Chronic steroid-response pancytopenia and increased bone density due to thromboxane synthase deficiency.

Diagnosis of bone marrow failure (BMF) disorders is challenging but essential for optimal patient management. Here, we report a young adult from nonconsanguineous parents with progressive pancytopenia since childhood, bone pain, increased bone density, and haphazard ossification replacing hematopoiesis within the bone marrow. Sequencing revealed two novel biallelic variants of unknown significance within the thromboxane A synthase gene, TBXAS1 (c.266T > C; c.989T > C), bioinformatically predicted to disrupt the protein. TBXAS1 mutations result in Ghosal hematodiaphyseal dysplasia (OMIM 231095), the autosomal recessive syndrome associated with abnormal bone structure and BMF. Identification of the genetic defect prompted steroid therapy leading to resolution of symptoms.

Disruption of the FEN-1/PCNA interaction results in DNA replication defects, pulmonary hypoplasia, pancytopenia, and newborn lethality in mice.

The interaction between flap endonuclease 1 (FEN-1) and proliferation cell nuclear antigen (PCNA) is critical for faithful and efficient Okazaki fragment maturation. In a living cell, this interaction is probably important for PCNA to load FEN-1 to the replication fork, to coordinate the sequential functions of FEN-1 and other enzymes, and to stimulate its enzyme activity. The FEN-1/PCNA interaction is mediated by the motif (337)QGRLDDFFK(345) of FEN-1, such that an F343AF344A (FFAA) mutant cannot bind to PCNA but retains its nuclease activities. To determine the physiological roles of the FEN-1/PCNA interaction in a mammalian system, we knocked the FFAA Fen1 mutation into the Fen1 gene locus of mice. FFAA/FFAA mouse embryo fibroblasts underwent DNA replication and division at a slower pace, and FFAA/FFAA mutant embryos displayed significant defects in growth and development, particularly in the lung and blood systems. All newborn FFAA mutant pups died at birth, likely due to pulmonary hypoplasia and pancytopenia. Collectively, our data demonstrate the importance of the FEN-1/PCNA complex in DNA replication and in the embryonic development of mice.

Pancytopenia as a clonal disorder of a multipotent hematopoietic stem cell.

Hematopoiesis was investigated in a 14-yr-old girl who had a 2-yr history of stable asymptomatic pancytopenia and who was also heterozygous at the structural locus for glucose-6-phosphate dehydrogenase (G-6-PD). There was no morphologic or cytogenetic evidence for preleukemia and no suggestion of Fanconi anemia. In the skin and sheep erythrocytes-rosetted T lymphocytes, the ratio of G-6-PD A/B activities was 1:1. However, only type B activity was found in peripheral blood erythrocytes, granulocytes, and platelets. Most erythroid bursts and all granulocyte/macrophage colonies formed in methylcellulose culture were derived from the abnormal clone. These findings demonstrate that (a) some cases of pancytopenia are stem cell diseases that apparently develop clonally; (b) circulating differentiated cells originate from this clone; (c) despite a hypoproliferative anemia, the in vivo expression of presumably normal (nonclonal) progenitors is suppressed. In this patient, the relationship between clonal dominance and possible malignancy may be assessed prospectively.

[New polymerase gene in pancytopenia (author's transl)]. / Reverse Transkriptase in der Differentialdiagnose leukämischer Erkrankungen

Increasing evidence has accumulated that the direct assay of reverse transcriptase in human blood cells is of value in the diagnosis of leukaemia. The isolation and characterization of this enzyme has shown that it possesses remarkable similarities to the DNA-polymerase of the RNA-tumour virus of simian sarcoma. Hence, leukaemic cells in humans are thought to possess a virus-related gene, namely, reverse transcriptase. Various clinical reports have established the presence of this enzyme in blood cells, not only in the case of morphologically-proven malignant change, but also in cases classified as non-leukaemic from the morphological picture, such as acute leukaemia in remission and in the pre-leukaemic state. In confirmation and augmentation of earlier views we now report on the presence of reverse transcriptase in a patient with pancytopenia, who subsequently developed acute leukaemia i.e. isolation of the enzyme occurred in the pre-leukaemic state.

Paradoxical elevated thiopurine S-methyltransferase activity after pancytopenia during azathioprine therapy: potential influence of red blood cell age.

There is an increased risk of developing bone marrow depression and infections during azathioprine therapy for inflammatory bowel disease. Patients with low or absent thiopurine S-methyltransferase (TPMT) activity have an increased risk of developing myelotoxicity. We describe a patient who developed pancytopenia combined with cytomegalovirus pneumonia after several years of azathioprine use. The bone marrow depression was probably caused by the viral infection, as all others causative factors were unlikely. Surprisingly, we observed grossly elevated TPMT activity (182 nmol/g/h) during the recovery phase, following the pancytopenic period. After complete recovery of the bone marrow suppression, TPMT activity returned to usual reference activity (43 nmol/g/h). This remarkable change in enzymatic activity of TPMT may be explained by differences in the age of red blood cells, as younger erythrocytes have a higher TPMT activity. Determination of a patient's TPMT status by phenotyping should therefore not be performed just after bone marrow depression or in cases of activated erythropoieses.

[The Lesch-Nyhan syndrome as a rare cause of hemolytic anemia]. / Das Lesch-Nyhan-Syndrom als seltene Ursache einer hämolytischen Anämie.

The Lesch Nyhan Syndrome is a rare cause of hemolytic anemia. By electron microscopy, platelets of a patient with this disorder lacked a marginal bundle nearly completely--and had morphologically an abnormal structure. This may be a hint with respect to the pathogenesis of this unresolved syndrome.

Serum lysozyme activity in some myeloproliferative diseases.

Serum lysozyme activity has been determined in patients suffering from myeloproliferative diseases, chronic myelogenous leukaemia (CML), acute myelogenous leukaemia (AML), chronic lymphatic leukaemia (CLL) and pancytopenia (P). Lysozyme activity was tested in undiluted and tenfold diluted sera. Increased lysozyme activity was found in patients with CML and CLI, whereas there was no change in patients with AML and P. Dilution of sera enhanced lysozyme activity. These data may indicate the presence of inhibitor in the sera tested. The diagnostic significance of the presented findings is discussed.