[Misdiagnosis of Gaucher disease in real life: Retrospective study of the French Gaucher's disease registry]. / Les erreurs diagnostiques de la maladie de Gaucher dans la vraie vie : étude rétrospective du Registre français de la Maladie de Gaucher.

INTRODUCTION: Gaucher disease is an autosomal recessive genetic disorder. It is caused by a deficiency of the lysosomal enzyme, glucocerebrosidase which leads to an accumulation of glucosylceramide in the macrophages. Splenomegaly, hepatomegaly, cytopenias (anemia, thrombocytopenia) and bone disorders are the main symptoms. The diagnosis is often delayed, leading to unnecessary investigations and treatments, and delaying the specific treatment. The primary objective of our study was to establish, in patients who had a diagnostic delay of more than one year, the reported misdiagnoses before the final diagnosis. The secondary objectives were to investigate the risk factors associated with error and delayed diagnosis. METHODS: Retrospective study including patients with Gaucher disease from the French Gaucher Disease Registry. Collection of data by a single investigator from a standardized form. RESULTS: Among 83 patients with a known diagnostic delay, 13 patients (15 %) had one or two misdiagnoses. These included osteo-articular diagnoses (osteomyelitis, osteoarthritis, arthritis, osteochondritis, rheumatic fever, n=8), haematological diagnoses (gestational thrombocytopenia, immunological thrombocytopenia, n=4), infectious diagnoses (visceral leishmaniasis, mononucleosis, n=2) and hemochromatosis. The osteo-articular and infectious diagnoses concerned the child and the adolescent while the haematological diagnoses and the hemochromatosis concerned the adult. No factors were found associated with misdiagnoses. Patients with a diagnostic delay greater than one year were less likely to have hepatosplenomegaly as the first symptom. CONCLUSION: There is a risk of diagnostic error related to phenotypic heterogeneity and lack of specificity of Gaucher disease symptoms. This study helps to better identify the misdiagnoses associated with Gaucher disease.

[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.

[Mucopolysaccharidosis: A review]. / Mucopolysaccharidoses : quand y penser ?

Mucopolysaccharidosis are lysosomal storage diseases, secondary to the accumulation of mucopolysaccharides. Type 1 mucopolysaccharidosis is the most common form and affects between 0.69 and 1.66 newborns per 100,000. The severity of mucopolysaccharidosis is variable with lethal forms in utero and attenuated forms diagnosed in adults. The most common symptoms are short stature, facial dysmorphism, chronic articular pains that can mimic chronic inflammatory rheumatism, axial and peripheral bone involvement, hepatosplenomegaly and an early carpal tunnel. Depending on the type of mucopolysaccharidosis, corneal, cerebral or cardiac involvements are possible. Screening is based on the analysis of urinary glycosaminoglycans. The deficient enzyme assay and the gene analysis confirm the diagnosis. Mucopolysaccharidosis recognition is important for patient management and family screening. In addition, specific enzyme replacement therapy exists for certain types of mucopolysaccharidosis. Role of clinician is important to evoke and diagnose mucopolysaccharidosis.

[Gaucher disease: A review]. / La maladie de Gaucher : quand y penser ?

Gaucher disease is a rare autosomal recessive genetic disease, caused by a deficiency of the lysosomal enzyme, glucocerebrosidase that leads to the accumulation of its substrate (glucosylceramide) in lysosomal macrophages. In the general population, its incidence varies between 0.4 and 5.8/100,000 inhabitants. Type 1 Gaucher disease is the most frequent and is characterized by its extreme heterogeneity including asymptomatic or more severe presentations. The most frequent symptoms are anemia, thrombocytopenia, splenomegaly, and/or hepatomegaly, and a potentially severe bone involvement. Type 2 and type 3 Gaucher diseases are associated with neurological involvement that can be severe. Diagnosis is confirmed by demonstrating a deficiency of glucocerebrosidase activity in leucocytes, and by the identification of biallelic pathogenic variants in GBA1 gene. Type 1 Gaucher disease is associated with a higher risk of Parkinson disease, some solid cancers, and hematologic diseases in particularly multiple myeloma. Specific treatment, such as enzyme replacement therapy or substrate reduction therapy is indicated in symptomatic type 1 Gaucher disease. Only enzyme replacement therapy is indicated in type 3 Gaucher disease. Treatment improves quality of life and prognosis. The rarity of Gaucher disease and its wide variability in clinical presentations lead to diagnosis delays. There is a strong need for a better knowledge of its symptoms among physicians, to reduce irreversible complications.

Transition from pediatric to adult care in adolescents with hereditary metabolic diseases: Specific guidelines from the French network for rare inherited metabolic diseases (G2M).

