Medical, psychological and social features in a large cohort of adults with Prader-Willi syndrome: experience from a dedicated centre in France.

BACKGROUND: Prader-Willi syndrome (PWS) is a developmental genetic disorder characterised by a variable expression of medical, cognitive and behavioural symptoms. In adulthood, the prevalence and severity of these symptoms determine the quality of life of the affected persons. Because of their rare disease condition, data on health and social problems in adults with PWS are scarce. In this research, we present medical, psychological and social features of a large cohort of adults admitted to a specialised PWS centre in France and analyse the differences according to genotype, gender and age. METHODS: Data from 154 patients (68 men/86 women), with a median age of 27 years (range 16-54), were collected during their stay in our centre. Clinical histories were completed using information from parents or main caregivers, and the same medical team performed the diagnosis of different clinical conditions. Statistical analyses were performed to determine the influence of factors such as genotype, age or gender. RESULTS: Paternal deletion genotype was the most frequent (65%) at all ages. Most patients had mild or moderate intellectual disability (87%). Only 30% had studied beyond primary school and 70% were in some special educational or working programme. Most of them lived in the family home (57%). The most prevalent somatic comorbidities were scoliosis (78%), respiratory problems (75%), dermatological lesions (50%), hyperlipidaemia (35%), hypothyroidism (26%), Type 2 diabetes mellitus (25%) and lymph oedema (22%). Some form of psychotropic treatment was prescribed in 58% of subjects, and sex hormones in 43%. Patients with deletion had a higher body mass index (44 vs. 38.9 kg/m(2)) and displayed higher frequency of sleep apnoeas. Non-deletion patients received insulin treatment (19% vs. 4%) and antipsychotic treatment (54.8% vs. 32.7%) more frequently. No difference was observed in the prevalence of Type 2 diabetes between the two genotype groups. Patients >27 years of age had a higher rate of comorbidities (Type 2 diabetes, hypertension, respiratory problems and lymph oedema). Gender differences were minor. CONCLUSIONS: Adult patients with PWS showed high prevalence of comorbid health problems that need to be monitored for early treatment. Some of them are influenced by genotype and age. Another salient problem concerns the lack of adapted structures for better social integration. Further data about the real life and health conditions of adults with PWS are necessary to further our knowledge of the natural history of the disease and to design appropriate care strategies.

Ex vivo model of congenital cytomegalovirus infection and new combination therapies.

INTRODUCTION: Congenital human cytomegalovirus (HCMV) infection is a major public health problem due to severe sequelae in the fetus and newborns. Currently, due to their toxicity anti-CMV treatments cannot be administered to pregnant women. We thus developed an ex vivo model of 1(st) trimester placental CMV infection to observe the route of infection across the placenta and to test the efficacy of various new drugs targeting different stages of viral cycle. METHODS: After validation of the viability of floating villi explants by ELISA ß-HCG, the kinetics of placental infection were determined by immunochemistry and qPCR in this ex vivo model. Antiviral susceptibility was determined in vitro using focus reduction assay and by qPCR in the ex vivo model. RESULTS: The ex vivo model showed viral infection in trophoblasts and mesenchymal space of floating villi. In vitro, antiviral combinations of maribavir with baïcalein or artesunate inhibited viral infection by more than 90%. On the other hand, in ex vivo model, infection was reduced by 40% in presence of maribavir and artesunate. The synergistic effect observed in vitro was not observed ex vivo. DISCUSSION: This model allowed us to understand the CMV spread in 1(st) trimester floating villi better and to analyze the anti-CMV efficacy and toxicity of new drugs that could be administered to pregnant women, either alone or in combination. CONCLUSIONS: Such an ex vivo model could be applied to other viruses such as rubella or parvovirus B19 and in new drug development.

Interest of human papillomavirus DNA quantification and genotyping in paired cervical and urine samples to detect cervical lesions.

