Inherited thrombocytopenia caused by ANKRD26 mutations misdiagnosed and treated as myelodysplastic syndrome: report on two cases.

Essentials Thrombocytopenia 2 (THC2) is an inherited thrombocytopenia (IT) with dysmegakaryopoiesis. Physicians often do not suspect the genetic origin of thrombocytopenia in patients with THC2. We report two THC2 patients misdiagnosed with myelodysplasia and treated with chemotherapy. IT should be always considered in patients with isolated thrombocytopenia and dysmegakaryopoiesis. SUMMARY: Thrombocytopenia 2 (THC2) is an autosomal-dominant disorder caused by point substitutions in the 5'UTR of the ANKRD26 gene. Patients have congenital thrombocytopenia, normal platelet morphology and function, and dysmegakaryopoiesis. Thrombocytopenia is frequently discovered only in adulthood and physicians often do not suspect its genetic origin. We describe two unrelated patients referred to two different institutions for investigation of thrombocytopenia. Based on the finding of dysmegakaryopoiesis at bone marrow examination, patients were diagnosed with myelodysplastic syndrome (MDS) (refractory thrombocytopenia) and treated with several courses of 5-azacytidine. Subsequently, demonstration of thrombocytopenia in their relatives eventually led to molecular diagnosis of THC2 in both families. These cases highlight that patients with THC2 are at risk of being misdiagnosed with MDS and receiving undue myelosuppressive treatments. Because dysmegakaryopoiesis is a feature also of other forms of inherited thrombocytopenia, a genetic disorder must always be considered when a patient presents with isolated thrombocytopenia and dysmegakaryopoiesis.

Human herpesvirus 6-related pure red cell aplasia, secondary graft failure, and clinical severe immune suppression after allogeneic hematopoietic cell transplantation successfully treated with foscarnet.

Human herpesvirus 6 (HHV-6) is frequently detected after allogeneic hematopoietic cell transplantation (allo-HCT); however, the clinical interpretation of HHV-6 viremia in a transplant patient is challenging as it may signify asymptomatic reactivation, chromosomal integration of the virus genome in the donor or recipient with no clinical significance, or severe HHV-6 disease. Here we present a case of HHV-6 disease after allo-HCT presenting as pure red cell aplasia, secondary graft failure, and severe immunosuppression causing multiple severe bacterial super-infections. Examination of pre-transplant patient and donor samples as well as serial determination of HHV-6 DNA copy numbers after transplantation were necessary to definitively interpret HHV-6 viremia as active HHV-6 infection with a causative role in pancytopenia and immune suppression. Foscarnet treatment resulted both in viral load decline and disappearance of HHV-6-related bone marrow suppression and predisposition to severe infections. Clinicians should be aware of the wide array of clinical manifestations and the diagnostic pitfalls of post-transplant HHV-6 disease. These issues are extremely challenging, as they may result either in dangerous underestimation of HHV-6 disease or in the institution of unnecessary antiviral therapy. Late bone marrow aplasia and late severe infections after allo-HCT without other obvious causes may be HHV-6 related.

Constitutional pericentric inversion of chromosome 9 and hematopoietic recovery after allogeneic stem cell transplantation.

Recent reports suggest that hemopoietic stem cells with constitutional pericentric inversion of chromosome 9 [inv(9)] may be related to delayed engraftment or hemopoietic defect after stem cell transplantation (SCT). We conducted a retrospective study on five allogeneic SCT in which constitutional inv(9) was detected either in the donor or the recipient. The results showed that hematologic recovery was within the expected time range for all our patients. However, one patient exhibited decreasing blood counts between day +45 and +272 after transplantation, possibly due to protracted cytomegalovirus (CMV) infection and gansiclovir and imatinib treatment. Our findings suggest that constitutional inv(9) may not be associated with delayed hemopoietic recovery after SCT.

