Pierluigi Vuilleumier

Introduction: Congenital central hypoventilation syndrome (CCHS) is a rare disorder characterized by an impaired ventilatory response to hypercapnia and hypoxia, particularly during sleep, and frequently associated with autonomic dysfunction. It is caused by pathogenic variants in the PHOX2B gene. Although CCHS is typically diagnosed in the neonatal period, milder forms may present later in infancy or childhood, often triggered by respiratory infections. Case presentation: We report the case of 16-month-old male diagnosed with CCHS following an episode of hypoxemic–hypercapnic respiratory failure during respiratory syncytial virus (RSV) infection. His medical history included neonatal respiratory distress requiring oxygen therapy and recurrent wheezing. At 15 months, he developed acute respiratory distress with severe hypercapnia (PaCO₂ 70 mmHg), requiring admission to the Pediatric Intensive Care Unit and invasive mechanical ventilation. Persistent sleep-related hypercapnia and hypoxemia prompted evaluation for central hypoventilation, confirmed by means of transcutaneous capnography and nocturnal pulse oximetry. Genetic testing revealed a de novo nonsense mutation in exon 1 of PHOX2B (p.Tyr14Ter). Brain magnetic resonance imaging showed diffuse white matter changes suggestive of gliosis. Further investigations identified early-onset systemic hypertension, requiring antihypertensive therapy. The patient was discharged on nocturnal non-invasive ventilation and enrolled in a neurodevelopmental rehabilitation program. Conclusions: This case highlights the phenotypic variability of CCHS and the importance of considering this diagnosis in children presenting with unexplained hypercapnia and sleep-related hypoxemia. It underscores the need for comprehensive autonomic evaluation, including blood pressure monitoring. The p.Tyr14Ter variant may allow partial protein function, potentially accounting for the relatively mild phenotype.

Post-infectious bronchiolitis obliterans (PIBO) is a rare but severe chronic lung disease of childhood, characterized by irreversible small-airway obstruction following severe lower respiratory tract infections early in life. The disease course is often progressive and associated with long-term respiratory morbidity, while effective disease-modifying therapies remain limited. We report the case of a young child who developed severe PIBO following adenovirus pneumonia complicated by prolonged respiratory failure and multisystem involvement. Diagnosis was based on persistent respiratory symptoms, characteristic radiologic findings, and poor response to conventional anti-inflammatory treatment. Given the severity of the clinical course and steroid-refractory disease, an individualized immunomodulatory strategy, including hydroxychloroquine, was initiated within a multidisciplinary framework. During follow-up, the patient showed progressive clinical improvement, with gradual weaning from continuous oxygen supplementation, fewer respiratory exacerbations, simplification of systemic therapies, and radiologic findings consistent with partial improvement. Although causal conclusions regarding treatment efficacy cannot be drawn from a single case, the overall disease trajectory appeared more favorable than typically reported in PIBO cohorts. This case supports the emerging view of PIBO as an immune-mediated airway fibrotic disorder and underscores the importance of integrating detailed clinical phenotyping with evolving molecular insights to inform future precision medicine in pediatric post-infectious airway disease.

Background: Interstitial lung diseases (ILDs) are a heterogeneous group of disorders characterized by variable degrees of inflammation and fibrosis affecting the pulmonary interstitium. Advances in molecular biology and genetics have greatly expanded our understanding of ILD pathogenesis, uncovering novel mechanisms and supporting precision medicine approaches. Genetic Insights: Genetic factors play a pivotal role in ILD heterogeneity, influencing disease onset, severity, and progression. To date, more than 30 genes with different inheritance patterns (autosomal dominant, recessive, or X-linked) have been associated with ILDs. These genes are primarily involved in surfactant metabolism, telomere maintenance, immune regulation, and epithelial repair. Emerging evidence also implicates genes encoding aminoacyl-tRNA synthetases. This review summarizes the main genetic alterations underlying ILD pathogenesis and discusses their impact on diagnostic and therapeutic approaches, highlighting how identification of disease-causing variants can improve diagnostic accuracy, refine prognostic assessment, and inform recurrence risk. Methods: A narrative review was conducted through targeted PubMed and Embase searches using disease- and gene-related keywords. Studies were prioritized based on predefined conceptual criteria, including clinical relevance, strength and replication of genetic associations, and availability of functional or translational evidence. Conclusions: This synthesis brings together the latest genetic insights into pediatric ILDs and their clinical implications. Integrating genomic data into clinical practice may enable earlier diagnosis, tailored follow-up, individualized therapeutic strategies, and more informed genetic counseling. However, important challenges remain, including incomplete genotype–phenotype correlations and limited functional validation for several disease-associated genes, which currently constrain full clinical translation.

Background: Down syndrome (DS) is commonly associated with complex respiratory phenotypes due to anatomical, immunological, and vascular factors. Pulmonary sequestration (PS) is a rare congenital malformation of non-functioning lung tissue with anomalous systemic arterial supply, occasionally reported in syndromic individuals. Case presentation: We report the case of a female infant with DS who developed acute respiratory distress secondary to respiratory syncytial virus infection. Chest imaging revealed an intralobar pulmonary pseudosequestration in the right lower lobe, supplied by the celiac trunk and draining into the pulmonary veins, with a communication to the bronchial tree. The patient required pediatric intensive care support and nutritional rehabilitation. Surgical resection was deferred until adequate weight optimization could be achieved. Discussion: This is, to our knowledge, the first description of intralobar pulmonary pseudosequestration in a patient with DS. The association suggests possible overlapping developmental mechanisms involving abnormal angiogenesis and emphasizes the importance of considering congenital pulmonary malformations in DS patients presenting with recurrent or severe respiratory symptoms. Conclusions: Early recognition and tailored management may improve clinical outcomes in this vulnerable population.

Background: Interstitial lung diseases (ILDs) are a heterogeneous group of disorders characterized by variable degrees of inflammation and fibrosis affecting the pulmonary interstitium. Advances in molecular biology and genetics have greatly expanded our understanding of ILD pathogenesis, revealing novel mechanisms and supporting the development of precision medicine approaches. Genetic insights: Genetic factors play a pivotal role in ILD heterogeneity, influencing disease onset, severity, and progression. To date, more than 30 genes with different inheritance patterns (autosomal dominant, recessive, or X-linked) have been associated to ILDs. These genes are primarily involved in surfactant metabolism, telomere mainte-nance, immune regulation, and epithelial repair. Recent evidence also implicates genes encoding aminoacyl-tRNA synthetases. This review summarises the main genetic al-terations underlying ILD pathogenesis and discusses their impact on diagnostic and therapeutic approaches, highlighting how identification of disease-causing variants can improve diagnostic accuracy, refine prognostic assessment, and inform recurrence risk. Methods: A narrative review was conducted through targeted PubMed and Embase searches using disease- and gene-related keywords. Eligible publications included narrative and systematic reviews, meta-analyses, case series, prospective studies, society guidelines, and peer-reviewed editorials. Conclusions: This synthesis brings together the latest genetic insights into pediatric ILDs and their clinical implications. Integrating genomic data into clinical practice may enable earlier diagnosis, tailored follow-up, individualized therapeutic strategies, and more informed genetic counseling. Collectively, these advances hold promise for better out-comes in children affected by ILDs.