD1 encodes the mitochondrial glutamate dehydrogenase 1.
  • HNF4A encodes for hepatocyte nuclear factor 4-alpha.
  • GCK encodes the enzyme glucokinase.
  • HADH (previously known as HADHSC or SCHAD) encodes the mitochondrial hydroxylacyl-coenzyme A.
  • UCP2 encodes the mitochondrial uncoupling protein 2.

Evidence for locus heterogeneity. In approximately 40% of affected individuals, no mutations can be identified in ABCC8, KCNJ11, GLUD1, HNF4A, GCK, or HADH. It is not known if these individuals have regulatory or intronic mutations in these genes, major deletions/rearrangements that may have been missed by sequence analysis, or mutations in another as-yet unidentified gene(s). Recently, individuals with FHI associated mutations in UCP2 were reported, although they appear to be exceedingly rare [González-Barroso et al 2008]. Comprehensive screening of UCP2 in individuals with FHI without known mutations has not been reported to date.

See also Differential Diagnosis for disorders distinct from FHI that present with neonatal hypoglycemia.

Clinical testing

Table 2. Summary of Molecular Genetic Testing Used in Familial Hyperinsulinism

Gene SymbolProportion of FHI Attributed to Mutations in This Gene 1Test MethodMutations Detected
ABCC845% 2Targeted mutation analysisp.Phe1387del, c.3989-9G>A 3
p.Val187Asp, p.Glu1506Lys 4
Deletion / duplication analysis 5Exonic and multiexonic deletions 6
Sequence analysisSequence variants 7
KCNJ115% 8Sequence analysisSequence variants 7
Deletion / duplication analysis 5Unknown, none reported 9
GLUD15% 10Sequence analysisSequence variants 7
Sequence analysis of select exonsExons 6,7,10,11,12 11
HNF4A5% 12Sequence analysisSequence variants 7
Deletion / duplication analysis 5Unknown, none reported 9
GCK<1% 13Sequence analysisSequence variants 7
Deletion / duplication analysis 5None reported 14
HADH<1% 15Sequence analysisSequence variants 7
Deletion / duplication analysis 5Exonic and multiexonic deletions 16
UCP2<<1% 17Sequence analysisSequence variants 7

1. Percentages are different in populations with known founder mutations, such as the Ashkenazi Jewish and Finnish populations.

2. Approximately 40%-45% of affected individuals have mutations in ABCC8 (previously known as SUR1) [Nestorowicz et al 1998, Aguilar-Bryan & Bryan 1999, Meissner et al 1999, Fournet & Junien 2003, Tornovsky et al 2004].

3. In the Ashkenazi Jewish population, two ABCC8 founder mutations are responsible for approximately 97% of FHI [Glaser et al 2011].

4. Two founder mutations have been identified in Finnish population [Otonkoski et al 1999, Huopio et al 2000].

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

6. A few exonic or multiexonic deletions have been reported in ABCC8 (see Table A).

7. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

8. Approximately 5% of individuals have mutations in KCNJ11 (The proteins encoded by ABCC8 and KCNJ11 make up the beta cell KATP channel, which regulates insulin secretion.) [Thomas et al 1996, Nestorowicz et al 1997, Tornovsky et al 2004].

9. No deletions or duplications involving KCNJ11 or HNF4A have been reported to cause hyperinsulinism.

10. Approximately 5% of individuals have activating mutations in GLUD1, the gene encoding the enzyme glutamine dehydrogenase (GDH) [Stanley et al 2000, Bahi-Buisson et al 2008].

11. Exons sequenced may vary by laboratory.

12. Approximately 5% of patients with diazoxide-responsive FHI have HNF4A mutations [Flanagan et al 2010].

13. Rarely, individuals have activating mutations in GCK, the gene encoding the enzyme glucokinase [Glaser et al 1998, Christesen et al 2002, Cuesta-Muñoz et al 2004, Sayed et al 2009].

14. No deletions or duplications involving GCK have been reported to cause hyperinsulinism.

15. Rarely, individuals have recessive, inactivating mutations in HADH, the gene encoding the enzyme L-3-hydroxyacyl-coenzyme A dehydrogenase, short chain [Clayton et al 2001, Molven et al 2004, Di Candia et al 2009].

16. Rare large deletions including exon 1 have been reported [Flanagan et al 2011].

17. Two families with dominant mutations in UCP2, the gene encoding mitochondrial uncoupling protein 2, have been reported [González-Barroso et al 2008].

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband. The testing strategy should be tailored to the individual.

Targeted mutation analysis

  • In certain genetically homogeneous populations, the presence of founder mutations may allow targeted genetic testing in the initial diagnosis. These tests are easy, relatively inexpensive, and rapid, and can greatly aid in diagnosis and treatment in such cases:
    • Individuals of Ashkenazi Jewish descent should be tested for the two ABCC8 mutations commonly found in individuals with FHI in this ethnic group (Table 2).
    • Individuals of Finnish heritage should be tested for the founder mutations in ABCC8 identified in that population (Table 2).
  • Individuals with elevated serum ammonia should first be tested for mutations in GLUD1. Sequencing of exons 6, 7, 10, 11, and 12 identifies virtually all disease-causing mutations in this gene, although it is possible that causal mutations occur in other exons as well.

Comprehensive molecular genetic testing may focus on selected genes or on a multi-gene panel.

  • Individuals with neonatal onset of severe disease that is not responsive to diazoxide therapy should undergo molecular genetic testing of ABCC8 and KCNJ11 first. Unless a specific mutation has been previously identified in the individual's family or ethnic group, sequencing of the entire coding sequence and regulatory region is required. If no mutation is identified, sequence analysis of GCK should be pursued, as persons with mutations in this gene can present with severe disease that is phenotypically indistinguishable from FHI-KATP [Cuesta-Muñoz et al 2004, Kassem et al 2010].
  • In individuals with elevated urine 3-hydroxyglutaric acid, full gene sequencing followed by deletion/duplication analysis of HADH should be considered.

    Note: The finding of normal urinary 3-hydoxyglutaric acid and a normal plasma acylcarnitine profile does not exclude the diagnosis of FHI-HADH.
  • Some individuals who have relatively mild diazoxide-sensitive hypoglycemia may have mutations in HNF4A, HADH, GCK, KCNJ11, ABCC8, or (rarely) UCP2; in others, no mutation can be identified in any gene tested.
  • Tests of multi-gene panels is another strategy for comprehensive molecular diagnosis of a proband suspected of having familial hyperinsulinemia. The genes included and the methods used in multi-gene panels vary by laboratory and over time; a panel may not include a specific gene of interest.

