Dunia Ismail

The genetic basis of congenital hyperinsulinism

Congenital hyperinsulinism (CHI) is biochemically characterised by the dysregulated secretion of insulin from pancreatic β-cells. It is a major cause of persistent hyperinsulinaemic hypoglycaemia (HH) in the newborn and infancy period. Genetically CHI is a heterogeneous condition with mutations in seven different genes described. The genetic basis of CHI involves defects in key genes which regulate insulin secretion from β-cells. Recessive inactivating mutations in ABCC8 and KCNJ11 (which encode the two subunits of the adenosine triphosphate sensitive potassium channels (ATP sensitive KATP channels)) in β-cells are the most common cause of CHI. The other recessive form of CHI is due to mutations in HADH (encoding for-3-hydroxyacyl-coenzyme A dehydrogenase). Dominant forms of CHI are due to inactivating mutations in ABCC8 and KCNJ11, and activating mutations in GLUD1 (encoding glutamate dehydrogenase) and GCK (encoding glucokinase). Recently dominant mutations in HNF4A (encoding hepatocyte nuclear factor 4α) and SLC16A1 (encoding monocarboxylate transporter 1) have been described which lead to HH. Mutations in all these genes account for about 50% of the known causes of CHI. Histologically there are three (possibly others which have not been characterised yet) major subtypes of CHI: diffuse, focal and atypical forms. The diffuse form is inherited in an autosomal recessive (or dominant manner), the focal form being sporadic in inheritance. The diffuse form of the disease may require a near total pancreatectomy whereas the focal form requires a limited pancreatectomy potentially curing the patient. Understanding the genetic basis of CHI has not only provided novel insights into β-cell physiology but also aided in patient management and genetic counselling.

The predictive value of preoperative fluorine-18-L-3,4-dihydroxyphenylalanine positron emission tomography-computed tomography scans in children with congenital hyperinsulinism of infancy.

BACKGROUND/PURPOSE In congenital hyperinsulinism (CHI) of infancy, the use of preoperative fluorine-18-L-3,4-dihydroxyphenylalanine-positron emission tomography-computed tomography ((18)F-DOPA-PET-CT) scan has recently been reported. The aim of this study was to evaluate the accuracy of this technique in discriminating between diffuse and focal CHI and the anatomical localization of focal lesions. METHODS Between 2006 and 2010, (18)F-DOPA-PET scan was performed in 19 children with CHI (median age, 2 months; range, 1-12 months) who were not responding to medical therapy and underwent laparoscopic or open surgery. The findings of (18)F-DOPA-PET scan were correlated with histology. RESULTS In 5 children, (18)F-DOPA-PET scan showed diffuse pancreatic uptake, confirmed at histology and supporting the genetic suspicion of diffuse disease. In 14 children, (18)F-DOPA-PET scan indicated focal pancreatic uptake, which corresponded to histology. However, in 5 patients (36%), (18)F-DOPA-PET scan was inaccurate in defining the location of the lesion (n = 3), size of the lesion (n = 1), or both location and size (n = 1), leading to an inaccurate pancreatic resection. CONCLUSIONS Fluorine-18-L-3,4-dihydroxyphenylalanine-positron emission tomography-computed tomography scan discriminates between diffuse and focal forms of CHI. In focal forms, (18)F-DOPA-PET scan is useful in 2/3 of patients in defining the site and dimension of the focal lesion. Intraoperative histologic confirmation of complete focal lesion resection is needed.

Familial Focal Congenital Hyperinsulinism

This report describes focal congenital hyperinsulinism in siblings, and genetic counseling is recommended for this rare disease.

The Heterogeneity of Focal Forms of Congenital Hyperinsulinism

BACKGROUND Congenital hyperinsulinism (CHI) is a cause of persistent hypoglycemia due to unregulated insulin secretion from pancreatic β-cells. Histologically, there are two major subgroups, focal and diffuse. Focal CHI is typically unresponsive to diazoxide and can be cured with surgical removal of the focal lesion. AIMS We report on three patients with focal CHI to illustrate the marked clinical, genetic, radiological, and histological heterogeneity. METHODS AND RESULTS The first two patients had focal CHI due to a paternal (c.3992-9G→A) ABCC8 mutation. One of these patients was fully responsive to a small dose (5 mg/kg · d) of diazoxide, whereas the other patient was medically unresponsive. In both patients, the focal lesions were accurately localized preoperatively by [(18)F]dihydroxyphenylalanine (DOPA) positron emission tomography (PET) and surgically resected. The third patient had a paternally inherited ABCC8 (A1493T) mutation, and the initial [(18)F]DOPA PET scan indicated extensive uptake of DOPA in the body and tail of the pancreas. However, despite surgical resection of the body and tail, this patient continued to have severe CHI. A subsequent [(18)F]DOPA PET scan now showed markedly increased DOPA uptake in the remaining body and head of the pancreas. This focal lesion occupied virtually the whole of the pancreas. conclusions: These three cases illustrate that focal lesions even with the same genotype (c.3992-9G→A) may have a different clinical presentation and that [(18)F]DOPA PET scans in very large focal lesions may be difficult to interpret.

