Usual Interstitial Pneumonia Complicating Dyskeratosis Congenita

Abstract

Dyskeratosis congenita (DC) is a rare disorder characterized by skin hyperpigmentation, nail dystrophy, and leukoplakia of mucous membranes. Pulmonary complications occur in approximately 20% of patients, although the specific histopathologic features, the temporal relationship between the diagnosis of DC and the development of pulmonary fibrosis, and the response to specific treatment are largely undefined. We describe 2 patients with DC who developed usual interstitial pneumonia. Pulmonary fibrosis developed 18 and 38 years after the original manifestations of DC. Both patients died of respiratory failure, 4 and 6 months after lung biopsy. Pulmonary fibrosis in patients with DC may be linked to underlying abnormalities of fibroblast function. Dyskeratosis congenita (DC) is a rare disorder characterized by skin hyperpigmentation, nail dystrophy, and leukoplakia of mucous membranes. Pulmonary complications occur in approximately 20% of patients, although the specific histopathologic features, the temporal relationship between the diagnosis of DC and the development of pulmonary fibrosis, and the response to specific treatment are largely undefined. We describe 2 patients with DC who developed usual interstitial pneumonia. Pulmonary fibrosis developed 18 and 38 years after the original manifestations of DC. Both patients died of respiratory failure, 4 and 6 months after lung biopsy. Pulmonary fibrosis in patients with DC may be linked to underlying abnormalities of fibroblast function. Dyskeratosis congenita (DC) is a rare, progressive disorder characterized by the combination of skin hyperpigmentation, nail dystrophy, and leukoplakia of mucous membranes.1Dokal I Dyskeratosis congenita in all its forms.Br J Haematol. 2000; 110: 768-779Crossref PubMed Scopus (437) Google Scholar Bone marrow failure is a frequent finding, and a predisposition to malignancy has been noted. Pulmonary manifestations of DC were once believed to be uncommon, but recent data suggest that they may occur in as many as 20% of patients.1Dokal I Dyskeratosis congenita in all its forms.Br J Haematol. 2000; 110: 768-779Crossref PubMed Scopus (437) Google Scholar, 2Knight S Vulliamy T Copplestone A Gluckman E Mason P Dokal I Dyskeratosis Congenita (DC) Registry: identification of new features of DC.Br J Haematol. 1998; 103: 990-996Crossref PubMed Scopus (161) Google Scholar Specific histopathologic findings have been detailed only rarely in patients with DC. The temporal relationship between the diagnosis of DC and the onset of pulmonary problems is not well defined, nor is the response to specific therapeutic agents. We describe 2 patients with DC who developed pulmonary fibrosis characterized by usual interstitial pneumonia (UIP) on surgical lung biopsy. A 28-year-old man presented with a 6-month history of shortness of breath, dry cough, and fatigue. He had a minimal smoking history but no history of connective tissue disorder, known fibrogenic drug exposure, environmental or occupational exposure linked to pulmonary fibrosis, or cardiopulmonary disease. His medical history was remarkable for DC. His known family history was negative for DC (his father had been adopted and had died in an accident at age 25 years). His first recognized manifestation of DC was aplastic anemia diagnosed when he was 10 years old and resulting in bone marrow transplantation (BMT) by age 16 years. Dyskeratosis congenita was diagnosed at the time of BMT on the basis of the history of aplastic anemia, skin hyperpigmentation, dyskeratotic nails, and tongue leukoplakia; he had also had an esophageal stricture. On physical examination, the patient was dyspneic with minimal activity. Bilateral inspiratory crackles were noted on lung auscultation. No major skin