1054 Congenital Central Hypoventilation Syndrome and PHOX2B Testing

Abstract

Introduction Individuals with congenital central hypoventilation syndrome (CCHS) have marked nocturnal hypoventilation and autonomic dysfunction. CCHS is commonly caused by a polyalanine expansion repeat mutation in PHOX2B. We describe a case of a child with hypoventilation and negative PHOX2B testing. Report of Case 10-year-old boy with tracheostomy and nocturnal ventilatory dependence presented for further evaluation of sleep-related hypoventilation. He was born full term and required intubation after birth. Stridor was noted that was felt to be from bilateral vocal cord dyskinesia and mild subglottic stenosis. Head ultrasound and brain MRI within the first month were unremarkable. At 1 month old, he received a tracheostomy due to multiple failed extubation attempts. At 6 months old, he had negative screening PHOX2B testing (fragment analysis test). Notably, this sample was obtained a month after blood transfusion. He was discharged from the hospital with continuous ventilatory support. Additional pertinent history includes constipation and a history of pneumonias without signs of respiratory distress. The patient was gradually weaned to nocturnal ventilatory support by 4 years old. To evaluate further weaning support, polysomnography performed initially on room air demonstrated evidence of sleep-related hypoventilation with severe oxyhemoglobin desaturations (nadir = 75%) and a peak end-tidal CO2 of 68 Torr. Including time ventilated, 40% of total sleep was spent with end-tidal CO2 >50 Torr. Thus, he was continued on nocturnal ventilatory support. Physical exam is notable for bilateral esotropia, squarely shaped face, flattened forehead, possible inferior inflection of the lateral upper lip vermillion border, extremity hypertonia, right-sided 4/5 weakness, normal left-sided strength, brisk reflexes, and clonus bilaterally. Conclusion This case demonstrates the challenge of determining a diagnosis with initial negative genetic testing. Our patient had negative screening PHOX2B testing (fragment analysis test) in the setting of blood transfusion 1 month prior. He demonstrates physical features (esotropia, squarely shaped face, flattened forehead, possible inferior inflection of the lateral upper lip vermillion border), autonomic dysfunction, hypoventilation, and constipation suggestive of CCHS. In cases of clinical suspicion for CCHS and negative PHOX2B testing, more sensitive studies can be performed including PHOX2B sequence testing then deletion/duplication multiplex ligation-dependent probe amplification if needed.