Two cases with undefined childhood interstitial lung disease: Can it be related to telomere variants?

Childhood interstitial lung disease (chILD) is a distinct pathologic condition that affects the lungs diffusely.1, 2 Genetic factors play a significant role in the pathogenesis of chILD.3 Telomeres are nucleoprotein complexes composed of repetitive nucleotide sequences located at the ends of chromosomes, serving to protect these chromosomes. The function of telomerase is essential for maintaining telomeres.4 Telomere-related variants, such as telomerase reverse transcriptase (TERT), regulator of telomere length 1 (RTEL1), poly(A)-specific ribonuclease (PARN) and telomerase RNA component (TERC), are well-established causes of ILD in adults.5 However, only two cases have been reported in children.6 Here, we present two patients with undefined chILD who tested positive for telomere-related variants. Informed written and verbal consent has been obtained from patients and parents described in this report. A 16-year-old girl, with a known history of asthma and chILD (since age 2.5 years), was referred to our hospital at the age of 8 years, with progressive dyspnoea and a cough for the last 6 months. She was term-born with a non-remarkable pregnancy. Second-degree consanguinity was present between the parents with a history of two grandfathers who were siblings and died with a diagnosis of emphysema at the ages of 56 and 64 years. The patient had no exposure to cigarette smoke, and the grandfathers had no history of smoking. On her physical examination, her weight and height were within the appropriate range for age/sex normals. Her oxygen saturation was 95%, no clubbing and fine rales were positive. Chest computed tomography (CT) was performed when she was aged 8 years, which demonstrated focal hyperaeration areas in both lungs and peribronchial thickening in the lower zones (Fig. 1a). A follow-up chest CT performed at the age of 12 years showed the same findings. Immunodeficiency, cystic fibrosis (CF) and primary ciliary dyskinesia (PCD) were excluded. There was no variant for filamin A and surfactant-associated proteins. Although lung biopsy was reported as insufficient material, emphysematous changes were observed in the focal area. A heterozygous TERT variant, c.3046G>A p.Val1016Met, was identified through exome analysis. This variant is not found in the ClinVar database. It has not been associated with any clinic so far. In the GnomAD database, it was detected in a single individual. It was assessed as Uncertain Significance according to The American College of Medical Genetics and Genomics (ACMG) criteria. According to the segregation analysis, the mother was heterozygous, but the father was not carrying the variant. The patient was stable during the 8-year follow-up, and the last forced vital capacity (FVC) z-score was 1.10 (116%), and the 6-min walk test (6MWT) was 599 m. A 11-year-old girl was referred to our hospital at age 5 years due to recurrent low haemoglobin requiring blood transfusion since she was aged 3 months. She had tachypnoea, oxygen saturation was 78% and a haemogram revealed anaemia (9.7 g/dL). Chest CT at the first admission showed a diffuse ground-glass appearance in both lungs and a few subpleural small air cysts prominently in the upper lobes (Fig. 1b). She underwent surgery for omphalocele and correction of cleft palate, and recurrent lung infections. She was term-born with a non-remarkable pregnancy, and there was no consanguinity between her parents. Immunodeficiency, CF and PCD were excluded. Aplastic anaemia was excluded by examining the bone marrow. Antinuclear antibodies, anti-dsDNA antibodies and anti-neutrophil cytoplasmic antibodies were negative, and levels of C3 and C4 were normal. There was no variant for Copa syndrome. A heterozygous RTEL1 variant, c.2975C>T, p.(Pro992Leu), was identified through exome analysis. This variant is characterised as benign in the ClinVar database. There is information that it was detected in 1747 alleles in the GnomAD database. It was assessed as Benign according to ACMG criteria. According to the segregation analysis, the mother was heterozygous, but the father was not carrying the variant. She had shortened telomeres (1st percentile) in the peripheral blood. There were no findings related to dyskeratosis congenita. No pathology was detected in contrast-enhanced echocardiography performed to exclude pulmonary arteriovenous malformation. A chest CT image obtained during an acute presentation at age 8 years showed consolidation and ground-glass opacities with superimposed interlobular septal thickening consistent with pulmonary haemorrhage in both lungs, predominantly on the right side (Fig. 1c). Various treatments such as pulse steroids, hydroxychloroquine, mycophenolate mofetil and azithromycin were administered to the patient who had pulmonary haemorrhage attacks in the 6-year follow-up, with the decisions of a multidisciplinary team meeting. Follow-up chest CT at age 10 years showed resolution of previous radiologic findings (Fig. 1d). A lung biopsy showed minimal capillary congestion in the interstitial area, and vasculitis was excluded. At the last visit, the FVC z-score was −4.81 (55%), and the 6MWT was 401 m. These two patients with chILD, carriers of the telomere-related variants, had different phenotypes. Case 1 did not have a telomere length measurement, and case 2 had a short telomere length. Although presence of telomere related variants are generally expected to have a short telomere length, telomere length also depends on both the functioning of telomere maintenance proteins and inherited telomere length and environmental factors.7 Borie et al.8 analysed patients with RTEL1 variants and showed that telomere length was short in 35% of the patients whose telomere length was examined, similar to our case. Of the two paediatric cases reported in the literature by Salehian et al.,6 one of them had an RTEL1 variant, and the other had a PARN variant. The patient with the RTEL1 variant had a restrictive pulmonary function test, similar to our patient, but the first presentation was hypersensitivity pneumonia, which was very different. To determine the aetiology of chILD, special investigations are carried out in expert centres, and the results are discussed in multidisciplinary team meetings, as in our centre. Furthermore, patients who are not identified any aetiology are labelled as ‘undefined chILD’.3 Genetic analysis is recommended for all paediatric patients with chronic ILD with no identified cause, and this led to the discovery of new genetic entities in chILD.9-11 In our centre, whole-exome sequencing is performed on selected cases as in these two cases. These two cases did not have all the features of lung disease due to telomere-related variants. However, this was the only abnormality found on extensive testing, and it could only be an incidental finding. The second case had a variant which has been reported as benign. These children may or may not have other findings associated with telomere variants in adulthood, but there is a need to follow these patients in future. With this report, we aimed to increase awareness and keep the search for telomere variants in the minds of physicians in this patient group. Although the findings of ILD in telomere-related diseases are seen at older ages, these cases highlighted that there are still unknown aspects of telomere diseases. The data that support the findings of this study are available from the corresponding author upon reasonable request.