Objectives
Congenital central hypoventilation syndrome (CCHS) is a rare breathing disorder, pre-
dominantly caused by deleterious alterations in the PHOX2B gene. This report describes a rare case with PHOX2B-negative CCHS.
Methods
We conducted a 10-year follow-up, including a clinical evaluation, polysomnography, brain MRI, analyses of blood and CSF, electrodiagnostic testing, and comprehensive genetic analyses including trio-whole exome sequencing (trio-WES).
Results
In a female patient necessitating artificial ventilation immediately postnatally, trio-WES revealed a homozygous deleterious variant in the candidate gene DBX1 (p.Ala114Hisf-
sTer133), likely resulting in a complete loss of DBX1. Additional symptoms included central hypotonia, global developmental delay, seizures, and marked autoaggressive behavior.
Discussion
Dbx1 (developing brain homeobox 1) has an established critical role for mammalian in-
spiration, dramatically illustrated by the rapid postnatal demise of Dbx1 null mice because of asphyxia. Here, we describe the first human patient with atypical CCHS harboring a deleterious variant in the DBX1 gene. Surprisingly, over time, our patient gradually achieved the capability of ventilator-independent respiration, although with an irregular rhythm and only during the wake state. These findings suggest that DBX1-deficient individuals are able to install alternative neuronal circuits that maintain inspiratory drive during the wake state.