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Heavy chain diseases are rare gammopathies characterized by the production of a truncated heavy chain monoclonal immunoglobulin without associated light chain. These hemopathies, which are frequently associated with immunological or hematological disorders, are clinically closer to lymphomas than to myelomas. The case that we report illustrates the difficulty to characterize a heavy chain gammopathy discovered in an elderly woman admitted in the department of internal medicine for alteration of general condition.

given the lack of information about monoclonal gammopathies, our primary study outcome was to describe the epidemiological, clinical and biochemical profiles of monoclonal gammopathies in the Souss-Massa region, in southern Morocco.we conducted a retrospective study, by selecting only complete medical records. We used records of patients diagnosed with monoclonal gammopathy at the local oncology center during a period of over 10 years.one hundred and seventeen patients were included in the study, with a high male predominance (65%) and a male/female sex-ratio of 1.85. The average age of our study population was 61.44 (ET 14.54) years. Diagnoses (based on frequency) included: multiple myeloma 82.0% (n=96), solitary plasmacytoma 8.5% (n=10), monoclonal gammopathies of undetermined significance 2.6% (n=3), lymphoma 2.5% (n=3), secondary plasma cell leukaemia 1.7% (n=2), Waldenström´s disease 1.7%(n=2) and chronic lymphoid leukemia (n=1). The isotype distribution was as follows: IgG Kappa 33.7% (n=28), IgG lambda 21.7% (n=18), IgA Kappa 12.0% (n=10), IgA lambda 7.2% (n=6), IgM kappa 3.6% (n=3), and IgD lambda 2.4% (n=2). Biconal peak was reached in two cases, with a percentage of 2.4%.diagnostic delay was observed compared to international studies due to the unavailability of electrophoresis in the care structures.

Al amyloidosis, from diagnosis to treatment. AL amyloidosis is a rare hemopathy characterized by immunoglobulin light chains deposits in almost all organs causing organ failure. The main issue is the early dia¬gnosis, which must be made in front of an unexplained non-specific symptomatology, especially cardiac or renal, in frequently elderly patients with monoclonal gammo¬pathy. Non-invasive biopsies should be made for histolo¬gical confirmation revealing positive congo red and birefringent yellow-green deposits in polarized light specific for amyloidosis. Severity is assessed by biologi¬cal markers of cardiac involvement. The treatment consists in eliminating the plasma or lympho-plasma cell dyscrasia secreting the amyloidogenic light chain, and in proposing supportive care specific to this pathology.Amylose al, du diagnostic au traitement. L’amylose AL est une hémopathie rare, caractérisée par des dépôts de chaînes légères d’immunoglobulines, pouvant survenir dans presque tous les organes et pouvant entraîner leur défaillance. L’enjeu principal est le diagnostic précoce qui doit être évoqué devant une symptomatologie souvent aspécifique, surtout cardiaque ou rénale, non expliquée chez des patients fréquemment âgés et porteurs d’une gammapathie monoclonale. Des biopsies non invasives doivent rapidement permettre la confirmation histologique révélant des dépôts positifs au rouge congo et biréfringent jaune-vert en lumière polarisée spécifique de l’amylose. La gravité est évaluée par les marqueurs biologiques d’atteinte cardiaque. Le traitement consiste à éliminer le clone plas¬mocytaire ou lymphoplasmocytaire sécrétant la chaîne lé¬gère amyloïdogène, et à proposer des soins de support spécifiques à cette pathologie.

Monoclonal plasma cell gammopathies (MPCG) describe several forms of abnormal plasma cell proliferation. Their prevalence increases with age. Initially asymptomatic, MPCG can evolve differently and they can tend towards more advanced stages, sometimes associated with severe complications. Most patients are diagnosed by their general practitioner, who then offers a joint follow-up with the specialist. It therefore seems important to review the diagnostic and therapeutic management of MPCG, as well as their potential complications and treatments adverse effects.Les gammapathies monoclonales plasmocytaires (GMP) regroupent plusieurs pathologies secondaires à une anomalie de la prolifération plasmocytaire. Leur prévalence augmente avec l’âge. Initialement asymptomatiques, les GMP ont un potentiel évolutif variable pouvant néanmoins tendre vers des stades plus avancés grevés de complications, parfois sévères. La plupart des patients diagnostiqués le sont par leur médecin de premier recours, qui réalise ensuite souvent un suivi conjoint avec le spécialiste. Il nous semble donc important de parcourir les prises en charge diagnostiques et thérapeutiques des GMP, ainsi que de sensibiliser le lecteur à leurs potentielles complications et aux effets indésirables des traitements.

Monoclonal gammopathy related disorders. The presence of a monoclonal immunoglobulin in serum or urine reflects the existence of an abnormal clone of B cells. In case of large tumor mass, patient need treatment. Sometimes, the clone is nearly undetectable, but gammopathy is associated with complications not directly related to tumor cells but to the presence of the monoclonal immunoglobulin. Most often, lesions result from the deposit of monoclonal immunoglobulin, organized or not. Other mechanisms include autoantibody activity, immune complex formation or deregulation of the complement system. Finally, in some cases, the physiopathology remains to be determined. The downstream complications of gammopathies are protean and can affect various organs, mainly the kidney, the skin and the peripheral nervous system. A delayed diagnosis may be life-threatening or functional. A rigorous clinical examination, and appropriate explorations are therefore necessary in order to put in place a suitable therapy, targeting most often the underlying clone.Manifestations associées aux gammapathies monoclonales. La présence d’une immunoglobuline monoclonale dans le sérum ou l’urine traduit l’existence d’un clone anormal de cellules B. En cas de forte masse tumorale, le problème est celui du traitement. Parfois, le clone n’est pratiquement pas détectable, mais la gammapathie s’associe à des complications non directement liées aux cellules tumorales mais secondaires à la présence de l’immunoglobuline monoclonale. Le plus souvent, les lésions résultent de dépôts de l’immunoglobuline monoclonale, organisés ou non. Les autres mécanismes incluent une activité auto-anticorps, la formation d’immuns complexes ou une dérégulation du système complémentaire. Enfin, dans certains cas, la physiopathologie reste à déterminer. Les complications d’aval des gammapathies sont protéiformes et peuvent toucher divers organes, principalement le rein, la peau et le système nerveux périphérique. Un retard diagnostique peut mettre en jeu le pronostic vital ou fonctionnel. Un examen clinique rigoureux, et des explorations appropriées face à certaines situations sont donc nécessaires afin de mettre en place un traitement adapté, ciblant le plus souvent le clone sous-jacent.

