[Acquired alpha-thalassemia in an 86-year-old patient with myelodysplastic syndrome]. / Une alpha thalassémie acquise chez un patient de 86 ans avec un syndrome myélodysplasique.

BACKGROUND: Alpha thalassemia-myelodysplastic syndrome (ATMDS) is one of the possible complications related to the genetic instability typical of clonal hemopoietic disorders such as myelodysplastic syndromes (MDS). Hemoglobin H acquisition, which is hemoglobin without alpha chains and with 4 beta chains is the hallmark of this disease. OBSERVATION: An 86-year-old male with chronic, microcytic anemia was referred due to a fall in his hemoglobin level. The blood smear was remarkable for intense anisocytoses and poikilocytosis. Bone marrow analysis was followed by a diagnosis of MDS with a good prognostic score. Peripheral blood coloration with brilliant cresyl blue showed "golf ball-like" erythrocytes. Hemoglobin electrophoresis is notable for the presence of H hemoglobin. The new generation sequencing confirmed the diagnosis of ATMDS showing a non-sense mutation in the gene ATRX. CONCLUSION: The diagnosis of ATMDS should be considered in the presence of the association of MDS, microcytic anemia and marked blood smear abnormalities such as anisocytosis and poikilocytosis. A little less than 10% of all MDS are complicated by ATMDS.

[Acute disseminated encephalomyelitis presenting as an acute urinary febrile retention]. / Un cas d'encéphalomyélite aiguë disséminée post-infectieuse découvert devant une rétention vésicale fébrile.

INTRODUCTION: MRI should be performed in the presence of an acute febrile urinary retention, when septic and obstructive causes are eliminated. We report a case of post-infectious probable acute disseminated encephalomyelitis (ADEM) with a mostly spinal cord tropism of involving Campylobacter. CASE REPORT: A 32-year-old man with no medical history was admitted for an acute febrile urinary retention. He reported severe diarrhea 3 days before. Clinical course was then complicated by a progressive tetraparesis predominating in the lower limbs. Medullar MRI showed thoracic myelitis. A five-day course of intravenous corticosteroids allowed a full recovery of both the motor and urinary symptoms. Fecal culture isolated Campylobacter sp. Final diagnosis was post-bacterial ADEM. CONCLUSION: Clinical findings and MRI allow clinicians to suspect acute disseminated encephalomyelitis. This hypothesis implies to actively look for recent infections or vaccinations preceding the clinical presentation.

[Ganulomatosis with polyangiitis revealed by a cutaneous ulceration mimicking a pyoderma gangrenosum: Two patients]. / Granulomatose avec polyangéite révélée par une ulcération cutanée mimant un pyoderma gangrenosum : à propos de 2 cas.

INTRODUCTION: Granulomatosis with polyangiitis is a systemic and necrotizing vasculitis, and cutaneous involvement is uncommon. We report two cases of skin ulceration mimicking a pyoderma gangrenosum, and revealing granulomatosis with polyangiitis. CASE REPORTS: We report two patients who presented with atypical cutaneous ulcerations, with a chronic course. These wounds were large ulcerations with abrupt edges, with purulent and hemorrhagic exudates. The first hypothesis was a pyoderma gangrenosum, but the biopsies were not specific. New biopsies performed distant from the edges showed a necrotizing vasculitis associated with giant cells granuloma, typical from granulomatosis with polyangiitis. CONCLUSION: Cutaneous manifestations are uncommon in granulomatosis with polyangiitis, and can be misleading as they may precede the systemic symptoms. We report two cases of granulomatosis with polyangiitis revealed by cutaneous symptoms mimicking a pyoderma gangrenosum. Repetition of the skin biopsies were necessary to obtain the diagnosis.

Value of (18)F-FDG-PET/CT in patients with fever of unknown origin and unexplained prolonged inflammatory syndrome: a single centre analysis experience.

