PHOX2B deletion in congenital central hypoventilation syndrome: is this sufficient for pathogenesis?

Congenital central hypoventilation syndrome (CCHS) is primarily caused by dominant PHOX2B mutations, with recessive LBX1 or MYO1H mutations being rare. Among PHOX2B mutations, polyalanine repeat expansion mutations (PARMs) are common, whereas non-PARMs (NPARMs) are less frequent. PHOX2B mutations are believed to act through loss-of-function mechanisms combined with dominant-negative and/or toxic gain-of-function effects. However, the role of PHOX2B haploinsufficiency remains unclear. We investigated the role of PHOX2B deletion and other genetic modifiers in CCHS. Among 93 patients without PHOX2B mutations, four were found to carry PHOX2B deletions via multiplex ligation-dependent probe amplification. Two had typical CCHS, whereas two siblings presented with mild sleep hypoventilation following CCHS symptoms in infancy. After ruling out pathogenic variants in LBX1 and MYO1H, we explored potential modifiers by analyzing sequence and methylation changes in the wild-type PHOX2B promoter and 3' untranslated region (3'UTR), and the coding regions of PHOX2A and MIR204. One female patient with CCHS carried a 3'UTR haplotype predicted to reduce PHOX2B expression via MIR204 interaction. To date, 15 informative cases with PHOX2B deletions (eight males, seven females) have been reported. Respiratory phenotypes included: CCHS (n = 5), CCHS with obstructive sleep apnea (OSA) (n = 1), OSA alone (n = 2), mild central sleep apnea (n = 1), mild central sleep hypoventilation or apnea following CCHS symptoms in infancy (n = 3), and asymptomatic (n = 3). These indicate that although a heterozygous PHOX2B deficiency alone is insufficient to cause CCHS, it may delay or impair the development of respiratory control.