Carrier testing for relatives at risk of being carriers of autosomal recessive forms of FHI requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for these autosomal recessive disorders and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation(s) in the family.

Clinical Description

Natural History

Familial hyperinsulinism (FHI) is characterized by hypoglycemia, which ranges from severe neonatal-onset difficult-to-manage disease to childhood-onset disease with mild symptoms and difficult-to-diagnose hypoglycemia. Adult-onset diffuse hyperinsulinism has been reported, although it is not known whether the genetic pathogenesis of this entity is the same as for the childhood-onset disease [Service et al 1999, Won et al 2006]. Neonatal-onset disease manifests within hours to two days after birth; presenting symptoms may be nonspecific, including seizures, hypotonia, poor feeding, and apnea. "Late-onset" disease manifests during the first months or years of life. Even within the same family, disease manifestations can range from mild to severe and clinical presentation can range from immediately after birth to late in childhood.

Subgroups of diffuse FHI

FHI-KATP (FHI-KATP-related FHI, caused by mutations in either ABCC8 or KCNJ11) is the most common form and can be further subgrouped into autosomal recessive (more common) and autosomal dominant (rarer).

The ABCC8 mutation c.3989-9G>A, frequently found in individuals with autosomal recessive FHI in the Ashkenazi Jewish population, is associated with disease of variable severity. Neonates with autosomal recessive FHI-KATP tend to be large for gestational age (mean birth weight: 4.6 ± 0.7 kg) [Thornton et al 1998]; they usually present with severe refractory hypoglycemia in the first 48 hours of life and respond only partially to diet or medical management (i.e., diazoxide therapy), and thus may require pancreatic resection [de Lonlay et al 2002]. Persons with FHI-KATP who present with severe, neonatal hypoglycemia but who respond sufficiently well to medical treatment to avoid pancreatectomy, improve over time, first becoming more responsive to medical interventions and eventually entering clinical remission after months to years of treatment. Some may develop diabetes later in life [Mazor-Aronovitch et al 2007].

Individuals with autosomal dominant FHI-KATP appear to have a much milder disease that is responsive to diazoxide therapy [Huopio et al 2000, Pinney et al 2008, Macmullen et al 2011, Oçal et al 2011].

Approximately 40% of individuals with FHI-KATP have the focal form of the disease. Clinically, these individuals present like those with autosomal recessive FHI-KATP; however, the genetic and therapeutic aspects of this subtype of disease are distinctly different (see Management, Treatment of Manifestations, Surgical management and Genetic studies).

FHI-GCK (FHI-GCK-related FHI, caused by mutations in GCK). To date, only a few families, each with a different dominant mutation, have been reported [Glaser et al 1998, Christesen et al 2002, Cuesta-Muñoz et al 2004, Sayed et al 2009, Kassem et al 2010]. The clinical presentation of FHI-GCK varies from mild to severe. Insulin secretion in response to elevation and suppression of glucose levels is qualitatively normal, but the glucose set-point at which insulin secretion is turned off is abnormally low. Some (not all) individuals with GCK mutations respond well to diazoxide therapy.

Hyperammonemia/hyperinsulinism (HA/HI) is associated with mild-to-moderate hyperammonemia and with relatively mild hypoglycemia, usually appearing after the neonatal period. Most but not all affected individuals have mutations in GLUD1. Ammonia levels are not related to ambient glucose levels or to duration of fasting and appear to be benign. Hypoglycemia is typically relatively mild, becomes clinically evident after the newborn period, and may be associated with exquisite sensitivity to leucine challenge. Most individuals respond well to diazoxide therapy and only a minority require surgery to prevent recurrent hypoglycemia [Stanley et al 2000, de Lonlay et al 2001, Kelly et al 2001, MacMullen et al 2001, Bahi-Buisson et al 2008].

FHI-HADH (FHI-HADH-related FHI, caused by mutations in HADH) is associated with relatively mild, diazoxide-responsive hypoglycemia as well as elevated urine 3-hydroxyglutaric acid and serum 3-hydroxybutyryl-carnitine [Clayton et al 2001, Molven et al 2004, Hardy et al 2007]. Recently, HADH mutations have been identified in individuals without abnormal serum or urinary organic acid profiles [Flanagan et al 2011]. Mutant HADH fails to suppress beta-cell GLUD1 activity resulting in leucine-sensitive hypoglycemia very similar to that seen in individuals with FHI-GLUD1 [Stanley 2011]. Therefore, mutations in HADH should be sought in all individuals with diazoxide-responsive chronic hyperinsulinism (CHI), particularly those from consanguineous families and those who have leucine-induced hypoglycemia.

FHI-HNF4A (FHI-HNF4A-related FHI, caused by mutations in HNF4A) was recently reported in about 5% of diazoxide-responsive individuals with FHI. Hypoglycemia was sometimes transient, remitting after a few months; but in some cases longer-term treatment was needed. Since many of these affected individuals had de novo mutations, a family history of FHI or the maturity-onset diabetes of the young type 1 (MODY1) phenotype was not elicited. Therefore, it was concluded that HNF4A mutation analysis should be performed in all individuals with diazoxide-responsive FHI after mutations in ABCC8 and KCNJ11 are excluded [Flanagan et al 2010]. This finding was based on the observation that a history of transient fetal overgrowth and neonatal hypoglycemia can been elicited in some individuals with MODY1 caused by autosomal dominant mutations in HNF4A but not MODY3, which is caused by HNF1A mutations [Pearson et al 2007, Kapoor et al 2008]. The mechanism by which hyperinsulinemic hypoglycemia in the fetal and neonatal period develops into insulinopenic diabetes mellitus during adolescence and young adulthood is not yet understood.

FHI-UCP2 (FHI-UCP2-related FHI, caused by mutations in UCP2) was recently discovered in two unrelated persons with diazoxide-sensitive FHI. The patients were normal weight at birth, and the disease was transient in one whereas the other had persistent disease at last follow-up (age 2 years). This patient’s mother, who carried the same mutation, had a history of seizures during infancy, but hypoglycemia was not documented. The syndrome appears to be inherited as an autosomal dominant trait with variable penetrance.

Genotype-Phenotype Correlations

No genotype-phenotype correlations other than those described in Natural History are known.

Penetrance

Autosomal recessive FHI demonstrates nearly complete penetrance. Some splice mutations, particularly the ABCC8 mutation common in the Ashkenazi Jewish population, present with markedly variable clinical severity; some homozygous individuals may be asymptomatic.