Conduct in case of monoclonal gammapathy ? Monoclonal gammopathies are frequent in general population (about 3 % beyond 50 years) and their prevalence increases with age. They may be associated with malignant haemopathy (multiple myeloma for IgG and IgA, Waldenström disease for IgM). In absence of malignant haemopathy, the diagnosis is that of monoclonal gammopathy of indeterminate significance (MGUS). MGUS accounts for the majority (over 60 %) cases of monoclonal gammopathy. Only patients with multiple myeloma or Waldenström disease require treatment. For MGUS, smoldering myeloma and smoldering Waldenström disease, therapeutic abstention is recommended but regular and prolonged monitoring is necessary given the risk of progression to malignant hemopathy. Given the prevalence of monoclonal gammopathies in general population and the frequency of MGUS, it is rational to limit initial explorations in asymptomatic patients.Conduite à tenir devant une gammapathie monoclonale ? Les gammapathies monoclonales sont fréquentes dans la population générale (environ 3 % au-delà de 50 ans), et leur prévalence augmente avec l’âge. Elles peuvent être révélatrices d’une hémopathie maligne (myélome multiple pour les immunoglobulines [Ig] IgG et IgA, maladie de Waldenström pour les IgM). Lorsqu’une hémopathie maligne est éliminée, le diagnostic retenu est celui de gammapathie monoclonale de signification indéterminée (MGUS). Ces dernières représentent la majorité (plus de 60 %) des cas de gammapathie monoclonale. Seuls les patients ayant un myélome multiple ou une maladie de Waldenström relèvent d’un traitement. Pour les gammapathies monoclonales de signification indéterminée, les myélomes indolents et les maladies de Waldenström indolentes, l’abstention thérapeutique est préconisée, mais une surveillance régulière et prolongée est nécessaire compte tenu du risque de progression vers une hémopathie maligne. En raison de la prévalence des gammapathies monoclonales dans la population générale et de la fréquence de celles de signification indéterminée, il paraît légitime de limiter les explorations initiales chez les patients asymptomatiques.

Monoclonal gammopathy of renal significance. The term "monoclonal gammopathy of renal significance" regroups all renal disorders caused by a monoclonal immunoglobulin (Ig) secreted by a nonmalignant B-cell clone. However, a small clone can synthesize a very toxic protein, producing devastating renal and sometimes systemic damages. The spectrum of renal diseases in MGRS is wide. Renal lesions are classified according to the localization, either glomerular or tubular, and to the pattern of ultrastructural organization of Ig deposits. Physico-chemical characteristics of pathogenic monoclonal Ig are probably involved in their propensity to deposit or precipitate in the kidney, as illustrated by the high rate of recurrence of renal lesions after kidney transplantation if the underlying clone is not suppressed. Early diagnosis and efficient chemotherapy are mandatory to improve renal prognosis and patient survival, particularly in patients with systemic lesions such as AL amyloidosis.Gammapathies monoclonales de signification rénale. Le terme « gammapathie monoclonale de signification rénale » (MGRS) regroupe l’ensemble des néphropathies liées à la toxicité d’une immunoglobuline monoclonale produite par un clone B indolent, de faible malignité hématologique, mais potentiellement dangereux en raison de la toxicité rénale et parfois systémique de l’immunoglobuline sécrétée. Les lésions rénales des MGRS sont très diverses et classées en fonction du type d’atteinte, glomérulaire ou tubulaire, et du caractère organisé ou non des dépôts ou inclusions d’immunoglobulines monoclonales en microscopie électronique. Les caractéristiques physico-chimiques des immunoglobulines monoclonales jouent probablement un rôle majeur dans l’apparition des lésions comme en atteste la récidive du même type de néphropathie après transplantation rénale si le clone sous-jacent n’est pas contrôlé. Le pronostic rénal, et parfois vital lorsqu’il existe des manifestations systémiques comme au cours de l’amylose AL, dépend de la précocité du diagnostic et de la mise en route d’une chimiothérapie efficace pour contrôler rapidement la production de l’immunoglobuline monoclonale.

Renal involvement is common during monoclonal gammopathies and their occurrence impacts the survival of the patients. Our objective was to describe the renal features during monoclonal gammopathies from 2004 to 2016 at the University Hospital of Yopougon in Abidjan.Renal failure was defined as blood creatinine level20 mg/L and/or proteinuria500 mg/24 hours.We identified 42 cases of monoclonal gammopathiesincluding multiple myeloma (n=40) and monoclonal gammopathy of underdetermined significance (n=2). The rate of renal impairment was 57% (n=24) including tubular disease (n=20)and glomerular nephropathy (n=3). Two patients (one with cast nephropathy and another with Randall's disease) performed renal biopsy. The factors associated with renal impairment were mainly hyperuricemia (n=24)and hypercalcemia (n=23). Three cases were treated by hemodialysis. There were 6 (14.3%) deaths among patients with renal impairment.Tubular injury was common among patients with monoclonal gammopathy. It was associated with hypercalcemia and Hyperuricemia.Les atteintes rénales sont fréquentes au cours des gammapathies monoclonales (GM) et leur persistance impacte la survie des patients. Notre objectif était de décrire ces atteintes observées de 2004 à 2016 au CHU de Yopougon à Abidjan.L'atteinte rénale était définie par une créatinine20 mg/l et ou une protéinurie500 mg/24 heures.Nous avons recensé 42 cas de GM dont 40 cas de myélome multiple et 2 cas de gammapathie monoclonale de signification indéterminée. La fréquence de l'atteinte rénale était de 57% (n=24). Il s'agissait de 3 cas de néphropathie glomérulaires et 20 cas d'atteintes tubulaires. Deux patients ont bénéficié d'une ponction biopsie rénale et c'était un cas de tubulopathie myélomateuse, et un cas de maladie de Randall. Les facteurs favorisant l'atteinte rénale étaient dominée par l'hypercalcémie (23 cas) et l'hyperuricémie (24 cas). Trois cas ont été traités par hémodialyse conventionnelle. Il y eu 6 (14,3%) décès parmi les patients ayant l'atteinte rénale.l'atteinte tubulaire est plus fréquente au cours de la gammapathie monoclonale. Elle est favorisée par la prise de toxiques traditionnels, l'hypercalcémie et l'hyperuricémie.