Determination of plasma cell secreting potential as an index of maturity of myelomatous cells and a strong prognostic factor.

According to the widely accepted myeloma staging system, the bulk of paraprotein is the main determinant of disease stage. However, myelomatous plasma cells differ considerably in their ability to synthesize and secrete monoclonal paraprotein. We determined plasma cell secreting potential (PCSP) as the amount of M-component, divided by the percentage of marrow plasmacytic infiltration, in 240 patients with myeloma, and correlated our results with chain isotype, plasma cell morphology, severity of bone disease, well-recognized prognostic factors, such as serum LDH, CRP, albumin and beta2-microglobulin, treatment response and overall survival. PCSP was higher in IgG than in other myeloma types, and was an almost constant parameter for each individual patient, in 134/166 cases. A > 10% decrease of PCSP in 26 patients was associated with disease aggressiveness and treatment failure. Patients with MGUS had significantly higher PCSP than those with myeloma of the same chain type. Higher PCSP was associated with stage I, absence of Bence-Jones proteinuria and indolent forms of disease with lower proliferating cell nuclear antigen (PCNA) positivity, serum LDH, alpha2-globulins, CRP and beta2-microglobulin and higher albumin levels. Conversely, patients with immature/plasmablastic morphology and those with severe bone disease had lower PCSP. Good responders to treatment had significantly higher PCSP than moderate and poor responders and PCSP was strongly correlated with overall survival in IgG and IgA myeloma. In conclusion, PCSP reflects the maturation status of myelomatous cells and therefore can be used as a prognostic factor, since patients with high secreting potential represent a lower malignancy group, in comparison to those with a low secreting potential.

Ticlopidine-induced aplastic anemia: two new case reports, review, and meta-analysis of 55 additional cases.

Ticlopidine-induced aplastic anemia (TIAA) is considered very uncommon. We present two new cases, and we review 55 additional cases from the literature. The first case concerns a 70-year-old man who developed severe aplastic anemia 7 weeks after treatment with 500 mg of ticlopidine daily. The patient sustained a severe septic episode, was treated with antibiotics and GM-CSF, and recovered the 14(th) day after ticlopidine withdrawal. The second was an 82-year-old man receiving ticlopidine for 2 years when, during a febrile episode, he was found neutropenic with marrow aplasia. Ticlopidine withdrawal and treatment with antibiotics, transfusions, and G-CSF helped him to recover. When the data of the 57 patients are evaluated, a reversible direct cytotoxic effect of ticlopidine on the pluripotent/bipotent hematopoietic progenitor stem cell is proposed. It is estimated that the real incidence if TIAA is higher, and many cases, initially presented as agranulocytosis +/- thrombocytopenia, might be true aplastic anemias, not proven by marrow aspiration or trephine biopsy. There is no effective monitoring to prevent this side effect. Recombinant growth factors appear not to help in shortening the neutropenic period.

Collection of Ph-negative progenitor cells from interferon responsive patients with chronic myeloid leukemia: effect of granulocyte-colony-stimulating factor mobilization.

BACKGROUND AND OBJECTIVE: The observation that patients with chronic myeloid leukemia (CML) may relapse following stem cell transplantation because of Philadelphia positive cells contaminating the graft have led to a variety of strategies to reduce this contamination. This study investigate the feasibility of collective, Ph-re cells from patients with CML in chronic phase. DESIGN AND METHODS: A total of 18 patients with chronic myeloid leukemia in chronic phase who had responded to varying degrees to treatment with interferon-a (IFN) were subjected to mobilization with granulocyte colony-stimulating factors and peripheral blood progenitor cell collection. Nine patients were in complete cytogenetic remission (CCR) and nine were partial responders. IFN was stopped 2 to 4 weeks before the procedure. G-CSF was given by subcutaneous injection once daily at a dose of 10 microg/kg. RESULTS: Five patients underwent one collection procedure only, 10 underwent two procedures and 3 patients had three collections. The median number of nucleated cells (NC) per patient collected was 10.2 x 10(8)/kg (4.4-19.7) and the median number of CD34(+) cells was 2.5 x 10(6)/kg (0.4-9.4). Analyzable cytogenetic data were available for 26/34 (76%) leukapheresis procedures. The median percentage of Ph- negative metaphases for patients in CCR was 100% (73-100). Patients not in CCR had a higher level of Ph-positive cells in their collections (median 23%, range 0-79%, p=0.01). Of the nine patients in CCR, 8 had at least one apheresis from which progenitor cells were 100% Ph-negative; conversely, patients not in CCR had detectable Ph-positive cells in every collection. Four patients have undergone autologous stem cell transplantation. INTERPRETATION AND CONCLUSIONS: It was possible to collect sufficient Ph negative progenitor cells from patients in CCR but collections from other patients contained significant numbers of Ph-positive cells.