The focal form of FHI is inherited in an autosomal dominant manner with significantly reduced penetrance. It results from inheritance of a paternally derived ABCC8 or KCNJ11 mutation and a somatic event resulting in the loss of the maternal allele (loss of heterozygosity) [Ryan et al 1998, Verkarre et al 1998, Damaj et al 2008]. The risk for disease development to a fetus carrying a recessive ABCC8 or KCNJ11 mutation inherited from its father has been estimated at 1:270 [Glaser et al 2011].

A retrospective review of individuals diagnosed with MODY1 caused by mutations in HNF4A revealed an increased mean birth weight and increased incidence of hypoglycemia in the neonatal period [Pearson et al 2007]. However, significant macrosomia or clinical hypoglycemia were not common, suggesting that in individuals with HNF4A mutations, the FHI phenotype has a low penetrance, whereas in the MODY phenotype, penetrance appears to be quite high.

Anticipation

Children with autosomal dominant FHI frequently have more severe hypoglycemia than their genetically affected parents; it is not known if this is the result of anticipation or an ascertainment artifact.

Nomenclature

Since its initial description, FHI has been given a number of descriptive names. The most common is "nesidioblastosis." Derived from the Greek "nesidion" meaning islet, "blastos" meaning germ cell, and "osis" meaning tumor, this term refers to the apparent increase in the number of beta cells and to the apparent proliferation and disorganization of the islets of Langerhans, with pleomorphic, poorly formed islets and a large number of isolated beta cells apparently budding off of pancreatic ducts. More rigorous histologic evaluation and comparison with age-matched controls revealed that these findings are not specific for the disease. However, although universally considered to be technically inaccurate, the term nesidioblastosis is still in wide use.

FHI has also been called islet dysmaturation syndrome, a term derived from the observation that, like FHI beta cells, fetal beta cells respond poorly to glucose stimulation, and from the clinical observation that some individuals enter clinical remission after months or years of medical management. However, no molecular evidence exists for progressive normalization of beta-cell function over time, and thus the use of this term should be discontinued. The apparent clinical remission may be attributed to deceased beta-cell mass caused by increased apoptosis [Kassem et al 2000].

FHI has also been given names containing adjectives such as “congenital” and “persistent.” However, these have been opposed by some, since most cases are simplex (i.e., a single occurrence within a family), and some appear after the neonatal period and are thus not truly congenital. The descriptive name "persistent hyperinsulinemic hypoglycemia of infancy" is perhaps the most precise term, but has been rejected as being too cumbersome. Thus, the terminology most accepted today is simply "hyperinsulinism of infancy" (HI), adding descriptive terms such as familial, hyperammonemia, or the mutated gene whenever possible for individual cases.

Many of the individuals previously described as having leucine-sensitive hypoglycemia may have had the HA/HI syndrome or FHI-HADH.

Prevalence

Familial hyperinsulinism has been reported in virtually all major ethnic groups. Incidence has been estimated at 1:50,000 in the European population, whereas consanguineous populations of central Finland and Saudi Arabia have disease incidence of approximately 1:2,500. The incidence in Ashkenazi Jews is estimated at 1: 7,800, about 27% of whom have focal disease [Glaser et al 2011].

Differential Diagnosis

Familial hyperinsulinism (FHI) is the most common cause of persistent neonatal hypoglycemia and should be considered in every infant presenting with unexplained hypoglycemia. High birth weight for gestational age and elevated glucose requirement to prevent hypoglycemia strongly suggest the diagnosis of FHI. However, hyperinsulinemic hypoglycemia can be seen in disorders other than FHI. Furthermore, neonatal hypoglycemia can be caused by non-insulin mediated mechanisms, in which case plasma insulin concentrations are low and plasma glucose concentrations can be readily corrected with normal replacement doses of glucose (5-8 mg/kg/min).

Non-FHI Hyperinsulinemic Hypoglycemia

Hyperinsulinemic hypoglycemia may be differentiated clinically from the other causes of hypoglycemia described below by demonstrating non-suppressed plasma insulin concentrations, relative hypoketonemia, or very high glucose requirements to prevent recurrent hypoglycemia. The latter may be the first, and perhaps the most sensitive, indication of increased, unregulated insulin action.

Infants of diabetic mothers may present with a clinical picture identical to that of FHI; in such cases, however, the hypoglycemia is transient, resolving within days to weeks after birth.

Transient hyperinsulinemic hypoglycemia of infancy, not associated with maternal diabetes mellitus, is a poorly characterized entity that may be associated with perinatal stress or asphyxia or may occur without apparent precipitating factors. Individuals with transient neonatal hyperinsulinism typically respond well to diazoxide therapy.

Beckwith-Wiedemann syndrome. Approximately 30% of infants with Beckwith-Wiedemann syndrome have hyperinsulinemic hypoglycemia, although it is typically mild and responds to medical treatment with diazoxide.

Exercise-induced hyerpinsulinemic hypoglycemia (listed in OMIM as familial hyperinsulinemic hypoglycemia type 7) is caused by dominant mutations in SLC16A1. The clinical phenotype is quite different from that seen in other forms of FHI, as individuals with mutations in SLC16A1 typically present with severe hypoglycemia occurring after anaerobic and not aerobic exercise. In the majority of cases, hypoglycemia was first diagnosed during childhood or later and not during infancy or the neonatal period. Mutations in the regulatory region of SLC16A1 result in aberrant expression of the transporter in beta cells, allowing pyruvate and lactate to enter the beta cell and stimulate insulin secretion even in the absence of glucose [Otonkoski et al 2003, Otonkoski et al 2007].

Insulin receptor mutations have also been associated with hyperinsulinemic hypoglycemia and have been designated in OMIM as familial hyperinsulinemic hypoglycemia type 5. However, here too, the clinical symptoms are quite different from those seen in other forms of FHI, with affected individuals presenting with post-prandial hypoglycemia three to five hours after meals. An inactivating mutation in the gene for the insulin receptor, INSR (OMIM 147670), is thought to decrease insulin clearance, resulting in increased insulin/C-peptide ratio and prolonged postprandial insulin action [Højlund et al 2004]. Thus, unlike other forms of hyperinsulinemic hypoglycemia, the genetic defect is not thought to directly affect the beta cell itself.

Insulinoma. In children older than age one year, insulinoma must be excluded; it is rarely if ever seen before age one year. Familial insulinomas can be seen as part of multiple endocrine neoplasia type 1; however, in that disorder they rarely present during infancy or early childhood. Insulinomas are true adenomas or (rarely) carcinomas, visible macroscopically and composed of beta cells only, which are arranged in nests or cords [Rahier et al 2000].

