American Journal of Respiratory and Critical Care Medicine

To the Editor:

In January 2000, a 35-year-old white man was assessed in our institute for progressive dyspnea that he had had for several months.

A diagnosis of idiopathic marrow aplasia had been established at the age of 16 years. The patient had smoked 30 cigarettes per day since the age of 18 years. Physical examination revealed bilateral basal crackles. Skin examination was normal with the exception of digital clubbing. Laboratory analyses revealed chronic lymphopenia and polyclonal hypergammaglobulinemia. Chest X-ray showed diffuse interstitial infiltrates. High-resolution computed tomography (CT) of the chest revealed expansive fine or coarse irregular lines of attenuation involving predominantly the subpleural lung regions, and diffuse ground-glass opacities (Figure 1a). Fiberoptic bronchoscopy was normal. Bronchoalveolar lavage (BAL) revealed increased cellularity (420,000 cells/ml) with 85% macrophages, 8% neutrophils, and 7% lymphocytes. Most macrophages presented visible cytoplasmic accumulation of proteinaceous material. No pathogen was identified. The lung biopsy revealed filling of alveoli with periodic acid–Schiff–positive granular and eosinophilic material in preserved alveolar architecture (Figure 1b). At that time, the diagnosis was pulmonary alveolar proteinosis (PAP) secondary to idiopathic marrow aplasia. The progenitor cells of our patient did respond normally to granulocyte–macrophage colony–stimulating factor (GM-CSF) in vitro, and anti–GM-CSF autoantibodies were undetectable in the serum or BAL fluid (Immunology Department, Rennes University Hospital, Rennes, France). After failure of whole-lung lavages, daily treatment with subcutaneous recombinant GM-CSF improved clinical, functional, and radiological parameters for more than 1 year (Figure 1c) (1).

From 2003, the patient, who had continued to smoke, presented a progressive worsening of his respiratory state. A new trial of GM-CSF treatment did not improve the patient. In 2010, chest CT scan revealed an atypical pattern of pulmonary fibrosis (PF) with moderate ground-glass opacities, reticulations, traction bronchiectasis, and honeycombings with no basal or subpleural predominance (Figure 1d). Meanwhile, the patient developed severe pulmonary hypertension (mean pulmonary arterial pressure = 52 mm Hg, pulmonary arterial wedge pressure = 13 mm Hg, cardiac index = 2.5 L·min−1·m−2, pulmonary vascular resistance index = 760 dyn·s−1·cm−5·m−2).

At the same time, the patient’s 78-year-old father developed idiopathic PF (IPF) and died soon after from hepatocellular carcinoma in a context of preexisting cirrhosis. Based on these new elements of familial PF, a genetic study was performed. No mutation was found in the surfactant protein gene (SFTP C, SFTP B, and ABCA 3). However, gene sequencing revealed a heterozygous deleterious germline telomerase reverse transcriptase (TERT) mutation (TERT c.1234C>T;p.H412Y NM_198253.2), which causes a substitution of tyrosine for histidine at amino acid 412. The father of the patient was also a carrier of this mutation. Mean telomere length in our patient was 25% shorter than that of a reference group of healthy individuals of similar age (see Figure E1 and Methods in the online supplement). The patient died of severe respiratory failure in 2011.

This observation raises the question of the role of the TERT mutation (TERT c.1234C>T;p.H412Y) in the development of the series of rare diseases found in our patient: aplastic anemia, PAP, and severe PF (see Figure E2).

Telomeres are DNA sequences with a structure that protects chromosome ends from erosion. A specific enzyme, telomerase, is involved in their repair after mitosis. The telomerase complex is composed of several units, including the enzyme TERT. Our patient presented a pathogenic TERT mutation (c.1234C>T;p.H412Y). This mutation has been demonstrated to reduce telomerase activity down to 36% of normal (2). In our patient, this mutation was associated with a shortening of telomere length. The TERT mutations have been described in patients with pulmonary or hepatic fibrosis and aplastic anemia (3). The mutation found in our patient has previously been associated with aplastic anemia (4). The bone marrow failure of our patient appeared at the age of 16 years.

To our knowledge, this is the first reported case of PAP in the context of TERT disease. The PAP syndrome, characterized by accumulation of surfactant, can occur with disruption of GM-CSF signaling the presence of neutralizing GM-CSF autoantibodies. However, our patient had no anti–GM-CSF antibodies, and his progenitor cells responded normally to GM-CSF. A direct role of the TERT mutation in the occurrence of PAP cannot be excluded. TERT deletion in macrophages induces cellular senescence (5), which could reduce their ability to phagocytose particles and surfactant (6). By the induction of proliferation and inhibition of apoptosis in alveolar macrophages, GM-CSF treatment of our patient may have helped to correct surfactant homeostasis. However, it is possible that PAP was the result of aplastic anemia. PAP has been reported in association with hematological disorders (myelodysplastic syndrome and others) (7). Two cases of PAP secondary to Fanconi anemia (another disease characterized by marrow aplasia and a DNA repair disorder) have previously been reported (8). The pathogenic hypothesis is that PAP secondary to hematological disease occurs as a consequence of a reduction in either the number or function of alveolar macrophages. Defective monocyte-to-macrophage maturation could explain the induction of PAP during medullar aplasia linked to TERT mutations.

