Congenital hyperinsulinism is genetically heterogeneous disorder with mutations in a number of different genes reported. Hyperinsulinism may occur in isolation or can present as part of a syndrome. The phenotype of the patient is dependent on the genetic aetiology and in some cases the specific mutation within a gene can also influence the phenotype.
Currently a genetic diagnosis is possible for 40-50% of individuals with congenital hyperinsulinism, suggesting that mutations in novel genes remain to be discovered rapid genetic diagnosis is clinically important for patients. For example the mode of inheritance of a KATP channel mutation(s) can provide information regarding the histological subtype which will inform on the need for 18F-DOPA-PET scanning. A genetic diagnosis is also important for patients with medically managed hyperinsulinism. For example the identification of a GLUD1 or HADH mutation will inform the clinician of the protein sensitive nature of hypoglycaemia allowing for the manipulation of diet (protein restriction) as a useful, sometimes mandatory, adjunct to medical therapy. Furthermore, the presence of a HNF4A mutation would identify patients who are at a risk of developing maturity onset diabetes of the young (MODY) which can be successfully managed with low dose sulphonylureas. Finally, a genetic diagnosis will also allow for an accurate recurrence risk for siblings and future offspring.
Below is a brief overview of the most common genetic aetiologies for congenital hyperinsulinism for which our laboratory provide testing.
K-ATP Channel – ABCC8 and KCNJ11
Inactivating mutations in the KCNJ11 or ABCC8 genes which encode the pancreatic beta cell ATP-sensitive potassium (K-ATP) channel are the most common known cause of congenital hyperinulinism. Individuals with this genetic subtype often show a poor response to medical therapy and may require a partial or near total pancreatectomy. Diffuse disease results from the inheritance of a dominant or two recessively acting mutations. In contrast focal lesions result from paternal uniparental disomy (UPD) of chromosome 11p15.5–11p15.1 within a single pancreatic beta cell. The UPD unmasks the paternally inherited KATP channel mutation at 11p15.1 and causes altered expression of imprinted genes that include the maternally expressed tumor suppressor genes, H19 and CDKN1C, and the paternally expressed growth factor IGF2, at 11p15.5. This disruption in the expression of key cell cycle genes results in clonal expansion of the single cell and dysregulated insulin secretion from the resulting focal lesion. A genetic diagnosis of focal hyperinsulinism can be confirmed following surgery, by analysis of microsatellite makers on chromosome 11 to investigate loss of heterozygosity for the maternal allele within the focal lesion.
Location: Chromosome 11p15.1 (hg38: chr11:17,385,859-17,476,845)
Protein name: Inwardly rectifying K+ channel (Kir6.2), Sulphonylurea Receptor 1 (SUR1)
OMIM: # 601820 and #256450
Number of coding exons: 1 (KCNJ11), 39 (ABCC8)
Prevalence of mutations in Exeter Cohort: 37% of referral
Glutamate Dehydrogenase – GLUD1
Heterozygous activating mutations in GLUD1, which encodes the mitochondrial enzyme glutamate dehydrogenase (GDH), cause protein-sensitive hyperinsulinism. In the majority of cases the mutations arise spontaneously so there is often no family history of hyperinsulinism. In keeping with the dominant nature of these mutations future offspring of affected individuals will be at 50% risk of inheriting the mutation and developing hyperinsulinism. Individuals usually present with a milder form of HH that is often diagnosed outside of the neonatal period and shows good response to diazoxide therapy. In some patients dietary protein restriction may also be required. A consistent feature is the presence of hyperammonaemia with plasma ammonium levels being persistently raised to two to three times the upper limit of normal. This feature of the disease has resulted in this subtype of hyperinsulinism being referred to as Hyperinsulinism/Hyperammonaemia (HA/HA) syndrome. There is also an increased risk of epilepsy in some patients.
Location: Chromosome 10q23.2 (hg38: chr10: 87,050,486 – 87,094,866)
Protein name: Glutamate Dehydrogenase (GDH)
OMIM: # 606762
Number of coding exons: 13
Prevalence of mutations in Exeter Cohort: 2.5% of referrals
Glucokinase – GCK
Patients with heterozygous activating GCK mutations often have a dominant family history of hypoglycaemia. The absence of a family history of HH should however not preclude testing as de novo mutations have also been reported in some individuals. In those families with multiple affected individuals the severity of symptoms will often vary between family members. The age at presentation ranges from birth to adulthood and in some cases is asymptomatic. Whilst individuals are often diazoxide responsive a few cases who required surgery have been described.
