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 1999b, Kapoor et al 2009] (see Table 1):

1.

At time of hypoglycemia, either spontaneous or during monitored fasting (glucose <40 mg/dL^-1), 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^-1 to 0.03 mg/kg^-1 glucagon excludes primary hepatic or metabolic defect.

4.

Calculate glucose requirement. A requirement of greater than 15 mg/kg^-1/min^-1 is highly suggestive of HI. Normal requirements:

• Neonate: 5-8 mg/kg^-1/min^-1

• Older infant or child: 3-5 mg/kg^-1/min^-1

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

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 hard to define, largely because of marked differences in specificity and sensitivity of commercial insulin assays. The concentrations mentioned here must not be taken as hard cut-offs. (2) Pathologic hypoglycemia is 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 insulin plasma concentration 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 [exogenous glucose requirements 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].

Histology. Pancreatic beta cells, comprising fewer than 2% of all pancreatic cells, synthesize, store, and secrete insulin. Beta cells are located within the islets of Langerhans. Two major pancreatic histologic types are recognized in familial hyperinsulinism:

• 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 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 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.

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 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 [Mohnike et al 2008a, Otonkoski et al 2006]. Dopa is concentrated in secretory granules, where it is transformed to dopamine and trapped until secreted. Thus, functional beta cells take up the tracer, whereas resting cells do not. This test does not require the technical expertise needed to perform TPPVS, and more importantly, it does not require that the 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.

Molecular Genetic Testing

Genes. Five genes are known to be associated with FHI:

• ABCC8. Approximately 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].

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

• GLUD1. 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].

• GCK. 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].

• HADH (previously known as HADHSC or SCHAD). 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].

Other loci. In approximately 40% of affected individuals, no mutations can be identified in ABCC8, KCNJ11, GLUD1, 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 the testing methods used to date, or mutations in other as-yet unidentified genes.

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

Clinical testing

• Targeted mutation analysis

  • In the Ashkenazi Jewish population, two ABCC8 founder mutations are responsible for approximately 90% of FHI (Table 2) [Glaser et al 1999a].

  • The founder mutation, p.Val187Asp, is present in the Finnish population [Otonkoski et al 1999].

• Mutation scanning or sequence analysis. Most of the mutations that have been identified to date in ABCC8, KCNJ11, GLUD1, GCK, and HADH are unique occurrences in each family. Thus, unless the individual comes from a family with a known mutation or an ethnic group in which founder mutations are known, it is necessary to perform sequence analysis on the coding region of all five genes.

• Deletion/duplication analysis

  • ABCC8. A few exon or multiexon deletions have been reported in ABCC8 (see Table A).

  • KCNJ11. No deletions or duplications involving KCNJ11 have been reported. However, with newly available deletion/duplication testing methods, it is theoretically possible that such mutations may be identified in affected individuals who previously tested negative by sequence analysis.

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

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Gene Symbol	Proportion of FHI Attributed to Mutations in this Gene 1	Test Method	Mutations Detected	Mutation Detection Frequency by Gene and Test Method 2	Test Availability
ABCC8	45%	Targeted mutation analysis	p.Phe1387del, c.3989-9 G>A 3	100% 4	Clinical
			p.Val187Asp 5	100% 4
		Deletion / duplication analysis 6	Exonic and multiexonic deletions	Unknown
		Mutation scanning or sequence analysis	Sequence variants 7	Unknown
KCNJ11	5%	Mutation scanning or sequence analysis	Sequence variants 7	Sequence variations	Clinical
		Deletion / duplication analysis 5	Exonic and multiexonic deletions	Unknown
GLUD1	5%	Mutation scanning or sequence analysis	Sequence variants 7	100% 3	Clinical
GCK	<1%	Sequence analysis	Sequence variants 7	100% 3	Clinical
		Deletion / duplication analysis 5	Exonic and multiexonic deletions	Unknown
HADH	<1%	Sequence analysis	Sequence variants 7	?	Clinical

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

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

2. The ability of the test method used to detect a mutation that is present in the indicated gene

3. ~90% in Ashkenazi Jewish population

4. Because this disorder is defined by the presence of a causative mutation in the associated gene, the mutation detection rate is 100%.