abnormalities were seen, and tongue leukoplakia was no longer present. The patient stated that the skin and tongue abnormalities had regressed after BMT, and his mother confirmed this observation. Review of outside medical records indicated that multiple physicians had noted tongue leukoplakia and hyperpigmentation around his neck, described as a “dirty neck” appearance by his mother. He continued to exhibit nail dystrophy but no clubbing (Figure 1). Pulmonary function testing showed a moderate restrictive pattern (total lung capacity, 4.35 L; 67% predicted) with a considerably reduced diffusing capacity of lung for carbon monoxide (Dlco) (37% predicted). High-resolution computed tomography of the chest revealed bilateral subpleural reticular changes in the upper and lower lung fields with subpleural honeycombing and traction bronchiectasis compatible with UIP (Figure 2). The pulmonary function abnormalities and radiographic findings had not been present on testing 6 and 10 years, respectively, before the current admission. Surgical lung biopsy revealed histopathologic findings typical of UIP (Figure 3). The patient was referred for evaluation for lung transplantation but died of respiratory failure 4 months after the lung biopsy.FIGURE 3Case 1. Surgical lung biopsy specimen shows usual interstitial pneumonia. Left, Low-magnification photomicrograph reveals patchy chronic interstitial pneumonia dominated by peripheral and paraseptal collagen deposition with scarring and early honeycomb changes (hematoxylin-eosin, original magnification ×20). Right, Low-magnification photomicrograph shows area of scarring with honeycomb changes and fibroblast focus (arrows) typical of usual interstitial pneumonia (hematoxylin-eosin, original magnification ×40).View Large Image Figure ViewerDownload (PPT) A 48-year-old man was referred to our institution for evaluation of suspected pulmonary fibrosis. Dry cough and progressive dyspnea on exertion had been present during the preceding year. The patient was an ex-smoker and had no history of a connective tissue disorder, known fibrogenic drug exposure, environmental or occupational exposure linked to pulmonary fibrosis, or cardiopulmonary disease. His medical history was remarkable for DC. He had 2 maternal first cousins reported to have DC, 1 of whom died at age 42 years of pulmonary fibrosis. The patient's mother and maternal aunt had no signs of DC, which is compatible with X-linked recessive inheritance. He first noted dyskeratotic nails when he was about 10 years old, and brownish hyperpigmented areas developed on his skin approximately 2 years later. In his 20s, he began to note gradual loss of axillary and pubic hair, as well as thinning of his eyelashes. Additional findings consistent with DC included bilateral tube placement for obstructed tear ducts and circumcision as an adult for phimosis. Physical examination findings included dystrophic nails and hyperpigmentation of the skin, particularly on the groin and axillae. Multiple hypopigmented macules were present diffusely. Leukoplakia was noted on the tongue and oral mucosa. Auscultation of the chest revealed bibasilar inspiratory crackles. No digital clubbing was seen. Pulmonary function testing identified a severe restrictive pattern (total lung capacity, 2.40 L; 34% predicted) with markedly reduced Dlco (30% predicted) and oxygen desaturation with exercise while the patient breathed room air. High-resolution computed tomography revealed bilateral reticular changes in the upper and lower lung fields with peripheral honeycombing, traction bronchiectasis, and patchy ground-glass changes compatible with UIP (Figure 4). A surgical lung biopsy specimen showed UIP (Figure 5). The patient was treated with corticosteroids, colchicine, and aggressive management of gastroesophageal reflux. No improvement