BACKGROUND: Cervical cancer is caused by persistent infection with high-risk human papillomavirus (HR-HPV). Conventional human papillomavirus (HPV) testing requires cervical sampling. However, vaginal and urine self-sampling methods are more acceptable for patients and result in increased participation when they are available in screening programs. In this context, we have developed a non-invasive screening method via the detection of HPV DNA in urine samples. PURPOSE: To compare HPV viral loads and genotypes in paired cervical and urine samples, and to assess correlation between virological and cytological results in women seeking gynecological consultation. METHODS: Paired urine and cervical specimens were collected and analyzed from 230 of 245 women participating in the previously described prospective PapU study. HPV DNA detection and quantification were performed using a real-time PCR method with short fragment PCR primers. Genotyping was carried out using the INNO-LiPA HPV genotyping assay. RESULTS: The prevalence of HPV in the 230 paired urine and cervical smear samples was 42 and 49 %, respectively. Overall agreement for HPV positivity and negativity between the paired samples was 90 % (κ = 0.80). High HPV viral load in both cervical and urine samples was associated with cytological abnormalities. HPV-positive women were mostly infected with HR-HPV types. The agreement between high- and low-risk HPV (LR-HPV) detection in both samples was 97 % (κ = 0.95 for HR-HPV and κ = 0.97 for LR-HPV). CONCLUSIONS: High concordance rates for HPV-DNA quantification and high/low-risk HPV genotyping in paired urine/cervical samples suggest that urinary HPV DNA testing could be useful for cervical lesion screening.

Acute liver toxicity due to methylprednisolone: consider this diagnosis in the context of autoimmunity.

The occurrence of corticosteroid-induced hepatitis is a rare event that has been recently described in the literature. We report the case of an acute cytolytic hepatitis in a patient treated with methylprednisolone for multiple sclerosis associated with an autoimmune thyroid dysfunction. After ruling out other etiologies, we concluded that the acute liver injury was due to steroids, and we analyzed the specific circumstances in the literature where methylprednisolone may have been responsible for acute hepatitis.

[Historic malignant tumour: 27 observations]. / Tumeur maligne historique: 27 cas.

BACKGROUND: When used in the French medical literature to describe a pathological state, the word "historic" normally refers to tumours of startling appearance because of their size. It is difficult to understand how a patient can allow such tumours to continue to grow. We attempt to define this concept. PATIENTS AND METHODS: Two dermatologists carried out a retrospective, independent and comparative selection of photographs taken between 1978 and 2008 of malignant cutaneous tumours of unusual size given the histological diagnosis. Socio-professional, demographic, clinical, histological psychological data, and details of treatment history and progress were collected. RESULTS: Twenty-seven patients (11 M, 16 F) of mean age 74 years (34-99 years) presented a "historic" tumour. Twelve patients lived in rural regions. Five patients were company executives. The average duration of development of the "historic" tumours was 4.5 years (6-420 months). The tumours were classed histologically as epidermoid carcinomas (nine) and melanomas (seven). The mean size was 13 cm (6-30 cm). Psychiatric problems, membership of sects or dementia were noted for 13 patients. Treatment consisted of chemotherapy, radiotherapy or, less frequently, surgery. Eighteen patients died on average 13 months after diagnosis. DISCUSSION: "Historic" malignant tumour (also described in the literature as "giant" tumour) is a real-life fact. No studies have been made of a series of such patients. Despite histological diagnosis, the size was associated with slow tumoral progress and/or late treatment, chiefly accounted for by psychiatric disorders. Socio-professional data indicate that "historic" tumours are equally common in urban and rural areas.

[Calciphylaxis treated by cinacalcet: a medical alternative to parathyroidectomy]. / Le traitement de la calciphylaxie par cinacalcet: une alternative médicale à la parathyroïdectomie.

Calciphylaxis is a rare necrotizing calcifying arteriolopathy, with a poor prognosis, for which there is currently no effective treatment. One of the major challenges of the therapy is normalizing the calcium-phosphate balance. Therefore, cinacalcet, which inhibit the production of parathormone by negative feedback, was considered a treatment option to control the evolution of calciphylaxis in a dialysed patient suffering from cholangiocarcinoma.

Expression of c-Myc, neurofibromatosis Type 2, somatostatin receptor 2 and erb-B2 in human meningiomas: relation to grades or histotypes.

