Genetic factors contributing to late adverse musculoskeletal effects in childhood acute lymphoblastic leukemia survivors.

BACKGROUND: A substantial number of survivors of childhood acute lymphoblastic leukemia (ALL) suffer from treatment-related late adverse effects. While multiple studies have identified the effects of chemotherapeutics and radiation therapy on musculoskeletal outcomes, few have investigated their associations with genetic factors. METHODS: Here we analyzed musculoskeletal complications in relation to common and rare genetic variants derived through whole-exome sequencing of the PETALE cohort. Top-ranking associations were further assessed through stratified and multivariate analyses. RESULTS: DUOX2 variant was associated with skeletal muscle function deficit, as defined by peak muscle power Z score ≤ -2 SD (P = 4.5 × 10-5 for genotyping model). Upon risk stratification analysis, common variants in the APOL3, COL12A1, and LY75 genes were associated with Z score ≤ -2 SD at the cross-sectional area (CSA) at 4% radial length and lumbar bone mineral density (BMD) in high-risk patients (P ≤ 0.01). The modulation of the effect by risk group was driven by the interaction of the genotype with cumulative glucocorticoid dose. Identified variants remained significant throughout multivariate analyses incorporating non-genetic factors of the studied cohort. CONCLUSION: This exploratory study identified novel genetic variants associated with long-term musculoskeletal impairments in childhood ALL survivors. Replication in an independent cohort is needed to confirm the association found in this study.

[Retroperitoneal fibrosis in adults: Diagnostic approach based on a retrospective multicenter study on 32 cases]. / Fibrose rétropéritonéale de l'adulte : approche diagnostique à partir d'une série rétrospective multicentrique de 32 cas.

INTRODUCTION: Retroperitoneal fibrosis is a rare disease, typically with an insidious and various clinical course. The peak incidence is seen in patients 40 to 60 years of age and mostly in man. The characteristic finding in this disease is a periaortic fibrous mass that often surrounds the ureters. The diagnostic approach remains uncodified. We aimed to determine the different clinical, radiological and biological aspects of retroperitoneal fibrosis. PATIENTS AND METHODS: Retrospective multicenter study of 32 retroperitoneal fibrosis cases hospitalized between 1999 and 2014 in the Internal Medicine Department and Urology Department in the university hospital center Sahloul Sousse. RESULTS: There were 24 men and 8 women with a mean age of 58 years. The lumbar pain is the most common clinical signs (53.1%). An inflammatory syndrome and renal failure were the most common biological signs. The diagnosis was suspected on data from the abdominal ultrasound and confirmed by pelvic CT scan that showed a periaortic fibrous mass that often surrounds the ureters. Histological analysis of a surgical biopsy specimen was performed in only eight cases. CONCLUSION: The most common mode of presentation of retroperitoneal fibrosis remains lumbar pain with renal failure and a high sedimentation rate. Although abdominal ultrasound may contribute to the general evaluation of patients with retroperitoneal fibrosis, CT-scanner is the preferred imaging method. The imaging capability of magnetic resonance and the TEP-scan may facilitate assessment of disease extent. LEVEL OF EVIDENCE: 4.

[Unexplained diffuse arteriosclerosis in a 26-year-old patient]. / Artériosclérose diffuse inexpliquée chez une jeune patiente de 26 ans.

Arteriosclerosis is an alteration of the blood vessels whose walls calcify, lose their elasticity and thicken. The result is a decrease in circulating blood flow and ischemic manifestations. Calcification of the arteries is a physiological phenomenon in the elderly but young subjects may also be affected. Indeed, certain risk factors can favor the formation of plaques at the level of the vessels. These include classic cardiovascular risk factors, as well as systemic inflammatory diseases, connective tissue diseases, chronic hypercalcemia… We report the case of a 26-year-old female patient with diffuse arteriosclerosis discovered accidentally, and whose exhaustive etiological investigation remained negative.

[Seizures in patients with systemic lupus erythematosus]. / Lupus érythémateux systémique et épilepsies.

Seizures are one of the most serious neuropsychiatric manifestations of systemic lupus erythematous (SLE). This descriptive and retrospective study aims at describing clinical and paraclinical features and therapeutic approach of seizures in patients with SLE. The characteristics of the seizure group was compared to those of a control group (patients with LES who had not presented seizures). A total of 177 patients were included in these analyses. Among them, 14 (8 %) developed seizures before, at or after the SLE diagnosis. The age of occurrence of seizures was younger than for other complications of the disease. There was no significant association with the antiphospholipid syndrome. Disease activity in these patients was significantly higher than in the control group. During the follow up, the subjects being under anticonvulsants and/or corticosteroids and/or immunosuppressive therapy, we observed good outcomes (n=5), re-occurence of seizures (n=4), cognitive impairment (n=3 ) and death (n=2). Our study shows that seizures tend to occur early in the course of SLE, in the context of important disease activity and other serious clinical manifestations and in younger individuals. Seizures portend a negative impact on the overall long-term prognosis and quality of life in patients with SLE.

