CHEST Original Research www.chestpubs.org CHEST / 137 /  / , 2010 1 R ett Syndrome (MIM 312750) (RS) is a pervasive neurodevelopmental disorder affecting female patients and is considered to be the second most common cause of mental retardation in the female gender, with a reported frequency of approximately 1:10,000 to 1:15,000 female patients. Besides a classic type, characterized by four stages of developmental regression following an apparently normal develop- ment for 6 to 18 months, several different clinical forms are currently known and include congenital, forme fruste, early seizures, and preserved speech variants. 1,2 To date, no effective therapy to prevent the devel- opmental regression, autonomous nervous system dysfunction, and loss of communication skills is avail- [AQ5] able for these patients. The classic RS form is mainly caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2), 3 a key transcription regulator gene. 4 From a clinical point of view, disorders of respira- tory control are a prominent feature of RS, 5 with a wide spectrum of reported breathing irregularities, including breath holding, spontaneous Valsalva maneuvers, apnea, apneusis, hyperventilation, and rapid shallow breathing. Respiratory dysfunction is known to be present during wakefulness as well as during sleep 6 and is commonly attributed to brain- stem immaturity and central autonomic dysfunction, 6,7 or progressive neurochemical dysfunction in the respiratory network after birth. 8 Recently, we have Background: Breathing disorders in Rett Syndrome (RS) have been generally attributed to severe autonomic and/or brain stem dysfunction, and no information regarding lung morphologic char- acteristics exists to date. The aim of the present study was to determine if there are RS-associated pulmonary abnormalities. Methods: A total of 27 female subjects (age, M 6 SD: 12.6 6 5.9 y; age range: 3-32 y) with gene- encoding, methyl-CpG-binding-protein-2-mutation-confirmed RS underwent high-resolution CT (HRCT) scans of the thorax. A volumetric acquisition was used, and isotropic data sets were acquired with thin collimation ( , 1-mm slice), scanning through the lungs and processing on a high-spatial-resolution kernel (bony algorithm). Results: Abnormal HRCT scan findings were observed in 15 of 27 (55.5%) cases, consisting of centrilobular nodules (10/15, 66.7%), thickening of the bronchial walls (8/15, 53.33%), and patchy ground-glass opacities (4/15, 26.7%), with upper lobe predominance. In addition, bronchiolecta- sis were found in 9 of 15 (60%) patients. Conclusions: Pulmonary lesions, respiratory bronchiolitis-associated interstitial lung disease-like lesions, are present on imaging studies in about half of typical patients with RS. Further research is needed to clarify the epidemiologic characteristics and the pathogenesis of these previously unrecognized pulmonary abnormalities. CHEST 2010; 137():1–7 Abbreviations: DAB 5 diffuse aspiration bronchiolitis; DIP 5 desquamative interstitial pneumonia; GERD 5 gastroe- sophageal reflux disease; GGOs 5 ground-glass opacities; HRCT 5 high-resolution CT; ILD 5 interstitial lung disease; MeCP2 5 methyl-CpG-binding protein 2; PI 5 perfusion index; PVI 5 pleth variability index; RB-ILD 5 respiratory bronchiolitis-associated interstitial lung disease; RS 5 Rett syndrome; V/Q 5 ventilation perfusionratio; V t 5 tidal volume Unrecognized Lung Disease in Classic Rett Syndrome A Physiologic and High-Resolution CT Imaging Study Claudio De Felice, MD; Gianni Guazzi, MD; Marcello Rossi, MD, FCCP; Lucia Ciccoli, MD; Cinzia Signorini, PhD; Silvia Leoncini, PhD; Gabriele Tonni, MD, PhD; Giuseppe Latini, MD; Giuseppe Valacchi, PhD; and Joussef Hayek, MD