Meningiomas, which originate from arachnoid cells, represent one of the largest subgroups of intracranial tumors. They are generally benign, but can progress to malignancy. The aim of our study was to determine the expression of 4 genes, c-Myc, neurofibromatosis Type 2 (NF2), somatostatin receptor isoform 2 (sst2) and erb-B2, that have been associated with tumorogenesis or, possibly, with aggressive behavior or recurrence of meningiomas. We measured levels of mRNAs coding for these genes by qRT-PCR in 51 cases and levels ofc-Myc protooncogene and sst2 protein by immunohistochemistry in 26 cases of meningiomas of various grades and histotypes. C-Myc mRNA and protein levels were not grade-related, but validated subdivision of the 36 benign meningiomas into two groups, Groups IA and IB, based on histological and clinical features (Ki-67-proliferative index, absence or presence of mitoses, rate of recurrence and incidence of perilesional edema). In addition to histopathological grading, c-Myc expression may be useful in predicting tumor recurrence in patients with low-grade meningiomas. NF2 mRNA levels and sst2 mRNA and receptor levels were not grade-related, but were histotype-related, with significantly higher levels in the meningothelial subtype than in the fibroblastic subtype. Erb-B2 mRNA levels were not grade- or histotype-related. Furthermore, the high expression of sst2 in meningothelial meningioma suggests the possibility of a different tumorigenesis process in this meningioma subtype and may open perspectives for the diagnosis and therapy of this subtype using somatostatin as an antiproliferative agent.

Fatal-stroke syndrome revealing fungal cerebral vasculitis due to Arthrographis kalrae in an immunocompetent patient.

We report an uncommon clinical presentation of a unique case of fatal invasive fungal cerebral vasculitis due to Arthrographis kalrae in a nonimmunocompromised host. The identity of the fungus was determined by morphological characteristics and by analysis of internal transcribed spacer 1 sequences and was confirmed by postmortem examination of the brain tissues. Establishing rapidly the link between the clinical syndromes and the fungal infection of the central nervous system is essential to improve the outcome. As our case has shown, it is more challenging to make a diagnosis of fungal infection when there are no risk factors of immunodeficiency and when the clinical presentation seems uncommon.

[Verrucous carcinoma of the lower limbs]. / Carcinomes verruqueux des membres inférieurs.

BACKGROUND: Verrucous carcinoma is a rare, low-grade, slow-growing, well-differentiated squamous cell carcinoma affecting the skin (particularly on the foot) and mucosa. The diagnosis is often delayed. We report a study of twelve cases of verrucous carcinoma of the lower limbs. PATIENTS AND METHODS: We retrospectively studied a series of 12 patients (8 women, 4 men) who developed verrucous carcinoma of the lower limbs between 1978 and 2005 and we analyzed their follow-up data. RESULTS: The mean age of patients was 78 years (66-97 years). Eleven patients exhibited verrucous carcinoma in a previous lesion comprising varicose ulcer (5 cases), mixed ulcer (3 cases), burn (2 cases) or traumatic lesion (1 case). The mean time from onset of lesions to diagnosis was 28 years. Nine patients showed locoregional extension (8 bone involvement, 3 lymph node involvement). No visceral metastasis was detected. Three patients received medical treatment that proved ineffective. Two received secondary surgical treatment. Nine patients underwent surgery (6 amputations, 3 local excisions). Four patients were lost to follow-up, 4 died, 3 showed no recurrence and 1 had a chronic unhealed wound after surgery. DISCUSSION: Verrucous carcinoma of the lower limbs is a disease of the elderly, affecting both men and women, and occurring mainly on chronic venous ulcerations. The clinical presentation is evocative although histopathological diagnosis is difficult, particularly in the event of superinfection. Repeated and deep biopsies are needed to avoid delay in diagnosis. Extension is chiefly locoregional and visceral involvement is rare. Medical treatment is ineffective and may even be harmful, with surgery the best option. Regular monitoring is necessary because of the risk of relapse, although verrucous carcinoma does not seem to directly affect patient survival.

[Intracranial ependymomas in adult patients. Diagnosis and histological prognostic factors]. / Ependymomes intracrâniens de l'adulte. Diagnostic histologique et facteurs histopronostiques.