was noted, and he died of respiratory failure within 6 months after biopsy.FIGURE 5Case 2. Surgical lung biopsy specimen shows usual interstitial pneumonia. Left, Low-magnification photomicrograph illustrates chronic interstitial pneumonia characterized by a combination of inflammation and fibrosis. Fibrosis predominates and is distributed in a patchy, predominantly subpleural pattern characteristic of usual interstitial pneumonia (hematoxylin-eosin, original magnification ×20). Right, At higher magnification, a combination of fibrosis, smooth muscle proliferation, and fibroblast foci (arrows) typical of usual interstitial pneumonia is evident (hematoxylineosin, original magnification ×40).View Large Image Figure ViewerDownload (PPT) Dyskeratosis congenita is an inherited condition in which abnormal cutaneous pigmentation occurs in combination with nail dystrophy and mucosal leukoplakia.1Dokal I Dyskeratosis congenita in all its forms.Br J Haematol. 2000; 110: 768-779Crossref PubMed Scopus (437) Google Scholar These symptoms usually appear when patients are between 5 and 10 years old, although they may occur earlier or later.1Dokal I Dyskeratosis congenita in all its forms.Br J Haematol. 2000; 110: 768-779Crossref PubMed Scopus (437) Google Scholar Other features of DC include bone marrow failure, mental retardation, pulmonary disease, and genitourinary, skeletal, and gastrointestinal abnormalities.2Knight S Vulliamy T Copplestone A Gluckman E Mason P Dokal I Dyskeratosis Congenita (DC) Registry: identification of new features of DC.Br J Haematol. 1998; 103: 990-996Crossref PubMed Scopus (161) Google Scholar, 3Inoue S Mekanik G Mahallati M Zuelzer WW Dyskeratosis congenita with pancytopenia: another constitutional anemia.Am J Dis Child. 1973; 126: 389-396PubMed Google Scholar Bone marrow failure and pulmonary disease are the 2 most serious and lifethreatening complications. Bone marrow failure occurs in more than 80% of patients and is the principal cause of mortality.1Dokal I Dyskeratosis congenita in all its forms.Br J Haematol. 2000; 110: 768-779Crossref PubMed Scopus (437) Google Scholar Enthusiasm for BMT has been tempered by reports of increased early and late complications.4Berthou C Devergie A D'Agay MF et al.Late vascular complications after bone marrow transplantation for dyskeratosis congenita.Br J Haematol. 1991; 79: 335-336Crossref PubMed Scopus (40) Google Scholar, 5Yabe M Yabe H Hattori K et al.Fatal interstitial pulmonary disease in a patient with dyskeratosis congenita after allogeneic bone marrow transplantation.Bone Marrow Transplant. 1997; 19: 389-392Crossref PubMed Scopus (70) Google Scholar, 6Ghavamzadeh A Alimoghadam K Nasseri P Jahani M Khodabandeh A Ghahremani G Correction of bone marrow failure in dyskeratosis congenita by bone marrow transplantation.Bone Marrow Transplant. 1999; 23: 299-301Crossref PubMed Scopus (29) Google Scholar, 7Dror Y Freedman MH Leaker M et al.Low-intensity hematopoietic stem-cell transplantation across human leucocyte antigen barriers in dyskeratosis congenita.Bone Marrow Transplant. 2003; 31: 847-850Crossref PubMed Scopus (53) Google Scholar, 8Rocha V Devergie A Socie G et al.Unusual complications after bone marrow transplantation for dyskeratosis congenita.Br J Haematol. 1998; 103: 243-248Crossref PubMed Scopus (103) Google Scholar, 9Langston AA Sanders JE Deeg HJ et al.Allogeneic marrow transplantation for aplastic anaemia associated with dyskeratosis congenita.Br J Haematol. 1996; 92: 758-765Crossref PubMed Scopus (72) Google Scholar, 10Nobili B Rossi G De Stefano P et al.Successful umbilical cord blood transplantation in a child with dyskeratosis congenita after a fludarabine-based reduced-intensity conditioning regimen [letter].Br J Haematol. 