Location: Chromosome 7p13 (hg38: chr7:44,144,275 – 44,189,423)
Protein name: Glucokinase (GCK)
OMIM: # 602485
Number of coding exons: 10
Prevalence of mutations in Exeter Cohort: 0.8% of referrals
Hepatocyte Nuclear Factor 4 Alpha – HNF4A
Patients with heterozygous inactivating HNF4A mutations are often born macrosomic and approximately 10% of individuals are diagnosed with hyperinsulinism within the first week of life. The clinical severity ranges from mild transient hypoglycemia that does not require pharmacological treatment to persistent HH treated with diazoxide for up to 8 years. As HNF4A mutations cause maturity onset diabetes of the young (MODY) patients will be at increased risk of developing diabetes in later life and will often have a family history of diabetes. For further information on HNF4A-MODY see out diabetes genes website.
Location: Chromosome 20q13.12 (hg38: chr20:44,355,801-44,429,671)
Protein name: Hepatocyte Nuclear Factor 4 alpha
OMIM: # 125850
Number of coding exons: 10
Prevalence of mutations in Exeter Cohort: 1.7% of referrals
Hydroxyacyl-coenzyme A dehydrogenase – HADH
Recessively inherited inactivating mutations in HADH cause leucine-induce HH which responds well to diazoxide. The clinical presentation is heterogeneous, with age at presentation ranging from birth to late infancy. In some patients increased plasma hydroxybutyrylcarnitine and urinary 3-hydroxyglutarate levels are observed. Whilst the majority of mutations affect the protein coding regions of the gene a deep intronic mutation has been identified in the Turkish population.
Location: Chromosome 4q25 (hg38: chr4:107,989,784 – 108,035,175)
Protein name: Hydroxyacyl-CoA dehydrogenase
OMIM: # 609975
Number of coding exons: 8
Prevalence of mutations in Exeter Cohort: 2.6% of referrals
Monocarboxylate Transporter 1 (MCT1) – SLC16A1
Rare heterozygous activating mutations in SLC16A1 encoding the monocarboxylate transporter 1 (MCT-1), cause exercise-induced hyperinsulinism (EIHI). For these patients treatment is not usually necessary as hypoglycaemic episodes may be prevented by avoiding strenuous exercise.
Location: Chromosome 1p13.2 (hg38: chr1:112,911,847-112,956,353)
Protein name: Monocarboxylate Transporter 1
OMIM: # 610021
Number of coding exons: 5 (+1 non-coding exon)
Prevalence of mutations in Exeter Cohort: 0% of referrals
Syndromes featuring hyperinsulinaemic hypoglycaemia
Beckwith-Wiedemann Syndrome – Chromosome 11p15.5
Beckwith-Wiedemann Syndrome (BWS) is a severe overgrowth disorder characterized by macroglossia, abdominal wall defects, hemihypertrophy, macrosomia, hypoglycaemia and increased risk of tumors. A number of different genetic mechanisms can lead to BWS, all of which result in abnormalities in methylation at one of two imprinting centers (ICR1 and ICR2) on chromosome 11p15.5. In approximately 20-30% of cases BWS results from paternal uniparental disomy (UPD) across the 11p15.5 region leading to an imbalance in imprinting and dysregulation of genes that are important for cell cycle regulation. As UPD is a sporadic event which may occur during embryogenesis there is often variability in the tissues which are affected. This can explain the differences in phenotype observed between individuals with BWS. Testing for BWS is not a routine test, so please contact the laboratory directly to discuss individual cases.
Phosphomannomutase 2 – PMM2
Biallelic mutations in PMM2 cause the rare syndrome of hyperinsulinaemic hypoglycaemia and polycystic kidney disease (HIPKD). All reported patients have a promoter mutation (c.-167G>T) which is either homozygous or in trans with a PMM2 coding mutation (2).
PMM2 encodes a key enzyme in N-glycosylation. Abnormal glycosylation has previously been associated with polycystic kidney disease and deglycosylation in pancreatic β-cells alters insulin secretion. Recessive coding mutations in PMM2 cause congenital disorder of glycosylation type 1a (CDG1A), a devastating multi-system disorder with prominent neurological involvement. These typical clinical features of CDG1A are absent in patients with HIPKD the diagnostic testing of transferrin isoelectric focusing is normal in these individuals clearly separating HIPKD from CDG1A and establishing PMM2 pleiotropy.
Functional studies on the promoter mutation demonstrated decreased transcriptional
activity in the kidney cells of a patient and impaired binding of the transcription factor ZNF143 (2). In silico analysis suggests an important role of ZNF143 for the formation of a chromatin loop including PMM2. It has therefore been proposed that the promoter mutation alters tissue-specific chromatin loop formation with consequent organ-specific deficiency of PMM2 leading to the restricted phenotype of HIPKD
Location: Chromosome 16p13.2 (hg38: Chr16:8,797,817-8,849,331)
Protein name: Phosphomannomutase 2
Number of coding exons: 8
Prevalence of mutations in Exeter Cohort: <1% of referrals
A recessively inherited loss of function mutation has been identified in the TRMT10A gene, which encodes a methyltransferase involved in the post-transcriptional modification of RNA, has been reported in three siblings from a single family with microcephaly, intellectual disability, short stature, delayed puberty, seizures and hyperinsulinaemic hypoglycaemia diagnosed outside of infancy (2). Post-prandial hyperglycaemia was also reported in one of the siblings.