Our smoking patient also presented with PF. Diaz de Leon and colleagues found that smoking was a predisposing factor of PF in TERT mutation carriers (3). However, the PF phenotype of our patient was unusual: the CT was atypical for IPF, with neither basal nor posterior distribution. Only 13% of patients in Diaz de Leon and colleagues’ cohort presented an atypical pattern. Furthermore, the occurrence of lung fibrosis before the age of 45 years is unusual when compared with other reported cases of PF due to TERT mutations. These two features led us to hypothesize that elements other than smoking had been involved in the occurrence of lung fibrosis in our patient. Even if only a few cases have been reported (9), PAP could promote PF. The CT scan follow-up of our patient demonstrates that the opacities of PAP were replaced secondarily by profuse reticulations and traction bronchiectasis. PF in our patient occurred before the age of 45, whereas his father was diagnosed at the age of 78. Two previous reports described patients with TERT mutations, bone-marrow failure, and PF at a relatively young age (10, 11). Progressively shorter telomeres are inherited from generation to generation, resulting in disease anticipation (12). Another hypothesis could be the occurrence of a chronic viral infection secondary to aplastic anemia. Several studies have investigated the possible role of chronic viral infection in the pathophysiology of IPF (see References in Reference 13). However, no viruses were specifically sought in our patient.

1. Khanjari F, Watier H, Domenech J, Asquier E, Diot P, Nakata K. GM-CSF and proteinosis. Thorax 2003;58:645.
2. Du H-Y, Pumbo E, Manley P, Field JJ, Bayliss SJ, Wilson DB, Mason PJ, Bessler M. Complex inheritance pattern of dyskeratosis congenita in two families with 2 different mutations in the telomerase reverse transcriptase gene. Blood 2008;111:11281130.
3. Diaz de Leon A, Cronkhite JT, Katzenstein A-LA, Godwin JD, Raghu G, Glazer CS, Rosenblatt RL, Girod CE, Garrity ER, Xing C, et al. Telomere lengths, pulmonary fibrosis and telomerase (TERT) mutations. PLoS ONE 2010;5:e10680.
4. Yamaguchi H, Calado RT, Ly H, Kajigaya S, Baerlocher GM, Chanock SJ, Lansdorp PM, Young NS. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N Engl J Med 2005;352:14131424.
5. Gizard F, Heywood EB, Findeisen HM, Zhao Y, Jones KL, Cudejko C, Post GR, Staels B, Bruemmer D. Telomerase activation in atherosclerosis and induction of telomerase reverse transcriptase expression by inflammatory stimuli in macrophages. Arterioscler Thromb Vasc Biol 2011;31:245252.
6. Holt DJ, Grainger DW. Senescence and quiescence induced compromised function in cultured macrophages. Biomaterials 2012;33:74977507.
7. Carey B, Trapnell BC. The molecular basis of pulmonary alveolar proteinosis. Clin Immunol 2010;135:223235.
8. Eldar M, Shoenfeld Y, Zaizov R, Fogel R, Asherov J, Liban E, Pinkhas J. Pulmonary alveolar proteinosis associated with Fanconi’s anemia. Respiration 1979;38:177179.
9. Luisetti M, Bruno P, Kadija Z, Suzuki T, Raffa S, Torrisi MR, Campo I, Mariani F, Pozzi E, Trapnell BC, et al. Relationship between diffuse pulmonary fibrosis, alveolar proteinosis, and granulocyte-macrophage colony stimulating factor autoantibodies. Respir Care 2011;56:16081610.
10. Gansner JM, Rosas IO, Ebert BL. Pulmonary fibrosis, bone marrow failure, and telomerase mutation. N Engl J Med 2012;366:15511553.
11. Parry EM, Alder JK, Qi X, Chen JJ-L, Armanios M. Syndrome complex of bone marrow failure and pulmonary fibrosis predicts germline defects in telomerase. Blood 2011;117:56075611.
12. Savage SA, Bertuch AA. The genetics and clinical manifestations of telomere biology disorders. Genet Med 2010;12:753764.
13. Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, Colby TV, Cordier JF, Flaherty KR, Lasky JA, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011;183:788824.

Author Contributions: Conception and design: S.M.-A., P.M., A.D.M., B.D., and P.D.; analysis and interpretation: S.M.-A., C.G., C.K., A.L.-V., and P.D.; drafting the manuscript for important intellectual content: S.M.-A., C.K., I.D., A.T., and P.D.

This article has an online supplement, which is accessible from this issue's table of contents at

Author disclosures are available with the text of this letter at


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