Bone Status According to Neurofibromatosis Type 1 Phenotype: A Descriptive Study of 60 Women in France.

There is an increased risk of osteoporosis and an abnormal bone turn over in neurofibromatosis 1 (NF1). Our objective is to evaluate bone status in NF1 and to look for associations with cutaneous phenotype. We conducted a descriptive, monocentric study. We included 60 NF1 women, 18-51 years old, non-menopausal, divided in 2 groups: «at risk phenotype¼ (ARP) composed by 30 patients with at least 2 subcutaneous neurofibromas (SC-NF) and «classical phenotype¼ (CP) composed by 30 patients with none or 1 SC-NF. We evaluated low bone mineral density (BMD) risk factors and measured BMD, calcium and phosphorus homeostasis and bone turnover markers. Before 50 years old, Z-score has to be used to assess BMD. Z-score < - 2 is below expected range and represents 2.5% of the population. There was no difference between the two groups. Overall, Z-scores were low and 5 patients had a Z-score < - 2 (8.3%), which is 3 times general population low BMD frequency. 10 fragility fractures occurred in 8 patients, among which 2 were vertebral fractures. 85% had low calcium intake. 12 patients had hypophosphoremia, 25 elevated PTH. Vitamin D levels were low for 86.4%. 41 patients (69.5%) had at least one abnormal bone turnover markers. Low BMD is 3.3 times more frequent in NF1 than in general population, with high fracture risk, regardless of the skin phenotype, classical or at risk, because of high bone turn over and secondary hyperparathyroidism due to vitamin D deficiency and poor calcium intake.

Severe cutaneous adverse reactions to drugs.

During the past decade, major advances have been made in the accurate diagnosis of severe cutaneous adverse reactions (SCARs) to drugs, management of their manifestations, and identification of their pathogenetic mechanisms and at-risk populations. Early recognition and diagnosis of SCARs are key in the identification of culprit drugs. SCARS are potentially life threatening, and associated with various clinical patterns and morbidity during the acute stage of Stevens-Johnson syndrome and toxic epidermal necrolysis, drug reactions with eosinophilia and systemic symptoms, and acute generalised exanthematous pustulosis. Early drug withdrawal is mandatory in all SCARs. Physicians' knowledge is essential to the improvement of diagnosis and management, and in the limitation and prevention of long-term sequelae. This Seminar provides the tools to help physicians in their clinical approach and investigations of SCARs.

Ischemic myopathy revealing systemic calciphylaxis.

INTRODUCTION: Patients with renal failure who are being treated with dialysis frequently develop neuromuscular manifestations. Renal failure-associated calciphylaxis, also termed calcific uremic arteriolopathy (CUA), is a life-threatening condition usually observed in patients with end-stage renal disease on chronic dialysis or after renal transplantation. METHODS: We describe a hemodialyzed patient who presented with rapidly progressive unexplained systemic vasculopathy, muscle atrophy, and proximal weakness, that unexpectedly proved to be caused by calciphylaxis. RESULTS: Quadriceps muscle biopsy disclosed diffuse vascular calcific deposits on medium- and small-sized vessels, characteristic of CUA. Other changes included ischemic myopathy, focal intracellular calcium accumulation within myofibers, and calcium deposits in endomysial capillaries associated with marked complement activation and C5b9 formation. CONCLUSION: There are only a few descriptions of muscle involvement in the context of CUA, a condition with a prognosis that depends on early diagnosis and treatment. This report underscores the usefulness of muscle biopsy in the diagnosis of systemic calciphylaxis. Muscle Nerve 56: 529-533, 2017.

Patch testing in non-immediate cutaneous adverse drug reactions: value of extemporaneous patch tests.

BACKGROUND: Patch testing following a standardized protocol is reliable for identifying the culprit drug in cutaneous adverse drug reactions (CADRs). However, these patch tests (PTs) require pharmaceutical material and staff, which are not always easily available. OBJECTIVES: To evaluate an extemporaneous PT method in CADRs. METHODS: We retrospectively analysed data for all patients referred to our department between March 2009 and June 2013 for patch testing after a non-immediate CADR. The patients who supplied their own suspected drugs were tested both with extemporaneous PTs and with conventional PTs. Extemporaneous PTs involved a nurse crushing and diluting the drug in pet. in a ratio of approximately one-third to two-thirds. Standardized PTs were performed according to guidelines, with commercial drugs diluted to 30% or with active ingredients diluted to 10%. We analysed the data for the two PT methods in terms of the number of positive test reactions, drugs tested, and type of CADR for patients in whom the two PT methods were used. RESULTS: In total, 75 of 156 patients underwent the two PT procedures, including 91 double tests. Overall, 21 tests gave positive reactions with the two methods, and 69 other tests gave negative results with the two methods. CONCLUSION: Our series yielded results similar to those of published series concerning the types of CADR and the drugs responsible. Our results suggest that, for CADRs, if a patient supplies a suspected drug but if the pharmaceutical material and staff are not available for conventional PTs, extemporaneous PTs performed by the nurse with the commercial drug used by the patient can be useful and reliable.