OBJECTIVE: The aim of our study was to evaluate the diagnostic contribution of (18)F-fluoro-deoxyglucose ((18)F-FDG)-positron emission tomography (PET)/computed tomography (CT) in patients with fever of unknown origin (FUO) or unexplained prolonged inflammatory syndrome (UPIS) in real life. PATIENTS AND METHODS: We performed a retrospective study including 14 patients with FUO or UPIS hospitalised in our institution (Strasbourg University Hospital, France) between January 2005 and July 2006. (18)F-FDG-PET/CT was considered helpful when abnormal results allowed an accurate diagnosis. RESULTS: (18)F-FDG-PET/CT was helpful in half the patients (7/14) for final diagnosis. A diagnosis was reached in 87.5% of the patients (7/8) with an abnormal (18)F-FDG-PET/CT but only in 50% of the patients (3/6) with a normal (18)F-FDG-PET/CT. Conventional chest and abdominal CT was performed in 13 patients before ordering (18)F-FDG-PET/CT. We considered that (18)F-FDG-PET/CT was essential to establish the final diagnosis in only 23% of the patients (3/13) since neither chest nor abdominal CT identified abnormalities consistent with the final diagnosis. However, among the three patients, two were diagnosed with large vessel vasculitis and one patient with local prosthetic infection. CONCLUSIONS: Our study supports the potential interest of (18)F-FDG-PET/CT in the diagnostic workup of FUO and UPIS as it helped establish a fine diagnosis in half of the cases. However, (18)F-FDG-PET/CT appeared to be essential to the final diagnosis in only 23% of the cases. In our opinion, this protocol should be performed as a second level test, especially when conventional CT is normal or is unable to discriminate between active and silent lesions.

[Macroenzymes: macro-ASAT and macro-CPK. Two cases and literature review]. / Macroenzymes : macro-ASAT et macro-CPK. Deux observations et revue de la littérature.

INTRODUCTION: Macroenzymes are high molecular weight complex formed by the binding of one enzyme and a serum macromolecule, responsible for an increase in the activity of the corresponding enzyme in blood assay. CASE REPORTS: We report two cases: firstly, a macro-aspartate aminotransferase (macro-ASAT) discovered in an 82-year-old woman who presented with an isolated and persistent elevation of the ASAT activity that was discovered after sepsis, secondly, a macro-creatine-kinase (macro-CPK) diagnosed in a 62-year-old man after several years of investigations for a persistent CPK elevation. These two case reports allowed us to discuss the mechanism leading to the formation of macroenzymes and the usefulness of their determination. Although macroenzymes are generally non pathologic, they may be associated with auto-immune, neoplastic or infectious diseases. CONCLUSION: The possibility of a macroenzyme should be entertained in the presence of an unexplained and isolated increased enzyme activity. It prevents costly and unnecessary investigations.

Relevance of the antibody index to diagnose Lyme neuroborreliosis among seropositive patients.

BACKGROUND: No consensual criteria exist to diagnose neuroborreliosis. The intrathecal anti-Borrelia antibody index (AI) is a necessary criterion to diagnose neuroborreliosis in Europe, but not in the United States. Previous studies to determine the diagnostic value of the AI found a sensitivity ranging from 55% to 80%. However, these studies included only typical clinical cases of meningitis or meningoradiculitis, and none had a control group with CSF anti-Borrelia antibodies. METHODS: We studied a sample of 123 consecutive patients with clinical signs of neurologic involvement and CSF anti-Borrelia antibodies. We determined the AI for all patients and a final diagnosis was made. Patients were then divided into three groups (neuroborreliosis, possible neuroborreliosis, control). RESULTS: Thirty of the 40 patients with neuroborreliosis had a positive AI (AI sensitivity = 75%). Two of the 74 patients with another neurologic diagnosis had a positive AI (AI specificity = 97%). CONCLUSION: The antibody index has a very good specificity but only moderate sensitivity. Given the lack of consensual criteria for neuroborreliosis and the absence of a "gold standard" diagnostic test, we propose pragmatic diagnostic criteria for neuroborreliosis, namely the presence of four of the following five items: no past history of neuroborreliosis, positive CSF ELISA serology, positive anti-Borrelia antibody index, favorable outcome after specific antibiotic treatment, and no differential diagnosis. These new criteria will need to be tested in a larger, prospective cohort.