Hypoglycemias NOT Associated with Hyperinsulinemia

To exclude these other potential causes of hypoglycemia, plasma samples for C-peptide, free fatty acids, beta-hydroxybutyrate, acetoacetate, lactic acid, carnitine, growth hormone, cortisol, and thyroid hormones should be obtained at the same time as the plasma samples to be tested for glucose and insulin concentrations. Counter-regulatory hormones in individuals with familial hyperinsulinism are usually normal; however, recurrent hypoglycemia can significantly blunt the growth hormone and cortisol response.

  • Congenital deficiency of cortisol or growth hormone may first present with hypoglycemia, although it is also typically mild and responds well to hormone replacement therapy.
  • Ketotic, or substrate-deficient, hypoglycemia is rare and typically presents between ages 18 and 24 months.
  • Defects in fatty-acid, glucose, and amino acid metabolism are rare, but they frequently present with hypoglycemia, and the specific diagnosis is important for appropriate treatment.

Defects in glucose production. The glycogen storage diseases are a class of diseases caused by mutations in any of several enzymes responsible for the generation or breakdown of glycogen, including glycogen synthase (glycogen storage disease type 0) and glucose-6-phospatase (see Glycogen Storage Disease Type I). Since glycogen is the major source of glucose during a short fast, these diseases are characterized by fasting hypoglycemia, the severity of which depends on the specific gene mutated and the nature of the specific mutation.

Similarly, mutations in any of several of the enzymes in the gluconeogenesis pathway can result in hypoglycemia. For example, fructose 1,6-diphosphatase deficiency (F1,6 DH) (OMIM 229700) presents with lactic acidosis and hypoglycemia. Hypoglycemia in F1,6 DH is less severe than that caused by glucose-6-phosphatase deficiency (glycogen storage disease type Ia), occurring primarily during fasting or intercurrent illness (see Glycogen Storage Disease Type I). Glucose response to glucagon can be normal in the postprandial period, emphasizing the importance of performing the glucagon test during fasting hypoglycemia, when glycogen stores are depleted in the absence of circulating hyperinsulinism. Treatment consists of high-carbohydrate diet, avoidance of fasting, and treatment with intravenous glucose during catabolic situations.

Defects in fatty acid metabolism. Fatty acid beta-oxidation is an important energy source, particularly during fasting and times of metabolic stress such as acute illness. Disorders of fatty acid oxidation, including MCAD deficiency, are rare but important causes of hypoglycemia in the infant [Lteif & Schwenk 1999, Kompare & Rizzo 2008]. The process of fatty acid beta-oxidation is complex and involves a cascade of enzymes, transporters, and co-factors. Disruption of this process at any level results in failure to metabolize fatty acids, leading to loss of a critical energy source and failure to produce ketone bodies. During prolonged aerobic exercise, fasting, or any intercurrent illness, fatty acid oxidation accounts for a major part of muscle oxygen consumption. In contrast, brain energy requirements are supplied primarily by glucose and secondarily by oxidation of ketone bodies.

Individuals with fatty-acid oxidation disorders have both hypoglycemia and hypoketonemia and are thus particularly prone to neurologic damage. The mechanism by which these disorders cause hypoglycemia is unclear; it is thought to be the combined effect of at least two factors:

  • Increased peripheral glucose utilization resulting from the absence of fatty acids and ketone bodies as alternative energy sources may rapidly deplete glycogen stores and overtax the gluconeogenesis machinery.
  • Hepatic gluconeogenesis may be further inhibited nonspecifically because of decreased energy sources needed to drive the process or specifically by inhibition of pyruvate carboxylase, the first gluconeogenic enzyme, since this enzyme requires acetyl-CoA for optimal activity.

The clinical presentation of most fatty-acid oxidation disorders is similar. The diagnosis is suspected clinically when fasting hypoketotic hypoglycemia is found in the absence of hyperinsulinism. Myopathy and/or cardiomyopathy may also be prominent features. Acute symptoms are typically precipitated by fasting or by acute intercurrent illness.

The diagnosis can be made by urine organic acid analysis and measurement of the concentration of plasma carnitine and acylcarnitines. Electrospray tandem mass spectrometry can be used to obtain an acylcarnitine profile, which is usually diagnostic for specific defects [Rashed et al 1999, Kompare & Rizzo 2008].

Counter-regulatory hormone deficiency. Both growth hormone deficiency and cortisol deficiency result in decreased hepatic gluconeogenesis and decreased gluconeogenic substrate availability. In the adult, symptomatic hypoglycemia is rarely associated with deficiency of either or both of these hormones; however, in the neonate and small child, hypoglycemia is common, particularly if both hormones are deficient.

Primary adrenal insufficiency may be the result of congenital adrenal hyperplasia (see 21-Hydroxylase Deficiency) or primary adrenal hypoplasia (see X-Linked Congenital Adrenal Hypoplasia). Affected individuals typically present with ketotic hypoglycemia, suppressed plasma insulin levels, and blunted glycemic response to glucagon.

Pituitary hormone deficiencies can be single or multiple and can occur either as isolated entities (e.g., PIT1, PROP1-related combined pituitary hormone deficiency [CPHD]) or as part of a syndrome of midline defects (e.g., septo-optic dysplasia).

At initial presentation, individuals with isolated growth hormone deficiency may have low plasma concentrations of ketone bodies and may not have ketonuria. The diagnosis is made by measuring plasma growth hormone concentration and cortisol concentration during spontaneous or induced hypoglycemia. Recurrent hypoglycemia per se may secondarily blunt the cortisol response to acute hypoglycemia. Therefore, an isolated, blunted cortisol response in the face of recurrent hypoglycemia must be interpreted with caution. Another stimulatory test may be indicated to confirm the diagnosis.

Treatment of hypoglycemia resulting from deficiency of GH and/or cortisol is based on immediate correction of the hypoglycemia with intravenous glucose, followed by appropriate hormone replacement.

Infantile seizures. In individuals with mild FHI, the diagnosis of hypoglycemia may be made after age one year, but retrospective analysis typically suggests a much earlier onset. These individuals may be misdiagnosed as having infantile seizures if plasma glucose concentrations are not determined during an attack.

Hyperammonemia. It is necessary to evaluate individuals with hyperammonemia/hyperinsulinism for an organic acidemia (see Organic Acidemias Overview), a urea cycle defect (see Urea Cycle Disorders Overview), and defects in fatty acid metabolism (see MCAD Deficiency.)

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Treatment of Manifestations

Initial treatment. Once initial diagnostic blood samples are obtained, the hypoglycemia must be corrected immediately using intravenous glucose at a dose sufficient to prevent further hypoglycemia and irreversible brain damage. The dose of glucose may be high (>15 mg/kg/min) and frequently requires central venous access. The definition of adequate glucose control has been the subject of discussion. Most investigators recommend maintaining all glucose levels above 3.3 mmol/L (60 mg/dL), a level that leaves a sufficient margin to prevent frequent episodes of neuroglycopenia (i.e., transient or permanent brain dysfunction caused by inadequate glucose supplies) [Burns et al 2008, Inder 2008].