Facial Scars following Toxic Epidermal Necrolysis: Role of Adnexal Involvement?

Toxic epidermal necrolysis (TEN) is a severe cutaneous adverse drug reaction leading to extensive sloughing of the skin. Late cutaneous complications such as pigmentation disorders are frequently reported. In this report, we present particular facial cutaneous sequelae with histological analysis after TEN. Two young patients who had survived TEN presented permanent multiple hypopigmented papules on the face affecting their quality of life. Histological analysis revealed areas of scarring, dystrophic microcalcifications and sebaceous hyperplasia. Late cutaneous sequelae are well documented; however, the physiopathological mechanisms leading to different clinical presentations remain unknown. We suggest that the destruction of the hair follicle by necrolysis leads to secondary dermal microcalcifications, scarring and sebaceous hyperplasia. Further studies are needed for a better understanding of these findings.

Fatal toxic epidermal necrolysis in a patient on teriflunomide treatment for relapsing multiple sclerosis.

We report a case of toxic epidermal necrolysis in a 46-year-old woman on teriflunomide treatment. Such a severe adverse cutaneous drug reaction with this new therapy for relapsing forms of multiple sclerosis should be early recognized in order to ensure the rapid withdrawal of the drug.

Therapeutic management of DRESS: a retrospective study of 38 cases.

BACKGROUND: There is no consensus regarding treatment for drug reaction with eosinophilia and systemic symptoms (DRESS). OBJECTIVES: We report a single-center observational series of therapeutic management of DRESS. METHODS: We examined data for 50 consecutive patients admitted from March 2005 to June 2009 with a discharge diagnosis of DRESS (RegiSCAR score). RESULTS: For the 38 patients with a DRESS score of 4 or more, topical steroid treatment alone was initiated in 66% of cases. On admission, 13 patients received systemic steroids; in 7 of them, systemic steroid treatment was initiated or maintained for life-threatening organ failure, with kidney, lung, and/or nervous system involvement. Complications of DRESS, such as relapse, viral reactivation, and sepsis, were less frequent with topical steroid than with systemic steroids. None of the patients died during their stay in hospital. LIMITATIONS: Retrospective nonblinded design and dermatologic recruitment are limitations. The variables underlying the choice of treatment study were not analyzed. CONCLUSIONS: Systemic steroids may not be required for the management of mild forms of DRESS, and may thus be reserved for more severe cases. Prospective studies are required to evaluate strategies for treating DRESS.

Prognostic factors in necrotizing soft-tissue infections (NSTI): A cohort study.

BACKGROUND: Necrotizing soft-tissue infection (NSTI) is uncommon but life-threatening. A recent meta-analysis estimated the overall mortality at 23.5%. OBJECTIVE: We sought to identify risk factors associated with mortality in a cohort of patients with NSTI in a tertiary care center. METHODS: We identified 512 patients with NSTI between 1996 and 2012 in the national hospital database Program for Medicalization of Information Systems and examined risk factors of mortality with NSTI by univariate and multivariate analysis. RESULTS: We included 109 patients with a confirmed diagnosis of NSTI; 31 (28%) died at a median follow-up of 274 days (range 2-6135 days). On multivariate analysis, independent risk factors of mortality were age older than 75 years (hazard ratio [HR] 4.4, 95% confidence interval [CI] 1.8-10.3), multifocal NSTI (HR 5.9, 95% CI 1.9-18.5), severe peripheral vascular disease (HR 5.1, 95% CI 1.5-17.0), hospital-acquired infection (HR 3.9, 95% CI 1.4-10.7), severe sepsis (HR 7.4, 95% CI 1.7-33.1), and septic shock on hospital admission (HR 13.9, 95% CI 3.8-50.4). LIMITATIONS: This was a retrospective cohort, which disallows a precise record of the delay between diagnosis and surgery. CONCLUSION: Our findings for this robust cohort of patients with a definite diagnosis of NSTI could help clinicians stratify NSTI severity at clinical course onset.