[Update of pernicious anemia. A retrospective study of 49 cases]. / Données actuelles sur la maladie de Biermer. A propos d'une étude rétrospective de 49 observations.

PURPOSE: The aim of this study was to describe the present clinical characteristics of the pernicious anemia (PA). METHOD: It is a retrospective (1996-2002) multicenter (five departments of internal medicine) study of 49 patients presenting an established cobalamin deficiency related to PA. RESULTS: The median age of the patients was 74 years (25-93), the female/male ratio 2:9. Several autoimmune disorders were noted in 35% of the patients. Various clinical manifestations, mainly neurological, cutaneous and thrombotic, were found in 65.4% of the patients, at least one hematological abnormalities in 100%. Average serum vitamin B12 and homocystein levels were with 73 pg/ml (20-1960) and 42.9 micromol/l (7, 8-124). Anti-intrinsic factor or anti-parietal gastric cells antibodies were found in 87.5% and 62% of the patients (at least one antibody, in 96%) abnormal Schilling's test results in 86%. All the followed patients were successful treated with intramuscular (n = 27) or oral crystalline cyanocobalamin (n = 5). CONCLUSIONS: PA was associated with several autoimmune disorders; PA may be responsible of various clinical manifestations or biological abnormalities; and oral crystalline cyanocobalamin treatment may be successful.

[Left branch portal vein thrombosis associated with hyperhomocysteinemia]. / Thrombose de la branche gauche de la veine porte associée à une hyperhomocystéinémie.

A 34 year-old man, who was a smoker, was hospitalised because of severe epigastric and right upper quadrant pain. An isolated left branch portal vein thrombosis was diagnosed using ultrasonography and arteriography. Two thrombogenic pathologies were found: i) a latent myeloproliferative syndrome with spontaneous presence of erythroid colony forming unit (CFU-E) in bone marrow culture, normal blood cell count, platelet count and medullogram; ii) a hyperhomocysteinemia associated with low serum folate levels and a methyl tetrahydrofolate reductase mutation. The association of these two factors probably resulted in portal vein thrombosis. This is the first adult case of a portal vein thrombosis associated with hyperhomocysteinemia. Increased homocysteine serum levels could be a previously unrecognized factor for portal vein thrombosis. Homocysteinemia should be systematically investigated in patients with idiopathic portal vein thrombosis since folate supplements could prevent deleterious vascular effects of hyperhomocysteinemia.

Evidence that the V kappa III gene usage is nonstochastic in both adult and newborn peripheral B cells and that peripheral CD5+ adult B cells are oligoclonal.

There is evidence that in certain situations the expressed antibody repertoire is dominated by small subsets of V gene segments. They include fetal, CD5+, and autoantibody-forming B cells as well as low grade B cell malignancies. For instance, inside the V kappa III family of approximately 10 members, only 3 (humkv325, 328, and Vg) are used recurrently for autoantibody production. However, the significance of this recurrence is difficult to interpret without a clear vision of the actual repertoire in normal subjects. To address this, we have sequenced and compared two sets of rearranged V kappa III genes generated by cDNA PCR amplification from a normal newborn, a normal adult, and from CD5+ B cells of the same adult donor. The results show that: (a) only four V kappa III gene segments are used by neonatal and total adult B cells (humkv325, humkv328, Vg, and kv305), humkv325 being overexpressed in both repertoires; (b) there is no significant difference in terms of V kappa III gene usage between the adult and newborn repertoires; (c) regarding the junction regions, there is a favored use of the most 5' JK gene segments (Jk1-Jk2); approximately 20% of the newborn and adult junction sequences was characterized by one or two additional codons, most probably resulting from a nontemplate addition of nucleotides; (d) adult clones, in contrast to most newborn clones, show sequence divergences from prototype sequences with patterns which suggest antigen-driven diversity; (e) regarding the adult CD5+ B cell library, it is most probable that the 78 clones analyzed derived from no more than nine different VK-JK rearrangements. Humkv325 is used by at least six of them, and most of the expressed V genes were in exact or very near germline configuration. Collectively these results suggest that the expressed antibody V kappa III repertoire in the adult represents only a fraction of the potential genetic information and that it resembles the preimmune repertoire of the neonate. The data, which also suggest that the adult peripheral blood CD5+ B cell population may be dominated by a small number of B cell clones, are discussed with regards to the V kappa III usage in pathological situations.

