Sex-specific upper airway morphological alterations are associated with obstructive sleep apnea severity in Down syndrome.

Individuals with Down syndrome (DS) have a high risk of obstructive sleep apnea (OSA), likely driven by craniofacial and upper airway abnormalities. However, three-dimensional upper airway morphology and its association with OSA severity remain poorly characterized. Here, we provide the first comprehensive three-dimensional characterization of upper airway volume and shape in adults with DS and euploid controls (EU). Three-dimensional upper airway models were reconstructed from T1-weighted MRI scans of 164 adults (63 EU, 101 DS). Upper airway, nasal cavity, and pharyngeal morphology were quantified using volumetry and geometric morphometrics (23 landmarks). OSA associations were assessed in a DS subsample (n = 91) using the apnea-hypopnea index and OSA severity categories. Adults with DS exhibited significantly reduced upper airway, nasal cavity, and pharyngeal volumes and distinct shape alterations relative to EU controls, with sex-specific patterns. In DS, increasing OSA severity was associated with reduced upper airway and nasal cavity volumes, particularly in males. OSA-related shape differences were confined to the nasal cavity of males with severe OSA, characterized by bilateral constriction and anteroposterior shortening. These findings identify upper airway morphology, particularly nasal cavity volume and shape, as imaging-derived anatomical biomarkers associated with OSA severity in adults with DS.