Detection of paroxysmal nocturnal hemoglobinuria clones to exclude inherited bone marrow failure syndromes.

BACKGROUND: Inherited bone marrow failure syndromes (IBMFS) and acquired aplastic anemia (AA) are life-threatening marrow failure disorders. These entities can be difficult to distinguish because they present similarly. Correct diagnosis is imperative for proper therapy. DESIGN AND METHODS: This is a retrospective, single-center study of patients <40 yr of age, evaluated for bone marrow failure, and assayed for the presence of a PNH clone in the pediatric or adult hematology/oncology clinics from 2001 to present. Patients were also evaluated for IBMFS. RESULTS: We present results from 156 patients with marrow failure, 20 of whom have IBMFS. None of the IBMSF patients had paroxysmal nocturnal hemoglobinuria (PNH) clones. CONCLUSIONS: Although further studies are needed, our results suggest that the detection of a PNH clone can be a useful diagnostic tool to exclude the diagnosis of IBMFS and focus the work-up and treatment on an acquired form of marrow failure.

Short telomeres are a risk factor for idiopathic pulmonary fibrosis.

Idiopathic interstitial pneumonias (IIPs) have a progressive and often fatal course, and their enigmatic etiology has complicated approaches to effective therapies. Idiopathic pulmonary fibrosis (IPF) is the most common of IIPs and shares with IIPs an increased incidence with age and unexplained scarring in the lung. Short telomeres limit tissue renewal capacity in the lung and germ-line mutations in telomerase components, hTERT and hTR, underlie inheritance in a subset of families with IPF. To examine the hypothesis that short telomeres contribute to disease risk in sporadic IIPs, we recruited patients who have no family history and examined telomere length in leukocytes and in alveolar cells. To screen for mutations, we sequenced hTERT and hTR. We also reviewed the cases for features of a telomere syndrome. IIP patients had shorter leukocyte telomeres than age-matched controls (P < 0.0001). In a subset (10%), IIP patients had telomere lengths below the first percentile for their age. Similar to familial cases with mutations, IPF patients had short telomeres in alveolar epithelial cells (P < 0.0001). Although telomerase mutations were rare, detected in 1 of 100 patients, we identified a cluster of individuals (3%) with IPF and cryptogenic liver cirrhosis, another feature of a telomere syndrome. Short telomeres are thus a signature in IIPs and likely play a role in their age-related onset. The clustering of cryptogenic liver cirrhosis with IPF suggests that the telomere shortening we identify has consequences and can contribute to what appears clinically as idiopathic progressive organ failure in the lung and the liver.

Telomerase mutations in families with idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis is progressive and often fatal; causes of familial clustering of the disease are unknown. Germ-line mutations in the genes hTERT and hTR, encoding telomerase reverse transcriptase and telomerase RNA, respectively, cause autosomal dominant dyskeratosis congenita, a rare hereditary disorder associated with premature death from aplastic anemia and pulmonary fibrosis. METHODS: To test the hypothesis that familial idiopathic pulmonary fibrosis may be caused by short telomeres, we screened 73 probands from the Vanderbilt Familial Pulmonary Fibrosis Registry for mutations in hTERT and hTR. RESULTS: Six probands (8%) had heterozygous mutations in hTERT or hTR; mutant telomerase resulted in short telomeres. Asymptomatic subjects with mutant telomerase also had short telomeres, suggesting that they may be at risk for the disease. We did not identify any of the classic features of dyskeratosis congenita in five of the six families. CONCLUSIONS: Mutations in the genes encoding telomerase components can appear as familial idiopathic pulmonary fibrosis. Our findings support the idea that pathways leading to telomere shortening are involved in the pathogenesis of this disease.

Transmission of glioblastoma multiforme following bilateral lung transplantation from an affected donor: case study and review of the literature.

Donor-acquired solid organ malignancy is a rare complication of organ transplantation. We report a case of a patient who received bilateral lung transplants for pulmonary fibrosis from a donor with known glioblastoma multiforme (GBM). The lungs, heart, liver, and kidneys were harvested after a lethal intracranial bleed and accepted for transplantation by four centers. An enlarged hilar lymph node sampled at the time of transplant was found to contain GBM. Four months later, the patient developed diffuse interstitial pulmonary infiltrates with mediastinal lymphadenopathy. Lung biopsy confirmed metastatic GBM. The patient died 2 weeks after the diagnosis was established. The patient receiving the donor liver also developed GBM. We present a case study, review of the literature, and suggested interventions to minimize the risk of transmission.