Clinical Characteristics of Autosomal Dominant Giant Platelet Syndromes and Mutation Analysis of MYH9

BACKGROUND: The autosomal dominant giant platelet syndromes (GPS), characterized by triads of giant platelets, thrombocytopenia, and Dohle-like leukocyte inclusions are caused by MYH9 mutation, a gene encoding the nonmuscle myosin heavy chain-IIA. This study was aimed to identify the Korean GPS patients and to define clinical findings and molecular characteristics on them. METHODS: After taking a family history, platelets were counted using hematologic autoanalyzer and peripheral blood smear (PBS) was examined for platelet size and number, and the presence of leukocyte inclusions. Mutation of MYH9 was studied from mononuclear cells from PB by direct sequencing of previously known 8 exons after PCR amplification of genomic DNA. RESULTS: Twenty patients from 5 unrelated families were diagnosed as GPS. Giant platelets, greater than red cells on PBS, were found to be 3.1% of platelet (range, 1~11%). The median platelet count was 61,000/microliter. Inclusion bodies were found in 3 families. Two families had previously reported mutations. Family I had Arg1944Ter in exon 40, located in the tail portion of myosin, while Family IV had Lys373Asn in exon 10, located in the proximal portion of myosin head. The mutations were found only in affected patients, but not in normal siblings or unrelated families. CONCLUSION: In this study, we identified several families with autosomal dominant GPS. Two families had known MYH9 mutations, Arg1944Ter and Lys373Asn. The search for unknown mutations in the remaining families as well as study of protein structural and functional alteration seems to be necessary for further delineation of these rare genetic disorders.

Clinical Characteristics and Treatment Outcome of Childhood Langerhans Cell Histiocytosis / 대한소아혈액종양학회지

PURPOSE: We analyzed a cohort of patients with Langerhans cell histiocytosis (LCH) to understand the clinical findings, optimal management, and outcome of the disease. METHODS: We performed a retrospective clinical study of LCH from January 1993 to August 2002 at Chonnam National University Hospital. All 39 patients with histologically proven histiocytosis were categorized into Class I (n=22), Class II (n=15) and Class III (n=2) by WHO classification. RESULTS: There were 18 males and 21 females. Mean age at diagnosis was 3.2 years. The common clinical manifestations of Class I were soft tissue swelling, skin rash or nodule, otorrhea; and those of Class II were hepatosplenomegaly, fever, and respiratory symptoms. The most commonly involved organ of Class I was the skeleton; and that of Class II was bone marrow. Abnormal hematologic findings were found in 23 patients, especially in all Class II patients. Infectious etiology was documented in 5 Class II patients (CMV in 3, EBV in 1, mycoplasma in 1). Chemotherapy was given to 19 out of 22 Class I patients. Six of them showed complete remission. Four died during chemotherapy. The overall survival of Class I patients was 78% and that of Class II 63%. Poor prognostic factors of Class I were age 1.5 mg/dL. CONCLUSION: The Langerhans cell histiocytosis is a heterogeneous disorder of significant morbidity and mortality. Early recognition and aggressive medical treatment might improve the survival rate.

Hepatic Veno-occlusive Disease Following Hematopoietic Stem Cell Transplantation in Children: Retrospective Analysis in a Single Institution / 대한소아혈액종양학회지

PURPOSE: Hepatic veno-occlusive disease (VOD) is a life-threatening complication occurring early after stem cell transplantation (SCT). Early diagnosis and effective treatment has not been established in severe VOD. Because there are few reports on VOD in Korean children, we evaluated the clinical characteristics of VOD following SCT in children. METHODS: We retrospectively reviewed the chart of all patients (n=116) receiving SCTs in CNUH Pediatric BMT center between May, 1991 and June, 2004. RESULTS: VOD developed in 11 patients (9.5%) (median age, 9.8 years; range, 2 to 13.9). Underlying diagnoses were ALL (n=3), severe aplastic anemia (n=3), AML (n=2), acute biphenotypic leukemia (n=1), neuroblastoma (n=1), and myelodysplastic syndrome (n=1). The median day of onset of VOD was D+9 (range, D-3 to D+19). VOD was classified as moderate in 5 and severe in 6 cases. Maximum level of serum total bilirubin was 2.9 mg/dL (range, 2.1 to 9.2) in moderate VOD and 7.3 mg/dL in severe VOD (range, 2.0 to 24.2) at D+18 (range, D-5 to D+59). We successfully treated VOD with various combinations including tPA and heparin (2/5, 40%), ursodeoxycholic acid (2/5, 40%), N-acetylcysteine (3/5, 60%), and defibrotide (1/2, 50%). All of 5 patients with moderate VOD survived at D+100 (range, 5.5+ to 66.6+ months). Five of 6 (83%) patients with severe VOD died within first 19 day from complications of VOD. CONCLUSION: This retrospective study showed that the incidence of VOD was 9.5%, and the mortality of severe VOD was still high which would necessitate early diagnosis, effective prevention and treatment.