Long-term medical management. The next phase of treatment, designed to decrease and stop parenteral glucose requirement, is empiric and involves a combination of medical therapies, which may include the following:

  • Diazoxide, which binds to the ABCC8 subunit of the KATP channel, increases the channel's probability of being open, resulting in membrane hyperpolarization and inhibition of insulin release. Some evidence suggests that diazoxide binding to mutant channels may correct abnormal protein folding and thus facilitate the transit of more channels to the membrane. The effective therapeutic dose varies but may be as high as 20 mg/kg/day in divided doses. A thiazide diuretic is always given along with diazoxide to prevent fluid retention, which may be severe [Hussain et al 2004].
  • Somatostatin analogs (e.g., octreotide or lanreotide) suppress insulin secretion by binding to specific beta-cell receptors and initiating a number of intracellular signaling pathways. The clinical efficacy of these analogs may be limited by the relatively short duration of inhibition of insulin secretion after subcutaneous bolus injection (~3 hours) and by the fact that these drugs also inhibit glucagon and growth hormone secretion, thus impairing hepatic glucose production. Careful attention to dosage (typically 10/40 μg/kg/day for octreotide) as well as the use of continuous subcutaneous injection using a portable pump greatly enhances clinical efficacy [Glaser et al 1989, Hussain et al 2004]. Simultaneous treatment with glucagon or growth hormone may enhance efficacy.
  • Nifedipine, which acts as an inhibitor of the voltage-dependent calcium channels present in the beta cell, inhibits insulin secretion by decreasing calcium influx [Hussain et al 2004]. In vitro, this drug effectively suppresses insulin secretion depending on the mutation; however, in vivo side effects are usually dose limiting, and the drug is only rarely clinically effective.
  • Glucagon, which increases hepatic gluconeogenesis, helps prevents hypoglycemia. The drug can be used acutely to treat severe hypoglycemia, or chronically as replacement therapy to counteract suppression by somatostatin analogs [Mohnike et al 2008b].
  • Recombinant IGF-I has been shown to suppress insulin secretion in individuals with FHI [Katz et al 1999]; however, therapeutic success has not been confirmed.
  • Glucocorticoids induce resistance to endogenous insulin and correct the inadequate cortisol response sometimes seen in affected individuals. Their use in the treatment algorithm of FHI is, however, very limited.
  • Growth hormone may be given in combination with somatostatin analogs in order to counteract GH suppression by the analogs.
  • Novel treatment approaches, such as the use of a GLP1 receptor antagonist, have been attempted, but their therapeutic efficacy and safety have yet to be determined [Calabria et al 2012].
  • Dietary intervention:
    • Frequent high-carbohydrate feedings, including formula supplemented with glucose polymer
    • Night-time continuous gastric drip containing glucose or glucose polymer
    • Feeding gastrostomy to simplify the process of continuous night-time feeding and to provide access for emergency home treatment of hypoglycemia

Some individuals, particularly those with FHI-GLUD1, FHI-HADH, FHI-GCK, or dominant mutations in either ABCC8 or KCNJ11, respond very well to medical therapy. Individuals with severe FHI-KATP may also respond to medical therapy; however, these individuals often require aggressive medical management, including a combination of several of the above-mentioned drugs along with dietary intervention to maintain plasma glucose concentration in a clinically safe range without the use of parenteral glucose administration. This management protocol may be extremely demanding and, even if successful in the hospital setting, may not be appropriate for many families on an outpatient basis. The overall success of medical management in FHI-KATP as reported by different groups is extremely variable [Mazor-Aronovitch et al 2009]. The discrepancy may result from different mutations being common in various populations, or by differences in physician and patient expectations and willingness to invest time and effort in achieving success using medical management.

If medical treatment can be safely maintained, glycemic control usually becomes easier with time, and most individuals treated medically enter clinical remission after several months or years of treatment [Mazor-Aronovitch et al 2009]. It is generally accepted that those individuals who respond well to medical treatment can be treated chronically without undue risk for long-term complications. Long-term follow up of medically treated individuals shows that some eventually develop glucose intolerance, which can be effectively managed with mild dietary restrictions [Mazor-Aronovitch et al 2009].

Surgical management. Once an individual is stabilized, a decision must be made as to the need for surgical intervention and the extent of such intervention. In some severe cases, even the most aggressive medical management fails to maintain plasma glucose concentration consistently within the safe limits (>60 mg/dL). In such individuals, surgery must be considered. Prior to surgical intervention, differentiation between focal and diffuse disease using one of the following techniques is important, as the surgical approach and the clinical outcome are quite different:

Note: None of the techniques described is 100% accurate and more research is needed to develop tools to diagnose and localize focal FHI more accurately without the need for invasive testing.

  • Genetic studies, in certain circumstances, can be useful in differentiating focal from diffuse disease:
    • Finding two recessive mutations or a single dominant mutation is diagnostic of diffuse disease.
    • Finding a single recessive mutation on the maternal allele suggests diffuse disease; it is assumed that the other mutation on the paternal allele was missed because of technical limitations of the molecular genetic testing.
    • Finding a single recessive mutation on the paternal allele is consistent with and highly suggestive of focal disease, although it cannot be considered diagnostic, as molecular genetic testing methods could have failed to detect a mutation on the maternal allele. In such individuals, further testing diagnose and localize focal disease is indicated.

      Because of the large size of ABCC8 and KNCJ11, complete sequencing and analysis of all variants discovered is expensive and time-consuming and may not be completed in time to aid in clinical decision making for a severely ill individual. With the incorporation of modern sequencing techniques, rapid complete sequencing of all relevant genes is becoming feasible. In contrast, for a person from an ethnic group with a known founder mutation (e.g., Ashkenazi Jews), targeted mutation analysis can provide rapid and inexpensive clinically useful information.
  • Transhepatic percutaneous pancreatic venous sampling (TPPVS) was the first effective method for diagnosing and localizing focal lesions, but has now been largely replaced by F-DOPA-PET scanning, which is easier and considerably safer to perform.
  • Intraoperative histologic evaluation of a pancreatic biopsy in very experienced hands can be used to differentiate between diffuse FHI and a normal, suppressed pancreas in an individual with a focal lesion. Since interoperative identification of the focal lesion can be very difficult or impossible, resection of the lesion is usually only possible if its location is determined preoperatively.
  • Acute insulin response to calcium, tolbutamide, and glucose can be used to diagnose the focal FHI [Grimberg et al 1999, Ferry et al 2000, Grimberg et al 2001, Huopio et al 2002], while selective arterial calcium infusion may be useful in localizing the lesion [Abernethy et al 1998, Stanley et al 2004]. The former, however, will not help to localize the lesion, and the latter is invasive and not without potentially serious side effects.
  • Fluoro-DOPA positron emission tomography (F-DOPA-PET) has been used successfully for the preoperative localization of focal lesions [Otonkoski et al 2006, Mohnike et al 2008a] (see Diagnosis). While the scan itself is relatively easy to perform, the radiopharmaceutical is not readily available in many centers and the scan can be difficult to interpret, requiring extensive experience to obtain reliable results.

