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Congenital hyperinsulinism is considered to be the most frequent cause of persistent recurrent hypoglycaemia in infants. The clinical presentation and response to pharmacological treatment may vary significantly depending on the underlying pathology. We report a case of a female infant with mild but early onset of recurrent hypoglycaemia. Metabolic workup revealed hyperinsulinism combined with mild hyperammonaemia as well as elevation of α-ketoglutarate in urine. Genetic testing demonstrated a de novo mutation in exon 7 of the glutamate dehydrogenase gene on chromosome 10. Episodes of hypoglycaemia responded to treatment with diazoxide. The differential diagnosis, pathophysiology and treatment of congenital hyperinsulinism is discussed.
Congenital hyperinsulinism (CHI), previously termed “nesidioblastosis”, is considered to be the most frequent cause of persistent recurrent hypoglycaemia in infants. Incidence is estimated 1:40,000 births in central Europe. In ethnic groups with high proportions of consanguineous parents, the incidence can be as high as 1:2500.1,2 The clinical presentation varies depending on the underlying pathology with respect to both the severity of hypoglycaemia as well as in the response to pharmacological treatment.
Sixty per cent of CHI are diagnosed within the first 3 days of life, with the remaining 40% being diagnosed later; 85% of the remainder are diagnosed in months 2–12, and 15% after the first year of life.3 Clinical symptoms include seizures, pallor, muscle weakness, cyanosis and cardiac failure, but neonates may be asymptomatic (20%).3
CHI is an important diagnosis to consider in neonatal hypoglycaemia as it is an important cause of severe neurodevelopmental impairment.
A female infant (weight 2700g (small for gestational age, SGA), length 47 cm, occipitofrontal circumference (OFC) 32 cm) was born at 38+6 weeks to a 33-year-old G1/P1 by elective caesarean section. There was no maternal history of unexplained primary sterility, spontaneous abortions or peri/neonatal deaths as well as no maternal health issues during pregnancy and no suggestion of maternal diabetes mellitus or gestational diabetes. Postnatal adaptation was normal with APGAR scores of 9, 10 and 10 after 1, 5 and 10 min, respectively. Early medical examination did not reveal any abnormalities. On the first day of life, the infant showed hypoglycaemia with blood glucose values between 1.7–2.2 mmol/l despite early feeding with maltodextrine. Blood glucose values normalised on an intravenous glucose infusion. During the following days ongoing intravenous glucose administration was necessary despite increased oral feeding. The initial metabolic workup included cortisol, insulin, growth hormone, lactate and ammonia. These bloods were sampled at a glucose concentration of 2.7 mmol/l. The results were normal other than a slight hyperammonaemia at 141 μmol/l (controlled 159 μmol/l). A screen for inborn errors of metabolism showed no distinctive features.
With a presumed diagnosis of prolonged transient hyperinsulinism secondary to growth restriction we began treatment with hydrocortisone (2 mg twice daily), which stabilised blood glucose values with normal feeding.
At the age of 8 weeks hydrocortisone medication was terminated. Blood glucose values remained within the normal range, ammonia was slightly elevated at 92 μmol/l.
The infant was readmitted at the age of 5½ months for observation after a fall to the floor from a “babysafe” carry system. Clinical examination was inconspicuous. Sensorimotor development as well as growth was normal for its age. No neurological symptoms appeared until discharge 2 days later.
Three hours after returning back home, an episode of abnormal jerky movements of the head with an empty gaze was observed over a period of 5 min. Feeding had been normal that morning with 180–200 ml formula milk every 4–5 h plus a half portion of porridge. On admission to hospital, the blood glucose concentration was measured at 2.2 mmol/l. A computed tomography (CT) scan of the skull excluded acute intracranial haemorrhage and the electroencephalogram (EEG) recordings showed no pathologic activity. Intensified metabolic workup showed the following results.
At blood glucose concentration of 3.0 mmol/l:
At blood glucose concentration of 2.2 mmol/l:
Box 1 lists the diagnostic criteria for CHI.
Carbohydrates were supplemented up to 20 g/kg/day by oral feeding of formula milk with 15% maltodextrine plus intravenous glucose infusion, according to a theoretical glucose demand of 14 mg/kg/min.
Although the relevant blood samples could not be taken in real hypoglycaemia (defined as blood glucose <2 mmol/l), the insulin concentration demonstrated was inappropriately high given the low blood glucose concentration. Furthermore the suppression of lipolysis and ketogenesis seen are characteristic of congenital hyperinsulinism.
The concomitant hyperammonaemia and elevation of α-ketoglutarate seen in urine are indicative of a defect of the glutamate dehydrogenase.4
Box 2 lists the differential diagnosis for CHI
In our patient the acyl-carnitine-profile was normal, ruling out SCHAD (lack of short-chain-L-3-hydroxylacetyl-CoA-dehydrogenase) as an important differential diagnosis. Growth hormone values were elevated due to a counter-regulatory rise caused by hypoglycaemia.
After the diagnosis of CHI was established, treatment was commenced with diazoxide 5 mg/kg/day orally, increasing to 10 mg/kg/day after 3 days.
Following treatment we observed an elevation of pre- and post-prandial blood glucose concentrations up to the normal range (fig 1).
Neurodevelopmental follow-up examination until the age of 2 years was normal. Blood glucose values remained stable on diazoxide medication.
To understand the background of CHI, the physiologic regulation of the pancreatic β-cell has to be understood:
The molecular mechanism of hyperinsulinism is caused by the impairment of either the intramembranous or intracellular proteins of the pancreatic β-cell (table 1).
In our patient a heterozygotic sporadic mutation (GLUD1 exon 7 c.965G>A p.Arg322His) was detected which was not present in the parents.
Pathological mutations of the same region have been described previously, firstly in a domain encoded by exons 11 and 127 and subsequently in a second domain encoded by exons 6 and 7.6 Our case demonstrated the latter mutation. All these mutations impair the sensitivity of the enzyme to allosteric inhibition by GTP. In a study of 48 examined cases, all of the affected patients were heterozygous, and 75% had the mutation de novo rather than inherited.7
In our case the metabolic investigations were done during low blood glucose concentrations but not during a severe hypoglycaemic episode because an intravenous glucose infusion had already been commenced before blood sampling. This resulted in hormone values (for example, insulin) which were difficult to interpret. This is a common scenario in neonatal practice because of the importance of early correction of profound hypoglycaemia to prevent neurological sequelae. It is therefore crucial to consider hyperinsulinism early in the diagnostic process when treating infants with hypoglycaemia.
Metabolic diagnostics were carried out by the Stoffwechselzentrum Heidelberg, Germany. Genetic testing was carried out by IntraGen GmbH Bonn, Germany.
Competing interests: None.
Patient consent: Patient/guardian consent was obtained for publication.