In recent years, a number of monogenic disorders have been described that are characterized by immune dysregulation. A subset of these ‘primary immune regulatory disorders’ can cause severe interstitial lung disease, often recognized in late childhood or adolescence. Patients presenting to pulmonary clinic may have long and complex medical histories but lack a unifying genetic diagnosis. It is crucial for pulmonologists to recognize features suggestive of multisystem immune dysregulation and to initiate genetic workup, since targeted therapies based on underlying genetics may halt or even reverese pulmonary disease progression. Through such an approach, our center has been able to diagnose and treat a cohort of patients with interstitial lung disease from gene defects that affect immune regulation. Here we present representative cases related to pathogenic mutations in three distinct pathways and summarize disease manifestations and treatment approaches. We conclude with a discussion of our perspective on the outstanding challenges for diagnosing and managing these complex life-threatening and chronic disorders.

Objective: The primary immunodeficiency syndromes of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) haploinsufficiency and lipopolysaccharide-responsive and beige-like anchor protein (LRBA) deficiency present with multisystem immune dysregulation. The aim of this study was to characterize and compare the pulmonary manifestations of these two diseases. Methods: We retrospectively analyzed the pulmonary clinical, radiologic, and histopathologic characteristics of 6 patients with CTLA-4 haploinsufficiency and 4 patients with LRBA deficiency with pulmonary involvement followed at a large tertiary care center. Results: Chronic respiratory symptoms were more frequent in patients with LRBA deficiency versus CTLA-4 haploinsufficiency (4/4 versus 1/6). Cough was the most common respiratory symptom. Abnormalities in pulmonary exam and pulmonary function testing were more frequent in LRBA deficiency (4/4, 2/4) compared to CTLA-4 haploinsufficiency (1/6, 2/6). Chest CT findings included mediastinal lymphadenopathy (4/4 in LRBA deficiency versus 1/4 in CTLA-4 haploinsufficiency), pulmonary nodules (4/4, 3/4), ground-glass opacification (4/4, 3/4), and bronchiectasis (3/4, 1/4). Lymphocytic inflammation, concentrated bronchovasculocentrically and paraseptally, was observed in all patients who had lung biopsies (N=3 with LRBA deficiency; N=3 with CTLA-4 haploinsufficiency). Granulomas were seen in all patients with CTLA-4 haploinsufficiency and in no patients with LRBA deficiency. Conclusion: Despite phenotypic overlap amongst these diseases, LRBA deficiency demonstrated greater severity of pulmonary disease, indicated by respiratory symptoms, pulmonary exam, and intrathoracic radiologic findings. Lymphocytic inflammation is a key histologic feature of both of these disorders. Pediatric pulmonologists should suspect these disorders in the appropriate clinical, radiological, and pathological context to better diagnose and treat these patients.