Abstract
Congenital central hypoventilation syndrome (CCHS) is a rare and severe neurocristopathy caused by PHOX2B
gene mutations. CCHS is characterized by profound hypoventilation and autonomic nervous system
dysregulation, necessitating life-long artificial ventilation. Patients may suffer repetitive hypoxemic and
hypercarbic exposure resulting in potential neurocognitive compromise. Autonomic cardiovascular dysfunction
leads to risk of hypertension, blood pressure lability, impaired responses to orthostatic stress, and sinus pauses
often requiring a cardiac pacemaker. Additionally, CCHS is associated with high risk of Hirschsprung’s disease
and tumors of neural crest origin. There is substantial variability in presentation and disease severity and there
is a lack of consensus among expert clinicians on optimal management. Currently, there are no pharmacologic
interventions approved to decrease disease burden in CCHS, and the limited treatment options available are
highly invasive, burdensome and offer only palliative support. Despite promising pre-clinical models, anecdotal
reports of off-label drug successes, and approved drugs and devices in other populations with considerable
potential in CCHS, therapeutic development is hampered by a lack of established measures of disease state
and comprehensive Natural History (NH) data. Factors leading to the wide phenotypic variability in CCHS are
not well understood, and severity stratification criteria are lacking. Importantly, the impact of disease and different
treatment approaches (e.g., tracheostomy vs. mask ventilation) on patient and caregiver quality of life (QOL)
remains unquantified. Addressing these knowledge gaps is critical to advance CCHS treatment and inform
effective therapeutic strategies. Accurate clinical, functional, and quality of life assessments are paramount to
understanding disease progression, stratifying disease severity, formulating effective treatment strategies, and
assessing therapeutic interventions. This proposal assembles preeminent CCHS experts, leading international
CCHS centers of excellence, CCHS patient advocacy groups, and industry partners currently developing
interventions for CCHS to address this gap in the science. Together, this team has identified candidate measures
that reflect the core CCHS phenotype but are lacking validation data. This project will capture extensive,
longitudinal NH data using rigorously defined protocols, common data elements (CDEs), and established
measures reflecting patient and caregiver voices. Ultimately, we will develop a flexible, adaptable data hub of
core measures of CCHS NH which will inform future therapeutic development, intervention trials, research and
clinical care. By merging traditionally siloed CCHS data, expertise, resources and cohorts, this study will enrich
knowledge of CCHS NH, establish measures that best correlate with disease severity, inform therapeutic
development, and accelerate progress toward clinical trials. Recent advances in preclinical models and ongoing
therapeutic development makes this study time-sensitive, and success paramount to advancing toward approved
therapeutics in this underserved population.
