Case report:
A previously healthy 13-year-old Japanese boy was admitted to our hospital with a 1-month history of fatigue, poor complexion, and purpura. He had no history of congenital anomalies, prior association with hepatitis, radiation exposure, or ingestion of drugs that might be associated with AA. At admission to our hospital, his vital signs were normal, and there was no clinical evidence of hepatomegaly or splenomegaly. Heart sounds and lungs were normal. Laboratory data on admission were as follows: red blood cell count, 1.43×1012 /L; white blood cell count, 2.38×109 /L with 14% neutrophils, 80% lymphocytes, 2% monocytes, 4% eosinophils and no myeloblasts; hemoglobin level, 5.1 g/dL; platelet count, 0.9×109 /L; and reticulocyte count, 25.7×109 /L. A bone marrow biopsy showed markedly hypocellular bone marrow without apparent dysplasia or blasts, the karyotype was 46,XY [20], and 1.0% of marrow cells had monosomy 7 as determined by 7q31 interphase fluorescence in situhybridization (FISH) analysis. We diagnosed idiopathic AA after excluding congenital AA based on a normal chromosomal breakage test and no shortening of the telomere length. IST was started with rabbit anti-thymocyte globulin (2.5 mg/kg, 110 mg/day, days 1 to 5), cyclosporine (CsA; 5 mg/kg, 220 mg/day), methylprednisolone (2 mg/kg, 88 mg/day, days 1 to 7), and prednisolone (45 mg/day, days 8 to 14; 30 mg/day, days 15 to 19; 20 mg/day, days 20 to 24; and 10 mg/day, days 25 to 29). Transfusions were given as needed for anemia and thrombocytopenia during IST. Recovery of hematopoiesis was gradually observed, and transfusions became unnecessary from 54 days after IST. A bone marrow biopsy at 4 months after the start of IST showed normocellular bone marrow without apparent dysplasia or blasts, but 14.0% of the marrow cells had monosomy 7 as determined by FISH analysis. The proportion of cells with monosomy 7 fluctuated over the course of regular bone marrow biopsies, but the dosage of CsA was gradually decreased without any additional treatment, because no dysplasia and blasts were seen. However, about 3 years after the diagnosis of AA, the patient was readmitted to our hospital due to a sudden weight gain of 10 kg and anasarca.
At the time of NS onset at readmission, a physical examination showed the following: body height, 169 cm; body weight, 65.9 kg; body temperature 36.4°C; respiratory rate, 12 breaths/min; blood pressure, 115/61 mmHg; and anasarca edema, including on the eyelids, face, and pretibial regions. A blood test at the same time showed the following: total protein, 4.2 g/dL; albumin, 2.1 g/dL; lactate dehydrogenase, 237 U/L; and total cholesterol, 361 mg/dL. Urinary examinations showed the following: urinary protein, 4+; occult blood in urine, 3+; urine density, 1.015; and urinary protein, 8.32g/day, and urinary protein-to-creatinine ratio, 7.09 g/g creatinine, by 24-h urine collection. Pathological examination of a renal biopsy sample revealed minor glomerular abnormalities (WHO 1995) without mesangial cell proliferation, segmental glomerulosclerosis, or crescentic formation. Based on the above results, we diagnosed minimal change NS (Figure 1).
The patient was started on corticosteroid therapy with 60 mg/day of prednisolone in addition to the previously administered CsA. At 17 days after the start of treatment, he achieved a complete response with a urinary protein level of 0.11g/day and urinary protein-to-creatinine ratio of 0.1 g/g creatinine by 24-h urine collection, and a serum albumin level of 2.5 mg/dL. He was tapered off prednisolone 1 week later, and was discharged 21 days after the start of treatment. The proportion of bone marrow cells with monosomy 7 by FISH analysis was the highest at 81% after the onset of NS. Figure 2 shows the course of the case from the onset of AA, including the proportions of cells with monosomy 7. We performed genetic testing, because the combination of both diseases is rare but this case did not have any mutations in germline SAMD9/9L mutation (SAMD9/9Lmut ) or somatic GATA2 mutation (GATA2mut ). At this time, the genetic factors that lead to the development of both diseases remain unknown.