Inherited metabolic diseases (IMD) form a heterogeneous group of genetic disorders that surface primarily during childhood and result in significant morbidity and mortality. A prevalence of 1 in 2500-5000 live births is often reported. The transfer of adolescents from pediatric care to adult health facilities is often difficult for patients and their families and can lead to a breakdown in medical follow-up and therefore serious complications. Existing recommendations for the successful transition of patients with chronic disorders do not specifically address patients with IMDs associated with dietary treatment. Here, the French network for rare inherited metabolic diseases (G2M) presents its reflections and recommendations for a successful transition. Preparations for the transfer must be made well in advance. The transfer must aim for adolescents gaining autonomy by making them responsible and providing them with the knowledge that will enable them to manage their care themselves, know how to react appropriately if there is any change in their condition, and move comfortably within the adult healthcare system. This requires the active participation of the patient, his or her family, and pediatric and adult care teams. It involves multidisciplinary management plus the production and maintenance of an educational therapy program. Finally, the identification of physicians and dietitians trained in IMDs, relevant subspecialists, and even expert patients could improve the continuum of complete and appropriate care for these patients within adult medicine.

Management goals for type 1 Gaucher disease: An expert consensus document from the European working group on Gaucher disease.

Gaucher Disease type 1 (GD1) is a lysosomal disorder that affects many systems. Therapy improves the principal manifestations of the condition and, as a consequence, many patients show a modified phenotype which reflects manifestations of their disease that are refractory to treatment. More generally, it is increasingly recognised that information as to how a patient feels and functions [obtained by patient- reported outcome measurements (PROMs)] is critical to any comprehensive evaluation of treatment. A new set of management goals for GD1 in which both trends are reflected is needed. To this end, a modified Delphi procedure among 25 experts was performed. Based on a literature review and with input from patients, 65 potential goals were formulated as statements. Consensus was considered to be reached when ≥75% of the participants agreed to include that specific statement in the management goals. There was agreement on 42 statements. In addition to the traditional goals concerning haematological, visceral and bone manifestations, improvement in quality of life, fatigue and social participation, as well as early detection of long-term complications or associated diseases were included. When applying this set of goals in medical practice, the clinical status of the individual patient should be taken into account.

[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.

[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.

Management of non-neuronopathic Gaucher disease with special reference to pregnancy, splenectomy, bisphosphonate therapy, use of biomarkers and bone disease monitoring.

Enzyme replacement was introduced as treatment for non-neuronopathic Gaucher disease more than 15 years ago. To ensure the best use of this costly ultra-orphan agent, a systematic disease management approach has been proposed by an international panel; this includes the development, by consensus, of achievable treatment goals. Here we critically review these goals and monitoring guidelines and incorporate emerging experience of the disease in the therapeutic era, as well as contemporary clinical research. This review makes recommendations related specifically to the management of pregnancy; the appropriate use of splenectomy and bisphosphonate treatment; the relevance of biochemical markers to disease monitoring; and the use of semi-quantitative methods for assessing bone marrow infiltration. In addition, we identify key areas for development, including the requirement for a validated index of disease severity; the need to correlate widely used biomarkers with long-term disease outcomes, and the desirability of establishing agreed standards for monitoring of bone disease particularly in infants and children with Gaucher disease.

[Organization of Gaucher disease management in France]. / Organisation de la prise en charge de la maladie de Gaucher en France.

Gaucher disease management in France is facilitated by CETG (Comitee of Evaluation and Treatment of Gaucher disease). Four hundred and fifty-six patients are enrolled in 2006 in the French Gaucher registry of CETG. Two hundred and thirty patients had treatment. Eighty five % are type 1, 10.5% type 2 and 5.5% type 3. Only 1 patient had a saposin C deficiency. Information on CETG is available on www.cetl.net.

Schnitzler's syndrome: 3-year radiological follow-up.

Schnitzler's syndrome comprises urticaria, monoclonal gammapathy, inflammatory signs (fever, enlarged lymph nodes, hyperleukocytosis), and bone lesions. We report the imaging findings and follow-up of a new case with extensive osteosclerosis of the iliac bone, associated with inflammatory signal changes on MRI and foci of increased uptake on bone scintigraphy. When a diagnosis of Schnitzler's syndrome is established, treatment should be towards symptoms only; a long follow-up is warranted, as a delayed evolution towards a lymphoproliferative syndrome is possible.

Langerhans' cell histiocytosis of the labyrinth in adults.

OBJECTIVE: To describe and analyze three unusual cases of Langerhans' cell histiocytosis of the temporal bone in adults. STUDY DESIGN: Retrospective case review. SETTING: A tertiary referral center. PATIENTS: Three adult patients with progressive sensorineural or mixed hearing loss, vertigo, and tinnitus as presenting symptoms of Langerhans' cell histiocytosis of the temporal bone. INTERVENTION: Patients were evaluated by means of computed tomography and magnetic resonance imaging. All patients underwent complete surgical excision of the lesion via a transmastoid approach, extended to a translabyrinthine approach in one case. One patient with a multifocal disease underwent excision of a mandibular lesion 1 year later, followed-up by chemotherapy. RESULTS: The Langerhans' cell histiocytosis was located adjacent to or within the area of the endolymphatic sac region in all cases. The middle ear was spared. Hearing function was preserved in the two patients who had serviceable hearing preoperatively. No complication occurred. CONCLUSION: Langerhans' cell histiocytosis of the temporal bone is centered on or adjacent to the endolymphatic sac. The fact that the endolymphatic sac plays an immunologic role in the inner ear suggests that the infiltration of the Langerhans' cell may derive from it.

