Lung disease in crisponi/cold-induced sweating syndrome type 1: expanding the clinical phenotype spectrum

Abstract Crisponi/Cold-Induced Sweating Syndrome Type 1 (CS/CISS1) is an ultra-rare genetic disorder caused by biallelic variants in the cytokine receptor-like factor-1 ( CRLF1 ) gene and is associated with several comorbidities. Comprehensive data on the respiratory phenotype of this condition are lacking despite being associated with high mortality in infancy, often due to severe respiratory complications like aspiration pneumonia and sudden death related to hyperthermic crises. Our study investigates respiratory complications and lung ultrasound characteristics, enhancing the comprehension of the natural history and pathophysiology of the disease. We enrolled 13 individuals (8 children) carrying a biallelic molecular defect of the CRLF1 gene, either in a homozygous or compound heterozygous state. All were of Italian ancestry, with the majority (77%) being Sardinian. The pathogenic variant c.676dup (p.Thr226fs) in exon 4 was confirmed as the most commonly recurrent variant and was identified in 9 of the 13 patients (69%) of our cohort. Over half of the participants exhibited an ultrasound lung pattern suggestive of sonographic interstitial syndrome findings. Fifteen percent had a documented aspiration pneumonia in infancy, which required hospitalization or ventilatory support. Additionally, one adult patient showed bilateral fibrotic findings, which were validated by a CT scan. Conclusions : Respiratory involvement appears to be a frequent and under-investigated feature in patients with CS/CISS1. Although lung ultrasound patterns observed in this study were largely nonspecific, LUS may represent a practical, non-invasive screening tool to identify early morphological lung changes potentially related to recurrent or chronic inflammatory processes. What is Known: • Crisponi/Cold-Induced Sweating Syndrome Type 1 (CS/CISS1) is associated with early-life respiratory complications. • Data on the long-term pulmonary involvement in CS/CISS1 patients are insufficiently documented. What is New: • This is the first study to systematically evaluate lung ultrasound (LUS) findings in a cohort of CS/CISS1 patients, across pediatric and adult ages. • We identified recurrent nonspecific interstitial patterns that suggest chronic inflammatory or fibrotic lung involvement, supporting LUS as a feasible screening tool in disease monitoring.