Paroxysmal Nocturnal Hemoglobinuria: Diagnostic Challenges in Pediatric Patient

Case Reports in Pediatrics
14 Jun, 2019 ,

A 17-year-old boywas hospitalized with a history of recurrent abdominal pain, fever, and dark-colored urine. Laboratory tests revealed anemia, thrombocytopenia, and elevated inflammatory markers. Urinalysis was positive for protein and red blood cells, too many to be counted.  Abdominal computed tomography showed a segment of the small bowel with wall thickening and signs of possible microperforation. Flow cytometry detected deficiency of CD59 leading to the diagnosis of Paroxysmal Nocturnal Hemoglobinuria. 

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A 17-year-old Caucasian boy presented with several months of abdominal pain, fever, and dark-colored urine. Three months prior to this admission, he was hospitalized with similar complaints of epigastric abdominal pain, associated with vomiting, and fever. His initial CBC did not reveal pancytopenia and was within normal limits with WBC of 8.8 × 109/L, hemoglobin of 110 g/dL, and platelet count of 155 × 109/L.

While laboratory studies indicated the presence of anemia and thrombocytopenia, urinalysis revealed too numerous to count red blood cells. Abdominal CT showed normal-appearing kidneys and thickening of the wall of the small bowel, cecum, and ascending colon. In the context of persistent pancytopenia, fatigue, gross hematuria, and abdominal pain, our initial differential diagnosis included acute glomerulonephritis. Initial anemia was attributed to ongoing blood losses. Thrombocytopenia was attributed to acute illness.

Differential diagnosis also included inflammatory bowel disease with anemia of chronic disease, intestinal lymphoma, vasculitis, and leukemia. Clostridium difficile toxin was detected by PCR in his stool. The patient was diagnosed with infectious colitis and IgA nephropathy. Cystoscopy was not performed as bladder pathology was low on our differential diagnosis. He was treated with metronidazole and discharged. The patient’s gross hematuria and abdominal pain resolved, but he continued to have fatigue, anemia, and thrombocytopenia.

During his second presentation, the patient complained of severe abdominal pain, fever, and reappearance of dark-colored urine. He was a muscular teenage boy, with weight in the 84th percentile, height in the 95th percentile, and BMI in 95th percentile. On physical examination, he appeared alert, oriented, and in moderate distress due to abdominal pain. His abdomen was nondistended, soft, with tenderness on palpation in the left lower quadrant. No hepatosplenomegaly or lymphadenopathy was noted on exam.

Laboratory results showed a white blood cell count of 3.9 × 109/L, hemoglobin of 96 g/dL, platelet count of 109 × 109/L, and reticulocyte count of 4.1% (reference range, 0.5–2.5%). Differential count included 59% neutrophils, 13% bands, 22% lymphocytes, and 6% monocytes. Mean corpuscular volume noted to be 79.8 fl/cells. Serum ferritin noted to be 124 ng/ml. The erythrocyte sedimentation rate (ESR) was 56 mm/hr. Inflammatory markers were elevated, and C-reactive protein was 196.8 mg/L. Patient did not appear to be jaundiced on exam; however, his total bilirubin was elevated at 1.8 mg/dL with a direct bilirubin of 0.8 mg/dL.

His serum lactate dehydrogenase was elevated at 1225 IU/L. With 13 mg/dL of blood urea nitrogen and 0.91 mg/dL of creatinine, his renal functions were within normal limits. Urine protein to creatinine ratio was normal at 0.15. His total bilirubin was 1.8 mg/dL (30.7 μmol/L), and conjugated bilirubin was 0.8 mg/dL. Antistreptolysin O was 378 IU/ml (reference range, 0–200 IU/ml) and complement component 3 (C3) was 120 mg/dL (reference range, 85–183 mg/dL). The direct Coombs test was negative. A repeat urinalysis showed urine of amber color and too numerous to count red blood cells. Urine dipstick following microscopic urinalysis was performed. Dipstick was positive for 4 + blood. Microscopic urinalysis was positive for too numerous to count red blood cells. Hemoglobin and myoglobin were not additionally sent, as microscopic examination confirmed that there were too numerous to count red blood cells.

Due to ongoing abdominal pain, a CT of the abdomen was performed, which revealed thickening of a segment of the small bowel wall and signs of possible microperforation. Due to worsening of abdominal pain, the onset of new peritoneal signs, and elevation of inflammatory markers, an exploratory laparotomy was performed. Surgical exploration showed a necrotic segment of the jejunum, 45 cm of the mid-jejunum was resected.

 Histopathology report confirmed the presence of hemorrhage, necrosis of the resected segment, and acute inflammation of the intestine and mesentery with the presence of eosinophils. Clinical presentation and histological evaluation were consistent with an autoimmune process with small vessel vasculitis.

 At this time, the differential diagnosis was broader and included polyarthritis nodosa, granulomatosis with polyangiitis, and eosinophilic granulomatosis with polyangiitis. After surgery, the patient continued to have pancytopenia and gross hematuria. Due to a further drop in hemoglobin (77 g/L), he required transfusion of packed red blood cells. To further determine the etiology of pancytopenia and hematuria, the hematology, gastroenterology, and nephrology services were contacted. The differential diagnosis was broad and included hematologic, rheumatologic, and neoplastic etiologies.

The antinuclear antibody titer was 1 : 80 (reference range, <1 : 40); anti-double-stranded DNA titer was 1 IU/ml (reference range, <4 IU/ml); haptoglobin level, <15 mg/dL (reference range, 30–200 mg/dL). The prothrombin time was mildly elevated at 16.9 seconds (reference range, 9.6–13.4 seconds), partial thromboplastin time was 23.7 seconds (reference range, 23.5–39.6 seconds), and the international normalized ratio was 1.5 (reference range, 0.9–1.1). Tests for hepatitis A, B, and C, Epstein-Barr, and human immunodeficiency viruses were all negative. Persistent pancytopenia in our patient triggered a bone marrow investigation. Bone marrow biopsy showed hypocellular marrow with a decreased number of myeloid cells, the normal number of megakaryocytes, and signs of erythroid hyperplasia. PNH flow cytometry panel results were pending, and the patient was discharged with the recommendation to follow-up with multiple subspecialists.

The patient later presented to an outside facility with recurrent abdominal pain and dark-colored urine. He also had generalized malaise and signs of upper respiratory symptoms, secondary to influenza infection, and CBC was remarkable for neutropenia with WBC 2,000 × 109/L, with an absolute neutrophil count of 860/mcL . The urinalysis during his third hospital stay revealed hemoglobinuria.

Although the urinalysis during the two previous hospitalizations was positive for too numerous to count red blood cells which was consistent with hematuria and not hemoglobinuria, the findings were consistent with a diagnosis of PNH: 22% GPI-deficient erythrocytes, 21.49% GPI-deficient granulocytes, and 50% GPI-deficient monocytes. Since patients with PNH have an interindividual (and in time) variable degree of bone marrow failure, they can also develop aplastic anemia. Our patient was noted to have an elevated reticulocyte count of 4.3%, which was attributed to his ongoing hemolysis.

His elevated LDH levels may have been secondary to his hemolytic anemia and increased breakdown of red blood cells. The patient was started on eculizumab infusions for lifelong management. Repeat CH50 level was low at 8 Units, indicating the efficacy of eculizumab. During the first 2 months of treatment due to the high risk of thrombosis, he also received the anticoagulant enoxaparin. A repeat bone marrow evaluation showed normocellular marrow with normal trilineage hematopoiesis.