Individuals with diffuse disease require extensive (80%-95%) pancreatic resection and are at risk for persistent hypoglycemia postoperatively and/or insulin-requiring diabetes mellitus later in childhood. Individuals with focal disease can be cured by localized resection of the hyperplastic region. Although the apparent risk for postoperative diabetes appears to be very low after limited pancreatectomy, very long-term follow up is not yet available on these individuals [Beltrand et al 2012]. Since focal lesions can only rarely be identified grossly at the time of surgery, perioperative diagnosis and localization of focal lesions is needed.

Prevention of Secondary Complications

Aggressive treatment to prevent hypoglycemia helps avoid irreversible brain damage.

Surveillance

In persons with clinically mild disease, episodes of subtle, undiagnosed hypoglycemia can cause permanent brain damage. Therefore close monitoring and vigilance is just as critical in mild cases as it is in severe cases. Furthermore, in persons with mild disease and in those with severe disease in clinical remission, severe hypoglycemia may be precipitated by intercurrent viral illness. Thus, it is imperative that parents monitor glucose concentrations closely especially during intercurrent illness, even in the absence of symptomatic hypoglycemia.

Agents/Circumstances to Avoid

Prolonged fasting of any sort should be avoided. Emergency treatment options for hypoglycemia must be available at all times in case of an unexpected hypoglycemic episode.

Evaluation of Relatives at Risk

Molecular genetic testing is appropriate in the sibs of affected individuals to identify those with the disease-causing mutations known to be present in the family so that appropriate evaluation and treatment can be initiated before hypoglycemia occurs. Because of the severe neurologic consequences of delayed diagnosis and treatment, it is imperative that at-risk individuals be tested and a definitive diagnosis be made as rapidly as possible. Once the causative mutations have been identified in a proband, it is prudent to test all at-risk relatives. Depending on the findings, more extensive family investigations may be warranted. For further discussion of prenatal diagnosis, see Prenatal Testing.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Affected individuals who previously underwent near-total or sub-total pancreatectomy typically have insulin-requiring diabetes by the time they become pregnant. In this case, treatment is the same as for individuals with preexisting diabetes from any cause. There is little, if any, experience with pregnancy in individuals who were treated conservatively or who underwent limited pancreatectomy for focal FHI, as these treatments are relatively new. In this situation, close monitoring of glucose to detect both recurrent hypoglycemia and hyperglycemia is warranted. If hyperglycemia is documented, treatment should be instituted as for any woman with gestational diabetes. A fetus at risk for FHI should be monitored for size and weight. Excessive fetal weight gain during the last trimester of pregnancy increases the risk of obstetric complications and of cesarean delivery. In pregnant women with a history of FHI and gestational hyperglycemia due to prior surgical treatment, the fetus should be monitored as for any case of preexisting type 1, preexisting type 2, or gestational diabetes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

FHI-KATP, caused by mutations in either ABCC8 or KCNJ11, is most commonly inherited in an autosomal recessive manner, and rarely in an autosomal dominant manner.

FHI-GCK, FHI-GLUD1, FHI-HNF4A and FHI-UCP2 are inherited in an autosomal dominant manner.

FHI-HADH, caused by mutations in HADH, is inherited in an autosomal recessive manner.

The focal form of FHI is caused by a mutation of ABCC8 or KCNJ11 inherited in an autosomal dominant manner with markedly reduced penetrance.

Risk to Family Members — Autosomal Recessive Inheritance

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and therefore each carry one mutant allele.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband

  • The offspring of an individual with FHI are obligate heterozygotes (carriers) for a disease-causing mutation.
  • The risk to offspring of being affected depends on the mutation frequency in the reproductive partner's ethnic group. In most cases, the carrier frequency appears to be approximately 1% or less; however, genetic isolates with very high mutant allele frequency have been reported. In Ashkenazi Jews, for example, the mutation carrier rate is estimated to be 1:52; the risk to the child of a proband would be approximately 1:104 or 1% [Glaser et al 2011].
  • Offspring of a male carrier are at risk of developing focal FHI even if the mother does not have the mutation (see Risk to Family Members – AD Focal Form, Offspring of a proband). Recent studies in the Ashkenazi Jewish population suggest that the risk of the focal form of HI in a fetus of a male carrier of a recessive ABCC8 or KNCJ11 mutation is approximately 1:540. This risk is expected to be independent of the specific mutation involved [Glaser et al 2011].

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing is possible if the disease-causing mutations in the family are known.

Risk to Family Members — Autosomal Dominant Inheritance, Diffuse Form

Parents of a proband

Note: Although most individuals diagnosed with dominant HI have a de novo mutation, the family history may also appear to be negative even when the mutation is inherited from a parent because of failure to recognize the disorder in the affected parent or other family members.

Sibs of a proband

Offspring of a proband. Each child of an individual with FHI has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members are at risk.

Risk to Family Members — Autosomal Dominant Inheritance, Focal Form

Parents of a proband

  • The fathers of individuals with focal FHI are heterozygous for an ABCC8 or KCNJ11 mutation and will not have hyperinsulinism.
  • Although no instances of focal FHI caused by de novo mutation on the paternally derived ABCC8 or KCNJ11 allele have been reported, it remains a possibility.

Sibs of a proband

  • Sibs of a proband with focal FHI have a 50% chance of inheriting the mutant allele from their father. However, the focal form of FHI manifests only when the mutation occurs on the paternally derived allele and a separate, independent somatic event results in the loss of the maternal allele (loss of heterozygosity).
  • The risk for focal FHI in a sib of a proband has been estimated to be approximately 1:540 [Glaser et al 2011].

Offspring of a proband

  • Each child of an individual with focal FHI has a 50% chance of inheriting the mutation.
  • The risk to offspring of having the diffuse form of hyperinsulinemia is related to the mutation frequency in the reproductive partner's ethnic group, as offspring will have this form of hyperinsulinemia only if they inherit a mutant allele from both parents.
  • Each child of a male proband with focal FHI is also at risk of developing focal FHI. To develop FHI, the individual must inherit the mutation from the father (50% chance) and a second somatic event must occur, the latter being quite uncommon. The estimated risk for focal FHI to the offspring of a male proband with focal FHI is approximately 1:540 [Glaser et al 2011].

