1284 Beyond Childhood: Unexplained Hypercapnia Reveals Adult-Onset CCHS

Abstract Introduction Congenital Central Hypoventilation Syndrome (CCHS) is a rare genetic disorder of autonomic respiratory control, typically diagnosed in infancy. Adult-onset presentations are exceedingly uncommon but may manifest as unexplained hypercapnia and nocturnal hypoventilation. Early recognition and genetic testing are essential for diagnosis and management. Report of case(s) A 45-year-old woman with a history of anxiety and depression presented in January 2024 after referral from an orthopedic clinic due to hypoxia. Evaluation revealed chronic hypercapnic respiratory failure of unclear etiology. Physical examination showed normal breath sounds, while neurologic and neuromuscular assessments were notable for persistent chest wall discomfort and reduced maximal inspiratory and expiratory pressures (MIP/MEP). Pulmonary function testing demonstrated mild restriction, and chest CT was unremarkable. She required 4 L/min of supplemental oxygen for nocturnal hypoxemia and was started on BiPAP for hypercapnia. A comprehensive neuromuscular workup—including diaphragm ultrasound, fluoroscopic sniff test, EMG, and brain imaging—was normal. Serologic studies, including autoimmune, neuromuscular, and metabolic panels, were unremarkable except for elevated serum bicarbonate levels. Genetic testing revealed a PHOX2B mutation with 20/25 polyalanine repeats, establishing the diagnosis of adult-onset CCHS. She was transitioned to noninvasive ventilation with a backup rate. Genetic counseling was advised, and cardiac evaluation was recommended due to an increased risk of arrhythmias. Conclusion Adult-onset CCHS is extremely rare and most often associated with mild PHOX2B polyalanine expansions, typically 20/24–20/27. Diagnosis requires both a compatible clinical phenotype—chronic hypercapnia, nocturnal hypoventilation, reduced MIP/MEP—and exclusion of other pulmonary, neuromuscular, or metabolic causes, confirmed by pathogenic PHOX2B variants. The 20/25 repeat expansion is the most frequently reported genotype in symptomatic adults. Management centers on lifelong ventilatory support, ideally noninvasive modes such as AVAPS. Supplemental oxygen alone may worsen hypercapnia if ventilatory drive remains impaired. Patients require ongoing monitoring for autonomic complications, particularly cardiac arrhythmias, and avoidance of respiratory depressants. Genetic counseling is recommended due to the heritable nature and variable expression of PHOX2B mutations. This case highlights the importance of considering adult-onset CCHS in patients with unexplained hypercapnia and nocturnal hypoventilation, even after a negative pulmonary and neuromuscular workup, and underscores the role of physiologic assessment combined with genetic testing for diagnosis, management, and counseling. Support (if any)