[Pulmonary phenotypes of inborn errors of metabolism]. / Manifestations pulmonaires des maladies héréditaires du métabolisme.

Inborn metabolic diseases or inborn errors of metabolism comprise a large number of rare and heterogeneous genetic diseases categorized in several subgroups depending on their pathophysiologic mechanisms. In this review, we focus on different metabolic diseases with respiratory symptoms in adults: lysosomal glycosphingolipidoses such as acid sphingomyelinase deficiency (Niemann-Pick types A and B disease), Gaucher, Fabry, Pompe diseases and mucopolysaccharidoses in general. We also address classical homocystinuria, which is a monogenic vascular disease, Hermansky-Pudlak syndrome, which is associated with disorders in the lysosomal-related-organelles, and lysinuric protein intolerance, which is due to an amino-acid transporter defect. Presentation and prognosis of these diseases are highly heterogeneous, and respiratory impairment may be central and prognostic. Many are primarily pediatric, and diagnoses are often delivered during childhood. Improved pediatric management has enabled better prognosis and new phenotype of the diseases in the adulthood. Some others can be diagnosed during adulthood. While some diseases call for specific, specialized treatment, all necessitate systematic multidisciplinary management. It is of paramount importance that a pneumologist be familiar with these phenotypes, most of which can benefit from early diagnosis and early therapeutic management with dedicated innovative treatments.

[Fatal nutrient deficiencies after gastric bypass]. / Syndrome multicarentiel catastrophique post bypass gastrique.

INTRODUCTION: Bariatric surgery is a very effective treatment for obesity. After gastric bypass, micronutrient deficiencies frequently occur which can have dramatic consequences. CASE REPORT: We report the case of a 55-year-old woman who was admitted for psychomotor retardation, bilateral leg pitting edema and psoriasis-like rash that had been ongoing for 3 months. Pancytopenia, encephalopathy and heart failure rapidly occurred leading to multiorgan dysfunction syndrome and death. We retrospectively identified severe selenium deficiency with possible secondary cardiomyopathy, niacin deficiency resulting in pellagrous encephalopathy with skin lesions and gelatinous transformation of bone marrow. CONCLUSION: Micronutrient deficiency should systematically be assessed when new symptoms occur in a patient with a history of bariatric surgery. Selenium deficiency should be considered in the presence of any heart failure in this context.

Standardising clinical outcomes measures for adult clinical trials in Fabry disease: A global Delphi consensus.

BACKGROUND: Recent years have witnessed a considerable increase in clinical trials of new investigational agents for Fabry disease (FD). Several trials investigating different agents are currently in progress; however, lack of standardisation results in challenges to interpretation and comparison. To facilitate the standardisation of investigational programs, we have developed a common framework for future clinical trials in FD. METHODS AND FINDINGS: A broad consensus regarding clinical outcomes and ways to measure them was obtained via the Delphi methodology. 35 FD clinical experts from 4 continents, representing 3389 FD patients, participated in 3 rounds of Delphi procedure. The aim was to reach a consensus regarding clinical trial design, best treatment comparator, clinical outcomes, measurement of those clinical outcomes and inclusion and exclusion criteria. Consensus results of this initiative included: the selection of the adaptative clinical trial as the ideal study design and agalsidase beta as ideal comparator treatment due to its longstanding use in FD. Renal and cardiac outcomes, such as glomerular filtration rate, proteinuria and left ventricular mass index, were prioritised, whereas neurological outcomes including cerebrovascular and white matter lesions were dismissed as a primary or secondary outcome measure. Besides, there was a consensus regarding the importance of patient-related outcomes such as general quality of life, pain, and gastrointestinal symptoms. Also, unity about lysoGb3 and Gb3 tissue deposits as useful surrogate markers of the disease was obtained. The group recognised that cardiac T1 mapping still has potential but requires further development before its widespread introduction in clinical trials. Finally, patients with end-stage renal disease or renal transplant should be excluded unless a particular group for them is created inside the clinical trial. CONCLUSION: This consensus will help to shape the future of clinical trials in FD. We note that the FDA has, coincidentally, recently published draft guidelines on clinical trials in FD and welcome this contribution.

[Fabry disease: A review]. / Maladie de Fabry : quand y penser ?

