Respiratory and other organ manifestations in NKX2-1-related disorders: a systematic review

Abstract

Background: NKX2-1-related disorders (NKX2-1-RD) encompass a spectrum of conditions arising from pathogenic deletions or variants in the NKX2-1 gene, crucial for thyroid, lung, and brain development. Respiratory manifestations in NKX2-1-RD range from neonatal respiratory distress to severe lung diseases, constituting a leading cause of mortality. This study will review and synthesize NKX2-1-RD respiratory phenotypes, genetic alterations, and long-term trajectories.

Methods: We conducted a systematic review using PRISMA and PICO question formats. From January 2002 to July 2023, major biomedical databases and rare disease resources were searched. Genetically confirmed NKX2-1-RD patients with respiratory symptoms were eligible for this study.

Results: Out of 4,569 studies, 38 met inclusion criteria, predominantly case reports and series. The study included 148 patients, revealing diverse respiratory phenotypes and treatments. Respiratory manifestations emerged at various ages, with neonatal respiratory distress, asthma, interstitial lung disease, and lung cancer observed. Nonsense mutations in NKX2-1 were linked to lung cancer. Treatment varied, including oxygen supplementation, ventilation, antibiotics, and lung transplantation. Long-term follow-up disclosed heterogeneous respiratory outcomes, with some patients asymptomatic while others faced chronic insufficiency or recurrent infections. The overall survival of informed cases was about 60%.

Conclusion: This study highlights the complex respiratory manifestations of NKX2-1-RD and their impact on patient outcomes. The findings support standardized respiratory follow-up protocols and provide clinical management insights despite study quality and sample size limitations. We discuss the challenges of treating diverse respiratory conditions in this rare clinical entity and lay the groundwork for future research.

Keywords: NKX2-1; asthma; benign hereditary chorea; brain-thyroid-lung syndrome; interstitial lung disease; neonatal respiratory distress; recurrent respiratory infection; systematic review.

Figure 1

Illustrates the PRISMA flowchart depicting the title-abstract and full-text screening of the articles related to the respiratory manifestations in patients with NKX2-1-RD. (A) What are the best procedures for the diagnosis of lung diseases in patients with NKX2-1-related disorders? (B) What are the best procedures for treatment and follow-up of lung diseases in patients with NKX2-1-related disorders?

Figure 2

Distribution of (A) sex and (B) gestational age classification among the studied patients.

Figure 3

Distribution of patients across various respiratory phenotypes, highlighting the presence of conditions such as neonatal respiratory distress syndrome (RDS), interstitial lung disease (ILD), recurrent infections, chronic respiratory insufficiency, pulmonary hypertension, asthma, and lung cancer.

Figure 4

(A) An alluvial diagram illustrating the transition of patients from one respiratory phenotype to another over time. (B) Multi-step alluvial diagram depicting cases with complex trajectories, where patients exhibited multiple respiratory phenotypes throughout their clinical course.

Figure 5

Distribution of 67 NKX2-1 variants with respect to the functional domains of NKX2-1 isoform 2 (RefSeq NM_003317.3). Distal and proximal promoters are indicated by arrows. Functional domains are shown in dark grey: tn (TIN domain), hd (homeodomain), and nk2 (NK2 domain).

Figure 6

Distribution of patients across respiratory phenotypes and types of variants or deletions in the NKX2-1 gene.

Figure 7

(A) Distribution of patients across respiratory phenotypes stratified by vital status. (B) Kaplan–Meier survival curve of NKX2-1 RD patients with respiratory manifestations, comparing those who have undergone lung transplantation (LTX) and those who have not. Note: All LTX occurred before age 20y.