Case Presentation

A 59-year-old woman presented with progressive dyspnea at rest, orthopnea, paroxysmal nocturnal dyspnea, and a significant decline in functional capacity over the past 6 months. She had a history of post-COVID pulmonary fibrosis since 2021, initially treated with high-dose steroids and azathioprine. Off-license pirfenidone was trialed but discontinued due to hepatotoxicity as evidenced by a rise in liver transaminases (Table 1).

Table 1. Liver function trends showing a drug-induced liver injury on the introduction of pirfenidone in August 2024.

Her condition deteriorated following cessation of antifibrotics with the development of fluid overload secondary to right heart failure requiring hospitalization for intravenous diuresis. At presentation, she was on long-term oxygen therapy at 5 l/min continuously and unable to perform basic activities of daily living.

The patient had a strong family history of ILD (Figure 1). Her father passed away at age 80 with IPF [usual interstitial pneumonia (UIP) pattern], and her sister passed away at the age of 52 with respiratory failure secondary to IPF (UIP pattern). There was no family history of consanguinity, liver cirrhosis, or hematological malignancies.

Figure 1. Pedigree chart of the family with FPF: Black and unfilled shapes represent affected and unaffected individuals, respectively. Squares represent males and circles represent females, respectively. The black line running through a circle or square denotes deceased individuals. A small arrow indicates the proband.

Physical examination revealed finger clubbing and bilateral end-inspiratory crackles in the lower and middle lung areas. There was no evidence of nail dystrophy, skin pigmentation changes, or oral leukoplakia.

Pulmonary function tests revealed a restrictive pattern with progressive decline (Forced Vital Capacity declined to 48%, diffusing capacity to 19%). Retrospective assessment of her CT pulmonary artery (CTPA) in 2021 demonstrated bilateral, symmetrical peripheral consolidation and ground glass changes. Confluent consolidation was demonstrated in the lower lobes bilaterally with subpleural sparing (Figure 2A-C). Recent high-resolution CT (HRCT) showed stable, established bilateral fibrosis with lower lobe predominance with evidence of multifocal mid- to lower-zone-predominant thickening of interlobular septa associated with severe traction bronchiectasis, particularly affecting the inferior lingula, middle lobe, and medial segments of bilateral lower lobe (Figure 2D and E). The main pulmonary artery was dilated, measuring 30 mm, in keeping with underlying possible pulmonary hypertension. Echo and right heart catheterization revealed severe right ventricular dysfunction and pulmonary hypertension (mean pulmonary arterial pressure 38 mmHg) consistent with Group 3 pulmonary hypertension due to ILD, as classified by the 2022 ESC/ERS Guidelines, indicating poor prognosis and reinforced the urgency of transplant referral. Due to the patient’s condition, histological verification by transbronchial cryobiopsy was contraindicated, and diagnosis was established on the basis of characteristic HRCT findings, a likely pathogenic CTC1 variant, a strong family history of ILD, and the clinical course.

Figure 2. Serial thoracic imaging demonstrating disease progression. (A-C) CTPA in lung window demonstrating bilateral symmetrical peripheral consolidation and ground-glass opacification consistent with organizing pneumonia secondary to COVID-19. Confluent consolidation is visible in the bilateral lower lobes with areas of subpleural sparing. (D-E) HRCT at current presentation demonstrating established bilateral lower-lobe predominant fibrosis with multifocal interlobular septal thickening, severe traction bronchiectasis involving the inferior lingula, middle lobe, and medial segments of the bilateral lower lobes, and a dilated main pulmonary artery measuring 30 mm consistent with pulmonary hypertension.

Autoimmune serology showed anti-nuclear antibody (ANA) positivity but no systemic connective tissue disease (Table 2). Liver function improved following withdrawal of pirfenidone, suggesting drug-induced liver injury (Table 1).

Table 2. Immunology panel.

Genetic testing using CentoXome^® Solo by Centogene, Germany, identified a heterozygous CTC1 mutation [NM_025099.5:c.2518C>T, p.(Arg840Trp)], classified as likely pathogenic according to ACMG/AMP criteria, supported by evidence of a deleterious missense change at a conserved residue within a functionally critical domain of CTC1, absence from population databases at disease-relevant frequency, and segregation with ILD in this family. This variant has been previously reported in association with telomere biology disorders and ILD, including in a Chinese family with CTC1-related ILD described by Liu et al. [5], providing additional evidence for its clinical significance. This mutation has been associated with cerebroretinal microangiopathy with calcifications and cysts as well as telomere biology disorders, including pulmonary fibrosis, bone marrow failure, and hepatic dysfunction, reflecting the pleiotropic phenotype of CTC1-STN1-TEN1 complex dysfunction.

Nintedanib was started at the standard dose of 150 mg twice daily after multidisciplinary team discussion and liver function normalization, with observation of liver function tests to avoid a subsequent drug-induced liver injury. The patient was referred to a tertiary center for lung transplant listing, but unfortunately, despite all efforts, the patient passed away in the tertiary center with a massive pulmonary embolism while awaiting transplantation.