Original Article
Paroxysmal Nocturnal Hemoglobinuria with Onset in Childhood and Adolescence
N Engl J Med 1991; 325:991-996October 3, 1991
- Abstract
- Abstract
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. (N Engl J Med 1991;325:991–6.)
Media in This Article
Figure 1
Kaplan–Meier Survival Curve for 26 Young Patients with PNH.Table 1
Clinical and Laboratory Characteristics of 26 Patients with PNH.Article Activity
- Article
PAROXYSMAL nocturnal hemoglobinuria (PNH) is an acquired clonal stem-cell disorder1 , 2 with resultant defective and deficient hematopoiesis.3 , 4 It is characterized by an increased sensitivity of erythrocytes to the hemolytic action of complement.5 This unusual susceptibility of erythrocytes to intravascular lysis leads to intermittent hemoglobinuria, from which the name of the disorder is derived. Other important clinical manifestations include infection, venous thrombosis, and a tendency toward the development of bone marrow aplasia.
Previous reports of PNH indicate that the vast majority of patients are adults when the signs and symptoms of the illness develop.6 7 8 There are few accounts of children with PNH,6 , 7 and whether their clinical course and prognosis are the same as those of adults is not known.
We report clinical and laboratory data on 26 patients who had PNH in childhood or adolescence. This study involved the largest group of young patients with this disease described to date and demonstrated substantial clinical differences between them and adults with PNH.
Methods
Identifying Patients
Since 1966, the diagnosis of PNH has been established or confirmed in 236 patients at Duke University Medical Center with the use of the complement-lysis sensitivity (CLS) test.9 The majority (144 patients) received medical care at our institution, but for some patients, only peripheral-blood samples were sent from other institutions to ours. The histories and laboratory results of all patients were available for review.
All patients who had a positive CLS test by the age of 21 years were eligible for this retrospective evaluation; a total of 28 patients (11.9 percent of the total population) were identified. Two patients were excluded because their initial medical records, interval history (information on clinical events occurring since presentation), and information regarding their current clinical status were not available. For the remaining 26 patients, clinical information was gathered from referring physicians, hospital records, and the patients themselves regarding their initial signs and symptoms, laboratory tests, and diagnosis, as well as their interval history, therapy, and duration of follow-up.
CLS Testing
The CLS test has been previously described.10 By convention,11 three types of erythrocytes may be distinguished with this test: PNH I cells, which appear to be normal in their sensitivity to complement; PNH III cells, which are markedly sensitive; and PNH II cells, which are intermediate in sensitivity.
Results
Characteristics of the Patients
Twenty-six patients could be evaluated fully (Table 1Table 1
Clinical and Laboratory Characteristics of 26 Patients with PNH.). There were 13 male and 13 female patients. The mean age at presentation was 13.1 years, and the median age 14.3 years (range, 0.8 to 21.4).Clinical Presentation
Thirteen of the 26 patients (50 percent) presented with signs and symptoms referable to anemia, such as pallor, fatigue, or shortness of breath (Table 1). Six children (two with concurrent symptoms due to anemia and four without them) had symptoms secondary to thrombocytopenia — typically, excessive bruising and bleeding. Four patients (15 percent) had dark urine, but none described it as occurring in the early morning. Other clinical manifestations at presentation were abdominal pain (two patients), jaundice (two), and ascites (one). Four patients had no clinical signs or symptoms but had abnormal hematologice values on routine blood testing — in one patient during pregnancy and in three during preoperative evaluation for elective orthopedic surgery.
Initial Hematologice Laboratory Values
The patients' peripheral-blood counts at the time of initial presentation are shown in Table 1. The mean hemoglobin concentration was 85 g per liter (8.5 g per deciliter); 16 of the 25 patients (64 percent) for whom the value was available had an initial concentration below 100 g per liter ( 10 g per deciliter). Most patients had macrocytosis, with an average mean corpuscular volume of 99 fl. Only one patient had microcytosis (unique patient number [UPN] 192; mean corpuscular volume, 64 fl), which was due to excessive renal iron loss and resultant iron deficiency. Initial reticulocyte counts ranged from 0.2 percent to 32 percent, but 16 of 25 patients (64 percent) had a count above 3 percent and 7 (28 percent) had a count of at least 5 percent.
