American Journal of Respiratory and Critical Care Medicine

To the Editor:

We read with interest the article by Alder and colleagues (1), demonstrating that short telomeres lowered the threshold of cigarette smoke–induced damage in a model of telomerase null mice, and may contribute to the age-related onset of emphysema in humans. Telomere length, with or without germline mutation in telomerase genes (TERC or TERT), is known to be associated with familial and sporadic idiopathic interstitial pneumonias (IIPs) (2). Heterogeneous pulmonary disease phenotypes have been observed in telomerase mutation carriers within the same family. Interestingly, the authors identified a family with a deletion in the box H domain of TERC, including the proband affected with emphysema, her father with idiopathic pulmonary fibrosis, and her sister with combined pulmonary fibrosis and emphysema syndrome (CPFE) (1). We report a family with TERT mutation and a similar combined emphysema–fibrosis spectrum of lung disease.

A 53-year-old male, a current smoker (56 pack-years), was referred to our department for the detection of IIP in September 2009 in a context of recurrent respiratory infections. He worked as a general practitioner and declared no other environmental exposure. High-resolution computed tomography (HRCT) showed characteristic CPFE. Surgical lung biopsy revealed a pattern of nonspecific interstitial pneumonia, which was particular for the presence of scarce, ill-defined granulomas. The patient was given low-dose steroids. At last visit in July 2013 he was doing well. FVC was 97% of the predicted value, FEV1 was 97%, and diffusing capacity of the lungs for carbon monoxide (DlCO) was 47%.

His mother was a secretary. She had quit smoking 6 years before being diagnosed with IIP in 1998 at the age of 63. Apart from premature hair graying (3), her previous history was irrelevant. HRCT showed a pattern suggestive of nonspecific interstitial pneumonia without associated emphysema. On surgical lung biopsy, pulmonary fibrosis was unclassifiable, but scattered granulomas were also described. Her respiratory condition worsened progressively despite steroid therapy, until she died in 2008.

His maternal uncle was an ex-smoker of 45 pack-years with a previous history of atrial fibrillation and coronary heart disease. He worked as a carpenter with a significant exposure to wood dusts. In 2000, he presented with left pneumothorax, which led to the diagnosis of emphysema. In May 2010, he was investigated for breathlessness increasing over the last 3 years. HRCT showed CPFE with a definite pattern of usual interstitial pneumonia. FVC was 74% of the predicted value, FEV1 was 84%, and DlCO was 35%. He refused to be enrolled in a clinical trial and received an association of N-acetylcysteine, low-dose steroids, and oxygen therapy. He developed pulmonary hypertension and eventually succumbed to an acute exacerbation in May 2012.

His only younger brother was given a diagnosis of emphysema alone when he was 28 years old. At this time he used to smoke 20 cigarettes per day and mentioned premature hair graying. The most recent HRCT showed apical emphysema and mild pulmonary fibrosis of the lower lobes.

The proband, his uncle, and brother have a duplication of 22 nucleotides in the first exon of TERT at a heterozygous state (TERT reference sequences NM_, NP_: official nomenclature of the mutation NM_198253, NP_ NP_937983: c.22_43dup22, p. p.Arg15ProfsX). This mutation is not present in the Telomerase Database, nor in variant databases (Exome Variant Server, 1000 genomes) (4). His mother is an obligatory carrier. This case study supports the hypothesis that tobacco may trigger young-onset emphysema and pulmonary fibrosis alone or in combination in subjects with inherited mutations in telomerase, with a possible role of coexposures (1). The breadth of clinical features in multiple patients in this family demonstrates the need for further investigation of a possible genetic basis for CPFE.

1. Alder JK, Guo N, Kembou F, Parry EM, Anderson CJ, Gorgy AI, Walsh MF, Sussan T, Biswal S, Mitzner W, et al. Telomere length is a determinant of emphysema susceptibility. Am J Respir Crit Care Med 2011;184:904912.
2. Armanios M. Telomerase and idiopathic pulmonary fibrosis. Mutat Res 2012;730:5258.
3. Diaz de Leon A, Cronkhite JT, Yilmaz C, Brewington C, Wang R, Xing C, Hsia CC, Garcia CK. Subclinical lung disease, macrocytosis, and premature graying in kindreds with telomerase (TERT) mutations. Chest 2011;140:753763.
4. Podlevsky JD, Bley CJ, Omana RV, Qi X, Chen JJ. The Telomerase Database. Nucleic Acids Res 2008;36:D339D343.

Author disclosures are available with the text of this letter at


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American Journal of Respiratory and Critical Care Medicine

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