Treatment of neurofibromas with a carbon dioxide laser: a retrospective cross-sectional study of 106 patients.

BACKGROUND: Few studies have evaluated the efficacy of carbon dioxide (CO2) laser ablation for treating neurofibromatosis type 1 (NF1). OBJECTIVE: To evaluate laser treatment safety and patient satisfaction at the French National Referral Centre for Neurofibromatosis. METHODS: Retrospective survey with a specific questionnaire. The principal outcome measures included pain evaluation and assessments of treatment safety. RESULTS: We included 106 patients, 70% of whom had more than 50 neurofibromas. Laser treatment was performed mostly for aesthetic reasons, or due to pain, recurrent local trauma or familial influence, under a local anaesthetic, during outpatient visits. The mean pain score was 4.0 ± 2.7 during the administration of local anaesthesia, 2.4 ± 2.1 during laser treatment and <2 48 h after treatment in 56% of cases. The mean satisfaction score for the treatment was 4.6 ± 3.4 and was not associated with disease phenotype. CONCLUSIONS: CO2 laser treatment for NF could be considered more frequently and might help to decrease the social impact of the disease.

[DRUG INDUCED EXANTHEMA AND SEVERE CUTANEOUS DRUG REACTIONS]. / Exanthèmes médicamenteux et toxidermies sévères Signes généraux et muqueux imposent l'arrêt immédiat du médicament.

Cutaneous adverse drug reactions (CADR) are delayed hypersensivities. Their clinical presentation and severity are very diverse ranging from the frequent and benign exanthemas to the rare but severe CADR involving deep organs in the case of drug reaction with eosinophilia and systemic symptoms (DRESS) or leading to skin bulla and epidermal detachment in toxic epidermal necrolysis. The main differential diagnoses are infections, especially viral ones, which could give clinical symptoms identical to those occurring in CADR.

Somatic NF1 inactivation is a frequent event in sporadic pheochromocytoma.

Germline mutations in the RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, MAX, TMEM127, NF1 or VHL genes are identified in about 30% of patients with pheochromocytoma or paraganglioma and somatic mutations in RET, VHL or MAX genes are reported in 17% of sporadic tumors. In the present study, using mutation screening of the NF1 gene, mapping of chromosome aberrations by single nucleotide polymorphism (SNP) array, microarray-based expression profiling and immunohistochemistry (IHC), we addressed the implication of NF1 somatic alterations in pheochromocytomas and paragangliomas. We studied 53 sporadic tumors, selected because of their classification with RET/NF1/TMEM127-related tumors by genome wide expression studies, as well as a second set of 11 independent tumors selected on their low individual levels of NF1 expression evaluated by microarray. Direct sequencing of the NF1 gene in tumor DNA identified the presence of an inactivating NF1 somatic mutation in 41% (25/61) of analyzed sporadic tumors, associated with loss of the wild-type allele in 84% (21/25) of cases. Gene expression signature of NF1-related tumors highlighted the downregulation of NF1 and the major overexpression of SOX9. Among the second set of 11 tumors, two sporadic tumors carried somatic mutations in NF1 as well as in another susceptibility gene. These new findings suggest that NF1 loss of function is a frequent event in the tumorigenesis of sporadic pheochromocytoma and strengthen the new concept of molecular-based targeted therapy for pheochromocytoma or paraganglioma.

Acute respiratory failure in patients with toxic epidermal necrolysis: clinical features and factors associated with mechanical ventilation.

