Congenital isolated hyperinsulinism (ORPHA:657)
A rare endocrine disease characterized by an excessive or uncontrolled insulin secretion and recurrent episodes of hypoglycemia that can result in neurological sequelae if left untreated. There are two forms according to the response to first line treatment: diazoxide-sensitive and diazoxide-resistant hyperinsulinism; and three histopathological forms: focal, diffuse and atypical forms. Focal forms are only observed in early-onset cases of diazoxide unresponsive patients.
Epidemiology
Isolated Congenital hyperinsulinism (CHI) is the most frequent cause of severe and persistent hypoglycemia in the neonatal period and early infancy. The average birth prevalence is 1/27,000 worldwide, but it may be as high as 1/2,500 in communities with substantial consanguinity.
Clinical description
CHI can present from birth through early adulthood according to the severity of hypoglycemia. Neonatal onset is the most frequent; newborns, often macrosomic, present with poor feeding, intolerance to fasting and persistent hypoglycemia. Hypoglycemic episodes range from mild (lethargy, hypotonia and irritability) to severe (apnea, seizures or coma) that lead to neurologic sequelae. Patients who present later have recurrent, typical hypoglycemia (pallor, profuse sweating and tachycardia).
Etiology
Nine genes are associated to CHI; the most common variants involve ABCC8 (11p15.1) and KCNJ11 (11p15.1), the genes encoding the ATP-sensitive potassium channel in pancreatic beta cell.
Diagnostic methods
Detectable serum insulin/C-peptide, low ketone bodies and suppressed fatty acids during hypoglycemic episodes are diagnostic of hyperinsulinemic hypoglycemia. Requirement of continuous glucose above the physiological rate of liver glucose production is pathognomonic of hyperinsulinism (HI). Later onset CHI may require provocative testing. The congenital (genetic) form should be established via family history consistent with HI or monogenic diabetes, abnormal biochemical features (hyperammonemia in association with GDH variants, or high plasma C4-OH and urine 3OH-glutarate with HADH variants), and genetic testing. Lastly, in cases unresponsive to diazoxide urgent genetic testing for ABCC8 / KCNJ11 variants and, when necessary, 18F-DOPA-Positron emission tomography (PET) imaging is indicated in order to differentiate the focal and diffuse forms.
Differential diagnosis
Differential diagnosis include all the other causes of recurrent hypoglycemia: for HI observed from birth these include transient neonatal HI as well as syndromic CHI (more than 30 syndromes feature HI at birth, the most frequent are Beckwith-Wiedemann, Kabuki and Turner syndrome); later in life, these may include insulinoma, post bariatric surgery HI, drug-induced HI, and auto-immune syndromes (HI due to anti-insulin antibodies) etc.
Antenatal diagnosis
Antenatal genetic testing is possible when the molecular etiology has been identified in a proband.
Genetic counseling
The disorder can be autosomal dominant or recessive, and thus genetic counseling will depend on the variants responsible (de novo, germline or somatic mutations). Genetic testing may be offered to affected families when the molecular etiology has been identified in a proband.
Management and treatment
Normoglycemia must be rapidly recovered and maintained to prevent irreversible brain damage, especially in neonates. At birth, severe hypoglycemia might require continuous glucose infusion and glucagon injection. Diazoxide is the first line of medical therapy and octreotide is added as an adjunct in diazoxide unresponsive patients. Partial pancreatic resection is curative for focal HI. For patients with diffuse disease, a conservative treatment is proposed when safely possible; for patients resistant to diet and medical management, near-total pancreatectomy may be necessary.
Prognosis
For neonatal-onset CHI, the main concern is the cognitive outcome, which might be impaired in up to 30 to 50% of patients, especially in those who suffered from prolonged and severe hypoglycemia. The spontaneous evolution of glycemia varies: in children the disease severity reduces with time, and sometimes might even resolve, while in others it persists through adulthood. When resolved, a life-long follow-up is advised due to a risk of diabetes. In cases of subtotal pancreatectomy, glucose intolerance and diabetes mellitus requiring insulin is inevitable, occurring within 15 years after the surgery.

                            Last update: 
                            June 2022


                            - Expert reviewer(s): 
                            Dr Jean-Baptiste ARNOUX | MetabERN* - Dr Cécile SAINT-MARTIN 


                                * European Reference Network