• paediatric interstitial lung disease
• paediatric lung disaese

A 16-year-old boy with persisting fixed obstructive spirometry is approaching transition to adult services. He has been under long-term follow-up, initially referred aged 2 months by his local team for tachypnoea and mild respiratory distress since birth. He was born at term by vaginal delivery with meconium suctioned from his oropharynx and admitted to a special care baby unit for observation and intravenous antibiotics. Chest X-ray (CXR) at birth was reportedly consistent with possible meconium aspiration, although there was no neonatal resuscitation or ventilation required and he was discharged home after 4 days without an oxygen requirement.

Flexible bronchoscopy was arranged that was unremarkable, there was no evidence of aspiration or infection, he had a negative congenital infection screen and normal echocardiogram. CT chest showed linear atelectasis, occasional thickened interlobular septa and areas of secondary pulmonary lobular hyperinflation. Neither bronchopulmonary dysplasia (BPD) nor meconium aspiration syndrome really fits his neonatal history or imaging appearance. He was well in himself and so was discharged with a plan for regular outpatient review. Follow-up CT chest age 3 years (figure 1A) demonstrated persistent abnormality with an extensive emphysema-like appearance, superadded interlobular septal thickening, parenchymal distortion and persistent foci of marked lobular hyperinflation.

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Figure 1

A) Case 1: CT chest age 3 years demonstrating bilateral areas of hyperinflation and atelectasis. (B) Case 1: follow-up CT chest age 16 years with hyperinflation, atelectasis and subpleural tags throughout both lungs. (C) Case 1: circulating telomere length <1st percentile (red square) compared with normal controls of same decade of age, indicating likely telomere disease. Telomere length measured by q-PCR analysis from peripheral blood mononuclear cell DNA. (D) Case 2: coronal section CT chest during first acute presentation demonstrates diffuse, well defined, coarse centrilobular nodules throughout both lungs with additional interlobular septal thickening. (E) Case 2: follow-up CT chest age 16 years showing resolution of previous changes. (F) Case 2: circulating telomere length <10th percentile (red square) compared with normal controls.

Once old enough to perform spirometry, a pattern of stable but persisting obstruction was noted and repeat CXR showed bilateral hyperinflation. He was trialled on inhaled corticosteroids for some years with little impact on spirometry and he had no bronchodilator reversibility. There were no significant systemic issues detected aside from mild incidental scoliosis and trivial tricuspid regurgitation. His abnormal spirometry remained unexplained with persisting obstructive pattern FEV₁ 2.34 L (55%), FVC 4.44 L (90%) and so a further CT scan was arranged at age 16 years, demonstrating the same extensive yet stable pattern as before (figure 1B). In view of these persisting findings at odds with a diagnosis of BPD, meconium aspiration or asthma, genetic testing for interstitial lung disease (ILD) was arranged with an extended 41-gene panel.

A variant that is so far of unknown significance in the Poly(A)-specific Ribonuclease (PARN) gene was found. PARN encodes the ribonuclease responsible for telomere mRNA turnover, maturation and stabilisation, and pathogenic variants reported in the literature are known to be associated with shortened telomere length and adult-onset pulmonary fibrosis.1 2

Parental genetic testing showed maternal inheritance of the same PARN variant. Mother subsequently had a CT chest that showed overall clear lungs. However, she also has numerous tiny subpleural ‘tags’, usually associated with chronic lung disease of prematurity, although she does not have a history of preterm birth or early life respiratory insult. Reviewing his family history, of interest there are late diagnoses of asthma reported in mother, a maternal uncle and maternal grandmother. There is sadly also a history of early cardiac death secondary to cardiomyopathy and congenital cardiac disease that affected maternal uncle and sister.

Telomeres are repetitive nucleotide sequences that cap all linear chromosomes, protecting against loss of material during mitosis. Telomeres shorten with progressive cell division, and hence shorten with advancing age until finally there is cell senescence. The role of telomerase is to maintain telomere length and limit chromosomal shortening3; genetic variations that impact on the function of telomerase may lead to prematurely shortened telomeres.