OBJECTIVES: Stevens-Johnson syndrome and toxic epidermal necrolysis are severe adverse cutaneous drug reactions characterized by widespread skin and mucous membrane detachments, including bronchial mucosa, which may be associated with respiratory failure requiring mechanical ventilation. The presentation and outcome of patients requiring mechanical ventilation and the characteristics of bronchial epithelial lesions among ventilated patients are reported. Predictors of mechanical ventilation available on hospital admission were identified using univariate and multivariate logistic regressions. DESIGN: Retrospective cohort study. SETTING: Medical ICU and dermatology department of a tertiary care hospital, which hosts the French national referral center for toxic epidermal necrolysis. PATIENTS: Patients admitted for Stevens-Johnson syndrome/toxic epidermal necrolysis over a 14-year period were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 221 patients included in the study, 56 patients (25.3%) required mechanical ventilation. None of the patients received noninvasive ventilation. Patients requiring mechanical ventilation had a larger baseline detached body surface area, higher Logistic Organ Dysfunction score, and Simplified Acute Physiology Score II, and they presented more often with shock, pulmonary infiltrates, and renal dysfunction (p < 0.0001 for all comparisons). Among patients receiving mechanical ventilation, 57% of the patients died; those having bronchial epithelial lesions (22 of 56) required intubation earlier than others (1 [1-4] vs 4 [1-6] d after hospital admission; p = 0.027). Variables associated with mechanical ventilation in multivariate analysis included serum bicarbonates less than 20 mM (odds ratio, 4.9 [95% CI, 1.1-22.7]; p = 0.041), serum urea greater than 10 mM (odds ratio, 7.0 [95% CI, 2.2-22.8]; p < 0.001), a detached body surface area between 10% and 29% (odds ratio, 3.7 [95% CI, 1.0-13.8]; p = 0.048) or greater than or equal to 30% (odds ratio, 19.7 [95% CI, 4.4-87.4]; p < 0.0001), WBCs more than 12,000/mm3 (odds ratio, 11.6 [95% CI, 2.8-48.1]; p < 0.001), blood hemoglobin less than 8 g/dL (odds ratio, 8.1 [95% CI, 1.2-55.2]; p = 0.032), and more extensive pulmonary infiltrates (odds ratio, 9.7 [95% CI, 3.6-25.9]; p < 0.0001). CONCLUSIONS: Mechanical ventilation is required in one of four Stevens-Johnson syndrome/toxic epidermal necrolysis patients and is associated with a poor outcome. Prompt identification of Stevens-Johnson syndrome/toxic epidermal necrolysis patients at higher risk of intubation could help guide their early management, particularly for those having bronchial epithelial lesions.

Severe cutaneous adverse reactions to drugs: from patients to the national office for compensation of medical accidents.

BACKGROUND: Administrative bodies for compensating medical accidents were created in France in 2002. OBJECTIVES: To evaluate the knowledge patients with severe cutaneous adverse reactions (SCARs) have of procedures and to compare the rate of compensation for SCARs for France and for our referral center. METHODS: A questionnaire was sent to 247 patients of our SCARs referral center and 225 patients with Stevens-Johnson syndrome and toxic epidermal necrolysis from the patient association AMALYSTE. We calculated the rate of compensation for France and our center. RESULTS: Among the 123 respondents (26%), 28 (23%) knew the compensation procedure; 13 (11%) had received compensation. The Commission of Conciliation and Compensation had received 63 applications for SCARs since 2002 and proposed compensation for 56%. The estimated rate of compensation for France was 2.6% and 2.5% for our referral center (p = 0.9). CONCLUSIONS: The procedure of compensation for SCARs is misunderstood. Better information should be disseminated for patients with threshold disability conditions.

MicroRNAome profiling in benign and malignant neurofibromatosis type 1-associated nerve sheath tumors: evidences of PTEN pathway alterations in early NF1 tumorigenesis.

BACKGROUND: Neurofibromatosis type 1 (NF1) is a common dominant tumor predisposition syndrome affecting 1 in 3,500 individuals. The hallmarks of NF1 are the development of peripheral nerve sheath tumors either benign (dermal and plexiform neurofibromas) or malignant (MPNSTs). RESULTS: To comprehensively characterize the role of microRNAs in NF1 tumorigenesis, we analyzed 377 miRNAs expression in a large panel of dermal and plexiform neurofibromas, and MPNSTs. The most significantly upregulated miRNA in plexiform neurofibromas was miR-486-3p that targets the major tumor suppressor gene, PTEN. We confirmed PTEN downregulation at mRNA level. In plexiform neurofibromas, we also report aberrant expression of four miRNAs involved in the RAS-MAPK pathway (miR-370, miR-143, miR-181a, and miR-145). In MPNSTs, significant deregulated miRNAs were involved in PTEN repression (miR-301a, miR-19a, and miR-106b), RAS-MAPK pathway regulation (Let-7b, miR-195, and miR-10b), mesenchymal transition (miR-200c, let-7b, miR-135a, miR-135b, and miR-9), HOX genes expression (miR-210, miR-196b, miR-10a, miR-10b, and miR-9), and cell cycle progression (miR-195, let-7b, miR-20a, miR-210, miR-129-3p, miR-449a, and miR-106b). CONCLUSION: We confirmed the implication of PTEN in genesis of plexiform neurofibromas and MPNSTs in NF1. Markedly deregulated miRNAs might have potential diagnostic or prognostic value and could represent novel strategies for effective pharmacological therapies of NF1 tumors.

Prognostic value of histologic features of toxic epidermal necrolysis.

