Sharon Hall

Paroxysmal Nocturnal Hemoglobinuria with Onset in Childhood and Adolescence

BACKGROUND Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematologic disorder characterized by hemoglobinuria, thrombosis, infection, and a tendency toward bone marrow aplasia. Onset usually occurs in adulthood. Few children and adolescents with PNH have been described, and data on diagnosis, clinical course, and survival in young patients are unavailable. METHODS We retrospectively reviewed clinical and laboratory data on all patients 21 years old or younger in whom PNH had been diagnosed at Duke University Medical Center from 1966 to 1991. RESULTS Medical records and clinical follow-up data were available for 26 young patients. Although 50 percent of adult patients present with hemoglobinuria, only four of our patients (15 percent) presented with this feature. In contrast, 15 of our patients (58 percent) had moderate or severe bone marrow failure at presentation, as compared with about 25 percent of adults in cases from the literature; all 26 patients eventually had evidence of bone marrow dysfunction. Eight patients (31 percent) have died, with a median survival of 13.5 years since their initial symptoms. CONCLUSIONS Children and adolescents with PNH have a greater prevalence of bone marrow failure than do adults with this disorder, and their morbidity and mortality are high. Bone marrow transplantation should be considered for selected young patients with PNH.

Serial Analysis of Clonal Expansion in PNH by Flow Cytometry

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic stem cell disorder caused by PIG-A mutations. To assess clonal expansion in PNH over time, patients with serial testing by flow cytometry (interval of at least one year) were analyzed. This study involved 164 patients with PNH from Duke (DP) and 151 patients from Japan (JP). The mean fraction of PMNs deficient in CD59 (mean±SE) was 75.2±4.2% in DP and 40.0 + 8.3% (n=21) in JP at the initial analysis, and were 74.1 ±4.7% and 50.7 + 8.6% at the latest analysis (P=NS). However, in individual cases, the proportion of affected PMNs varied considerably from -84% to +98%. Some DP and JP pts, however, had a diminution in their CD59-deficient PMNs over time, which was associated with the development of overall hematopoietic failure (P=.04 for DP, P=.05 for JP). These data illustrate the complexity of clonal expansion in PNH, and the marked variability over time. GPI-deficient populations vary considerably over time for individual patients, but a decreasing PNH clone indicates impending hematopoietic failure. Correlation between clonal expansion or diminution and the development or recovery from aplasia will help our understanding of the natural history of PNH.

The Clinical Course of PNH in the USA and in JAPAN

PNH, which is characterized by intravascular hemolysis and venous thrombosis, is an uncommon disorder of hematopoietic stem cells with an acquired somatic mutation of PIG-A. An understanding of the natural history of PNH is essential to improve therapy. To determine and to directly compare the clinical courses of PNH patients from the USA and Japan, data were collected for 385 patients with PNH. There were 176 patients from Duke (DP) and 209 patients from Japan (JP). The mean age at diagnosis (mean ± SE) was 32.8 ±1.2 years (4-80) in DP, and 45.1 ±1.3 years (10-86) in JP. The incidence of various chnical events was analyzed. These analyses provide important diagnostic and long-term data on two large cohorts of PNH patients, and identify important differences between Caucasian and Asian patients with PNH. Caucasians tend to be younger and have classical symptoms of PNH including thrombosis, while Asians tend to be older and have symptoms of aplasia. Multivariate analysis of factors influencing survival was also undertaken. By this study, estimates of PNH prognostic factors may provide a better understanding of the complications of the disease so that therapeutic interventions may be sought. Further, by noting differences in the two populations, possible genetic modifiers of the course of the disease may be identified for further investigation.