The role of the iminosugar N-butyldeoxynojirimycin (miglustat) in the management of type I (non-neuronopathic) Gaucher disease: a position statement.

N-Butyldeoxynojirimycin (NB-DNJ, miglustat 'Zavesca') is an orally active iminosugar which inhibits the biosynthesis of macromolecular substrates that accumulate pathologically in glycosphingolipidoses. Clinical trials of NB-DNJ in patients with Gaucher's disease demonstrate the therapeutic potential of such substrate inhibitors in the glycolipid storage disorders. However, macrophage-targetted enzyme replacement using intravenous mannose-terminated human glucocerebrosidase (imiglucerase, Cerezyme) is highly effective in ameliorating many of the manifestations of Gaucher's disease and is a treatment in widespread use. Given that imiglucerase and miglustat are now both licensed for the treatment of Gaucher's disease, there is a need to review their therapeutic status. Here the treatment of type 1 (non-neuronopathic) Gaucher disease is evaluated with particular reference to the emerging role of oral N-butyldeoxynojirimycin (miglustat) as a substrate-reducing agent. This position statement represents the consensus viewpoint of an independent international advisory council to the European Working Group on Gaucher Disease.

[Gaucher's disease in children: first clinical signs, natural course and benefits of enzyme replacement therapy]. / La maladie de Gaucher chez l'enfant: mode de révélation, évolution naturelle, apports du traitement par l'enzyme de remplacement.

OBJECTIVES: Gaucher's disease is a rare genetic disease. Paediatric patients present with highly severe disease and, until now, literature does not provide many descriptions in children only. A specific enzyme replacement therapy has been available for the last decade. Quality of life has been improved by the treatment. POPULATION AND METHODS: We studied 17 Gaucher patients (14 type 1 and 3 type 3) diagnosed before the age of 15 and treated afterwards. The first clinical signs and the course of the disease are described before and during treatment. To appreciate the impact of the treatment on quality of life, we established a clinical score with the functional symptoms of the patients. RESULTS: The mean age was 6.4 years at diagnosis and 18.3 years at the beginning of the treatment. With specific treatment, all clinical and biological symptoms dramatically improved but some specific organic damages were irreversible. CONCLUSION: The comparison of our patients with other reported paediatric cases confirm that Gaucher's disease in children is severe and has to be precociously diagnosed and treated. Clinical scores appeared to be helpful to choose the moment for treating and to follow-up the patients under treatment.

Two cases of cerebral aspergillosis successfully treated with voriconazole.

Described here are two cases of cerebral aspergillosis successfully treated with voriconazole after the failure of first-line treatment with amphotericin B deoxycholate. In both cases, clinical and radiological cure was achieved within 6 weeks. Voriconazole should be considered as first-line therapy for cerebral aspergillosis.

Cervical involvement in SAPHO syndrome: imaging findings with a 10-year follow-up.

Osteoarticular manifestations of SAPHO syndrome include vertebral lesions, typically in the thoracic segment. Chronic inflammatory changes are well depicted by MRI. We report the imaging findings with a 10-year follow-up in a case of SAPHO syndrome with marked cervical lesions.

Deflazacort versus prednisone in patients with giant cell arteritis: effects on bone mass loss.

OBJECTIVE: To compare bone mass loss due to deflazacort versus prednisone in longterm treatment of patients with giant cell arteritis (GCA) in a randomized double blind comparative trial. METHODS: Seventy-four patients were included in a prospective multicenter study. Half received deflazacort (DFZ) and the other half prednisone (PR) for a minimum of 12 months. Calcium and vitamin D supplements were also provided to all subjects. Our intent was (1) to evaluate bone mineral density, using dual energy x-ray absorptiometry, at baseline and comparatively at 3, 6, and 12 mo; vertebral fractures by Meunier score and size variations after 12 mo treatments were also analyzed; (2) to assess calcium/phosphate metabolism modifications in both groups at baseline and after 12 mo. RESULTS: No significant difference was observed between the 2 groups in terms of treatment efficacy. Patients taking PR were slightly older on average versus the DFZ group (74 vs 70 yrs). Bone mass loss between entry and month 12 was not statistically different in the PR group (-0.026 +/- 0.007 g/cm2) compared to the DFZ group (-0.03 +/- 0.005 g/cm2). No significant difference was found in Meunier score variations (0.77 and 1.18 in the PR and DFZ groups, respectively; p = 0.3), nor in vertebral size variations (-0.4 and -0.2 in the PR and DFZ groups, respectively; p = 0.4). There was no difference in calcium/phosphate metabolism evaluations at month 12. CONCLUSION: In older patients taking longterm glucocorticoids who are at risk of osteoporosis, deflazacort did not result in less bone loss than prednisone.