Sjögren's syndrome in patients with newly diagnosed untreated non-Hodgkin's lymphoma.

The purpose of the study was to detect cases of Sjögren's syndrome among newly diagnosed untreated patients with non-Hodgkin's lymphoma and, furthermore, to identify in such cases clinical and serologic features known to occur more frequently in Sjögren's syndrome patients who evolve into lymphoma. Accordingly, thirty-three cases of newly diagnosed non-Hodgkin's lymphoma, prior to any treatment administration, were thoroughly studied for evidence of Sjögren's syndrome. Immunophenotyping for T and B cells and kappa and lambda light chains was concomitantly performed on both lymphomatous tissues and minor salivary glands. There were 5 patients with T cell and 28 with B cell lymphoma of various histologic subtypes and grades. Two of the latter (7.1%) had a positive for Sjögren's syndrome minor labial salivary gland biopsy, positive responses to the specific questionnaires for both eye and mouth dryness and abnormal Schirmer's and rose Bengal eye tests, substantiating the diagnosis of Sjögren's syndrome. Both were male with lung and stomach non-Hodgkin's lymphoma respectively, enlargement of the lacrimal glands, monoclonal gammapathy of the IgM kappa type and, one of them had high titer and of fine speckled pattern positive antinuclear antibodies and anti-Ro(SSA) and anti-La(SSB) antibodies in his serum. A monotypic infiltrate with kappa light chain restriction, identical to that in the lymphomatous tissue of these two patients, was present in their minor salivary gland biopsy as well. Such a finding was not encountered in any of the remaining patients. Although our sample is relatively small, our results confirm the relationship between Sjögren's syndrome and non-Hodgkin's lymphoma, looked at from the opposite direction. Obviously, studies involving larger populations would be more definitive, regarding the issue of what percentage of this lymphoma patients originates from Sjögren's syndrome.

Incidence of scoliosis in beta-thalassemia and follow-up evaluation.

STUDY DESIGN: One hundred fifteen of 120 patients with beta-thalassemia followed in the thalassemia unit were studied for the presence of scoliosis. Forty-nine of these patients were reevaluated 1 year later. OBJECTIVES: To determine the frequency and the course of scoliosis in beta-thalassemia and to compare the findings with those of patients with idiopathic scoliosis. SUMMARY AND BACKGROUND DATA: There is only one report indicating increased frequency of scoliosis in a limited number of patients with thalassemia. In this study, the authors assessed the frequency of scoliosis in a large sample of patients and followed the evolution of this spinal deformity. METHODS: Patients with beta-thalassemia aged 3-35 years were examined clinically and radiologically for scoliosis. Forty-nine of them were reexamined 1 year later for determination of the evolution of scoliosis. RESULTS: Lateral curves of at least 5 degrees Cobb were found in 77 patients (67%), with a male-to-female ratio of 0.9. Scoliosis of at least 10 degrees was found in 21.7% of the male and 20% of the female patients with thalassemia. The ratio was 1.18 for curves of at least 10 degrees and 0.77 for curves of a smaller magnitude. The most common curve pattern was the left lumbar (35.1%), followed by the double-curve pattern (16.9%). Forty-nine randomly selected patients (42.6%) of the 115 included in the study were reexamined 1 year later. Seven male and 7 female patients (total, 28.6%) showed a progression of at least 5 degrees. Six patients (12.2%) experienced spontaneous improvement of less than 6 degrees. The pattern and the evolution of scoliosis observed in patients with beta-thalassemia differ from those found in Greek children with idiopathic scoliosis. CONCLUSIONS: The findings of this study show that the incidence, evolution, and etiology of scoliosis in beta-thalassemia differ from those of idiopathic scoliosis, indicating that the spinal deformities in patients with beta-thalassemia represents a distinct type of scoliosis. Longer follow-up is needed to investigate the natural history of this type of scoliosis.

