Facial appearance in persistent hyperinsulinemic hypoglycemia

Abstract

Persistent hyperinsulinism is the most common cause of recurrent hypoglycemia in infancy because of inappropriate oversecretion of insulin by the pancreas. Pancreatic lesions can be either focal or diffuse, and they have distinct molecular bases. We have studied the facial features in 17 unrelated patients presenting with neonatal (n = 8) or infancy-onset (n = 9) hyperinsulinism. Hyperinsulinism was related to focal adenomatous hyperplasia (n = 7), diffuse hyperinsulinism (n = 5), non-operated hyperinsulinism (n = 2), and hyperinsulinism with hyperammonemia (n = 3). SUR1 or Kir6.2 mutations were found in six of seven focal adenomatous hyperplasia and three of five diffuse hyperinsulinism. A loss of the maternal allele from chromosome 11p15 in the lesion was found in all focal adenomatous hyperplasia. GLUD1 mutations were found in all patients with hyperammonemia. Large birth weight (mean > 3,800 g) was consistently observed (11/17) but protruding tongue, exomphalos, or visceromegaly were never noted and Wiedemann-Beckwith syndrome could always be ruled out. All patients presented with high forehead, small nasal tip, and short columella giving the impression that the nose is large and bulbous, smooth philtrum, and thin upper lip. A square appearance to the face was more obvious in younger patients. These specific facial features, observed in patients with hyperinsulinism of various molecular mechanisms, could be the consequence of fetal intoxication by insulin. However, to date, facial anomalies have not been noted in infants of diabetic mothers and inversely, malformations that are commonly reported in infants of diabetic mothers were not present in our hyperinsulinemic patients.

Activating glucokinase (GCK) mutations as a cause of medically responsive congenital hyperinsulinism: prevalence in children and characterisation of a novel GCK mutation.

“…The exclusion criteria 'syndromic CHI' was defined as Beckwith-Wiedemann syndrome or other syndromes with gross anatomical morphological changes. Biochemical alterations suggesting CHI-GLUD1, CHI-HADH, CHI-INSR or CHI-SLC16A1 and mild dysmorphic facial features typical of CHI were not considered (12,14,15,(25)(26)(27). Informed consent was obtained according to national standards.…”

Diagnosis and Management of Hyperinsulinaemic Hypoglycaemia of Infancy

“…Some infants with CHI are macrosomic which may reflect their exposure to perinatal hyperinsulinaemia, but the absence of macrosomia does not exclude CHI, as not all infants with CHI are macrosomic. Some patients with CHI may have mild facial dysmorphism such as a high forehead, a small nasal tip, and short columella with a square face, although the reason for this is unclear [14]. …”

Molecular Mechanisms of Neonatal Hyperinsulinism

“…Mild hepatomegaly is common and does not prevent the diagnosis of hyperinsulinism. Facial dysmorphism with high forehead, large and bulbous nose with short columella, smooth philtrum and thin upper lip is frequently observed in all types of hyperinsulinism [11]. Epilepsy seems to be frequent in patients with hyperinsulinism associated to hyperammonaemia and is not explained by hypoglycaemia only [12].…”