BACKGROUND: The prognosis of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), and SJS/TEN overlap syndrome has been assessed using a disease-specific severity score (SCORTEN) based on clinical and laboratory data. Histologic data may improve outcome prediction. OBJECTIVE: We sought to evaluate whether dermal mononuclear infiltration and epidermal necrosis predict survival of patients with TEN, SJS, or SJS/TEN. METHODS: We conducted a retrospective review of clinical records and skin biopsy specimens read without knowledge of clinical data. RESULTS: We identified 108 patients (SJS, n = 42; SJS/TEN, n = 36; TEN, n = 30). Overall mortality was 21.3%. Dermal infiltration and epidermal necrosis were not associated with time from disease onset to biopsy. Extensive dermal infiltrates were seen in 19 (18.5%) patients and full-thickness epidermal necrosis in 56 (52%) patients. Dermal infiltrate severity was not associated with day-1 (D1) SCORTEN or hospital death. Epidermal necrosis severity showed trends toward associations with D1 SCORTEN (P = .11) and hospital death (P = .06). In univariate analyses, full-thickness epidermal necrosis was significantly associated with hospital death (32.1% vs 11.4%, P = .017) and worse D1 SCORTEN values (1.98 ± 1.29 vs 1.55 ± 1.21; P = .04). In the bivariate analysis, however, D1 SCORTEN remained significantly associated with hospital death (odds ratio = 3.07, 95% confidence interval 1.83-5.16) but the association with full-thickness epidermal necrosis was no longer significant (odds ratio = 2.02, 95% confidence interval 0.65-7.12). LIMITATIONS: Retrospective study design and indirect assessment of progression are limitations. CONCLUSION: Full-thickness epidermal necrosis was associated with mortality but did not independently predict hospital death after adjustment based on the SCORTEN value. Dermal infiltrate severity was not associated with hospital death.

Skin Testing and Drug Provocation Tests in Epidermal Necrolysis: A French Experience.

BACKGROUND: There are limited data on the use of skin testing, other than patch testing, and challenges in the evaluation of epidermal necrolysis (EN), including Stevens-Johnson syndrome and toxic epidermal necrolysis. OBJECTIVE: To report a French multicenter experience in skin testing and challenges in EN, and investigate the factors associated with tests' positivity. METHODS: All patients who were evaluated by patch tests (PTs), skin prick tests, intradermal tests (IDTs), or drug provocation tests (DPTs) for EN between 2010 and 2020 were retrospectively included through 2 French drug reaction networks. RESULTS: In total, 113 patients were included from 8 centers. Median (interquartile range) time from EN to hypersensitivity workup was 7.9 months (5.1-15 months). All patients had PTs, 17 (15%) had skin prick tests or IDTs with delayed readings and 32 (28.3%) had DPTs. One mild reaction occurred after a DPT. Overall, 22 patients (19.5%) had positive PTs, and the only factors associated with positivity were Algorithm of Drug Causality for Epidermal Necrolysis (ALDEN) score and drug class. Only 1 IDT was positive but considered irrelevant. The DPTs were never performed to prove responsibility of a highly suspected drug but were used to confirm current tolerance of needed medications. CONCLUSIONS: Allergological workup in EN, performed by specialists involved in EN, seems safe. Skin tests, although of limited sensitivity, can be helpful for considering the reintroduction of essential drugs according to a benefit-to-risk decision. We propose an algorithm for approaching hypersensitivity testing in patients with EN, to be adapted to each patient.

Identification of genes potentially involved in the increased risk of malignancy in NF1-microdeleted patients.

Patients with NF1 microdeletion develop more neurofibromas at a younger age, and have an increased risk of malignant peripheral nerve sheath tumors (MPNSTs). We postulated that the increased risk of malignancy could be due to inactivation, in addition to NF1, of a second tumor suppressor gene located in the typical 1.4-Mb microdeletion found in most of the microdeleted patients. We investigated the expression of NF1, the other 16 protein-coding genes and the 2 microRNAs located in the 1.4-Mb microdeletion by means of real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR) in a large series of human dermal and plexiform neurofibromas and MPNSTs. Five genes were significantly upregulated: OMG and SUZ12 in plexiform neurofibromas and ATAD5, EVI2A and C17orf79 in MPNSTs. More interestingly, two genes were significantly downregulated (RNF135 and CENTA2) in tumor Schwann cells from MPNST biopsies and in MPNST cell lines. This study points to the involvement of several genes (particularly RNF135 and CENTA2) in the increased risk of malignancy observed in NF1-microdeleted patients.