Type 3 von Willebrand disease (VWD) is a severe autosomal recessive inherited bleeding disorder. In affected individuals the underlying von Willebrand factor gene (VWF) mutations frequently remain uncharacterized. The aim of this study was to investigate the molecular basis of type 3 VWD in patients (11 Caucasians and 9 of Asian origin) attending the haemophilia centres at Central Manchester NHS Trust. A combination of DNA sequencing of VWF genomic and complementary DNA was performed to identify mutations in the patient cohort. Fifteen different VWF mutations were identified at the genomic DNA level: two gene conversion events, three nonsense, three frameshift, one missense, two splice site, one insertion-deletion and three deletion mutations. Homozygosity or compound heterozygosity for mutations was present in 15 of the 20 patients. In the remaining five individuals, heterozygosity for a single VWF mutation was identified in four cases and one patient had no detectable VWF mutation. Analysis of platelet-derived VWF RNA from these five individuals revealed heterozygosity for a deletion of exons 4 and 5 in four cases. The remaining patient was heterozygous for a three base deletion which had already been identified at the DNA level. Overall the observed VWF genotype explained the phenotype in 18 of the 20 patients investigated. In genetic studies in type 3 VWD, if VWF mutations are not detected at the DNA level, RNA analysis should be performed to search for intronic mutations, heterozygous deletions or aberrant splicing/post-transcriptional events. However, this may still not explain all cases of previously phenotypically diagnosed type 3 VWD.
Haemophagocytic lymphohistiocytosis (HLH) is a disease characterised by peripheral blood pancytopenia secondary to haemophagocytosis of formed blood cells by activated histiocytes. The demonstration of haemophagocytosis may be diYcult and the diagnosis may require repeated tissue sampling (including bone marrow, cerebrospinal fluid, lymph nodes, spleen, and liver) and the demonstration of associated clinical or laboratory features. This report describes pronounced dyserythropoiesis in the bone marrow aspirates in four patients with HLH, including familial and secondary cases. In three patients, bone marrow haemophagocytosis was inconspicuous or absent, and the prominent dyserythropoiesis may have suggested an alternative diagnosis. The dyserythropoiesis observed should be added to the constellation of clinical and laboratory features associated with HLH. (J Clin Pathol 2001;54:961-963) Keywords: haemophagocytic lymphohistiocytosis; dyserythropoiesis; familial haemophagocytic lymphohistiocytosis Haemophagocytic lymphohistiocytosis (HLH) is a generalised, non-malignant histiocytic proliferation with prominent phagocytosis of formed blood cells resulting in pancytopenia. It presents with fever and symptoms of anaemia, thrombocytopenia, and neutropenia. On clinical examination there is typically splenomegaly and there may be a macular rash, lymphadenopathy, and evidence of central nervous system (CNS) involvement. Pathologically, there is accumulation of haemophagocytic histiocytes in the bone marrow, spleen, lymph nodes, and CNS.HLH can be acquired or inherited in an autosomal recessive fashion (familial haemophagocytic lymphohistiocytosis (FHL)). FHL is a rare and rapidly fatal disorder presenting in infancy and early childhood with the typical features of HLH. The diagnosis is justified by a family history of HLH or parental consanguinity. Epstein-Barr virus infection is an important trigger of both FHL and acquired HLH. Cytomegalovirus, herpes simplex, human immunodeficiency virus, bacteria, and parasitic agents have also been implicated. [1][2][3][4] Non-Hodgkin's lymphoma and connective tissue diseases may also be associated with HLH. 5The diagnosis of HLH requires the demonstration of haemophagocytic histiocytes in tissue biopsies in association with pancytopenia, fever, and hepatosplenomegaly, and may be supported by the demonstration of hypofibrinogenemia or hypertriglyceridemia.6 Raised cerebrospinal fluid (CSF) protein concentrations and CSF pleocytosis are found in 50% of patients. However, haemophagocytosis in the marrow aspirate and other tissues may be inconspicuous and repeated biopsies may be necessary.We describe four cases of HLH in which pronounced dyserythropoiesis was seen in the bone marrow aspirate. In three cases, this was the only abnormality in the presentation sample. Case reports CASE 1A 14 week old boy presented with seven days of fever, abdominal swelling, and upper respiratory tract symptoms. Findings on examination were a fever of 39.9°C, jaundice, and pronounced hepatospl...
