A comparative analysis of clinical phenotypes and outcomes in childhood interstitial lung disease due to surfactant dysfunction disorders: focusing on mutations in SFTPC, ABCA3, and NKX2-1 genes.

Abstract

Background: Surfactant dysfunction disorders are a group of rare diseases that lead to childhood interstitial lung diseases (ILD). SFTPC, ABCA3, and NKX2-1 are the three genetic forms of this condition. The differences in clinical presentations and prognostic outcomes across these genotypes are not well understood, warranting comparative analysis.

Methods: We conducted a retrospective cohort study of 22 children with genetically confirmed surfactant dysfunction disorders (11 SFTPC, 5 ABCA3, 6 NKX2-1). Comprehensive evaluations included clinical features, high-resolution computed tomography (HRCT), serum Krebs von den Lungen-6 antigen (KL-6) levels, autoantibody profiles, immune function assessments, bronchoalveolar lavage fluid analysis, echocardiography, pathology, genetic testing, treatment regimens, and outcomes.

Results: The median age at onset was 0.7 years, with the earliest onset in the NKX2-1 group (0.4 years) and the latest in the ABCA3 group (1.7 years). At presentation, the SFTPC group had the lowest respiratory symptom scores, followed by the ABCA3 group, while the NKX2-1 group showed the highest scores (P = 0.034). Pulmonary hypertension prevalence varied significantly among groups (P = 0.005), being highest in the NKX2-1 group (66.7%) and absent in the SFTPC group. KL-6 levels were lowest in the SFTPC group (1302 U/mL), intermediate in the ABCA3 group (4780 U/mL), and highest in the NKX2-1 group (6106.5 U/mL) (P = 0.064). Positive autoantibodies were detected in 27.3% of cases, and diffuse alveolar hemorrhage (DAH) occurred in 13.6%. At the last follow-up, the NKX2-1 group had significantly higher HRCT scores (P = 0.030) and KL-6 levels (P = 0.024) compared to the SFTPC group. The SFTPC group showed significant improvements in symptom scores (median 4 to 2, P = 0.001), HRCT scores (median 24 to 11, P = 0.001), and KL-6 levels (median 1302 U/mL to 620.5 U/mL, P = 0.008) after treatment. In contrast, the NKX2-1 group had worsening symptom scores (median 4.5 to 5.5, P = 0.031) and HRCT scores (median 17.5 to 30, P = 0.031). Among patients receiving combination therapy of corticosteroid and hydroxychloroquine, the SFTPC group had the lowest mortality rate (0%), while the NKX2-1 group had the highest (60%) (P = 0.041).

Conclusion: Patients in the SFTPC group were associated with milder phenotypes and better prognosis than patients in the NKX2-1 group in our cohort. A potential association between surfactant dysfunction disorders and autoimmune conditions, as well as DAH, may exist, warranting further investigation.