5. Founder mutation in Finnish population

6^. Testing that detects deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, real-time PCR, multiplex ligation-dependent probe amplification (MLPA), or array GH may be used.

7. Small intragenic deletions/insertions, missense, nonsense, and splice site mutations.

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

Testing Strategy

To establish the diagnosis in a proband

• The testing strategy should be tailored to the individual.

• In certain genetically homogeneous populations, the presence of founder mutations may allow genetic testing a primary role in the initial diagnosis. Such 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.

  • Individuals of Finnish heritage should be tested for the founder mutations identified in that population.

• Individuals with elevated serum ammonia should first be tested for mutations in GLUD1. Sequencing of exons 6, 7, 11, and 12 identifies most disease-causing mutations in this gene, although mutations may occur in other exons.

• Some individuals without the above findings who have relatively mild diazoxide-sensitive hypoglycemia may have GCK, KCNJ11 or ABCC8 mutations; in others, no mutation can be identified in any gene tested.

• Individuals with neonatal onset of severe disease that is not responsive to diazoxide should be tested for mutations in ABCC8 and KCNJ11. 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, they should be tested for mutations in GCK, as persons with mutations in this gene can present with severe disease that is phenotypically indistinguishable from FHI-K_ATP.

• In individuals with elevated urine 3-hydroxyglutaric, the entire HADH gene should be sequenced.

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.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

ABCC8 and KCNJ11. Polymorphisms in the ABCC8 and KCNJ11 genes (particularly the p.Glu23Lys polymorphism in KCNJ11) have been associated with type 2 diabetes mellitus (DM) in some but not all studies [Hani et al 1998, Gloyn et al 2001, Hansen et al 2001, t Hart et al 2002, Gloyn et al 2003]. These findings are still controversial and the overall importance of ABCC8 and KCNJ11 in the genetic risk associated with type 2 DM is still unknown. A dominant ABCC8 mutation is associated with hyperinsulinemic hypoglycemia in the neonatal period and diabetes mellitus later in life [Glaser 2003, Huopio et al 2003].

Dominant and recessive activating mutations of either ABCC8 or KCNJ11 can cause severe neonatal diabetes mellitus with and without associated neurologic defects. Many such individuals can be managed with oral sulfonylurea treatment and do not require insulin [Gloyn et al 2004, Zung et al 2004, Flanagan et al 2009] (see Permanent Neonatal Diabetes Mellitus).

Activating mutations in either ABCC8 or KCNJ11 with less severe effects on channel function have been found to cause transient neonatal diabetes mellitus (TNDM) as well as both childhood-onset diabetes mellitus and adult-onset autosomal dominantly inherited type 2 DM [Gloyn et al 2005, Yorifuji et al 2005, Flanagan et al 2009].

GCK. Heterozygosity for inactivating mutations in GCK is a common cause of maturity-onset diabetes of the young (MODY) (OMIM 606391), a rare form of type 2 diabetes mellitus inherited in an autosomal dominant manner [Sagen et al 2008].

Homozygosity for inactivating mutations in GCK results in severe, persistent neonatal diabetes mellitus [Njolstad et al 2001, Turkkahraman et al 2008] (see Permanent Neonatal Diabetes Mellitus).

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 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.

Subgroups of diffuse FHI

FHI-K_ATP, 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 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-K_ATP 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-K_ATP appear to have a much milder disease that is responsive to diazoxide therapy [Huopio et al 2000; Pinney et al 2008; Stanley, personal communication].

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

FHI-GCK is 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].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, but 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 is associated with relatively mild, diazoxide-responsive hypoglycemia as well as elevated urine 3-hydroxyglutaric acid and serum 3-hydroxybutyryl-carnitine. As only a few individuals with this disorder have been reported, the full clinical spectrum is not yet known [Clayton et al 2001, Molven et al 2004, Hardy et al 2007].

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 ABCC7 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, Damaj et al 2008]. The risk for disease, however, is very small (reduced penetrance) as the somatic event is rare, occurring in fewer than 1%-2% of individuals with a paternally derived ABCC8 or KCNJ11 mutation.