Serum free light chains (sFLC) assay is an important marker in plasma cell dyscrasia. It is thus recommended for the diagnosis of monoclonal gammopathy, together with serum protein electrophoresis and immunofixation. sFLC assay has also a prognostic value and is a criterion for treatment response and relapse of some monoclonal gammopathies. Three assays are currently available in France, the gold standard being the Freelite

Impairment of dermal elastic tissue occurs in different entities associated with immunoglobulins or immunoglobulin-derived protein-secreting clonal plasma cell proliferations, such as amyloid elastosis, anetodermic nodular amyloidosis or monoclonal gammopathy-associated cutis laxa. We report a case of cutaneous immunoglobulinemic amyloidosis revealed by a unique chalazodermic presentation and we review elastic tissue impairment in patients with monoclonal gammopathies.A 67-year-old woman consulted for non-infiltrated anetodermic lesions on the upper left quadrant of her abdomen present for ten years. She also had a chalazodermic plaque with abnormal skin wrinkling and laxity in her right axilla. Biopsies revealed deep dermal and subcutaneous amyloid deposits. Immunohistochemistry with lambda light chain was positive. Orcein staining and electron microscopy showed extensive elastolysis. The patient presented no signs of systemic involvement, but a very small amount of monoclonal IgGλ gammopathy was detected during follow-up.This is a unique chalazodermic presentation of immunoglobulinemic amyloidosis that does not fit into a clearly-defined nosological setting. It highlights the complex interactions between immunoglobulin-derived proteins, including light and heavy chains, and elastic tissue components, leading to different types of impairment of the latter. We therefore suggest the unifying concept of immunoglobulinemic elastopathy, underscoring the need to screen for monoclonal gammopathy in patients presenting elastic tissue impairments.

Beta-blockers are widely prescribed in elderly patients and may induce severe adverse drug reactions. We report a case of bisoprolol-induced bradycardia in an elderly patient with impaired renal function and use of cytochrome P450 inhibitors. A literature review has been performed in order to analyze pharmacokinetic risk factors of beta-blockers overdosing in geriatrics. Various mechanisms can result in decreased elimination of beta-blockers. These mechanisms vary according to the beta-blocker agent and may be combined in some individuals, especially elderly patients. This can lead to unexpected overexposure. Knowledge about drug interactions and pharmacokinetic elimination pathways is important for preventing overexposure and adverse drug reactions when using beta-blockers.

The natural history of orphan lung diseases is often unclear. We report the long-term follow-up of a case of bronchiectasis due to pulmonary non amyloid light chain deposition disease (LCDD).A 50-year-old woman who was a smoker, was diagnosed with diffuse thin walled bronchiectasis of uncertain origin after presenting with a respiratory tract infection. Ten years later, the combination of bronchiectasis, the appearance of pulmonary cysts and the identification of increased kappa free light chains evoked the diagnosis of pulmonary LCDD. The diagnosis was confirmed by lung biopsy. No immunoproliferative disorder was identified. During the 12 years follow-up, dyspnea worsened progressively and bronchiectasis and lung cysts extended leading to multicystic lung disease. Pulmonary function tests did not show any ventilatory defect but a small decrease in carbon monoxide transfer factor occurred.We describe the evolution of a rare presentation of isolated pulmonary LCDD, characterized by cystic diffuse atypical bronchiectasis with thin walls, associated with progressive cystic destruction of the lung parenchyma. The possibility of pulmonary LCDD should be considered in cases of atypical bronchiectasis of unknown etiology.

During the last ten years, significant advances have been made in the field of monoclonal gammopathy-associated renal diseases. These have consisted in a better recognition of their pathological and clinical significations and correlation. Furthermore, therapeutic advances have allowed improving the prognosis of B-cell monoclonal proliferations and of the related renal complications. In the peculiar case of the multiple myeloma with severe renal failure requiring dialysis, one can now expect better survival and chance of recovering renal function.Au cours des dix dernières années, la prise en charge des maladies rénales associées aux gammapathies monoclonales a connu d’importants progrès. Ceux-ci ont consisté en une caractérisation pathologique plus précise des lésions rénales et une meilleure compréhension de leur signification clinique. En parallèle, les progrès thérapeutiques des proliférations monoclonales de la cellule B ont permis d’améliorer le pronostic de celles-ci et des atteintes rénales associées. Dans le cas particulier du myélome multiple, les patients souffrant d’insuffisance rénale sévère peuvent aujourd’hui bénéficier, avec peu de restrictions, de plusieurs nouveaux traitements efficaces. Cela autorise de meilleurs espoirs de survie et de récupération de la fonction rénale.