Location: Chromosome 4q23 (hg38: chr4:99,546,709-99,564,017)
Protein name: tRNA methyltransferase 10A
Number of coding exons: 13
We have identified a p.G403D de novo mutation in CACNA1D in a child with persistent diazoxide-responsive HH, mild aortic insufficiency, severe hypotonia, and developmental delay. CACNA1D encodes the main L-type voltage-gated calcium channel in the pancreatic β-cell, a key component of the insulin secretion pathway. The p.G403D mutation had been reported previously as an activating mutation in an individual with primary hyperaldosteronism, neuromuscular abnormalities, and transient hypoglycaemia (3).
Location: Chromosome 3p21.1 (hg38: chr3:53,495,049-53,813,733)
Protein name: Calcium voltage-gated channel subunit alpha 1 D
Number of coding exons: 49
Prevalence of mutations in Exeter Cohort: <1%
Hypoinsulinaemic Hypoketotic Hypoglycaemia – AKT2
Our laboratory can provide screening of the AKT2 gene. AKT2 encodes a serine/threonine protein kinase which is acts to mediate the physiological effects of insulin downstream to the insulin receptor. Activating AKT2 mutations lead to the autonomous activation of the downstream insulin signaling pathway resulting in hypoinsulinemic hypoketotic hypo-fatty-acidemic hypoglycemia. Individuals are also reported to have hemi-hypertophy.
Genetic testing for AKT2 is not offered as a routine test by the laboratory so please contact us directly if you would like to discuss the possibility of testing for an individual patient.
Location: Chromosome 19q13.2 (hg38: chr19:40,230,317-40,285,395)
Protein name: v-akt murine thymoma viral oncogene homolog 2
Number of coding exons: 13
Kabuki Syndrome – KMT2D and KDM6A
Kabuki syndrome is a rare congenital disorder with characteristic facial appearance (long palpebral fissures, long and dense eyelashes and arched eyebrows, short nasal columella with a depressed nasal tip, prominent ears and a mouth with a thin upper lip and a full lower lip), poor postnatal growth, short stature, variable congenital malformations (cleft palate and cardiovascular defects), learning disabilities, seizures, neonatal hyperinsulinaemic hypoglycaemia, hypothyroidism, and immune dysfunction.
Autosomal dominant Kabuki syndrome as a result of heterozygous disease-causing variants in KMT2D account for ~56-75% of cases. Disease causing variants in KDM6A result in an X-linked dominant form of Kabuki and account for ~3-8% of cases.
- Cabezas OR, Flanagan SE, Stanescu H, García-Martínez E, Caswell R, Lango-Allen
H, Antón-Gamero M, Argente J, Bussell AM, Brandli A, Cheshire C, Crowne E,
Dumitriu S, Drynda R, Hamilton-Shield JP, Hayes W, Hofherr A, Iancu D, Issler N,
Jefferies C, Jones P, Johnson M, Kesselheim A, Klootwijk E, Koettgen M, Lewis W,
Martos JM, Mozere M, Norman J, Patel V, Parrish A, Pérez-Cerdá C, Pozo J, Rahman
SA, Sebire N, Tekman M, Turnpenny PD, Hoff WV, Viering DHHM, Weedon MN, Wilson P, Guay-Woodford L, Kleta R, Hussain K, Ellard S, Bockenhauer D. Polycystic Kidney Disease with Hyperinsulinemic Hypoglycemia Caused by a Promoter Mutation in Phosphomannomutase 2. J Am Soc Nephrol. 2017 Aug;28(8):2529-2539. doi:10.1681/ASN.2016121312. Epub 2017 Apr 3. PubMed PMID: 28373276; PubMed Central PMCID: PMC5533241.
- Gillis et al. TRMT10A dysfunction is associated with abnormalities in glucose homeostasis, short stature and microcephaly. J Med Genet. 2014 Sep;51(9):581-6.
- Flanagan SE, Vairo F, Johnson MB, Caswell R, Laver TW, Lango Allen H, Hussain
K, Ellard S. A CACNA1D mutation in a patient with persistent hyperinsulinaemic
hypoglycaemia, heart defects, and severe hypotonia. Pediatr Diabetes. 2017
Jun;18(4):320-323. doi: 10.1111/pedi.12512. Epub 2017 Mar 20. PubMed PMID:
28318089; PubMed Central PMCID: PMC5434855.