Familial Hyperinsulinism (FHI)

[Persistent Hyperinsulinemic Hypoglycemia of Infancy (PHHI). Includes: ABCC8-Related Hyperinsulinism, GCK-Related Hyperinsulinism, GLUD1-Related Hyperinsulinism, KCNJ11-Related Hyperinsulinism]

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 can be made rapidly if the appropriate blood and urine samples are obtained during an episode of spontaneous hypoglycemia; see Glaser et al [1999b] for detailed review.

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 times the upper limit of normal for specific assay) suggests the presence of the hyperammonemia/hyperinsulinism syndrome.

Hyperinsulinism caused by mutations in HADHSC (SCHAD). 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 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). This procedure is used to differentiate between diffuse and focal FHI and 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 only be interpreted appropriately 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 [Dubois et al 1995].

Fluorodopa positron emission tomography (F-Dopa-PET). Initial observations support the use of F-Dopa PET to localize focal lesions [Hussain, Otonkoski; personal communication]. 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.

Molecular Genetic Testing

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.—ED.

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

• ABCC8. Approximately 45% of affected individuals have mutations in ABCC8 (SUR1) [Nestorowicz et al 1998, Aguilar-Bryan & Bryan 1999, Meissner et al 1999, Fournet & Junien 2003].

• 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.)

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

• GCK. Rarely, individuals have activating mutations in GCK, the gene encoding the enzyme glucokinase [Glaser et al 1998, Christesen et al 2002].

• HADHSC. Rarely, individuals have recessive, inactivating mutations in HADHSC (alias SCHAD), the gene encoding the enzyme L-3-hydroxyacyl-coenzyme A dehydrogenase, short chain [Clayton et al 2001, Molven et al 2004].

Other loci. In approximately 40% of affected individuals, no mutations can be identified in ABCC8, KCNJ11, GLUD1, GCK, or HADHSC. 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.

Clinical uses

• Diagnostic testing

• Carrier testing

• Prenatal diagnosis

Clinical testing

• Targeted mutation analysis

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

  • The founder mutation, V187D, 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 HADHSC 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.

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in Familial Hyperinsulinism

Gene	% of FHI Attributed to Mutations in This Gene 1	Test Method	Mutations Detected	Test Availability
ABCC8	45%	Targeted mutation analysis	V187D, del F 1388 3992-9G>A ABCC8	Clinical
		Mutation scanning or sequence analysis	ABCC8 sequence variants
KCNJ11	5%		KCNJ11 sequence variants	Clinical
GLUD1	5%		GLUD1 sequence variants	Clinical
GCK	<1%		GCK sequence variants	Clinical
HADHSC	<1%		HADHSC sequence variants	Research only

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

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

Testing Strategy for a Proband

The testing strategy should be individualized for each person.

In certain genetically homogeneous populations, the presence of founder mutations may allow genetic testing a primary role in the initial diagnosis. These tests are easy, relatively inexpensive, and very rapid, and can greatly aid in the diagnosis and treatment of these individuals.

• Individuals of Ashkenazi Jewish decent 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.

In individuals with elevated urine 3-hydroxyglutaric, the HADHSC gene should be entirely sequenced.

Some individuals without the above findings who have relatively mild diazoxide-sensitive hypoglycemia may have GCK 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.

Genetically Related Disorders

ABCC8 and KCNJ11. Polymorphisms in the ABCC8 and KCNJ11 genes, particularly the E23K polymorphism in KCNJ11, have been associated with type 2 diabetes mellitus 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 these genes 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 activating mutations of 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].

Recently, activating mutations in 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 T2DM [Gloyn et al 2005, Yorifuji et al 2005].

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 [Vionnet et al 1992].

Homozygosity for inactivating mutations in GCK results in severe, persistent neonatal diabetes mellitus [Njolstad et al 2001].