Acquired C1-esterase inhibitor (C1-INH) deficiency angioedema (C1-INH-AAE) is a form of bradykinin-mediated angioedema. This rare disorder is due to acquired consumption of C1-INH, hyperactivation of the classic pathway of human complement, and potentially fatal recurrent angioedema symptoms. Clinical symptoms of C1-INH-AAE are very similar to those of hereditary angioedema (HAE) but usually appear after the fourth decade of life and induce abdominal pain less frequently. Laboratory tests are essential in establishing the diagnosis with low levels or abnormal structure and function of C1-INH. Most patients present C1-INH autoantibodies. Furthermore, C1q is reduced in AAE, contrary to HAE. The long-term prognosis is determined by associated hematologic malignancies.We report 4 cases of C1-INH-AAE associated with lymphoproliferative disorders referred to the Reference Centre for Angioedema of Besançon, France. The patients were aged between 60 and 77 years. C1 INH antibodies were found in three patients. Symptoms were triggered by angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) in 3 patients. Hematologic malignancy was present at diagnosis (one case of chronic lymphoid leukemia) or was diagnosed during follow-up (one case of indolent marginal zone non-Hodgkin lymphoma and two cases of monoclonal gammopathy).C1-INH-AAE induced by ACE inhibitors or ARBs may be associated with hematologic malignancies. This form of revelation does not necessarily indicate a diagnosis of ACE or ARBs angioedema, and screening should therefore be performed for C1 Inh and C1q. An underlying hematologic malignancy should be routinely sought and the long-term prognosis determined.

Two categories of renal disorders associated with monoclonal gammopathies are to be distinguished, according to the characteristics of the underlying B-cell clone. The first group of renal diseases always occurs in the setting of high tumor mass with production of large amounts of monoclonal immunoglobulins. The main complication is the so-called myeloma cast nephropathy, which almost invariably complicates high tumor mass myeloma. The second group includes all renal disorders caused by a monoclonal immunoglobulin secreted by a nonmalignant B-cell clone, and currently referred as a "monoclonal gammopathy of renal significance (MGRS)". This term was introduced to distinguish monoclonal gammopathies that are responsible for the development of kidney damage from those that are truly benign. The spectrum of renal diseases in MGRS is wide and its classification relies on the localization of renal lesions, either glomerular or tubular, and on the pattern of ultrastructural organization of immunoglobulin deposits. Physicochemical characteristics of the pathogenic monoclonal immunoglobulin are probably involved in their propensity to deposit or precipitate in the kidney, as illustrated by the high rate of recurrence of each specific type after kidney transplantation. Early diagnosis and efficient chemotherapy targeting the causal B-cell clone are mandatory to improve renal prognosis and patient survival.

Monoclonal immunoglobulin (Ig) deposition disease (MIDD) is a rare complication of plasma cell disorders, defined by linear Congo red-negative deposits of monoclonal light chain (LCDD), heavy chain (HCDD) or both (LHCDD) along basement membranes. MIDD should be suspected in patients presenting with glomerular proteinuria and monoclonal gammopathy, but none of these criteria is necessary for the diagnosis although renal involvement is prominent. Since an abnormal serum κ/λ ratio is found in virtually all MIDD patients, including those with HCDD, serum free light chain assay should be included in the initial workup in patients older than 50 presenting with kidney disease. Bortezomib-based regimens are efficient and well tolerated, resulting in improvement in both renal and global survival, comparatively to historical series. High dose melphalan with autologous stem cell transplantation may be proposed as second line therapy in selected patients. The achievement of hematological response, based on the difference between involved and uninvolved serum free light chains (dFLC), is mandatory. In a recent series, post-treatment dFLC40mg/L was the major predictive factor of renal response and was associated with improvement of both renal and global survival. In MIDD, bortezomib-based therapy is safe and efficient when introduced early after diagnosis. dFLC response is a favorable prognostic factor for renal survival.

Skin manifestations associated with monoclonal gammapathy are common and can present with various clinical and pathological aspects. They can be the first events leading to the diagnosis of monoclonal gammapathy. They may be present either as specific lesions, including lymphoplasmacytic or pure plasma cell neoplastic infiltrates and monoclonal immunoglobulin deposits, or as non-specific dermatitis, such as leukocytoclastic vasculitis, neutrophilic dermatoses, mucinoses or xanthomatosis, giving little clues for the diagnosis of the underlying disease.

Paraprotein interferences assays are known but rather unusual in clinical chemistry.we here report a paraprotein interference with a bicarbonate assay in a IgA kappa-type myeloma patient. Serum bicarbonate level was assessed by the enzymatic method of a multiparametric chemistry analyzer (Advia 1800, Siemens) as well as a specific electrode assay on a blood gas analyzer (GEM 4000, IL). Paraprotein interference with the enzymatic assay was evidenced by an abnomally low bicarbonate level measured by the enzymatic method in contrast with usual levels obtained by using the gas analyzer and with the clinical status of the patient. Therefore, gammapathy has to be taken into consideration when interpreting biological data.

National audience; Whatever their aetiology, monoclonal gammopathies can be associated to several clinical features. Mechanisms are various and sometimes unknown. Skin is frequently involved and may represent a challenging diagnosis. Indeed, skin manifestations are either the presenting features and isolated, or at the background of a systemic syndrome. Our objective was to review the various skin manifestations that have been associated with monoclonal gammopathies.

What's new in internal medicine will be dedicated to three topics: i) inflammatory myopathies constituting a heterogenous group of diseases whose clinical manifestations, immunological abnormalities, treatment response and outcomes vary widely; ii) alterations of gut microbiota contributing to the occurrence or development of a range of conditions, including autoimmune diseases for which further work is necessary to understand the correlation of dysbiosis with these diseases; iii) the reciprocal relationship between obesity, metabolic syndrome, atherosclerosis and autoimmune diseases. New data concerning systemic sclerosis, cutaneous vasculitis, adult Still's disease, autoantibodies anti DFS70, Epstein Barr virus and autoimmune diseases were also highlighted.

Monoclonal gammopathy of undetermined significance (MGUS) is a frequent condition affecting at least 3% of the general population over 50 years. Usually, the diagnosis of MGUS is made accidentally during a biological assessment for other conditions. Although MGUS is most frequently a benign and asymptomatic disorder, it has well been described that MGUS could be a premalignant status and that the risk of transformation into myeloma or other lymphoproliferative disorders is estimated at 1% per year. MGUS can also be associated with other diseases than malignant disorders such as Infections, autoimmune diseases. In some case it could reflect rare but severe disorders that will be crucial not to miss the diagnosis.