2002; 119: 573-574Crossref PubMed Scopus (37) Google Scholar Data from the Dyskeratosis Congenita Registry suggest that approximately 70% of DC-associated mortality can be attributed to bone marrow failure or its complications.1Dokal I Dyskeratosis congenita in all its forms.Br J Haematol. 2000; 110: 768-779Crossref PubMed Scopus (437) Google Scholar, 2Knight S Vulliamy T Copplestone A Gluckman E Mason P Dokal I Dyskeratosis Congenita (DC) Registry: identification of new features of DC.Br J Haematol. 1998; 103: 990-996Crossref PubMed Scopus (161) Google Scholar Pulmonary involvement occurs in a minority of patients with DC and contributes disproportionately to morbidity and mortality. A 1973 review of the literature identified fibrotic lung changes in only 2 of 35 reported patients.3Inoue S Mekanik G Mahallati M Zuelzer WW Dyskeratosis congenita with pancytopenia: another constitutional anemia.Am J Dis Child. 1973; 126: 389-396PubMed Google Scholar A more recent review of data from the Dyskeratosis Congenita Registry indicates pulmonary disease in 20.3% of 148 patients from 92 families.1Dokal I Dyskeratosis congenita in all its forms.Br J Haematol. 2000; 110: 768-779Crossref PubMed Scopus (437) Google Scholar Affected patients had reduced Dlco and/or a restrictive defect on pulmonary function testing. Pulmonary complications are the second most common cause of death in patients with DC, about half occurring in patients who undergo BMT. Our findings suggest that UIP is a common pattern of interstitial pneumonia in DC patients with diffuse lung disease. Specific histopathologic findings in patients with underlying DC have been characterized infrequently. In 2 patients from the Dyskeratosis Congenita Registry, postmortem studies after acute respiratory death showed “abnormal levels of pulmonary fibrosis and abnormalities in the pulmonary microvasculature.”1Dokal I Dyskeratosis congenita in all its forms.Br J Haematol. 2000; 110: 768-779Crossref PubMed Scopus (437) Google Scholar Autopsy or surgical lung biopsy findings have been described in only 8 patients reported previously in the English language literature (Table 1).5Yabe M Yabe H Hattori K et al.Fatal interstitial pulmonary disease in a patient with dyskeratosis congenita after allogeneic bone marrow transplantation.Bone Marrow Transplant. 1997; 19: 389-392Crossref PubMed Scopus (70) Google Scholar, 11Safa WF Lestringant GG Frossard PM X-linked dyskeratosis congenita: restrictive pulmonary disease and a novel mutation.Thorax. 2001; 56: 891-894Crossref PubMed Scopus (37) Google Scholar, 12Vanbiervliet P Blockmans D Bobbaers H Dyskeratosis congenita and associated interstitial lung disease: a case report.Acta Clin Belg. 1998; 53: 198-202PubMed Google Scholar, 13Imokawa S Sato A Toyoshima M et al.Dyskeratosis congenita showing usual interstitial pneumonia.Intern Med. 1994; 33: 226-230Crossref PubMed Scopus (22) Google Scholar, 14Paul SR Perez-Atayde A Williams DA Interstitial pulmonary disease associated with dyskeratosis congenita [letter].Am J Pediatr Hematol Oncol. Spring 1992; 14: 89-92Crossref PubMed Scopus (25) Google Scholar, 15Kilic S Kose H Ozturk H Pulmonary involvement in a patient with dyskeratosis congenita.Pediatr Int. 2003; 45: 740-742Crossref PubMed Scopus (6) Google Scholar, 16Verra F Kouzan S Saiag P Bignon J de Cremoux H Bronchoalveolar disease in dyskeratosis congenita.Eur Respir J. 1992; 5: 497-499PubMed Google Scholar Usual interstitial pneumonia was described in surgical lung biopsy specimens from 3 of these patients, none of whom had undergone BMT.11Safa WF Lestringant GG Frossard PM X-linked dyskeratosis congenita: restrictive pulmonary disease and a novel mutation.Thorax. 