ORPHA: 79299; DO: 0070216;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7p13 | Hyperinsulinemic hypoglycemia, familial, 3 | 602485 | Autosomal dominant | 3 | GCK | 138079 |
A number sign (#) is used with this entry because of evidence that familial hyperinsulinemic hypoglycemia-3 (HHF3) is caused by heterozygous mutation in the glucokinase gene (GCK; 138079) on chromosome 7p13.
For a phenotypic description and a discussion of genetic heterogeneity of familial hyperinsulinemic hypoglycemia, see HHF1 (256450).
Thornton et al. (1998) described 3 families with vertical transmission of hyperinsulinism of infancy, suggesting autosomal dominant inheritance. This form of the disorder appeared to be both phenotypically and genetically distinct from autosomal recessive persistent hyperinsulinemic hypoglycemia of infancy. Thornton et al. (1998) compared clinical features of 11 patients from these 3 apparent autosomal dominant inheritance pattern families with those of 14 patients with autosomal recessive hyperinsulinism investigated in the same hospital. The median age of onset was 1 year and 1 day, respectively; birth weight was 3.3 and 4.6 kg, respectively; and response to diet and diazoxide was observed in 10 of the autosomal dominant cases and none of the autosomal recessive cases. None of the mutations previously identified in the SUR1 gene were found in these families.
Cuesta-Munoz et al. (2004) reported a Finnish woman who had hypoglycemic seizures from birth and inappropriate hyperinsulinemia. Despite a leucine-free diet, high-dose glucose infusion, hydrocortisone, and glucagon, hypoglycemia persisted. She underwent subtotal pancreatectomy at the age of 6 months with no resolution of hypoglycemia; treatment with diazoxide, which continued for 22 years, was also unsuccessful. She was severely mentally retarded, and had seizures until her death at age 29. Histologic analysis of the pancreatic specimens from age 6 months showed pancreatic islets that were 2.5-fold larger than those of controls, and 8- to 10-fold larger compared to those of hyperinsulinemic patients with focal or diffuse pancreatic lesions, respectively. Cuesta-Munoz et al. (2004) noted that this phenotype was considerably more severe than that of previously reported patients.
The transmission pattern of HHF3 in the family reported by Thornton et al. (1998) and studied by Glaser et al. (1998) was consistent with autosomal dominant inheritance.
In 'family 3' studied by Thornton et al. (1998), Glaser et al. (1998) identified a heterozygous activating mutation in the glucokinase gene (138079.0009). The authors noted that age at onset and severity of symptoms varied markedly in this family, and the oldest affected family member developed diabetes mellitus later in life.
In a 14-year-old obese boy with a history of neonatal hypoglycemia treated with diazoxide, who was experiencing hypoglycemic episodes associated with seizures and unconsciousness, Christesen et al. (2002) identified heterozygosity for an activating mutation in the GCK gene (138079.0012). The boy's normal-weight mother, who had asymptomatic fasting hypoglycemia, carried the same mutation. Christesen et al. (2002) noted the striking contrast in clinical presentation between the mother and son with the same mutation, and recalled a similar situation in the family reported by Glaser et al. (1998), in which the proband was obese and severely hyperinsulinemic, whereas his sister who carried the same mutation was of normal weight, had relatively low insulin levels, and milder clinical symptoms.
In a Finnish woman with severe hyperinsulinemic hypoglycemia from birth, Cuesta-Munoz et al. (2004) identified heterozygosity for a de novo activating mutation in the GCK gene (138079.0013). Although paternity was confirmed, the mutation was not found in her parents or her 2 healthy sisters.
Kassem et al. (2010) studied a young girl with severe neonatal hypoglycemia due to a missense mutation in the GCK gene (V91L; 138079.0015). Her father had a similar clinical course but neither his DNA nor pancreatic tissue was available for study. Diazoxide and octreotide therapy did not control the patient's hypoglycemia, and a subtotal pancreatectomy was performed at 3 years of age. Quantitative histologic examination revealed abnormally large islets, with some beta cells containing a large nucleus. The mean islet cell areas in both the head and the tail of the pancreas were significantly larger than those of 5 age-matched controls and those of 2 age-matched patients with diffuse hypoglycemia due to ABCC8 (600509) mutations (see HHF1, 256450), with a relative beta-cell area of 2.9% in the head and 6.7% in the tail of the patient's pancreas, compared with 1.8% in the controls and 1.1% in the patients with ABCC8-related hypoglycemia. Noting a previously reported case in which quantitative histologic analysis showed a similar increase in the mean islet profile (Cuesta-Munoz et al., 2004), Kassem et al. (2010) suggested that histologic findings in infants with hyperinsulinemic hypoglycemia might differ according to the genetic cause of the condition.
Christesen, H. B. T., Jacobsen, B. B., Odili, S., Buettger, C., Cuesta-Munoz, A., Hansen, T., Brusgaard, K., Massa, O., Magnuson, M. A., Shiota, C., Matschinsky, F., Barbetti, F. The second activating glucokinase mutation (A456V): implications for glucose homeostasis and diabetes therapy. Diabetes 51: 1240-1246, 2002. [PubMed: 11916951] [Full Text: https://doi.org/10.2337/diabetes.51.4.1240]
Cuesta-Munoz, A. L., Huopio, H., Otonkoski, T., Gomez-Zumaquero, J. M., Nanto-Salonen, K., Rahier, J., Lopez-Enriquez, S., Garcia-Gimeno, M. A., Sanz, P., Soriguer, F. C., Laakso, M. Severe persistent hyperinsulinemic hypoglycemia due to a de novo glucokinase mutation. Diabetes 53: 2164-2168, 2004. [PubMed: 15277402] [Full Text: https://doi.org/10.2337/diabetes.53.8.2164]
Glaser, B., Kesavan, P., Heyman, M., Davis, E., Cuesta, A., Buchs, A., Stanley, C. A., Thornton, P. S., Permutt, M. A., Matschinsky, F. M., Herold, K. C. Familial hyperinsulinism caused by an activating glucokinase mutation. New Eng. J. Med. 338: 226-230, 1998. [PubMed: 9435328] [Full Text: https://doi.org/10.1056/NEJM199801223380404]
Kassem, S., Bhandari, S., Rodriguez-Bada, P., Motaghedi, R., Heyman, M., Garcia-Gimeno, M. A., Cobo-Vuilleumier, N., Sanz, P., Maclaren, N. K., Rahier, J., Glaser, B., Cuesta-Munoz, A. L. Large islets, beta-cell proliferation, and a glucokinase mutation. New Eng. J. Med. 362: 1348-1350, 2010. Note: Erratum: New Eng. J. Med. 363: 2178 only, 2010. [PubMed: 20375417] [Full Text: https://doi.org/10.1056/NEJMc0909845]
Thornton, P. S., Satin-Smith, M. S., Herold, K., Glaser, B., Chiu, K. C., Nestorowicz, A., Permutt, M. A., Baker, L., Stanley, C. A. Familial hyperinsulinism with apparent autosomal dominant inheritance: clinical and genetic differences from the autosomal recessive variant. J. Pediat. 132: 9-14, 1998. [PubMed: 9469993] [Full Text: https://doi.org/10.1016/s0022-3476(98)70477-9]