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 HI 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.

Prevalence

Familial hyperinsulinism has been reported in virtually all major ethnic groups. Prevalence has been estimated at 1:50,000 in the European population, whereas consanguineous populations of central Finland and Saudi Arabia have disease prevalence of approximately 1:2,500. The apparent increased prevalence among Ashkenazi Jews has not been rigorously studied.

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 K_ATP 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) 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 (approximately three 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.

• Growth hormone may be given in combination with somatostatin analogs in order to counteract GH suppression by the analogs

• Dietary intervention:

  • Frequent high-carbohydrate feedings, including formula supplemented with glucose polymer

  • Nighttime 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 some with FHI-GLUD1 or FHI-GCK, respond very well to medical therapy. Individuals with severe FHI-K_ATP 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-K_ATP 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 of 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 of two recessive mutations or a single dominant mutation is diagnostic of diffuse disease.

  • Finding of 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 of a single recessive mutation on the paternal allele is consistent with 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 is indicated to diagnose and localize focal disease.
    
    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. In contrast, for a person from an ethnic group with a known founder mutation (e.g., Ashkenazi Jews), targeted mutation analysis may provide clinically useful information in a more timely manner.

• 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. Resection of the lesion is 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].

• 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).

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. 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 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.

Evaluation of Relatives at Risk

Molecular genetic testing is appropriate in the sibs of affected individuals to identify those with the two disease-causing mutations known to be present in the family so that appropriate evaluation and treatment can be initiated before hypoglycemia occurs.

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

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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

FHI-K_ATP, 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, caused by mutations in GCK, and HA/HI, caused by mutations in GLUD1, 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.

• 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). The actual risk is not known but is estimated at roughly 1%-2%.

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

• One of the parents of an affected child may have a mutant allele, and thus be affected by FHI.

• A proband with HI may have the disorder as the result of a de novo gene mutation. The proportion of cases caused by de novo mutations is estimated at approximately 75% for HA/HI.

• Neither of the two families with FHI-GCK reported by Glaser et al [1998] or Christesen et al [2002] were de novo in the proband's generation. However, Cuesta-Muñoz et al [2004] reported a de novo activating GCK mutation that resulted in severe hyperinsulinemia in a female infant.

• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include molecular genetic testing, and, if positive, clinical testing for fasting and postprandial hypoglycemia.

Note: Although most individuals diagnosed with HI have a de novo mutation, the family history may also appear to be negative because of failure to recognize the disorder in family members.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband's parents:

  • If a parent of the proband is affected or has a disease-causing mutation, the risk to the sibs is 50%.

  • When the parents are clinically unaffected and do not have a disease-causing mutation, the risk to the sibs of a proband appears to be negligible.

• If a disease-causing mutation cannot be detected in the DNA from leukocytes of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.

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 a ABCC8 or KCNJ11 mutation and will not have hyperinsulinemia. 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 somatic event resulting in the loss of the maternal allele occurs (loss of heterozygosity). Because loss of heterozygosity in this disorder is a rare event, the risk of disease is small (~ <1%-2%), although the exact incidence has yet to be determined.

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, since 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 risk of the secondary somatic event that causes this disease is apparently low, probably on the order of 1% to 2%.

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). Because loss of heterozygosity in this disorder is a rare event, the risk of disease in other family members is small.

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.

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. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk for the diffuse form of FHI and for pregnancies at increased risk for HADH 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.

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, prenatal diagnosis is not possible, since even though the paternal mutation can be identified in the DNA of an at-risk fetus, no testing is available to identify which fetuses will also have a somatic event leading to loss of the maternal allele.

Preimplantation genetic diagnosis (PGD). Preimplantation genetic diagnosis may be available for families in which the disease-causing mutation(s) have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

Mutations in either ABCC8 or KCNJ11, encoding (respectively) the proteins SUR1 (sulfonylurea receptor 1) and K_IR6.2 (ATP-sensitive inward rectifier potassium channel 11), which are subunits of the beta cell K_ATP 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 fail to respond appropriately to intracellular signals such as ATP and Mg-ADP levels. 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.

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Revision History

• 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