2001; 56: 891-894Crossref PubMed Scopus (37) Google Scholar, 12Vanbiervliet P Blockmans D Bobbaers H Dyskeratosis congenita and associated interstitial lung disease: a case report.Acta Clin Belg. 1998; 53: 198-202PubMed Google Scholar, 13Imokawa S Sato A Toyoshima M et al.Dyskeratosis congenita showing usual interstitial pneumonia.Intern Med. 1994; 33: 226-230Crossref PubMed Scopus (22) Google Scholar With the addition of our 2 patients, UIP was present in 5 of 7 patients who underwent surgical lung biopsy. Less specific findings were described in 2 patients who had changes that the authors suggested resembled extrinsic allergic alveolitis (Table 1).14Paul SR Perez-Atayde A Williams DA Interstitial pulmonary disease associated with dyskeratosis congenita [letter].Am J Pediatr Hematol Oncol. Spring 1992; 14: 89-92Crossref PubMed Scopus (25) Google Scholar In both cases, the onset of pulmonary disease occurred years after the diagnosis of DC. Some degree of pulmonary fibrosis was described at autopsy in 3 other patients, although a specific histopathologic diagnosis was not made.TABLE 1Findings in Patients With DC Who Underwent Lung Biopsy*BMT = bone marrow transplantation; DC = dyskeratosis congenita; Dx = diagnosis; ellipses = not applicable; NA = not available; postop = postoperative.ReferenceAge at biopsy (y) and sexTime from DC Dx to biopsy (y)Type of biopsyHistopathologic findingsBMTTime from BMT to biopsy (y)Corticosteroid responsiveOutcome after biopsyCurrent report28/M18SurgicalUsual interstitial pneumoniaYes12…Dead at 4 mo48/M38SurgicalUsual interstitial pneumoniaNo…NoDead at 6 moSafa et al, 11Safa WF Lestringant GG Frossard PM X-linked dyskeratosis congenita: restrictive pulmonary disease and a novel mutation.Thorax. 2001; 56: 891-894Crossref PubMed Scopus (37) Google Scholar 200140/M30SurgicalUsual interstitial pneumoniaNo…NoDead at 38 moVanbiervliet et al, 12Vanbiervliet P Blockmans D Bobbaers H Dyskeratosis congenita and associated interstitial lung disease: a case report.Acta Clin Belg. 1998; 53: 198-202PubMed Google Scholar 199837/M4SurgicalUsual interstitial pneumoniaNo…NoAlive at 15 moImokawa et al, 13Imokawa S Sato A Toyoshima M et al.Dyskeratosis congenita showing usual interstitial pneumonia.Intern Med. 1994; 33: 226-230Crossref PubMed Scopus (22) Google Scholar 199446/M31SurgicalUsual interstitial pneumoniaNo…NANAPaul et al, 14Paul SR Perez-Atayde A Williams DA Interstitial pulmonary disease associated with dyskeratosis congenita [letter].Am J Pediatr Hematol Oncol. Spring 1992; 14: 89-92Crossref PubMed Scopus (25) Google Scholar 199220/F8SurgicalBronchiocentric mixed inflammatory processNo…NADied of postop respiratory failure12/M8SurgicalBronchiocentric granulomatosisNo…NANAKilic et al, 15Kilic S Kose H Ozturk H Pulmonary involvement in a patient with dyskeratosis congenita.Pediatr Int. 2003; 45: 740-742Crossref PubMed Scopus (6) Google Scholar 200310/M9AutopsyAbnormal levels of fibrosis and dense, thick reticular fibers in stromaNo…NoNAYabe et al, 5Yabe M Yabe H Hattori K et al.Fatal interstitial pulmonary disease in a patient with dyskeratosis congenita after allogeneic bone marrow transplantation.Bone Marrow Transplant. 1997; 19: 389-392Crossref PubMed Scopus (70) Google Scholar 19979/M7AutopsyMixed inflammatory cell infiltrate of bronchioles and alveoli with interstitial fibrosisYes7NoNAVerra et al, 16Verra F Kouzan S Saiag P Bignon J de Cremoux H Bronchoalveolar disease in dyskeratosis congenita.Eur Respir J. 1992; 5: 497-499PubMed Google Scholar 199239/M15AutopsyNonspecific collagenous interstitial fibrosisNo…NANA* BMT = bone marrow transplantation; DC = dyskeratosis congenita; Dx = diagnosis; ellipses = not applicable; NA = not available; postop = postoperative. Open table in a new tab Usual interstitial pneumonia is most often associated with the clinical syndrome of idiopathic pulmonary fibrosis and portends a poor prognosis, with an average survival of 2 to 3 years after diagnosis.17Bjoraker JA Ryu JH Edwin MK et al.Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 1998; 157: 199-203Crossref PubMed Scopus (979) Google Scholar Three of 4 patients with DC complicated by UIP for whom follow-up was available died of respiratory failure, indicating a similarly aggressive course (Table 1). Although experience with UIP in patients with DC is limited, it does not appear to be corticosteroid responsive, consistent with the more widespread experience with UIP in patients with idiopathic pulmonary fibrosis. In all patients for whom pathologic information was available, pulmonary fibrosis developed years after the diagnosis of DC (Table 1). Another reported patient with DC developed chronic liver disease and hypoxemia compatible with hepatopulmonary syndrome.2Knight S Vulliamy T Copplestone A Gluckman E Mason P Dokal I Dyskeratosis Congenita (DC) Registry: identification of new features of DC.Br J Haematol. 1998; 103: 990-996Crossref PubMed Scopus (161) Google Scholar Pulmonary complications have also been described after BMT. Concerns regarding early and late complications after BMT in patients with DC, including noninfectious pulmonary disease, have dampened enthusiasm for this technique.1Dokal I Dyskeratosis congenita in all its forms.Br J Haematol. 2000; 110: 768-779Crossref PubMed Scopus (437) Google Scholar, 2Knight S Vulliamy T Copplestone A Gluckman E Mason P Dokal I Dyskeratosis Congenita (DC) Registry: identification of new features of DC.Br J Haematol. 1998; 103: 990-996Crossref PubMed Scopus (161) Google Scholar, 10Nobili B Rossi G De Stefano P et al.Successful umbilical cord blood transplantation in a child with dyskeratosis congenita after a fludarabine-based reduced-intensity conditioning regimen [letter].Br J Haematol. 2002; 119: 573-574Crossref PubMed Scopus (37) Google Scholar Busulfan and ionizing radiation may contribute to the incidence of pulmonary complications in some patients.8Rocha V Devergie A Socie G et al.Unusual complications after bone marrow transplantation for dyskeratosis congenita.Br J Haematol. 1998; 103: 243-248Crossref PubMed Scopus (103) Google Scholar Examination of the Dyskeratosis Congenita Registry in 1998 identified 7 patients who were treated with BMT.2Knight S Vulliamy T Copplestone A Gluckman E Mason P Dokal I Dyskeratosis Congenita (DC) Registry: identification of new features of DC.Br J Haematol. 1998; 103: 990-996Crossref PubMed Scopus (161) Google Scholar Four of the 7 patients died but only 1 of respiratory failure. That patient died before engraftment and had severe “pulmonary disease” before BMT. The remaining patients died of nonpulmonary complications at 2, 8, and 8 years. Only 1 of 5 patients with DC reported by Rocha et al8Rocha V Devergie A Socie G et al.Unusual complications after bone marrow transplantation for dyskeratosis congenita.Br J Haematol. 1998; 103: 243-248Crossref PubMed Scopus (103) Google Scholar survived BMT, and that patient developed dyspnea 3 years later. A lung biopsy of unspecified type was described as showing interstitial lymphocytic infiltrates and “fibrosis” 7½ years after BMT. In 2002, Nobili et al10Nobili B Rossi G De Stefano P et al.Successful umbilical cord blood transplantation in a child with dyskeratosis congenita after a fludarabine-based reduced-intensity conditioning regimen [letter].Br J Haematol. 2002; 119: 573-574Crossref PubMed Scopus (37) Google Scholar summarized the known experience with BMT for bone marrow failure in patients with DC. Fifteen of 23 DC patients who underwent BMT had died at the time of follow-up. Four of these 15 died of “pulmonary fibrosis,” and a fifth died of “respiratory failure” during rejection. One of the 5 patients who died of “pulmonary fibrosis” or “respiratory failure” received ionizing radiation, and none received busulfan. Therefore, it is unclear whether either of these interventions increases the risk of death from pulmonary causes after BMT in patients with DC. Furthermore, death from “pulmonary fibrosis” occurred years after the transplantation in 3 of the 5 patients (at 7, 8, and 20 years), suggesting that “pulmonary fibrosis” may have been a manifestation of the underlying disease rather than a complication of BMT (Table 1). Dyskeratosis congenita primarily exhibits X-linked recessive inheritance, although autosomal recessive and autosomal dominant transmission have been reported.1Dokal I Dyskeratosis congenita in all its forms.Br J Haematol. 