La comitialité est une des manifestations neurologiques les plus sévères du lupus érythémateux systémique (LES). Notre objectif est de décrire les caractéristiques des épilepsies chez les patients lupiques. Dans une étude rétrospective descriptive, les données cliniques et paracliniques des patients lupiques présentant une épilepsie ont été comparées à celles des patients lupiques n'ayant pas présenté de crises convulsives. Nous avons recensé 177 patients lupiques dont 14 (8 %) avaient présenté une épilepsie avant, au moment ou après le diagnostic de LES. L'âge de survenue des épilepsies était plus jeune que celui des autres manifestations. L'association à un syndrome des antiphospholipides n'était pas significative. Les patients lupiques présentant une épilepsie avaient un score d'activité de la maladie lupique (SLEDAI) significativement plus élevé que celui du groupe contrôle. L'évolution était marquée par la disparition des crises convulsives (n=5), la récidive (n=4), l'installation de troubles cognitifs (n=3 ) et le décès (n=2). Cette étude montre que la comitialité tend à survenir de façon précoce au cours du LES, aggravant alors le pronostic fonctionnel et vital. Elle associe un SLEDAI assez élevé ainsi qu'un âge de survenue plus jeune.

Polymorphisms of ABCC5 and NOS3 genes influence doxorubicin cardiotoxicity in survivors of childhood acute lymphoblastic leukemia.

Anthracyclines are efficient chemotherapy agents. However, their use is limited by anthracycline-induced cardiotoxicity (CT). We investigated the influence of polymorphisms in doxorubicin metabolic and functional pathways on late-onset CT as estimated by echocardiography in 251 childhood acute lymphoblastic leukemia (cALL) patients. Association analyses revealed a modulating effect of two variants: A-1629 T in ABCC5, an ATP-binding cassette transporter, and G894T in the NOS3 endothelial nitric oxide synthase gene. Individuals with the ABCC5 TT-1629 genotype had an average of 8-12% reduction of ejection (EF) and shortening fractions (SF; EF: P<0.0001, and SF: P=0.001, respectively). A protective effect of the NOS3 TT894 genotype on EF was seen in high-risk patients (P=0.02), especially in those who did not receive dexrazoxane (P=0.002). Analysis of an additional cohort of 44 cALL patients replicated the ABCC5 association but was underpowered for NOS3. In summary, we identified two biomarkers that may contribute to cALL anthracycline CT risk stratification.

[Vertebral primary malignant germ cell tumor of thoracic spine: an exceptional observation]. / Tumeur germinale primitive à localisation vertébrale dorsale chez un adulte : une observation exceptionnelle.

Vertebral primary malignant germ cell tumors are rarely located in thoracic spine. We report the case of a 44-year-old female, in which a symptomatology including dorsal rachidial pain, intercostal neuralgia, straight and transit disorder revealed a thoracic vertebral primary malignant germ cell tumor. The sole location of a vertebral primary malignant germ cell tumor in adult, exceptionally reported in the literature, prompted us to relate this observation.

[Lupus hepatitis: a case series of 12 patients]. / Hépatite lupique: une série de 12 patients.

PURPOSE: Several liver manifestations have been reported in systemic lupus erythematosus (SLE) and are usually non specific. We report on our experience of lupus hepatitis. METHODS: A retrospective monocenter study of 73 patients with SLE. The diagnosis of lupus hepatitis was established after exclusion of other causes of hepatitis and hepatic vein thrombosis. RESULTS: Liver involvement was noted in 12 patients (16.4%). There were nine female and three male patients; the mean age of these patients was 29 years. In seven patients liver involvement was concurrent with the diagnosis of SLE and it occurred later during an exacerbation of the disease in the five remaining patients. In all patients, liver manifestations were associated with other organ involvement. Clinical manifestations were: hepatomegaly (n=4), jaundice (n=4), abdominal pain (n=3), ascites (n=2), portal hypertension (n=1) and hepatic failure with encephalopathy (n=1). Elevated liver enzyme was noted in 11 cases and liver cholestasis in eight cases. Presence of anti-ribosomal P antibodies was noted in one case. Liver biopsy was performed in five patients, and revealed chronic active hepatitis in three cases, chronic hepatic granulomas in one case and nonspecific inflammation in one case. The outcome was favorable in 11 patients without relapse, and one patient died of encephalopathy and liver failure. CONCLUSION: Liver involvement associated with SLE is not uncommon. It is frequently asymptomatic and limited to liver test abnormalities. The role of anti-ribosomal P autoantibodies remains uncertain.

[Takayasu's disease in central Tunisia: 27 cases]. / La maladie de Takayasu dans la région centre de la Tunisie. A propos de 27 cas.

BACKGROUND: Takayasu's arteritis is a rare inflammatory disease and few data are available in Tunisia. The aim of this study is to evaluate clinical and radiological features of the disease in the centre of Tunisia. METHODS: We retrospectively studied medical records of patients treated in departments of internal medicine or cardiology from three university hospitals in Sousse and Monastir over the period 1985-2005. The criteria for inclusion were those proposed by the American College of Rheumatology. RESULTS: Twenty-seven patients were identified. The mean age at presentation was 33.2 years (range 16-68 years) and 88.9% were female. The mean delay from the onset of the symptoms to the time of diagnosis was 4.2 years. Intermittent claudication was the most common presentation (81.5%) and hypertension was noted in 40.7% of cases. Arterial localization most frequently involved was subclavian artery. The aorta was involved in 52.3% and renal arteries in 36.3% of cases. Stenosis or occlusions was constant but aneurysms were noted in 7.4%. Functional difficulty was the main complaint in the follow-up, death related to Takayasu's disease was noted in 3.7%. The mean follow-up time was 75.8 months (6.3 years). CONCLUSION: There is no epidemiologic particularity of Takayasu's disease in Tunisia, however involvement of the subclavian artery was more frequent than the aortic localization.