The reported patient is enrolled in National Cancer Institute protocol 02-C-0052 (NCT00056121, http://www.marrowfailure.cancer.gov
), which is approved by the Institutional Review Board.
Case: A 14-year-old Asian boy (NCI-204-1) presented with anemia and thrombocytopenia at three years of age. This rapidly progressed to SAA, and he underwent a Human Leukocyte Antigen-identical sibling donor HSCT at age four. The preparative regimen consisted of cyclophosphamide (50 mg/kg × 4 days) and anti-thymocyte globulin (30 mg/kg × 3 days). Cyclosporine and methotrexate were used for graft versus
host disease (GvHD) prophylaxis. He engrafted rapidly, without evidence of acute GvHD, infections or other HSCT-related complications. Review of his medical records indicated that he had a "geographic tongue" and toenail dystrophy noted prior to HSCT, but the diagnosis of DC was not made at that time. During the next two to three years after HSCT, his mucocutaneous findings evolved into the classic DC triad of oral (tongue) leukoplakia, finger and toe nail dystrophy, and reticular skin pigmentation. He also developed bilateral lacrimal duct obstruction, trichiasis and urethral stenosis. This constellation of findings led to the clinical diagnosis of DC at age seven, four years after he presented with BMF. He was subsequently found to have an heterozygous mutation in TINF2
(c.851_852delCA resulting in Thr284SerfsX5) in his skin fibroblasts. This mutation results in a truncation of the protein product of TINF2
in the same region as other mutations in this gene reported to cause DC [9
]. There was no family history of DC-related illnesses, and all family members were negative for mutations in TINF2
At age 11, seven years after HSCT, the patient developed a chronic persistent dry cough and exertional dyspnea. Spirometry revealed a forced vital capacity (FVC) of 0.78L (31% of predicted), forced expiratory volume in 1 second (FEV1) of 0.73L (33% of predicted), and the flow/volume loop suggested a restrictive pattern (Table ). A short course of oral prednisone (60 mg [2 mg/kg] for 10 days) resulted in transient improvement (FVC 51% predicted; FEV1 48% predicted). Pulmonary function testing (PFT) obtained following the steroid pulse confirmed moderate to severe restrictive lung disease, with total lung capacity (TLC) 56% predicted, mild air trapping (RV/TLC 33%), and a significant reduction in diffusion capacity for carbon monoxide (DLCO) at 27% of predicted (Table ). Chest radiograph demonstrated a diffuse interstitial pattern which was consistent with pulmonary fibrosis. High-resolution computerized tomography (CT) of the lungs showed bilateral diffuse areas of ground glass opacities and fibrosis (Figure ). Lung biopsy was interpreted as severe interstitial fibrosis, confirming the clinical diagnosis.
Pulmonary function at diagnosis of pulmonary fibrosis, before and after lung transplantation
Figure 1 Chest computerized tomography of the patient at age 11 years, 7 years after hematopoietic stem cell transplantation and 17 months prior to lung transplantation. At the time of this evaluation, he had dyspnea on exertion, a chronic, non-productive cough, (more ...)
The patient received every other day oral steroids (0.5 mg/kg/dose) as maintenance therapy. However, after approximately 9 months, his symptoms progressed and his pulmonary function declined, despite escalating immunosuppressive therapy which included high-dose pulse steroids (30 mg/kg methylprednisolone IV for 3 days per month), alternate day low-dose prednisone (0.5 mg/kg/dose), azathioprine (50 mg daily) and N-acetyl-cysteine (600 mg three times daily). He became wheelchair-bound and required 24-hour ventilatory support with nasal Bi-level Positive Airway Pressure, at age 12. After three months on the lung transplant waiting list a deceased donor was identified. He underwent bilateral lung transplantation at age 13.
On gross examination, the explanted lungs were firm and poorly aerated, with thickening of small airway walls. Microscopic examination was consistent with a severe interstitial fibrosing process. Throughout most of the lung, there were both established fibrosis and ongoing fibroblastic proliferation, with obliteration of alveolar spaces, extension of smooth muscle into interstitium and chronic inflammation, and marked pneumocyte hyperplasia of residual alveoli. In addition, there was extensive bronchiolitis obliterans, including both established dense collagen deposition and fibroblastic proliferation within the airways (Figure ). Alveolar architecture was more intact in a minority of lobules, with mild alveolar septal widening, pneumocyte hyperplasia and fibroblastic proliferation, but without the heterogeneous temporal and peripheral pattern characteristic of usual interstitial fibrosis. Hyaline membranes and end-stage "honey-comb" parenchyma were not present.
Figure 2 Pulmonary histology at the time of lung transplantation. A: Representative microscopic field of explanted lung shows diffuse fibrosis, with both established collagen deposition (yellow-green hue) and fibroblastic proliferation (arrow, blue-green hue). (more ...)