In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the third annual series of workshops which brought together practitioners from all member centers and took place in October 2012 in Lille. Here we report our results and recommendations regarding the management of common issues related to the donor: pre-transplant pregnancy and monoclonal gammopathy.

Whatever their aetiology, monoclonal gammopathies can be associated to several clinical features. Mechanisms are various and sometimes unknown. Skin is frequently involved and may represent a challenging diagnosis. Indeed, skin manifestations are either the presenting features and isolated, or at the background of a systemic syndrome. Our objective was to review the various skin manifestations that have been associated with monoclonal gammopathies.

Light chain deposition disease is a rare clinical entity characterized by deposition of monoclonal immunoglobulin light chains in organs. The kidneys are almost always affected, while the lung manifestations that have been reported, including nodular or diffuse disease, especially cystic lesions, are unusual.We report the case of a 60-year-old man with a diffuse infiltrative lung disease characterized by numerous apical cysts. The diagnosis of light chain deposition cystic lung disease was obtained by surgical lung biopsy. Light chain deposits in the salivary glands were the only extrapulmonary manifestation. Despite 12 chemotherapy cycles, the patient's lung function and radiological appearances worsened.This is the fourth case describing a cystic lung disease due to light chain deposition in the literature. It highlights the need for comprehensive investigations so as not to miss this rare cause of cystic lung disease, which appears to be related to a primary pulmonary lymphoproliferative disorder. The only treatment that appears to be effective is lung transplantation.

Acquired haemophilia A (AHA) is a rare bleeding disorder, due to the presence of an inhibitor directed against factor VIII (FVIII). About 50% of the AHA are idiopathic, while the remaining 50% are related to an underlying disorder or condition (autoimmune diseases, malignancies, postpartum, etc.).We report on a monocentric retrospective cohort of 39 patients with AHA. Data were collected and compared to recent published data.Thirty-nine patients were admitted for AHA between 1993 et 2011. Mean age at diagnosis was 71.3 years, and we noted a marked male predominance. Although the majority of patients presented a bleeding event at diagnosis (94.9%), the hemorrhagic mortality was low (2.6%). On the contrary, immunosuppressive morbidity and mortality were high in this elderly population. There was a clear correlation between initial FVIII inhibitor titer and complete remission delay. We did not identify prognostic factor for global survival.AHA is a rare but potentially fatal disorder. Rapidity of diagnosis and treatment initiation is crucial. Morbidity and mortality, particularly of infectious cause, due to immunosuppressive treatment, should lead to consider other available therapeutical options.

Cryofibrinogenaemia is an under-recognized cutaneous thrombotic vasculopathy that may be revealed by purpura or chronic necrotic ulcerations. We report two original cases characterized by their severity, their association with a monoclonal gammopathy and their excellent response to treatment.A 38-year-old woman was admitted for large necrotic leg ulcers appearing 1 year earlier and already investigated. Non-specific signs were seen on a previous skin biopsy and the diagnosis of a factitious disorder was considered at that time. Further investigations revealed circulating cryofibrinogen associated with IgG kappa monoclonal gammopathy without cryoglobulinaemia. Plasmapheresis followed by bortezomid-dexamethasone to treat the monoclonal gammopathy resulted in rapid and complete healing of the ulcers, militating in favour of its involvement in cryofibrinogen formation. The second patient, a 91-year-old woman, was referred to our department for acute necrotic purpura of the legs. Skin biopsy revealed leukocytoclastic vasculitis. Glomerular nephropathy with acute renal failure and multiple arterial thromboses were associated with the skin condition. The cryofibrinogen assay was positive without cryoglobulinaemia and other causes of vasculitis were ruled out. The main component was monoclonal IgG lambda. Prednisone-cyclophosphamide treatment led to complete healing of the skin lesions and to recovery from the systemic consequences of cryofibrinogen without sequelae.Routine screening for cryofibrinogen in plasma should be performed to explore cutaneous symptoms of unexplained thrombotic vasculopathy, even in the presence of a non-specific skin biopsy. Specific treatment of cryofibrinogenaemia associated monoclonal gammopathy appears to be highly effective against manifestations of cryofibrinogenaemia.

Schnitzler syndrome (SS) is a rare clinical entity, which belongs to the spectrum of monoclonal gammapathy-associated systemic disorders. Its pathophysiology remains elusive, even if it is tempting to consider it as a late onset and probably acquired auto-inflammatory syndrome. SS mainly occurs in the fifth and sixth decade, and present with an urticariform rash with periodic fever and/or osteoarticular pain. Systemic inflammation and monoclonal gammapathy (overwhelmingly IgM kappa) are constant features. SS is a chronic disease, which can severely impair quality of life of the affected individuals. Many drugs have been used and proved disappointing. In the last few years, accumulating reports provided evidence for the dramatic efficacy of anakinra, which has revolutionized the management of most severe cases. The main long-term threat to these patients is to develop a lymphoproliferative disorder (mainly Waldenström's macroglobulinemia). The mechanisms underlying the different facets of the disease remain to be elucidated.

Monoclonal IgM anti-MAG associated peripheral neuropathies are part of demyelinating dysimmune peripheral neuropathies. The hematological disease probably does not influence the outcome of the neuropathy. Neuropathies associated with IgM anti-MAG antibodies are predominantly sensory and distal polyneuropathies associated with ataxia, unsteadiness and tremor. The neurophysiological features include a symmetric sensorimotor demyelinating neuropathy with more slowing of conduction in the distal than in the proximal nerve segments, a length-dependence, and a variable degree of denervation. High titers of IgM anti-MAG antibodies confirm the diagnosis. The natural history is mostly slow with mild to moderate functional impairment. However, some patients have a faster evolution associated with a more severe handicap. Immunotherapies studies have failed to demonstrate significant efficacy of these treatments. Furthermore, severe adverse effects are not uncommon with any of these therapies. Thus, the risk of possible severe adverse effects must be balanced against any possible benefits. More research is needed to improve the management of anti-MAG neuropathies: research on treatment, on prognostic factors, and development of specific assessment scales adapted to the particularities of anti-MAG neuropathies.