Two Cases of Malignant Lymphomas in Children with Selective IgA and IgG Subclass Deficiency / 대한소아혈액종양학회지

Selective IgA deficiency is one of the most common primary immunodeficiency. Some patients with IgA deficiency also have deficits in one or more immunoglobulin G subclasses. It has been estimated that up to 25% of patients with certain primary immunodeficiencies will develop tumors, primarily B-cell lymphomas during their lifetime. We hereby present 2 cases of malignant lymphomas, one diffuse large cell lymphoma and another mixed cellularity Hodgkin's disease, respectively, which developed in patients with selective IgA and IgG subclass deficiency.

Dyskeratosis Congenita in a Girl / 대한소아혈액종양학회지

Dyskeratosis congenita (DC) is a rare genetic disorder encompassing abnormal skin pigmentation, dystrophic nails, leukoplakia of mucous membranes and others. Bone marrow failure is the cause of early mortality. Moreover, DC is known for its predisposition to malignancy. X-linked recessive, autosomal dominant and autosomal recessive forms of the disease are recognized. We describe here a rare case of DC in a 4-year-old girl showing dark skin, dystrophic toe nails, and mild bone marrow failure. Autosomal recessive disease was suggested as the patient is female, and tests for DKC1 and hTR mutations were negative. Intermittent treatment with oxymetholone and prednisolone for about 26 months resulted in stable hemoglobin and platelet response.

Fatal Bronchiolitis Obliterans with Very Severe Subcutaneous Emphysema and Pneumomediastinum after Unrelated BMT / 대한소아혈액종양학회지

Bronchiolitis obliterans (BO) is a particularly severe complication that occurs in 10% to 15 % of the patients with extensive graft-versus-host disease (GVHD) and is often refractory to treatment. We report herewith a child with chronic GVHD and BO after unrelated BMT. A 8 year-old girl with Ph ALL (Philadelphia-chromosome positive acute lymphoblastic leukemia) underwent an unrelated BMT in the first complete remission. Engraftment was uneventful. Acute GVHD of the skin developed, and was treated with methylprednisolone. No evidence of GVHD flare was documented, and immunosuppression was tapered off by 7 months posttransplant. On 9 months posttransplant, chronic GVHD involving skin, liver, mouth, eyes, gastrointestinal tract, and lungs developed. Despite conservative managements, the patient developed pneumomediastinum and subcutaneous emphysema secondary to severe BO. Her condition continued to deteriorate, and she died of respiratory failure 10 months after transplant. Further studies are required to identify risk factors and to develop newer methods of effective treatment for this rare complication.

MYH9-related Disorder in a Family: Autosomal Dominant Epstein Giant Platelet Syndrome / 대한소아혈액종양학회지

The term MYH9-related disorders indicates a group of autosomal dominant illnesses, formerly known as May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome and Epstein syndrome, caused by mutations of MYH9, the gene encoding for the heavy chain of non-muscle myosin IIA (NMMHC-IIA). We experienced a family with macrothrombocytopenia without leukocyte inclusion. A 5-year-old girl was found to have macrothrombocytopenia incidentally. Her father also had macrothromtocytopenia, but had been suffering from hearing loss and chronic renal failure. Meticulous search by light and electron microscopy failed to detect leukocyte inclusions. To our knowledge, these cases seem to be the first description of autosomal dominant Epstein giant platelet syndrome in Korea.

Long-term Follow-up of an Evans Syndrome with Chronic, Refractory Course: Response to 5 Different Regimens / 대한소아혈액종양학회지

Evans syndrome is the combination of direct Coombs' positive hemolytic anemia and immune thrombocytopenic purpura, in the absence of a known underlying etiology. Being reported rarely in pediatric patients, the syndrome is characterized by periods of remission and exacerbation with viable responses to therapy. Management of the disease remains a challenge despite a variety of therapeutic trials. We experienced a 11-years old male patient of Evans syndrome who was initially presented as having an autoimmune hemolytic anemia 17 months before. Over the 5 years of follow-up, he had a chronic, relapsing courses, showing partial responses to a variety of therapeutic trials, including IVIG, oral prednisolone, methylprednisolone pulse therapy, cyclosporine A and vincristine. A brief review of the literature ensues with the case report.