Prevalence of scoliosis in beta-thalassemia.

The objective of this study was to determine the prevalence and possible pathogenesis of scoliosis in beta-thalassemia in our country, and to compare its characteristics to those of patients with idiopathic scoliosis from the same geographic area. Twenty-four [13 male and 11 female thalassemic patients aged 16 +/- 7 years (range 7-32 years)] of 115 examined patients with beta-thalassemia showed scoliosis of 14 degrees +/- 11 (range 10-65 degrees) radiologically. The prevalence of scoliosis in the thalassemic population was 21% in this series, whereas the overall prevalence of scoliosis in the general Greek population was 6% (Smyrnis PN, Valavanis J, Alexopoulos A, Siderakis G, Giannestras NJ: School screening for scoliosis in Athens, J Bone Joint Surg 61B:215-217, 1979). The scoliosis prevalence in the general population was significantly higher in the females (5%) than in the males (1%), whereas no difference in prevalence was found between the two sexes in the thalassemic population. The most common curve pattern in thalassemia was the left lumbar (38%) followed by the right lumbar (21%), whereas in patients with idiopathic scoliosis the left thoracolumbar most commonly appeared (25%) followed by the left lumbar (14%). No patient with thalassemia showed radiographic signs of congenital spinal deformities and spinal fractures, whereas all patients showed a significant retardation of their skeletal maturation. The age of the thalassemic patients with scoliosis was significantly (p = 0.0003) higher than in patients without scoliosis. The hematocrit of the thalassemic patients with scoliosis was significantly (p = 0.0012) lower than in those without scoliosis, whereas the rate of transfusions was not correlated with the magnitude of the scoliosis. The level of ferritin was significantly (p = 0.025) higher in the thalassemic patients with scoliosis than in those without scoliosis. The duration of Desferal treatment was significantly (p = 0.0357) longer in thalassemic patients with scoliosis when compared with those without scoliosis. Thus, the prevalence, curve pattern, and etiology of scoliosis in beta-thalassemia differ from those of idiopathic scoliosis, indicating that the spinal deformities in thalassemia represent a distinct type of scoliosis.

Immune function parameters at diagnosis in patients with myelodysplastic syndromes: correlation with the FAB classification and prognosis.

We determined nine immune function parameters at diagnosis in patients with myelodysplastic syndromes (MDS) and correlated the results with the FAB classification and prognosis by univariate and multivariate analyses. Patients with refractory anaemia (RA) and refractory anaemia with ring sideroblasts (RAS) tended to have a higher CD4/CD8 ratio and a lower amount of gamma-globulins and soluble interleukin-2 receptors in serum in comparison to those suffering from the other three subgroups of MDS. FAB classification, neutrophil and CD8+ T-cell number had the best discriminatory capacity for predicting survival less than 1 year, and FAB classification, neutrophil number and serum TNF levels were predictors for conversion to acute leukaemia. The frequent occurrence of infections, on the other hand, could be better predicted by the absolute numbers of neutrophils and CD4+ cells and by the skin test score.