Natural History

Familial hyperinsulinism 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]. Neonatal-onset disease manifests within hours to 1-2 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 3992-9 G>A mutation of ABCC8, frequently found in individuals with FHI in the Ashkenazi Jewish population, is associated with disease of variable severity. Individuals with autosomal recessive familial hyperinsulinism tend to be large for gestational age (mean birth weight = 4.6 kg ± 0.7) [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]. Individuals with autosomal dominant FHI-K_ATP appear to have a much milder disease that is responsive to diazoxide therapy [Huopio et al 2000; 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, 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-Munoz et al 2004]. The clinical presentation of FHI-GCK is variable with both mild and severe cases reported. 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].

FHI-HADHSC 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.

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, presents 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) [de Lonlay et al 1997, Ryan et al 1998]. 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 affected 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, nesidioblastosis is still in wide use.

FHI has also been called islet dysmaturation syndrome, a term derived from the fact 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 about 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) [Baker et al 1991].

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.

• 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 (about 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 mcg per kg per day for octreotide) as well as the use of continuous subcutaneous injection using a portable pump greatly enhances clinical efficacy [Glaser et al 1989]. 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 [Lindley et al 1996]. 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 [Grimberg et al 1997].

• Recombinant IGF-I has been shown to suppress insulin secretion in individuals with FHI [Katz et al 1999].

• 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. 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 [Glaser et al 1989]. 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 most eventually develop glucose intolerance, which can be effectively managed with mild dietary restrictions [Leibowitz et al 1995].

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 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 the ABCC8 and KNCJ11 genes, 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, the most studied and currently most effective way of diagnosing and localizing focal lesions, is an invasive procedure that requires extensive experience to perform and to interpret [Dubois et al 1995].

• Intraoperative histologic evaluation of a pancreatic biopsy in very experienced hands can be used to differentiate between diffuse-FHI and normal, suppressed pancreas in an individual with a focal lesion. However, 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, Huopio et al 2002], while selective arterial calcium infusion may be useful in localizing the lesion [Abernethy et al 1998].

• Fluoro-dopa positron emission tomography (F-Dopa-PET) has been proposed as an effective and noninvasive method to identify and localize focal lesions [Hussain, Otonkoski; personal communication]. The utility of this test in the treatment of FHI has not yet been established.

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 during intercurrent illness, even in the absence of symptomatic hypoglycemia.

Agents/Circumstances to Avoid

Prolonged fasting of any sort should be avoided.

Testing of Relatives at Risk

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 instituted before hypoglycemia occurs.

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 or rarely in an autosomal dominant manner.

FHI-GCK, caused by mutations in the GCK gene, and HA/HI, caused by mutations in the GLUD1 gene, are inherited in an autosomal dominant manner.

FHI-HADHSC, caused by mutations in the HADHSC gene, 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 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 about 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 Focal Form). The actual risk is not known but is roughly estimated to be 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 available on a clinical basis once the mutation(s) has/have been identified in the proband.

Risk to Family Members ─ Autosomal Dominant Inheritance, Diffuse Form

Parents of a proband

• 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 about 75% for HA/HI.

• Neither of the two families with GCK reported by Glaser et al [1998] or Christesen et al [2002] were de novo in the proband's generation. However Cuesta-Munoz et al [2004] reported a de novo GCK activating 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 upon 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 upon the status of the proband's parents. If a parent is found to be 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% risk 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 (approximately <1% to 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 also has a 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%.

Related Genetic Counseling Issues

Mode of inheritance when no mutation is identified. About 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. The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.

DNA banking. 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. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk for the diffuse form of FHI is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15-18 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) may be available for families in which the disease-causing mutation(s) have been identified in an affected family member in a research or clinical laboratory. For laboratories offering PGD, see .

Molecular Genetic Pathogenesis

Mutations in either ABCC8 or KCNJ11, encoding the proteins, SUR1 and K_IR6.2 respectively, 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.

Literature Cited

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Suggested Reading

Revision History

• 2 December 2005 (me) Comprehensive update posted to live Web site

• 19 August 2003 (me) Review posted to live Web site

• 12 May 2003 (bg) Original submission