Fabry disease is the second most frequent lysosomal storage disorder. It is a X-linked genetic disease secondary to alpha-galactosidase A enzyme deficiency. This is a progressive and systemic disease that affects both males and females. Classical symptoms and organ involvements are acral pain crisis, cornea verticillata, hypertrophic cardiomyopathy, stroke and chronic kidney disease with proteinuria. Nevertheless, organ damages can be missing or pauci-symptomatic and other common symptoms are poorly recognised, such as gastrointestinal or ear involvement. In classical Fabry disease, symptoms first appear during childhood or teenage in males, but later in females. Patients may have non-classical or late-onset Fabry disease with delayed manifestations or with single-organ involvement. Recognition of Fabry disease is important because treatments are available, but it may be challenging. Diagnosis is easy in males, with dosage of alpha-galactosidase A enzyme activity into leukocytes, but more difficult in females who can express normal residual activity. Other plasmatic biomarkers, such as lyso-globotriaosylceramide (lyso-Gb3), are interesting in females, but need to be associated with GLA gene analysis. In this review, we aimed at summarize the main clinical manifestations of Fabry disease and propose a practical algorithm to know how to diagnose this complex disease.

[Delays in the management of ocular complications of giant cell arteritis: A retrospective monocentric study of 33 patients]. / Délais de prise en charge des complications visuelles d'artérite à cellules géantes : étude rétrospective monocentrique de 33 patients.

INTRODUCTION: Ocular complications of giant cell arteritis (GCA) can lead to irreversible bilateral blindness and represent a therapeutic emergency. Recommendations for the management of GCA have recently been updated. The objective of the study was to evaluate delays in appropriate management of the ocular complications of GCA and its determinants. METHOD: Retrospective, monocentric study, conducted over the period January 2013-November 2018. All consecutive patients with a final diagnosis of GCA and related visual impairment (permanent visual loss and/or alteration of visual field) were included. RESULTS: Thirty-three patients were included (women: 21, men: 12; mean age at diagnosis: 79). Twenty-seven patients (82%) presented with symptoms suggestive of ACG prior to the visual complication, ranging from a few weeks to several months. Seventeen patients (52%) had a known biological inflammatory syndrome (median CRP at 64 mg/L) prior to hospital consultation. The median time from the onset of permanent ophthalmologic manifestations to appropriate corticosteroid management was 3 days (range: 0-134). Two of the 21 patients who consulted an out-of-hospital ophthalmologist received corticosteroid therapy before referral to hospital. Three patients (9%) were treated within 24 h of the onset of the disorders. CONCLUSION: There is a significant delay in the appropriate management of ophthalmological complications of ACG and deviations from current recommendations. Numerous actions must therefore be taken to improve the visual prognosis of patients with ACG, both preventively (i.e. early diagnosis and treatment of ACG before the possible occurrence of visual complications), and curatively (rapid recognition and immediate treatment of ocular complications). These elements support the relevance of specific fast-track pathways for GCA.

[Diagnostic journey of type 1 Gaucher Disease patients: A survey including internists and hematologists]. / Parcours diagnostique des patients atteints de maladie de Gaucher de type 1 : enquête auprès de médecins internistes et hématologues.

INTRODUCTION: Gaucher disease (GD) is a rare genetic lysosomal storage disorder caused by a beta-glucocerebrosidase deficiency and responsible for a lysosomal storage disorder. GD is characterized by haematological, visceral and bone involvements. The aim of this study was to describe the diagnostic journey of type 1 GD patients as well as the role of the internist. METHODS: A retrospective multicentric study involving type 1 GD patients has been conducted in 16 centers, between 2009 and 2011. RESULTS: Fifty-five type 1 GD patients were included, under the care of an internist or an haematologist. They were originally hospitalized in 8 different specialized units. Diagnosis was established by bone-marrow aspiration in 22 patients (40%), by enzymatic assay of glucocerebrosidase activity in 15 patients (27%), and by bone-marrow biopsy in 9 patients (16%). The use of enzymatic assay became more frequent after 1990. The delay between first hospitalization due to GD symptoms and definitive diagnosis was less than one year for 38 patients. Patients with suspected GD were mainly referred to an internist physician. CONCLUSION: GD seems to be better recognized and quickly diagnosed since 1990 in spite of the multiplicity of journeys. The role of the internist seems important.

[Anorectal manifestations in systemic diseases]. / Manifestations ano-rectales des maladies systémiques.