The mean white-cell count was normal (4.0 ×109 per liter). However, the mean absolute neutrophil count was low (1790×106 per liter); the count was below 1000×106 per liter in 10 of 22 patients (45 percent). The majority of patients had thrombocytopenia at presentation, with a mean platelet count of 87 × 109 per liter. Fourteen of 25 patients (56 percent) had an initial platelet count below 50×109 per liter, but most were asymptomatic despite this degree of thrombocytopenia.
Bone marrow aspiration and biopsy were performed in all but two patients (UPN 136 and UPN 146). Overall cellularity was low or normal in all but 1 patient, but hypercellularity of the erythroid lineage was observed in 13 of 23 patients (57 percent).
All patients had complement-sensitive erythrocytes (PNH cells) (Table 1). The percentage of abnormal cells ranged from 2 to 100 percent, with a mean of 39 percent and a median of 33 percent. Laboratory evidence of intravascular hemolysis was often present, including an elevated total bilirubin concentration, a highly elevated serum lactate dehydrogenase level, a positive direct antiglobulin test for the detection of complement but not for the detection of IgG, and an absence of circulating haptoglobin. When tested, urine was always positive for hemosiderin. red-cell lysis was assayed in some patients with use of the acidified serum test and sucrose lysis test, but they occasionally gave negative or discordant results.
Initial Diagnosis
Thirteen patients (50 percent) were initially given the diagnosis of aplastic anemia (Table 1). Although each of these patients had peripheral pancytopenia, bone marrow examination showed hypocellularity in only eight, with normal cellularity in four and hypercellularity in one (UPN 207). Similarly, the erythroid lineage was hypocellular in 7 of the 13 patients, normal in 2, and hypercellular in 4. In three patients (UPN 23, UPN 88, and UPN 191), both aplastic anemia and PNH were diagnosed at presentation.
Five other patients were given an initial diagnosis of PNH alone (Table 1). Two children (UPN 146 and UPN 213) presented with jaundice at other institutions and were considered to have primary hepatic disease. One child (UPN 136) presented with hemoglobinuria and was thought to have primary renal disease. Three patients (UPN 41, UPN 197, and UPN 231) were initially given a diagnosis of idiopathic thrombocytopenic purpura after they presented with hemorrhagic symptoms and thrombocytopenia. The remaining two patients (UPN 150 and UPN 153) had initial diagnoses of myelodysplasia and iron deficiency, respectively (Table 1).
In many patients, there was a prolonged delay between their initial presentation and the diagnosis of PNH (Table 1). Although PNH was diagnosed in nine children within 3 months of presentation,, the mean delay was 19 months. Ten children (38 percent) were followed for more than 2 years before the diagnosis was made; the longest delay was 68 months, occurring after initial symptoms of thrombocytopenia (UPN 231).
Interval History
Hemoglobinuria was an uncommon finding at presentation, occurring in 4 patients (15 percent), but it eventually developed in 17 patients (65 percent) (Table 2Table 2
Interval History of 26 Patients with PNH.). Most patients described symptoms of episodic hemolysis, usually attributing them to stress or a virus-like illness, which lasted from a few hours to several days.Severe abdominal pain was a frequent symptom in 10 patients (38 percent) and was possibly due to mesenteric thrombosis. Typically, the pain was crampy and epigastric or periumbilical in location, but was not associated with eating or activity. Pigmented gallstones secondary to chronic hemolysis developed in two patients (UPN 134 and UPN 216), who underwent cholecystectomy.
Serious infections occurred in 10 patients (38 percent), including persistent paranasal-sinus and pulmonary infections as well as systemic bacterial and fungal infections (Table 2). Five patients, three of whom had aplastic anemia with severe neutropenia, died of overwhelming infection.
Eight patients (31 percent) had confirmed venous thrombotic events (Table 2), including thrombosis of the inferior vena cava, renal vein, hepatic vein (Budd—Chiari syndrome), splenic vein, sagittal vein, and pelvic veins, or cutaneous thrombosis with purpura fulminans. Serious sequelae, including death, occurred in three patients (UPN 77, UPN 146, and UPN 153).