To better understand whether or not his genetic variant is pathological and could impact telomere function, both patient and mother had peripheral circulating telomere lengths tested. Both were found to have shortened telomeres; our patient’s is <1st percentile for age-matched healthy individuals (figure 1C), indicating that telomere disease is likely and his mother’s is <10th percentile. Both have been referred for genetic counselling and our patient has now been transitioned to adult respiratory care for follow-up of suspected telomere-associated ILD.

Our second case is a teenage girl with persisting restrictive spirometry and a presumed diagnosis of hypersensitivity pneumonitis (HP) following an acute respiratory illness earlier in childhood. She initially presented age 12 years to her local hospital with acute dyspnoea, hypoxia and a 3-week history of fever, cough and weight loss. There were no TB contacts, her family emigrated from Goa in 2011 and there had been no further foreign travel. Initial laboratory results demonstrated a normal white cell count and C reactive protein, with an elevated erythrocyte sedimentation rate of 70 and moderately raised immunoglobulins. Initial infection screen returned with negative Mantoux, atypical pneumonia screen, HIV and mycoplasma serology. CXR showed diffuse ground glass opacities and she was treated for a lower-respiratory tract infection with intravenous antibiotics and empirical anti-TB treatment. CT chest demonstrated coarse centrilobular ground-glass nodules throughout both lungs, with some additional interlobular septal thickening (figure 1D), felt to be most in keeping with subacute HP. She completed 7 days of intravenous antibiotics. TB medication was stopped once TB PCR result returned as negative, and she was started on a 10-day course of high dose oral prednisolone as management for HP.

Two weeks later she was reviewed as an outpatient with relapse of dyspnoea and had her first lung function test demonstrating restrictive spirometry FEV₁ 1.38 L (57%) and FVC 1.44 L (55%). She was restarted on oral steroids with a 3-week weaning regime and showed significant symptomatic improvement. After 2 years of stability off steroids, she presented again with shortness of breath and further decline in lung function, FEV₁ 1.13 L (41%) and FVC 1.2 L (37%). There were no clear precipitating factors or response to oral antibiotics. Repeat CT chest again demonstrated diffuse centrilobular ground glass nodules, less well-defined than previously and more in keeping with a new episode of acute HP. She again responded to oral steroids and had symptomatic improvement.

Over the following year, she continued in good health although spirometry remained significantly impaired, at best FEV₁ 1.86 L (65%) FVC 1.91 L (61%) despite apparent resolution of HP features on follow-up CT age 16 years (figure 1E).

Extensive investigations for an environmental exacerbating factor for presumed HP were repeated but all results were unremarkable. Unable to be certain that HP is the cause of her ongoing abnormal lung function and in the absence of an identified precipitating cause, further investigations were arranged including genetics for childhood interstitial lung disease (chILD), autoimmune and immunology screen and echocardiogram, all of which returned as normal.

The initial 12 gene chILD panel was extended to 38 genes and now detected a heterozygous frame shift mutation in the Regulator of Telomere Elongation Helicase 1 (RTEL1) gene, that encodes a DNA helicase responsible for maintaining telomere length, playing a role in DNA repair and replication.1 4 This mutation is recognised as pathological, autosomal dominantly inherited and leads to loss of function of the telomere length regulator. In adults, it is associated with ILD including idiopathic pulmonary fibrosis, chronic HP and extra-pulmonary conditions including autoimmune disease, bone marrow failure and liver disease.4

Her circulating telomere length was tested and found to be <10th percentile for age matched healthy controls (figure 1F). Her mother has subsequently been found to carry the same RTEL1 gene variation. Mother has liver disease and is awaiting further respiratory investigation. Both have received genetic counselling regarding associated risks of organ failure, ILD and referred to adult respiratory services for follow-up.