Significant phenotype variability of congenital central hypoventilation syndrome in a family with polyalanine expansion mutation of the PHOX2B gene

Background: Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder resulting from mutations in the PHOX2B gene located on chromosome 4p12.3, characterized by hypoventilation secondary to missing responses to both hypercapnia and hypoxia.

Case report: Proband. A girl, hospitalised 5 times for respiratory failure from 6 weeks old, presented at 4 years of age severe cyanosis related to pneumonia. Tracheostomy was done, and she was discharged home using a portable positive pressure ventilator during sleep. Proband's father: The father was retrospectively found out to suffer from severe headache and excessive daytime sleepiness. Molecular genetic evaluation of PHOX2B gene was performed and casual polyalanine repeat expansion mutation c.741_755dup15 in exon 3 was found both in proband and her father in heterozygous form. The proband's grandmother died of respiratory failure after administration of benzodiazepine at the age of fifty years. Considering the grandmother's history, she is highly suspected of having had CCHS as well.

Conclusion: Repeated respiratory failure of girl was explained by PHOX2B mutation and Ondina curse. Proband´s father has incompletely penetrated PHOX2B heterozygous mutation as well and proband´s grandmother died probably from the consequences of drug interaction with PHOX2B mutated background as well. Both daughter and father currently require overnight mechanical ventilatory support. Although most PHOX2B mutations occur de novo, our case is a rare three generation family affected by autosomal dominant inheritance with incomplete penetrance manifested as the late-form of CCHS and proven PHOX2B mutation in two generations.