The patient is now twenty-one months post-lung transplant, and is doing well, with resolution of respiratory symptoms and an excellent level of activity. He has no evidence of rejection either clinically or on transbronchial biopsy. His immunosuppression consists of tacrolimus, with goal trough levels of 8 ng/ml, and prednisone 12.5 mg daily. Because of mild neutropenia, he does not receive mycophenolate mofetil. His white blood cell count 18 months after lung transplant was 3000/mm3 (normal range 3300 - 8700/mm3), with an absolute neutrophil count of 1200/mm3 (normal range 1500 - 6090/mm3). His most recent oxyhemoglobin saturation was 99-100% on room air; and FVC, FEV1, and total lung capacity were essentially normal at 81%, 78%, and 81% of predicted, respectively. His DLCO adjusted for alveolar volume was in the normal range at 85% of predicted (Table ).
Literature review: The mortality from pulmonary disease in patients with DC is reported to be approximately 10-20% [11
]. In an effort to better understand the effect of pulmonary disease in patients with DC, we conducted a systematic review of the literature. We searched PubMed through September 1, 2010, using the following terms: "dyskeratosis congenita" combined with each of "interstitial lung disease," "pulmonary fibrosis," or "lung transplantation," as well as "dyskeratosis" combined with "lung." We also identified cases from the bibliographies of those articles, as well as from general reviews of DC. The terms reflective of lung disease used in the clinical reports included "interstitial pneumonitis," "usual interstitial pneumonitis," "pulmonary fibrosis," "restrictive pulmonary function," or "decreased DLCO." To be as comprehensive as possible, our data included reports of patients with DC, as well as those with pulmonary fibrosis who belonged to families where one or more individuals had some features of DC. Data were entered into Microsoft Excel 11.0, (Microsoft, Redmond, WA, USA), and analyzed using Excel and Stata 11.1 (StataCorp, College Station, TX, USA). Analyses included Fisher's exact and Student's t test. The Kaplan-Meier product limit estimator was used to calculate actuarial survival probabilities by age and cumulative incidences in the absence of competing risks; comparisons were made using the Wilcoxon rank-sum test.
We identified 48 DC patients who met criteria for pulmonary disease and 509 patients, reported in the same interval, in whom no pulmonary symptoms were described. Table summarizes the reports of pulmonary complications consistent with or suspicious for pulmonary fibrosis in 37 patients with DC who did not undergo HSCT. Cases 1 - 20 had classic DC with at least two of the three features of DC triad of nail dystrophy, oral leukoplakia and lacy reticular pigmentation. Cases 21 - 37 belonged to families with TERC
mutations, and had pulmonary fibrosis, with other DC-related features in at least one family member [5
]. In these families, the association of pulmonary fibrosis with DC in the previous generation was made only after a proband in a subsequent generation was identified with clinical features consistent with DC and/or a mutation in a DC gene. For example, in one family (the proband is case 9 in Table ), the proband's paternal grandmother (case 28 in Table ) had died from fibrosing alveolitis, and his father (case 29 in Table ) had received a heart/lung transplant for cryptogenic fibrosing alveolitis [20
Dyskeratosis congenita (DC) cases with reported pulmonary disease who did not have a hematopoietic stem cell transplant (HSCT)
Dyskeratosis congenita (DC) cases with reported pulmonary disease who had a hematopoietic stem cell transplant (HSCT)
The reports of pulmonary disease in 12 patients with DC (including our case) who did have a HSCT are summarized in Table . The presenting features of pulmonary disease were similar, regardless of whether the patient had received HSCT (Tables and ). These included persistent dry cough and progressive dyspnea. Evaluations of the patients revealed restrictive lung function impairment, markedly reduced DLCO, patchy or diffuse interstitial infiltrates, and interstitial fibrosis on chest radiographs or CT scans. These findings were documented by lung biopsy or at autopsy in many reported cases.
We compared the reported clinical features of patients with DC and pulmonary disease based on whether or not they had received an HSCT (Table ). Pulmonary disease was 2.2-fold more frequent in the HSCT group than in those without HSCT (p = 0.03). Patients who received HSCT developed pulmonary symptoms/disease at an earlier age (median 14 years) than those without HSCT (median 37 years, p < 0.001). In a time-dependent analysis (with censoring at death from non-pulmonary causes), the median survival free of pulmonary disease was 34 years for those who had a HSCT, and 61 years in the untransplanted group (Figure , Table , p < 0.001). Regardless of HSCT status, once the pulmonary findings became clinically apparent, the pulmonary disease was rapidly progressive in both patient groups. The median survival interval following pulmonary symptoms was brief, 2 years in the untransplanted and 1 year in the transplanted group (p = 0.5). Most patients died at a median interval of 3 months after pulmonary symptoms, range 0 to 8 years (Table ).
Comparison of DC Patients with Pulmonary Disease with and without HSCT*
Figure 3 Age at pulmonary symptoms. Patients with DC reported in the literature who received a bone marrow transplant (red) had pulmonary symptoms younger than patients who did not have a BMT (green). Data are Kaplan-Meier survival plots, showing cumulative probability (more ...)