Numerous systemic diseases (vasculitis, connective tissue disease or sarcoidosis) can display an involvement of the perianal skin, the rectum and/or the anus. Such knowledge is important in order to treat these complications specifically when possible. Lesions of the anorectum arising from systemic diseases can sometimes cause perforations in the peritoneal cavity (if concerning the higher portion of the rectum) and/or fistulization to the anal margin. Differential diagnosis, mostly infectious or inflammatory (Crohn's disease) must be ruled out in every case. Other systemic diseases can display specific manifestations as this is the case in scleroderma which can lead to anal incontinence. Despite the relative rarity of these manifestations, their ignorance would forbid global management of these complex diseases. It should thus be detected in each consultation and a regular follow-up must be provided with a proctologist and/or a gastroenterologist when needed.

[Glassy cell carcinoma of the uterine cervix: An aggressive type of cancer]. / Glassy cell carcinoma du col de l'utérus : une maladie tumorale agressive.

INTRODUCTION: Cervical cancer is the twelfth most frequent cancer in women in France. Glassy cell carcinoma is a rare histological entity, rapidly aggressive, associated with a poor prognosis. CASE REPORT: A 30-year-old woman was admitted in an internal medicine department for polyarthralgia with high grade fever, evolving for 3 weeks. There was an inflammatory syndrome. The 18-FDG-PET-scan showed inflammatory lymph nodes as well as disseminated osteolytic lesions, and a primitive pelvic tumor. A 3cm tumor of the cervix was found during the gynaecologic examination. Histological analysis elicited a high-index mitotic carcinoma, glassy cell carcinoma type. Despite chemotherapy, the outcome was poor, with early death occurring after three months of follow-up. CONCLUSION: The glassy cell carcinoma of the cervix should be considered as an aetiology of bone metastases in young female patients.

[Combined heart and kidney transplantation in Fabry's disease: Long-term outcomes in two patients]. / Transplantation combinée cœur­rein au cours de la maladie de Fabry : suivi à long terme de deux patients.

INTRODUCTION: Fabry disease is a lysosomal storage disorder linked to an alpha-galactosidase A deficiency that can lead to heart and kidney failure. There is little data about the prognosis of patients who undergo a combined heart and kidney transplantation. CASE REPORTS: Two brothers who were diagnosed with Fabry disease after the age of 30 years underwent a combined heart and kidney transplantation at respectively 49 and 42 years of age because of a severe hypertrophic cardiomyopathy with end stage renal failure. They are alive respectively 4 and 9 years after the transplantation. No recurrence of the disease in the transplanted organs has been found. CONCLUSION: Combined heart and kidney transplantation in Fabry disease is an efficient therapy for the cardiomyopathy and kidney failure. Its prognosis can be good when the patients are carefully selected. However, an early diagnosis is critical in order to avoid a procedure associated with a high perioperative mortality.

[Acid sphingomyelinase deficiency (Niemann-Pick disease type B) in adulthood: A retrospective multicentric study of 28 adult cases]. / Déficit en sphingomyélinase acide (maladie de Niemann-Pick B) : une étude rétrospective multicentrique de 28 patients adultes.

INTRODUCTION: Acid sphingomyelinase deficiency (ASMD) is an autosomal recessive disease with a clinical spectrum ranging from a neurovisceral infantile form (Niemann-Pick disease type A) to a chronic visceral form also encountered in adults (Niemann-Pick disease type B, NP-B). METHODS: Retrospective multicentric analysis of French adult patients with ASMD over the period 1985-March 2015. Clinical, biological, and imaging data were analyzed. RESULTS: Twenty-eight patients (19 males, 9 females) were analyzed. Diagnosis was made before the age of 10 years in 16 cases. Main symptoms at diagnosis were spleen/liver enlargement and interstitial lung disease. Biological abnormalities included: thrombocytopenia (platelet count <150 000/mm3) in 24 cases including 4 patients with platelet count <60 000/mm3, constantly low high-density lipoprotein (HDL) cholesterol, polyclonal hypergammaglobulinemia (n=6), monoclonal gammopathy of unknown significance (n=5), normal prothrombin level discordant with low factor V (n=5), elevated chitotriosidase level (n=11). The diagnosis was confirmed in all cases by deficient acid sphingomyelinase enzyme activity. SMPD1 gene sequencing was performed in 25 cases. The frequent p.R610del mutation was largely predominant, constituting 62% of the non-related alleles. During the follow-up period, three patients died before 50 years of age from cirrhosis, heart failure and lung insufficiency, respectively. CONCLUSION: ASMD in adulthood (NP-B) associates spleen/liver enlargement and interstitial lung disease. Early diagnosis and appropriate management are essential for reducing the risk of complications, improving quality of life, and avoiding inappropriate procedures such as splenectomy. To date, only symptomatic therapy is available. A phase 2/3 therapeutic trial with IV infusion of recombinant enzyme is on-going.

