Recognition of Hyperinsulinaemic Hypoglycaemia in Infants with Congenital Central Hypoventilation Syndrome

Introduction: Congenital central hypoventilation syndrome (CCHS) is a rare autosomal dominant condition due to mutations in the transcription factor PHOX2B. It is characterized by alveolar hypoventilation with symptoms of autonomic nervous system dysfunction. Hyperinsulinaemic hypoglycaemia (HH) due to glucose dysregulation caused by anomalous insulin secretion has been reported as a feature of CCHS. However, HH and glycaemic outcomes in the context of CCHS have not been characterized in longitudinal follow-up. We describe the variable phenotype of glucose dysregulation and glycaemic outcomes in children with CCHS.

Case presentation: We report 6 children with PHOX2B mutation-positive CCHS diagnosed with HH in a national cohort from two UK congenital hyperinsulinism specialist centres. We describe the initial presentation, the challenges in management, and glycaemic outcomes in longitudinal follow-up. All patients were term infants diagnosed with CCHS in the neonatal period due to PHOX2B mutations and required long-term ventilation by tracheostomy. HH was diagnosed at a median age of 222 days (median, range 36-594) with postprandial hypoglycaemia (4/6 patients) or fasting hypoglycaemia (2/6 patients). Two patients were treated with diazoxide monotherapy; one with diazoxide and overnight continuous gastrostomy feeds; one with acarbose; and two with dietary manifestations and use of continuous glucose monitoring sensor. Three patients who presented earlier in the observation period demonstrated a reduction in the severity of HH over time, leading to hypoglycaemia resolution at a median age of 4.8 years (range 4.45-5.5 years).

Conclusion: Patients with CCHS, due to PHOX2B mutations, may experience both fasting and postprandial hypoglycaemia, necessitating treatment for HH. Clinicians should screen children with CCHS for hypoglycaemia symptoms to quickly identify those affected by HH, initiate prompt treatment, and prevent potential brain injury from severe hypoglycaemia. The severity of hypoglycaemia due to HH tends to decrease over time, with glycaemic resolution potentially being achieved over several years.