2000; 110: 768-779Crossref PubMed Scopus (437) Google Scholar The X-linked form of DC has been localized to chromosome Xq28 and is due to mutations in the gene encoding dyskerin (DSK1), which is involved in processing the template RNA component of telomerase.18Shay JW Wright WE Telomeres in dyskeratosis congenita.Nat Genet. 2004; 36: 437-438Crossref PubMed Scopus (28) Google Scholar An autosomal dominant form of DC is localized to chromosome 3q21-28 and is due to deletions or mutations of the gene encoding telomerase RNA component (TERC).19Vulliamy T Marrone A Goldman F et al.The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita.Nature. 2001; 413: 432-435Crossref PubMed Scopus (767) Google Scholar This defect in TERC causes progressive shortening of the telomeres as the abnormality is transmitted from one generation to the next, resulting in earlier age at onset of the disease in successive generations. Clinical mutation testing for these 2 genes has only recently become available on a clinical basis and was not available when the subjects of our report were evaluated. The gene defect(s) for autosomal recessive DC remains unknown. The mechanism by which telomere abnormalities result in the phenotypic abnormalities of DC is incompletely understood, but less telomerase activity is available to maintain highly proliferative cells.1Dokal I Dyskeratosis congenita in all its forms.Br J Haematol. 2000; 110: 768-779Crossref PubMed Scopus (437) Google Scholar, 17Bjoraker JA Ryu JH Edwin MK et al.Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 1998; 157: 199-203Crossref PubMed Scopus (979) Google Scholar, 20Connor JM Gatherer D Gray FC Pirrit LA Affara NA Assignment of the gene for dyskeratosis congenita to Xq28.Hum Genet. 1986; 72: 348-351Crossref PubMed Scopus (98) Google Scholar, 21Devriendt K Matthijs G Legius E et al.Skewed X-chromosome inactivation in female carriers of dyskeratosis congenita.Am J Hum Genet. 1997; 60: 581-587PubMed Google Scholar Abnormal growth patterns of skin fibroblast cell cultures from patients with DC show both abnormal morphology and growth rate, and in some studies, chromosomal abnormalities have been reported as well.1Dokal I Dyskeratosis congenita in all its forms.Br J Haematol. 2000; 110: 768-779Crossref PubMed Scopus (437) Google Scholar, 22Scappaticci S Fraccaro M Cerimele D Chromosome abnormalities in dyskeratosis congenita [letter].Am J Med Genet. 1989; 34: 609-610Crossref PubMed Scopus (10) Google Scholar, 23Kehrer H Krone W Chromosome abnormalities in cell cultures derived from the leukoplakia of a female patient with dyskeratosis congenita.Am J Med Genet. 1992; 42: 217-218Crossref PubMed Scopus (12) Google Scholar, 24Kehrer H Krone W Schindler D Kaufmann R Schrezenmeier H Cytogenetic studies of skin fibroblast cultures from a karyotypically normal female with dyskeratosis congenita.Clin Genet. 1992; 41: 129-134Crossref PubMed Scopus (19) Google Scholar, 25Dokal I Bungey J Williamson P Oscier D Hows J Luzzatto L Dyskeratosis congenita fibroblasts are abnormal and have unbalanced chromosomal rearrangements.Blood. 1992; 80: 3090-3096PubMed Google Scholar The development of pulmonary fibrosis in these patients may be a manifestation of abnormal fibroblast function or lack of maintenance of some other pulmonary cell type.