[Tumor-induced osteomalacia caused by a late-revealing phosphaturic mesenchymal tumor]. / Ostéomalacie secondaire à une tumeur mésenchymateuse phosphaturique de révélation tardive.

INTRODUCTION: Osteomalacia is associated with diffuse pain and multiple fractures and therefore, diagnosis and treatment of this condition are necessary. Clinicians should be aware of an uncommon mechanism of osteomalacia where hypophosphataemia is secondary to renal phosphaturia because of the production by a mesenchymal phosphaturic tumor of FGF-23. This tumor should be localized and removed to cure this tumor-induced osteomalacia. OBSERVATION: A 70-year-old female patient was admitted to explore diffuse pain caused by multiple fractures secondary to osteomalacia. Despite vitamin D supplementation, she remained profoundly hypophosphoremic with major renal phosphaturia. A tumor-induced mechanism was suspected because of high level of FGF-23. It took more than three years of investigation to spot the causal phosphaturic mesenchymal tumor despite annual repetition of indium-labelled scintigraphy and PET-scan. The resection of the tumor, located between two phalanges of the right foot, cured the patient with sustained normal rate of serum level of phosphorus after two years. CONCLUSION: Tumor-induced osteomalacia is a diagnostic challenge because the localization of the tumor may be a long process. Patients should be monitored clinically and imaging studies repeated until a diagnosis is made and the causal tumor removed.

Efficacy of anti-TNF alpha in severe and/or refractory Behçet's disease: Multicenter study of 124 patients.

OBJECTIVE: To report the efficacy and safety of anti-TNF agents in patients with severe and/or refractory manifestations of Behçet's disease (BD). METHODS: We performed a multicenter study of main characteristics and outcomes of anti-TNF alpha treatments [mainly infliximab (62%), and adalimumab (30%)] in 124 BD patients [48% of men; median age of 33.5 (28-40) years]. RESULTS: Overall response (i.e. complete and partial) rate was 90.4%. Clinical responses were observed in 96.3%, 88%, 70%, 77.8%, 92.3% and 66.7% of patients with severe and/or refractory ocular, mucocutaneous, joint, gastro-intestinal manifestations, central nervous system manifestations and cardiovascular manifestations, respectively. No significant difference was found with respect to the efficacy of anti-TNF used as monotherapy or in association with an immunosuppressive agent. The incidence of BD flares/patient/year was significantly lower during anti-TNF treatment (0.2 ± 0.5 vs 1.7 ± 2.4 before the use of anti-TNF, p < 0.0001). The prednisone dose was significantly reduced at 6 and 12 months (p < 0.0001). In multivariate analysis, retinal vasculitis was negatively associated with complete response to anti-TNF (OR = 0.33 [0.12-0.89]; p = 0.03). The efficacy and relapse free survival were similar regardless of the type of anti-TNF agent used. After a median follow-up of 21 [7-36] months, side effects were reported in 28% of patients, including infections (16.3%) and hypersensitivity reactions (4.1%). Serious adverse events were reported in 13% of cases. CONCLUSION: Anti-TNF alpha therapy is efficient in all severe and refractory BD manifestations. Efficacy appears to be similar regardless of the anti-TNF agent used (infliximab or adalimumab).

[Acid sphingomyelinase deficiency and spleen trauma: splenectomy or not splenectomy?]. / Déficit en sphingomyélinase acide et rupture splénique : splénectomie ou traitement conservateur ?

INTRODUCTION: Acid sphingomyelinase deficiency leads to a severe infantile disease (Niemann-Pick disease type A) or an attenuated form of the disease encountered in adults (Niemann-Pick type B), including pulmonary fibrosis and splenomegaly. CASE REPORT: A 52-year-old man with Niemann-Pick disease type B was admitted with splenic rupture. Embolization of the splenic artery was initially performed. Three months later, the splenic volume had increased and functional asplenia was diagnosed. Splenic scintigraphy showed 20% of functional splenic tissue. Splenectomy was finally performed because of complete necrosis of the spleen. CONCLUSION: Despite its theoretical contra-indication in Niemann-Pick disease due to a risk of respiratory insufficiency, splenectomy must sometimes be considered.