Other family members of a proband. The sibs of the father of a proband with focal FHI may also carry an ABCC8 or KCNJ11 mutation. However, the focal form of FHI manifests only when the mutation occurs on the paternally derived allele and a somatic event resulting in the loss of the maternal allele occurs (loss of heterozygosity). As for any child whose father carries a recessive ABCC8 or KCNJ11 mutation, the risk for focal FHI is estimated at 1:540 [Glaser et al 2011].

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Mode of inheritance when no mutation is identified. Approximately 40% of individuals with HI do not have an identifiable mutation in any of the genes known to be associated with HI. Risk to family members in these families is not known.

Family planning — autosomal recessive inheritance

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or at risk of being carriers.
  • Because of the relatively high prevalence of two specific ABCC8 mutations in the Ashkenazi Jewish population, pre-conception genetic screening may be considered in this specific ethnic group. Similarly, such genetic screening may be considered in any ethnic group with a high carrier rate of known mutations.

Family planning — autosomal dominant inheritance

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk for the diffuse form of FHI-KATP (involvement of beta cells throughout the pancreas) and for pregnancies at increased risk for HADH, GLUD1, HNF4A and GCK mutations is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele(s) of an affected family member must be identified before prenatal testing can be performed. Parents who elect to continue a pregnancy in which the fetus has been determined to be affected have the advantage of initiating treatment immediately following birth, thus preventing early, severe hypoglycemia.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

In families of individuals with focal FHI (pancreatic adenomatous hyperplasia that involves a limited region of the pancreas), prenatal diagnosis is not possible, since even though the paternal mutation can be identified in the DNA of an at-risk fetus, no testing can identify which fetuses will also have a somatic event leading to loss of the maternal allele.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation(s) have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • SUR1.ORG: A Web Site for Families of Children with Hyperinsulinism
    This site has links to other related sites and patient discussion groups.
    Email: webmaster@sur1.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table B. OMIM Entries for Familial Hyperinsulinism (View All in OMIM)

138079GLUCOKINASE; GCK
138130GLUTAMATE DEHYDROGENASE 1; GLUD1
256450HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 1; HHF1
600281HEPATOCYTE NUCLEAR FACTOR 4-ALPHA; HNF4A
600509ATP-BINDING CASSETTE, SUBFAMILY C, MEMBER 8; ABCC8
600937POTASSIUM CHANNEL, INWARDLY RECTIFYING, SUBFAMILY J, MEMBER 11; KCNJ11
6016093-@HYDROXYACYL-CoA DEHYDROGENASE; HADH
601693UNCOUPLING PROTEIN 2; UCP2
601820HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 2; HHF2
602485HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 3; HHF3
606762HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 6; HHF6
609968HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 5; HHF5
609975HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 4; HHF4
610021HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 7; HHF7

Molecular Genetic Pathogenesis

Mutations in either ABCC8 or KCNJ11, encoding (respectively) the proteins SUR1 (sulfonylurea receptor 1) and KIR6.2 (ATP-sensitive inward rectifier potassium channel 11), which are subunits of the beta cell KATP channel, result in an altered or non-functional channel. The molecular mechanism by which this occurs depends on the specific mutation. Some mutations appear not to produce any protein, whereas others produce protein that is not incorporated into the plasma membrane. Other mutations result in channels that are expressed in the plasma membrane but that fail to respond appropriately to intracellular signals such as ATP and Mg-ADP levels. This latter type of mutation often causes dominant disease. GLUD1 mutations result in increased glutamate dehydrogenase enzymatic function, apparently by decreasing the inhibitory effect of GTP, a natural inhibitor of the enzyme. GCK mutations lower the glucose threshold at which glucokinase enzyme activity is high enough to cause insulin secretion. The mechanism by which this is accomplished differs with the different mutations known to date. HADH encodes the protein hydroxyacyl-coenzyme A dehydrogenase, mitochondrial, which appears to have at least two seemingly independent functions:

  • Catalyzing the penultimate step in the fatty acid oxidation pathway; and
  • Inhibiting the function of glutamate dehydrogenase in the beta-cell

It is the latter function that is thought to be responsible for the FHI phenotype, as decreased HADH protein de-suppresses glutamate dehydrogenase, causing increased flux into the Krebs cycle and ultimately increased insulin secretion. The mechanism by which HNF4A-inactivating mutations cause hyperinsulinism has not yet been elucidated. UCP2 mutations result in decreased protein expression or function which, in the beta-cell results in increased ATP production, leading to membrane depolarization and ultimately to insulin secretion.

ABCC8

Normal allelic variants. ABCC8 is located on chromosome 11p15.1, 4.5 kb centromeric to KCNJ11. ABCC8 spans approximately 84 kb of genomic DNA and comprises 39 exons. It is expressed primarily in the pancreatic beta cell and in certain specific regions of the nervous system.

Pathologic allelic variants. A large and growing number of ABCC8 mutations are known to be associated with FHI. Most have been identified in only a single family or in a single small genetic isolate. The c.3989-9G>A mutation was identified in several different ethnic groups; haplotype analysis suggests that this is a mutation hot spot. In the Ashkenazi Jewish population, this mutation represents approximately 86% of the disease-associated alleles, most of the others being p.Phe1387del. The c.560T>A mutation causes severe FHI in a specific genetic isolate in Finland [Otonkoski et al 1999].

Table 3. Selected ABCC8 Pathologic Allelic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
c.560T>Ap.Val187Asp 2NM_000352​.3
NP_000343​.2
c.3989-9G>A
(3992-9G>A)
--
c.4160_4162delTCTp.Phe1387del
c.4516G>Ap.Glu1506Lys 2

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. Founder mutations in the Finnish population

Normal gene product. ABCC8 and KCNJ11 code for the proteins SUR1 (sulfonylurea receptor 1) and KIR6.2 (ATP-sensitive inward rectifier potassium channel 11), two components of the beta-cell KATP channel. This channel determines the resting membrane potential, which is maintained at the necessary voltage to keep voltage-dependent calcium channels closed in a cell that does not secrete. When glucose enters the cell and is metabolized, there is an increase in the ATP/ADP ratio. KATP channels close and the membrane depolarizes. Subsequently, voltage-gated calcium channels open, initiating the insulin secretory cascade. Thus, the KATP channel functions as a link between the metabolic state of the cell and the electrical activity of the membrane, resulting in the stimulation or inhibition of insulin release.