Exacerbation of diazepam-induced phlebitis by oral penicillamine Penicillamine, a heavy metal antagonist, is used in the treatment of Wilson's disease, cystinuria, rheumatoid arthritis, and various other conditions. Adverse reactions to the drug are many and frequent and range in severity from gastrointestinal distress, stomatitis, unpleasant skin odours, and rashes to proteinuria, leucopenia, and thrombocytopenia.1 Up to one-third of patients given the drug for rheumatoid arthritis have to discontinue treatment because of toxicity.' Intravenous diazepam is widely used as a sedative, muscle relaxant, and anticonvulsant. Local complications with this drug, including pain at injection site, phlebitis, and thrombophlebitis, have likewise been reported frequently.2We describe a patient who developed phlebitis from intravenous diazepam. The phlebitis resolved with local heat but recurred on two separate occasions after oral penicillamine. Case reportA 33-ycar-old white man underwent endoseopic retrograde eholepanereatography for investigation of persistent raised activity of alkaline phosphatase and 5'-nucleotidase. He had had ulcerative colitis 10 years earlier which had been effectively treated with sulphasalazine. Five years later an asymptomatic rise of alkaline phosphatase and 5'-nucleotidase activities and findings on oral cholecystogram consistent with cholecystitis prompted a cholecystectomy. This showed acalculus cholecystitis. Minimal biliary duct inflammation was found on liver biopsy. Although the patient had remained asymptomatic the alkaline phosphatase activity remained raised at 70 to 225 IU/l (normal 13-40) as did the 5 '-nucleotidase activity at more than 17 Bodansky units (normal 0 3-3-2). Results of tests for antimitochondrial and antismooth muscle antibodies were negative and serum bile acid concentrations were normal. An endoscopic retrograde
Summary:We report the case of a 10-year-old boy with congenital pure red cell aplasia (Diamond-Blackfan anaemia) who received an allogeneic bone marrow transplant (BMT) from his HLA-identical sister. The transplant was complicated by moderate veno-occlusive disease (VOD). Despite cytogenetic evidence of complete donor haemopoietic stem cell engraftment there was selective failure of red cell engraftment and he remains red cell transfusion-dependent. This is the first case of a stem cell transplant failing to correct the defect in this condition despite engraftment. Keywords: Diamond-Blackfan anaemia; bone marrow transplantation Diamond-Blackfan anaemia (DBA) is a congenital pure red cell aplasia usually presenting in the first year of life with profound normocytic or macrocytic anaemia, reticulocytopenia and marrow erythroblastopenia. It is a heterogenous condition with variable inheritance patterns, associated features and response to treatment.1 Although most cases are sporadic about 10% of cases are familial with either a dominant or recessive inheritance. Failure of spontaneous recovery and failure to demonstrate evidence of Parvovirus B19 distinguish DBA from transient erythroblastosis of childhood and red cell aplasia secondary to Parvovirus infection. Craniofacial anomalies, short stature and abnormalities of the thumb are the most commonly reported features.2 The location of the abnormal gene has been mapped in some cases of dominantly inherited DBA to chromosome 19q23. About 70% of cases are steroid-responsive and many of these will remain transfusion-independent although they often remain steroid-dependent. In vitro a variable response to cytokines such as IL-3, SCF, GM-CSF and human recombinant erythropoietin has been demonstrated. 4,5 For patients who remain steroid-resistant the therapeutic options include regular transfusion therapy with chelation Correspondence: Dr RF Wynn, Royal Manchester Children's Hospital, Manchester, M27 4HA, UK Received 18 January 1999; accepted 13 May 1999 and stem cell transplantation. We report a case of failure of BMT to correct DBA, despite adequate engraftment. Case report and methodsThe patient presented at 3. weeks of age with pallor following Caesarean section for foetal distress. There was no family history of DBA. His height was below the third centile but no physical anomalies were present. Blood count showed a Hb 6.1 with slight macrocytosis and mild thrombocythemia. There was no evidence of granular lymphocytosis on the blood film. Bone marrow aspirate showed erythroblastopenia with otherwise normal marrow. ELISA analysis for Parvovirus B19 was negative.He was transfusion-dependent from the age of 3 months and iron chelation, by subcutaneous desferrioxamine, was started at 20 months. There was no response to steroids or IL-3 and there were no red cell alloantibodies associated with red cell transfusion. Prior to BMT ferritin was recorded at 8200 g/l and liver biopsy showed marked iron deposition with no cirrhosis. Hepatitis and EBV serology was negative.He was...
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