International audience; Various renal disorders are associated with monoclonal gammopathies, secondary to tissue deposition or precipitation of a monoclonal immunoglobulin (Ig) or a fragment thereof (isolated Ig light chain or heavy chain). They are classified according to the localization of renal lesions, either glomerular or tubular and to the pattern of ultrastructural organization of Ig deposits. Renal disease in monoclonal gammopathies may be isolated, or associated with various systemic symptoms particularly in AL amyloidosis, Randall-type monoclonal Ig deposition disease and monoclonal cryoglobulinemias. Except for myeloma cast nephropathy, which occurs in the setting of high-mass myeloma and is recognized after electrophoretic analysis of proteinuria and AL amyloidosis, which diagnosis is usually made after pathological examination of non-invasive tissue specimens (i.e. abdominal fat or minor salivary glands), a kidney biopsy is required to identify the other types of renal disorders associated with monoclonal gammopathies and to estimate renal prognosis. Renal pathological diagnosis is difficult and relies on careful examination of kidney biopsy samples, by light microscopy, immunofluorescence studies using conjugates specific for Ig light and heavy chains, IgG sub-classes and heavy chain constant domains and by electron microscopy. In some cases, additional studies are required to identify the nature of deposits, such as immuno-electron microscopy or mass spectrometric-based proteomic analysis after laser dissection. In patients with renal disorders related to Ig light chain precipitation or deposition (myeloma cast nephropathy, AL amyloidosis, Randall-type light chain deposition disease), measurement of serum free light chains at baseline and throughout follow-up is mandatory to evaluate clonal response to chemotherapy. A more than or equal to 50% decrease in serum free light chain levels is associated with increased renal and patient survival. In AL amyloidosis, serum levels of markers of cardiac disease (NT-proBNP and troponin) are also closely associated with prognosis. Efficient chemotherapy, tailored to the underlying plasma cell or lymphoproliferative disorder and adapted to renal function, should be promptly introduced, even in the absence of overt malignant haematological disease. Renal prognosis and patient survival (particularly in AL amyloidosis and cast nephropathy) are closely associated with the rapid achievement of an haematological response. The combination of melphalan plus dexamethasone (MDex) is currently used as first-line chemotherapy in systemic AL amyloidosis. Bortezomib-based regimens are commonly employed as first-line treatment in myeloma cast nephropathy and Randall-type monoclonal Ig deposition disease and as second line therapy in AL amyloidosis patients with advanced cardiomyopathy or refractory to previous chemotherapy. Solid organ transplantation (heart and kidney) should be considered in patients with AL amyloidosis or Randall-type monoclonal Ig deposition disease and advanced cardiac or renal failure. Prolonged graft and patient survival may be obtained, providing that recipients do not have other severe organ involvement or symptomatic myeloma and that haematological remission has been achieved with chemotherapy before or after organ transplantation.

International audience; Systemic AL amyloidosis is a rare complication of monoclonal gammopathies. Renal manifestations are frequent, mostly characterized by heavy proteinuria, with nephrotic syndrome and renal failure in more than half of the patients at diagnosis. Without treatment, median survival does not exceed 12 months. Amyloid heart disease and diffusion of amyloid deposits are associated with reduced survival. Treatment of systemic AL amyloidosis has been profoundly modified with the introduction of international criteria for the definition of organ involvement and hematologic response, and with the use of sensitive tests for the measurement of serum-free light chain levels. Melphalan plus dexamethasone is now established as the gold standard for first line treatment of systemic AL, with similar efficacy and reduced treatment-related mortality compared to high-dose therapy. Modern chemotherapy regimens, based on the use of novel agents such as bortezomib and lenalidomide, might further improve patient survival.

Papular mucinosis is characterized by primary reticular dermal mucin deposition in the absence of any thyroid abnormalities. There is extensive clinical variety in this disease, from benign localized forms to generalized forms, on occasion lethal. The current classification was established in 1991 in order to allow identification of these generalized forms of the disease and help ensure a better therapeutic approach. We report the case of a patient with atypical papular mucinosis having initial histological features consistent with granuloma annulare.A 55-year-old man consulted for a papular eruption of the hands. A diagnosis of granuloma annulare was initially made because of misleading histological findings. However, the eruption spread to the inner thighs and the hypogastric area despite dermocorticoid therapy. Laboratory evaluation showed a monoclonal gammopathy. Further biopsies revealed diffuse dermal mucin deposits. We finally concluded on atypical localized papular mucinosis.Papular mucinosis is a rare disease and its physiopathology remains to be elucidated. The diagnostic criteria are sometimes inadequate, and its classification includes both atypical and intermediate forms. Our case belongs to the latter class because of its extensive and unusual topography, and its association with a monoclonal gammopathy. Although granuloma annulare is not a classical differential diagnosis, two other cases with similar histological findings have already been published.