Abnormal gene product. Inactivating mutations in either ABCC8 or KCNJ11 result in non-functional or dysfunctional KATP channels. In either case, channels fail to open, and thus the cell membrane is depolarized even in the absence of an elevated intracellular ATP/ADP ratio. This results in opening of the voltage-gated calcium channels and initiation of the insulin secretion cascade, even in the absence of glucose or other metabolic stimulus. Activating mutations in either gene result in channels that fail to close despite increased ATP/ADP ratio. As a result, beta-cell membranes fail to depolarize in the presence of elevated glucose levels resulting in one form of neonatal diabetes (see Permanent Neonatal Diabetes Mellitus).

KCNJ11

Normal allelic variants. KCNJ11 is located on chromosome 11p15.1, 4.5 kb telomeric to ABCC8. The gene spans approximately 3.4 kb of genomic DNA and comprises a single exon.

Pathologic allelic variants. A large number of inactivating KCNJ11 mutations have been identified, most in only a single family or in a single small genetic isolate (for more information, see Table A).

Normal gene product. See ABCC8.

Abnormal gene product. See ABCC8.

GLUD1

Normal allelic variants. GLUD1 spans just over 44 kb of genomic DNA and is made up of 13 exons. The gene product is expressed in the mitochondrial matrix in all tissues.

Pathologic allelic variants. All GLUD1 mutations identified to date are located in exons 6, 7, 10, 11, and 12 of the gene and all appear to function by reducing glutamate dehydrogenase sensitivity to allosteric inhibition by GTP (for more information, see Table A).

Normal gene product. Glutamate dehydrogenase catalyzes the conversion of glutamate to alpha-ketoglutarate, a reaction that can proceed in either direction.

Abnormal gene product. Glutamate dehydrogenase mutations result in increased enzymatic activity. The mechanism by which this results in unregulated insulin secretion is still controversial and may relate either to increased direct mitochondrial signaling to the distal insulin secretory apparatus [Maechler & Wollheim 1999] or to increase in glutamate conversion to alpha-ketoglutarate, which enters the Krebs cycle and results in glucose-independent increase in intracellular ATP/ADP ratio [Stanley et al 2000].

GCK

Normal allelic variants. GCK spans just over 45 kb of genomic DNA and comprises ten exons.

Pathologic allelic variants. GCK mutations have been reported (for more information, see Table A).

Normal gene product. Glucokinase is the rate-limiting step of beta-cell glucose metabolism. Thus, it is effectively the beta-cell glucose sensor, linking changes in glucose levels with changes in intracellular ATP/ADP ratio [Matschinsky et al 1998]. The gene product is expressed primarily in the liver and the pancreatic beta cell but also in specific regions of the hypothalamus. Hepatic and beta-cell expression is regulated independently by tissue-specific promoters.

Abnormal gene product. Mutations with increased and decreased catalytic activity have been described. Those with decreased activity are associated with maturity-onset diabetes of the young (MODY) and severe neonatal diabetes, whereas activating mutations are associated with FHI.

HADH

Normal allelic variants. HADH spans approximately 45 kb of genomic DNA and comprises 12 exons. The gene is expressed in most tissues of the body.

Pathologic allelic variants. Recessive inactivating mutations have been identified in a small number of individuals with hyperinsulinemic hypoglycemia (for more information, see Table A).

Normal gene product. HADH codes for the enzyme 3-hydroxyacyl-CoA dehydrogenase (also known as short-chain hydroxyacyl-CoA dehydrogenase), which catalyzes the reversible dehydrogenation of 3-hydroxyacyl-CoAs to their corresponding 3-ketoacyl-CoAs with concomitant reduction of NAD to NADH and exerts its highest activity toward 3-hydroxydecanoyl-CoA (OMIM 601609). Recent studies have shown that this enzyme also acts as inhibitor of GLUD1 activity in the beta-cell.

Abnormal gene product. Recessive mutations result in decreased enzyme expression or function [Clayton et al 2001, Eaton et al 2003, Molven et al 2004, Hardy et al 2007]. Recent data suggest that the HADH gene product suppresses GLUD1 activity in the beta-cell. Thus, inactivating mutations result in increased GLUD1 activity, which increases insulin secretion through the same mechanism described above for FHI-GLUD1. This function is thought not to be important in the liver, thus explaining the absence of hyperammonemia in patients with HADH-related hyperinsulinemic hypoglycemia [Stanley 2011].

HNF4A

Normal allelic variants. HNF4A spans approximately 76 kb of genomic DNA and comprises ten exons. The gene is expressed primarily in the liver and the beta-cells under the control of two separate tissue-specific promoters.

Pathologic allelic variants. A large number of inactivating mutations have been identified throughout the gene that cause the monogenic diabetes syndrome, maturity-onset diabetes of the young type 1 (MODY1, OMIM 125850). Persons with these mutations can present with FHI in the neonatal period.

Normal gene product. HNF4A is a transcription factor, regulating the expression of a large number of genes in the liver and beta-cell.

Abnormal gene product. Mutations identified in patients with MODY1 and FHI-HNF4A result in decreased function of the transcription factor, thus affecting critical gene expression. The precise mechanism by which this results in transient hyperinsulinemic hypoglycemia, followed by permanent hypoinsulinemic diabetes is not clear.

UCP2

Normal allelic variants. UCP2 spans approximately 8.6 kb of genomic DNA and comprises eight exons. The gene is ubiquitously expressed.

Pathologic allelic variants. At the present time, only two families with dominant loss-of-function mutations in this gene have been reported.

Normal gene product. UCP2 is a mitochondrial protein that provides a pathway for dissipating the mitochondrial membrane proton gradient without coupling to other mitochondrial processes. As a result, excess calories are consumed and heat is generated.

Abnormal gene product. Mutations result in decreased function which, in the beta-cell, is thought to increase ATP production and thus insulin secretion.

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Suggested Reading

  1. Ludwig A, Ziegenhorn K, Empting S, Meissner T, Marquard J, Holl R. Diabetes Patienten-Verlaufsdokumentationssystem (DPV) Group, Mohnike K. Glucose metabolism and neurological outcome in congenital hyperinsulinism. Semin Pediatr Surg. 2011;20:45–9. [PubMed: 21186004]

Chapter Notes

Revision History

  • 24 January 2013 (me) Comprehensive update posted live
  • 15 June 2010 (cd) Revision: prenatal testing for HADH mutations available on a clinical basis
  • 23 February 2010 (me) Comprehensive update posted live
  • 19 August 2003 (me) Review posted to live Web site
  • 12 May 2003 (bg) Original submission
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