All 26 young patients with PNH had evidence of bone marrow dysfunction either at presentation or during their clinical course (Table 2). Fifteen patients presented with moderate or severe pancytopenia, and 5 others had severe hypoplasia during their illness, for a total of 20 patients (77 percent). The remaining six patients had mild bone marrow dysfunction, usually macrocytosis and thrombocytopenia. A single patient (UPN 15) had acute myelogenous leukemia that developed approximately six years after anemia was detected on a routine preoperative evaluation. She subsequently underwent bone marrow transplantation but died three months later.
Therapy
The majority of patients (22 of 26) received prednisone, given to some continuously and to others only during episodes of hemolysis. When possible, the drug was administered every other day, with booster doses during hemolytic crises. Androgens such as danazol, oxymetholone, or fluoxymesterone (Halotestin) were prescribed for 11 patients (42 percent), primarily as therapy for bone marrow hypoplasia. Oral iron therapy was prescribed for nine patients, at least one of whom felt that the medication caused increased hemolysis. Anticoagulants or thrombolytic agents were used in three of the eight patients (UPN 77, UPN 153, and UPN 216) who had severe thrombotic complications — i.e., streptokinase for short-term and warfarin (Coumadin) for long-term anticoagulation. Severe thrombosis of the inferior vena cava and right renal vein developed in one patient and was treated with warfarin, but she died of a subdural hematoma.
Treatment with antithymocyte globulin was given 11 times to eight patients with severe bone marrow aplasia. There were five sustained responses, as indicated by normal blood counts for at least one year after treatment. One patient (UPN 234) with aplastic anemia responded to cyclosporine.
Chronic unremitting hemoglobinuria unresponsive to high doses of prednisone developed in one patient (UPN 207), who then received bone marrow from an unrelated donor. Currently, eight months after transplantation, she has had minimal toxic reactions, normal peripheral-blood counts, and no hemoglobinuria. Repeat CLS testing has not been performed.
Follow-up Data
To date, eight patients (31 percent) have died 8 months to 28.1 years after initial presentation (mean, 7.7 years; median, 5.0). Four patients died of infection, three after thrombosis, and one after bone marrow transplantation.
The predicted 5-year survival in the 26 patients was 80 percent, the 10-year survival 60 percent, and the 20-year survival 28 percent (Fig. 1Figure 1
Kaplan–Meier Survival Curve for 26 Young Patients with PNH.). The 18 survivors have been followed an average of 8.5 years (range, 2.8 to 27.0). All but three patients have bone marrow dysfunction, most commonly macrocytic anemia and thrombocytopenia. All patients available for follow-up still have abnormally complement-sensitive erythrocytes, with no evidence of "cure" after elimination of the PNH clone.Five patients have been followed for at least 19 years since their initial presentation; four are still alive (one, UPN 74, had anemia that required transfusions and died of an overwhelming bacterial infection 28 years after presentation). Of the four long-term survivors, three have intermittent episodes of hemolysis with pallor and two require periodic transfusions of erythrocytes and prednisone therapy. Only one patient (UPN 4) has no symptoms referable to PNH.
Discussion
PNH was first described over a century ago,12 , 13 but only recently have biochemical defects been identified that might account for its clinical manifestations. A number of proteins are missing from the membrane of the abnormal blood cells found in PNH, including molecules that regulate the activation of complement (CD55,14 15 16 CD59,17 , 18 and C8-binding protein19 , 20), immunologically important molecules (FcγIII receptor,21 lymphocyte-function antigen 3,22 and CD 14 antigen23 , 24), membrane enzymes (erythrocyte acetylcholinesterase,25 , 26 leukocyte alkaline phosphatase,27 and lymphocyte 5'-ecto-nucleotidase [unpublished data]), and molecules of unknown function.28 Each of these proteins is normally attached to the cell membrane by a glycosyl phosphatidylinositol anchor affixed to the carboxyl terminus of the protein by an amide bond.29 , 30 PNH cells cannot assemble this anchor,31 suggesting that the biochemical defect resides in its biosynthesis.