[Granulomatous mastitis, erythema nodosa and oligoarthritis. Apropos of a case]. / Mastite granulomateuse, érythème noueux et oligoarthrite. A propos d'une observation.

The authors report a case of granulomatous mastitis associated with erythema nodosum and oligoarthritis. The skin and joint symptoms improved with potassium iodide. The breast lesion clinically simulated a tumor of high malignant grade. Granulomatous mastitis is a benign and rare disease. Its interest lies in the possible association with systemic manifestations and in its steroid responsiveness. This condition has been recently described as a distinct entity. When associated with systemic manifestations, sarcoidosis should be considered.

A minor group of rheumatoid factors isolated from a patient with rheumatoid arthritis is derived from somatically mutated Vk1 genes further evidence that rheumatoid factors during autoimmune diseases undergo an antigen driven maturation.

To better understand the structural basis for rheumatoid factor [RF] activity and the origin of autoantibodies in human autoimmune diseases, we isolated the RF producing B cells from the peripheral blood and from the synovial fluid of a patient suffering from rheumatoid arthritis [RA]. We previously demonstrated that a significant fraction of these RF were derived from three V kappa III genes known to encode most of the monoclonal RF light chain variable regions. To get more insight into the actual repertoire of RF-V kappa genes during RA, we analyzed the nucleotide sequences of RF light chain variable regions of other V kappa families. Using two sets of polymerase chain reactions in order to amplify the cDNA derived from RF producing cells from the same patient KRA, we isolated only three different rearranged V kappa-J kappa complexes: slkv5, slkv7 and bkv42, all derived from V kappa I germ-line genes not previously known to be associated with RF activity; this suggests that the repertoire of VL genes coding for RF during RA is more diverse than the one involved in the generation of paraprotein RF during monoclonal lymphoid proliferations, although there remains a possible bias in favor of the V kappa III family. Moreover, each of these genes is somatically mutated with a pattern suggesting a selective pressure of the antigen. Particularly interesting is the additional proline residue at the V kappa-J kappa junction of bkv42, an unorthodox feature that we found previously in more than 50% of RF V kappa III-J kappa gene complexes. Finally, the homogeneity of some non conservative mutations suggests the existence of a restricted set of pathogenic epitopes driving the production of RF during RA.

Molecular analysis of the V kappa III-J kappa junctional diversity of polyclonal rheumatoid factors during rheumatoid arthritis frequently reveals N addition.