Paraproteinaemia is frequent in the population above 50 years of age. It is commonly associated in patients with multiple myeloma with diverse renal involvements, such as cast nephropathy, light chain deposition disease, amyloidosis and Fanconi syndrome. A rapid diagnosis is necessary to implement a specific and aggressive treatment in order to prevent development of end-stage renal disease. Plasma exchanges or daily dialysis with high-cut off filter associated with chemotherapy may decrease the plasmatic concentration and production of monoclonal light chains. Bortezomib, thalidomide and lenalidomide are promising therapeutic agents, whose effects in patients with myeloma-associated renal diseases should be more thoroughly studied. Autologous hematopoietic cell transplantation remains the standard of care treatment for eligible patients.

scleromyxoedema is characterized by dermal mucin deposition associated with a monoclonal gammopathy. This is a rare disease, mostly reported as isolated cases. There is limited data regarding the course and prognosis of the disease. The aim of this study was to determine the clinical characteristics and course of scleromyxoedema.this was a retrospective study in patients from five French university hospitals between 1987 and 2007. Data were collected using a standardized questionnaire. The inclusion criteria were based on the disease diagnosis criteria proposed by Rongioletti and Rebora: (1) generalized, papular and sclerodermiform skin eruption, (2) mucin deposition in the dermis, fibroblastic proliferation and skin fibrosis, (3) presence of a monoclonal gammopathy, (4) absence of thyroid disease.eight patients were included. The mean age at disease onset was 51.5 years (range: 35-67). The mean time from primary symptoms and diagnosis was 41.6 months (range: 4-120). Seven patients had extra-cutaneous involvement: four with peripheral neuropathy and three with interstitial pneumonia. The mean follow-up time was 9 years. Four patients improved: two experienced partial remission and two complete remission. Complete remission was obtained under treatment with dexamethasone (one patient) and thalidomide (one patient). One patient presented a myeloma and one patient presented encephalopathy leading to death.our study shows the frequency of extra-cutaneous involvement and shows that complete remission occurs in some patients.

Monoclonal gammapathy (MG) affects about 1% of the general population, and its prevalence is higher in elderly subjects. Monoclonal gammapathy of undetermined significance (MGUS), the most common disorder, is asymptomatic and associated with normal hemoglobin, calcium and creatinine levels and a monoclonal component of less than 15 g/l. A B cell neoplasm should be suspected in patients with clinical manifestations and/or abnormal hemoglobin, calcium or creatinine levels, and/or a monoclonal component15 g/l. Multiple myeloma tends to be associated with IgG or IgA MG, and Waldenstrom's macroglobulinemia with IgM MG Patients with MGUS do not need treatment but only yearly follow-up (symptoms, protein electrophoresis, hemoglobin, calcium and creatinine assay), as the estimated annual risk of malignant transformation is about 1 %. Factors predictive of malignant transformation include the type of serum monoclonal protein, the monoclonal protein concentration, bone marrow plasmocytosis, and the serum free light chain ratio.

acroglobulinemia, AL amyloidosis and the POEMS syndrome. The hematologist must characterize the hematological disorder, evaluate the need for treatment, and choose the best treatment option. The neurologist must define the type of neuropathy and evaluate the relationship between the abnormal immunoglobulin and the peripheral neuropathy. Thus, close co-operation between the hematologist and neurologist is necessary when a patient presents with both monoclonal immunoglobulin and peripheral neuropathy.

Since the first report of a high prevalence of monoclonal gammapathy (MG) in patients with peripheral neuropathy (PN), some 25 years ago, a large number of such associations have been described. Neuropathies associated with MG have heterogeneous clinical, neurophysiological, neuropathological, and hematological features. The most pertinent relationship seems to be that between distal acquired demyelinating sensory (DADS) neuropathy associated with IgM MG of unknown significance (MGUS) and the presence of serum autoantibodies reacting with myelin-associated glycoprotein (MAG). Other interesting correlations were recently reported in CANOMAD (chronic ataxic neuropathy with ophthalmoplegia, M-protein and anti-disialosyl antibodies). Patients with demyelinating neuropathy (DNP) associated with MG should be screened for malignant plasma cell dyscrasia. MG is more likely to be responsible for the neuropathy if it consists of IgM, if autoantibodies (mainly directed to MAG) are found in serum or on nerve biopsy, and if the clinical manifestations correspond to chronic distal sensory neuropathy. DNP associated with IgM MGUS sometimes responds to immunotherapy but the potential benefits must be considered in view of possible adverse effects. Rituximab, an anti-CD20 monoclonal antibody, has shown promise in this setting. DNP associated with IgG or IgA MGUS may be indistinguishable from chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), in terms of clinical and electrophysiological features and the treatment response. In the POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes), appropriate treatment can lead to a drastic improvement in the neuropathy. Patients with chronic axonal polyneuropathy associated with IgG MG should be screened for Al amyloidosis. However, most axonal polyneuropathies associated with IgG or IgM MGUS are indistinguishable from chronic idiopathic axonal polyneuropathies.

We relate three cases of IgM gammopathy with haemostatic dysfunction in the perioperative period. The acquired von Willebrand syndrome due to IgM gammopathy is rare and sometimes serious. Its different treatments and their efficiency are discussed: desmopressin, intravenous gammaglobulin, chemotherapy and plasmapheresis.

Scleromyxoedema is a rare disorder of unknown pathogenesis that is very difficult to treat. We report a case resistant to corticosteroid treatment but controlled by intravenous gammaglobulin (IVIG).A 60-year-old woman presented progressive generalized papular eruption with infiltrated and itchy lesions of between 2 and 5mm in diameter. Otherwise, the clinical examination was normal. Monoclonal gammopathy of the IgG lambda type was found. Histology confirmed the diagnosis of scleromyxoedema. The disease continued to progress despite oral corticosteroids (0.5mg/kg per day). Thalidomide was introduced but was discontinued after 2 months due to side effects. Treatment comprising six monthly infusions of IVIG (2g/kg on 5 days) resulted in a marked reduction (50%) in lesions. Two months after discontinuation of IVIG, recurrence was observed and maintenance infusions of IVIG every 6 weeks were needed to control the disease.The course of scleromyxoedema is unpredictable and treatment is extremely difficult. Successful therapy with IGIV has been reported but this approach seems to afford only temporary relief and maintenance infusions are required, as confirmed by the initial efficacy of treatment in our patient and the rapid recurrence of lesions following withdrawal.