At least some of the clinical manifestations of PNH may be explained by the deficiency of certain of these proteins. The abnormal sensitivity to complement, which results in intravascular hemolysis and hemoglobinuria, is due primarily to the absence of the complement regulatory proteins CD59 and (to a lesser extent) CD55.31 The state of hypercoagulability may also be due to the lack of CD59 on platelets (unpublished data). The propensity to infection may be due in part to the lack of the FcγIII receptor on granulocytes or the lipopolysaccharide receptor on monocytes (CD14).32 At present, bone marrow hypofunction (which is common in PNH) and acute leukemia (which is rarer) cannot be directly attributed to the absence of a specific protein, although the lack of CD 14 may play a part in the leukemic transformation of myelogenous cells.32
Previous reports have shown that the vast majority of patients with PNH are adults.6 7 8 In one series,6 38 of 43 patients were more than 20 years old at presentation; only 2 patients were less than 15, and only 1 less than 10. In another cohort of patients with PNH, only 2.7 percent of patients were less than 10 years old.7 Our series is the largest that has focused on children and adolescents with PNH, with nine children below 10 years of age at the time of presentation (3.8 percent of all patients).
This retrospective review demonstrates important differences between young patients with PNH and adult patients. Although hemoglobinuria is found at presentation in 50 percent of adults,8 it occurred in only four (15 percent) of the children and adolescents in our study. In contrast, approximately 25 percent of adult patients present with bone marrow aplasia,33 34 35 whereas 15 of our patients (58 percent) had moderate to severe bone marrow failure; 13 were initially given a diagnosis of aplastic anemia. Virtually all our young patients with PNH presented with macrocytosis, which probably represented dysfunctional erythropoiesis. Most patients also had thrombocytopenia; since the life span of platelets is normal in PNH,36 this finding must reflect diminished production of platelets. The increased prevalence of bone marrow hypofunction or failure at presentation in young patients with PNH is not understood at this time.
PNH was not correctly diagnosed in many of our patients at presentation. The mean delay was 19 months, similar to that described in adults.7 This long delay may reflect the smaller proportion of our young patients presenting with hemoglobinuria. However, hemoglobinuria was itself misdiagnosed on two of four occasions, being mistaken for hepatic or renal disease. Another explanation for the delay in diagnosis was the rarity of the disease; most referring physicians were not aware that PNH could occur before adulthood. Finally, the high prevalence of bone marrow failure frequently led to an initial diagnosis of aplastic anemia rather than PNH. A clinical association has been noted between PNH and aplastic anemia33 34 35 and, more recently, between PNH and myelodysplasia37; the disorders may present simultaneously, or one may evolve into another. Review of the findings in our patients with an initial diagnosis of aplastic anemia or myelodysplasia revealed laboratory evidence of hemolytic anemia and erythroid hyperplasia in most cases, suggesting that PNH was present at the time of diagnosis and did not develop subsequently.
The interval history and prognosis of our 26 young patients were similar to those of adults with PNH,5 , 8 with substantial morbidity secondary to abdominal pain, hemoglobinuria, infection, and thrombosis. Although three fatal infections occurred in patients with severe aplastic anemia and neutropenia, most of the clinical illness was directly attributable to the sequelae of cell-membrane defects of PNH. In one young woman the cells underwent fatal leukemic transformation, an event previously reported to occur rarely in adult patients with PNH.38 , 39
A total of eight patients (31 percent) have died, for a calculated median survival of 13.5 years for all patients. Because only 5 of the 18 living patients have been followed for more than 10 years, however, the median survival may eventually be shorter. Most patients still have evidence of bone marrow dysfunction, particularly macrocytosis and thrombocytopenia. In view of the high incidence of serious morbidity and mortality, bone marrow transplantation should be considered for selected young patients with PNH.
Supported in part by a grant (5–R37-DK-31379) from the National Institutes of Health. Dr. Ware is the recipient of a Physician Scientist Award (K11–H02015) and a McDonnell Foundation Scholarship.
We are indebted to the medical staff for providing records and clinical information on the patients in this study, and to Ms. Wilma Stanley for biostatistical assistance.
Source Information
From the Division of Hematology/Oncology, Department of Pediatrics (R.E.W.), and the Division of Hematology/Oncology, Department of Medicine (S.E.H., W.F.R.), Duke University Medical Center, Durham, N.C. Address reprint requests to Dr. Ware at P.O. Box 2916, Department of Pediatrice Hematology/Oncology, Duke University Medical Center, Durham, NC 27710.
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