Role of 18F-DOPA PET/CT imaging in congenital hyperinsulinism.

Congenital hyperinsulinism is a leading cause of severe hypoglycaemia in the newborn period. There are two (diffuse and focal) histological subtypes of congenital hyperinsulinism. The diffuse form affects the entire pancreas and if medically unresponsive will require a near total (95%–98%) pancreatectomy. The focal form affects only a small region of the pancreas (with the rest of the pancreas being normal in endocrine and exocrine function) and only requires a limited pancreatectomy. This limited section of the focal lesion has the potential for curing the patient. Thus the pre-operative differentiation of these two subgroups is extremely important. Recent advances in Fluorine-18-L-dihydroxyphenylalanine positron emission tomography (18F-DOPA PET/CT) have radically changed the clinical approach to patient with congenital hyperinsulinism. In most patients this novel imaging technique is able to offer precise pre-operative localisation of the focal lesion, thus guiding the extent of surgical resection.

The heterogeneity of hyperinsulinaemic hypoglycaemia in 19 patients with Beckwith-Wiedemann syndrome due to KvDMR1 hypomethylation

Abstract Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome caused by multiple epigenetic and genetic changes affecting imprinted genes on chromosome 11p15.5. Hypomethylation of KvDMR1 on the maternal allele is the most common genetic cause, and hyperinsulinaemic hypoglycaemia (HH) is the most common biochemical abnormality. We evaluated the correlation between severity of HH and degree of hypomethylation in BWS. Out of the 19 patients with BWS due to KvDMR1 hypomethylation, 10 patients had no HH, 5 had mild transient HH that resolved spontaneously, and 4 required diazoxide therapy for up to 6 months. There was no correlation between the degree of KvDMR1 hypomethylation and severity of HH in the 6 patients studied. All patients also showed marked clinical heterogeneity with respect to the features of BWS. In patients with BWS due to hypomethylation of KvDMR1, the clinical presentation of HH is quite heterogeneous with no correlation with the degree of KvDMR1 hypomethylation.

Mutational analysis of the GYS2 gene in patients diagnosed with ketotic hypoglycaemia

Abstract Background: Ketotic hypoglycaemia is a common form of hypoglycaemia in childhood. Biochemically, patients present with fasting hypoglycaemia but with normal hormonal and metabolite profiles (low serum alanine levels in some patients). Glycogen Storage Disease Type 0 (GSD0) is an autosomal recessive disease due to mutations in the GYS2 gene. Patients with GSD0 also present with fasting ketotic hypoglycaemia. The frequency of GSD0 in patients presenting with ketotic hypoglycaemia is not known. Objective: To understand the frequency of GSD0 in patients presenting with ketotic hypoglycaemia and to report a novel mutation in the GYS2 gene. Subjects: The GYS2 gene was sequenced in 50 patients diagnosed with ketotic hypoglycaemia. Methods: All exons (including exon and intron boundaries) of the GYS2 gene were sequenced following amplification of the coding region by polymerase chain reaction (PCR). Results: No mutations in GYS2 were found in 49 patients. One patient had a novel homozygous mutation (c.1802T>G; p. Leu601X) in exon 14 of the GYS2 gene. We believe this is the 18th mutation reported so far. This mutation is predicted to lead to premature truncation of the glycogen synthase protein with no function. This patient presented with fasting ketotic hypoglycaemia associated with postprandial hyperglycaemia and elevated lactate level. Conclusions: GSD0 is relatively rare in patients presenting with ketotic hypoglycaemia and a normal biochemical profile. Sequencing of the GYS2 gene is more likely to be positive in patients with fasting ketotic hypoglycaemia and concomitant postprandial hyperglycaemia with hyperlactataemia.