[Black esophagus]. / Nécrose aiguë de l'œsophage.

INTRODUCTION: Acute necrosis of the esophagus, frequently referred to as black esophagus is a rare clinical entity. CASE REPORT: We here report a case of an acute necrosis of the esophagus secondary to hemodynamic compromise after total hip replacement. Past medical history of our 72-year-old patient was remarkable for coronary heart disease, obstructive arteriopathy of the lower limbs, diabetes mellitus and hypertension. He was referred for hematemesis and epigastric pain one day after the surgical intervention was performed. Gastric endoscopy showed necrosis of the esophagus. Treatment consisted on intravenous proton pump inhibitor, parenteral renutrition, and red blood cell transfusion. Fours days later, endoscopy found complete disappearance of necrosis. CONCLUSION: Black esophagus develops in debilitated patients during hypoperfusion and stress. The outcome is usually favourable in the absence of comorbidities.

[Antisynthetase syndrome and lung carcinoma: a fortuitous association?]. / Syndrome des antisynthétases et adénocarcinome pulmonaire: une association fortuite?

INTRODUCTION: Dermatomyositis and polymyositis are sometimes associated with neoplasia. Conversely, a link between antisynthetase syndrome and neoplasia has not been clearly demonstrated. CASE REPORT: We report a 54-year-old smoker male patient who presented with an antisynthetase syndrome with anti-Jo1 and anti-Ro-52 antibodies. An adenocarcinoma of the lung was diagnosed at the same time. CONCLUSION: Two recent studies showed that patients with an antisynthetase syndrome associated with anti-Jo1 antibodies have more severe prognosis than antisynthetase syndrome associated with other antibodies (i.e. PL7/PL12). The risk of cancer occurrence seems to be increased when the anti-Jo1 antisynthetase syndrome is associated with anti-Ro-52 antibodies. To date, there is no demonstrated association between antisynthetase syndrome and neoplasia.

Pituitary-adrenal function after prolonged glucocorticoid therapy for systemic inflammatory disorders: an observational study.

CONTEXT: Glucocorticoid therapy is being used in a wide variety of systemic disorders. Reference papers, published more than 20 years ago, showed no correlation between adrenal insufficiency risk and dose or duration of glucocorticoid therapy. OBJECTIVE: Our objective was to evaluate the extent to which long-term glucocorticoid therapy damages the pituitary-adrenal axis in patients with systemic inflammatory disorders. DESIGN: We conducted a retrospective observational study from January 2011 to August 2012. SETTING: This was a monocentric study at the Department of Internal Medicine, Bichat Hospital, Paris-Diderot University, Paris, France. PARTICIPANTS: Sixty consecutive patients who were receiving long-term prednisone therapy for systemic inflammatory disorders and in whom discontinuation of glucocorticoid treatment was planned. INTERVENTION: A short Synacthen test was performed. A bolus of 0.25 mg 1-24-ACTH was injected in the morning, 24 hours after the most recent dose of prednisone. Cortisol was measured at baseline and 60 minutes after Synacthen injection. MAIN OUTCOME MEASURES: We assessed frequency and risk estimate of pituitary-adrenal dysfunction. RESULTS: Twenty-nine patients (48.3%) had adrenal insufficiency defined by a plasmatic cortisol <100 nmol/L (n = 13) at baseline (time 0) or <550 nmol/L (n = 16) 60 minutes after Synacthen injection. Cumulative dose (area under the receiver operating characteristic curve = 0.77 [95% confidence interval = 0.62-0.91], P = .007) and exposure (area under the receiver operating characteristic curve 0.80 [95% confidence interval = 0.67-0.93], P = .002) to prednisone were predictive for adrenal insufficiency based on a T0 <100 nmol/L. Prednisone was stopped in 29 of 31 patients (93.5%) showing a normal response to short Synacthen test; none of these patients required hydrocortisone replacement with a mean follow-up of 10 (± 6) months. CONCLUSION: Adrenal insufficiency is frequent in patients treated with long-term glucocorticoids for systemic inflammatory disorders and is related to duration and cumulative dose of steroids.