International audience; INTRODUCTION: Light chain deposition disease is a systemic disorder characterised by tissue deposition of monoclonal immunoglobulin light chains without tinctorial properties. It has been exceptionally reported with salivary involvement mimicking Sjögren's syndrome and peripheral neuropathy. CASE REPORT: We report a case of light chain deposition disease associated with plasma cell dyscrasia presenting as sicca syndrome with salivary glands hypertrophy and polyneuropathy successfully treated by high dose melphalan and autologous blood stem transplantation. CONCLUSION: Light chain deposition disease should be recognized as an aetiology of sicca syndrome and peripheral neuropathy. Further studies should assess the prevalence of sicca syndrome in light chain deposition disease and better characterise the neurological manifestations.

Acquired von Willebrand syndrome is a rare bleeding disorder, which has been related in various diseases including lymphoproliferative disorders or autoimmune diseases. Its diagnosis is an important step before treatment of patients and particularly in case of bleeding. We report four cases from Caen Hemophilia Treatment Center, diagnosed and treated from 1999 to 2008. Mucocutaneous bleeds in every case were the same as in hereditary von Willebrand disease. All patients had no personal or family history of bleeding. Phenotype was identified as type 2 von Willebrand disease with a loss of high molecular weight multimers. Anti-von Willebrand factor inhibitor screening was positive for three patients. The etiological diagnosis was one chronic lymphocytic leukaemia, two monoclonal gammapathies of undetermined significance (MGUS) and one undetermined case. The management of patients need two stages: first infusions of factor von Willebrand/factor VIII concentrates to stop bleeds, then treatment of the underlying disease such as chemotherapy, corticotherapy and treatment with high doses of polyvalents immunoglobulins. In every case, treatment was effective and improved patient's quality of life.

Polyneuropathies associated with IgM paraproteinemia and anti-myelin associated glycoprotein (MAG) antibodies (MAG-PN) have to be differentiated from chronic inflammatory demyelinating polyneuropathies.In a retrospective study, we have analyzed clinical, electrophysiological, biological and pathological data from MAG-PN patients.Seven male and six female patients were followed in the department for a mean 2 years (0.5-6.5 years). Mean age at diagnosis was 61 years (44.5-85.5 years). Patients had symmetrical bilateral paresthesia (11/13) and hypoesthesia (11/13) prominent in the lower limbs. Nine patients developed gait ataxia and four patients had moderate distal weakness in the lower limbs. Mean Overall Neuropathy Limitation Scale was 2.3 (0-5). Nerve conduction study showed demyelinating features though delayed distal motor latency on median (206 % of normal value) and ulnar nerves (150% of normal value). Seven out of thirteen patients had at least two nerves with terminal latency index below 0.25. IgM paraproteinemia was of undetermined significance in ten cases and three patients had non-Hodgkin lymphoma. IgM deposits and widening of the peripheral myelin were observed in 5/7 sural nerve biopsies. Anti-MAG antibodies were detected in the sera of all patients using enzyme-linked immunosorbent assay and in 8/12 patients using western blot analysis.MAG-PN have distinctive clinical, electrophysiological and pathological features. It is a chronic, slowly progressive, predominantly sensory and ataxic neuropathy. Disability is usually moderate. Electrophysiological study shows distal demyelinating process and is highly suggestive of MAG-PN in more than one half of our patients. Several techniques may detect anti-MAG antibodies, they have to be associated to improve sensitivity and specificity of the test.

The PNS Euronet group criteria have classified paraneoplastic peripheral neuropathies as definite or possible according as to whether the neuropathy is a classical paraneoplastic disorder, the presence of onconeural antibodies, the delay between tumor and neuropathy, and improvement of the neuropathy with tumor treatment. Denny Brown's subacute sensory neuronopathy and neuropathies with anti-Hu or anti-CV2 antibodies are definite paraneoplastic disorders. Possible paraneoplastic neuropathies are heterogeneous. This classification is useful for the diagnostic of these disorders and the selection of patients in whom a search for cancer is warranted.

Systemic amyloidosis usually does not spare the digestive tract but its involvement is rarely symptomatic. The clinical manifestations are not specific. We report a 64-year-old patient, presenting with a weight loss related to an AL amyloidosis. The amyloidosis was apparently limited to the digestive tract. We discuss the various presentations of the digestive amyloidosis and we insist on the seriousness of this localization.

Monoclonal gammapathy of undetermined significance (MGUS) has rarely been reported in African literature. The purpose of this article is to describe 3 cases of MGUS observed in women aged 63, 54, and 44 years in Senegal. All three patients had previously documented autoimmune disease, i.e., auto-immune thrombopenia, multiple auto-immune disease (comprising Sjögren's syndrome, polymyositis and vitiligo), and Sjögren's syndrome. Diagnosis of MGUS was made thanks to routine protein electrophoresis that demonstrated a monoclonal peak in the gammaglobulin area in all patients. Serum protein binding showed the IgG lambda subtype in one case and IgG kappa subtype in two cases. Medullogram findings were unremarkable with nondystrophic plasma cell rates ranging from 1 to 4%. Bisphophonate therapy was undertaken along with the recommended treatments for the associated autoimmune diseases, i.e., prednisone, hydroxychloroquine, and methotrexate. Treatment was successful in all three patients with stabilization of the associated diseases and of the monoclonal peak on subsequent electrophoresis. As of this writing, the mean duration of follow-up was 3 years. MGUS that has been uncommon in the African hospital setting should be screened for in all older patients or in patients presenting infection (especially due to virus) or autoimmune disease (as in the three cases presented herein). More systematic use of serum protein electrophoresis should reveal an increased incidence of MGUS. Diagnosis of MGUS requires regular clinical and laboratory surveillance due to the risk for complications of malignant hemopathies, especially multiple myeloma.

Monoclonal free light chains are found in the serum and urine of patients with B-cell proliferative disorders, including multiple myeloma. Measuring free light chains in serum is useful for the diagnosis and monitoring of free light chains diseases. Moreover it could be interesting in the monitoring of treated multiple myeloma with complete immunoglobulin and of monoclonal gammapathy of undetermined significance (MGUS). The goal of our work was to analyze a large cohort of patients with multiple myeloma or MGUS from January 2003 to August 2006 in order to better understand the interest of free light chains.