Much interest was stirred in recent years by the evidence that rheumatoid factors (RF) variable regions are encoded by a restricted set of V genes, with little or no somatic mutations, that are often overexpressed in the fetal repertoire. This is reminiscent of what has been observed for natural autoantibodies. However, these data come from studies of monoclonal RF (mRF) isolated from patients with lymphoproliferative disorders who usually do not present autoimmune symptoms. The molecular characterization of RF during autoimmune diseases such as rheumatoid arthritis (RA) has been hampered for some time because of their polyclonality; recently using the polymerase chain reaction method, we have demonstrated that RF kappa variable regions from a patient with RA were encoded by V kappa III genes known to code for mRF but that these genes had undergone somatic mutations with a pattern suggesting an antigen-driven maturation. Because an important role of the light chain third complementarity-determining region (CDR3) in anti-IgG reactivity and idiotype expression has already been suspected for RF, we now report the molecular characterization of the junction regions of these rearranged V kappa gens. Surprisingly, our data show that in 55% of the cases there is addition of a proline and/or glycine amino acid residue at the recombination site between V kappa and J kappa. The sequence analysis of our patients' germ-line Vg and J kappa 4 genes segments and their flanking regions demonstrates that the additional codons are not readily explicable by recombination between germ-line sequences and probably result from an N addition process. Since we could not find such an additional codon in 15 previously published mRF kappa chains we suggest that "pathogenic" RF during RA and mRF derive from different, although overlapping, B cell subsets. Moreover, since additional codons at the recombination site of V kappa and J kappa seem exceptional in expressed human kappa chains and because the resulting amino acid residue is a proline in most cases, we think that RF kappa chain CDR3 is under a very strong selective pressure during RA.

[Rhabdomyolysis caused by simvastatinin a patient following heart transplantation and cyclosporine therapy]. / Rhabdomyolyse causée par la simvastatine chez un transplanté cardiaque sous ciclosporine.

Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are cholesterol-lowering agents which may induce rhabdomyolysis. The authors present a case of rhabdomyolysis attributed to simvastatin in a heart-transplant recipient. They stress the probability of a dose-dependent muscular toxicity and the risk of overdosage in patients already under treatment with drugs that interfere with the pharmacokinetics of HMG-CoA reductase inhibitors, notably ciclosporine.

[Rheumatoid factors]. / Les facteurs rhumatoïdes.

Rheumatoid factors (RF), which are auto-antibodies recognising the Fc fragment of IgGs, are the commonest auto-antibodies in man. They are present in polyclonal form in a large number of auto-immune disorders as well as in certain inflammatory states. In monoclonal form, they are frequently the product of "mature" malignant (chiefly Waldenström's macroglobulinemia and chronic lymphoid leukemia) and allegedly benign (such as cryoglobulinemias) lymphoid proliferations. In addition, RF account for a significant part of the normal antibody repertory, notably during the fetal and neonatal periods, suggesting that they may play an important role in the development and regulation of the immune system. As a result, RF are an excellent model for the analysis of auto-immunity in man. Thus many indirect (analysis of antigens recognised and of idiotopes carried) and, more recently, direct (protein or nucleotide sequencing of their various regions) studies have now provided the following conclusions. RF are coded by a very limited repertory of V genes. These genes are present in the normal genome and appear to be highly preserved in the human species. They are used with very few somatic mutations by monoclonal B proliferations (which opens up valuable therapeutic possibilities) as well as probably by RF producing B lymphocytes in normal individuals. In contrast, in the context of auto-immune disorders, these same genes have many somatic mutations suggesting maturation governed by the antigen and/or escape from idiotype control.

Molecular analysis of V kappa III variable regions of polyclonal rheumatoid factors during rheumatoid arthritis.

We report the first molecular characterization of V kappa regions of the main human autoantibodies occurring during rheumatoid arthritis, the polyclonal rheumatoid factors. Using two sets of polymerase chain reactions in order to amplify the cDNA derived from both peripheral blood and synovial fluid rheumatoid factor-secreting cells, nucleotide analysis of the V kappa III family usage shows the following: (a) at least three different V kappa III genes are used to encode polyclonal rheumatoid factors in a single patient, (b) each one of these genes seems more or less somatically mutated (from 1 to 14 mutations), (c) the mutation process preferentially affects the complementarity determining regions suggesting a selective pressure of antigen and (d) there is no clear difference between the mutation rates affecting the synovial fluid and peripheral blood rheumatoid factor-secreting cells. These results are able to explain some of the known idiotypic differences between monoclonal and polyclonal rheumatoid factors in humans. They also provide evidence that polyclonal autoantibodies arising during an autoimmune disease can be the products of multiple somatically mutated genes and suggest that this process is antigen driven, whether this antigen is the Fc piece of IgG or another unknown antigen.