BACKGROUND: Intracranial ependymomas are rare in adults and histopathological prognostic factors are poorly determined. PURPOSE: A retrospective multicentric study was conducted in France in order to assess the prognostic value of histology. MATERIAL: Between 1990 and 2004, 216 adult patients with newly diagnosed ependymomas were treated in 19 French centers. Eligibility required institutional histopathological confirmation of an ependymoma and available clinical history and MRI features (see comparison paper). METHODS: Histological preparations and one paraffin embedded block from each patient were sent to Pr D. Figarella-Branger in Marseille. Central review by four neuropathologists (D. Figarella-Branger, A. Maues de Paula, C. Fernandez and A. Jouvet) was performed. Specimens for which all pathologists agreed with the histological diagnosis of ependymomas were included, whereas cases for which all disagree were excluded and reclassified. In the event of doubt and/or discrepancies between pathologists immunostaining was performed in order to reach a consensus diagnosis. Diagnostic of ependymomas was confirmed in 121 cases (56%). In theses cases, ependymomas were classified according to the WHO system (subtype and grade). The potential prognostic value (overall survival OS and disease free survival DFS) of the following histological parameters was examined: perivascular pseudorosettes, ependymal rosettes, hyalinized vessels, mitotic index, microvascular proliferation, necrosis, area of increased cellularity, nuclear atypia, brain invasion and Mib-1 labelling index. RESULTS: Among the 121 ependymomas, 88 were grade II (47 classic, 17 cellular, 2 papillar, 6 clear cells and 16 tanicytic) and 33 grade III. WHO grading, occurrence of microvascular proliferation, necrosis, nuclear atypia and high proliferative index were correlated with both OS and DFS. Moreover, quantification of certain parameters enabled a reproducible grading system correlated with both OS and DFS.

[Granulocytic sarcoma in a 90-year-old patient]. / Sarcome granulocytaire (chlorome) chez un patient âgé de 90 ans.

Granulocytic sarcoma rarely involves the orbit. It is the local proliferation of immature myeloid cells and occurs most often in patients suffering from myelodysplastic syndromes. We report a case of granulocytic sarcoma that revealed acute myeloid leukemia in a patient suffering from chronic myelomonocytic leukemia. At the time of diagnosis, the lesion involved the nasal fossae, the ethmoidal sinus, and the orbit, with subperiosteal tumoral infiltration toward the skin. The treatment involved surgery and radiotherapy. The patient died 3 months later of complications of the hematological disease. This observation is original for the occurrence of granulocytic sarcoma during chronic and well-known leukemia, the age of onset, and the fatal outcome in just a few weeks. In this observation, the ophthalmologist revealed the acute nature of the myelodysplastic syndrome.

Platelet-activating factor and human meningiomas.

Meningiomas are common primary intracranial tumours. Platelet-activating factor (PAF) is an inflammatory and angiogenic lipid mediator involved in several types of cancer. The presence of PAF receptor (PAF-R) transcripts, the levels of PAF, the phospholipase A2 activity (PLA2, the enzymatic activity implicated in PAF formation) and the PAF acetylhydrolase activity (AHA, the PAF degrading enzyme) were investigated in 49 human meningiomas. PAF-R transcripts, PAF, PLA2 and AHA were detected in meningiomas. However, their levels did not correlate with biological parameters such as the tumour grade, the presence of associated oedema, necrosis, mitotic index as well as intensity of the neovascularization and chronic inflammatory response. In conclusion, PAF is present in meningiomas where it might act on tumour growth by altering the local angiogenic and/or cytokine networks as previously suggested for human breast and colorectal cancer.

[Pyogenic granuloma revealing fistula and deep infection: five cases]. / Botriomycomes révélant une fistule et un foyer infectieux profond: cinq cas.

BACKGROUND: Pyogenic granuloma, or botryomycosis, occurring after minor injury or scratching with a septic implement, is a rapidly growing benign inflammatory vascular tumour, often involving the skin or mucous membrane. We report 5 unusual cases of pyogenic granuloma revealing fistula tracking to foreign bodies such as a pace-maker or orthopaedic material, and deep infectious sites with fistula. METHODS: This retrospective study included 5 men of average age 72.2 years over a period of 22 years (between 1981 and 2003). Clinical images were recorded and a diagnosis of botryomycosis was confirmed in all patients by histological analysis. Four patients presented suppuration. The time from initial clinical signs to diagnosis, presence of traumatic events, screening for microscopic organisms, response to systemic antibiotic therapy, recurrence and clinical features of botriomycosis were analysed. RESULTS: All patients presented botryomycosis with fistula and suppuration revealing deep bone infection and in one patient, pace maker infection. Complete resolution of the lesions occurred after excision of foreign material and prolonged systemic antibiotic therapy. CONCLUSION: We report the first series of botryomycosis revealed by fistula and showing deep infectious disease. Pyogenic granuloma is a well-known but rarely reported dermatologic condition.

The vervet monkey (Chlorocebus aethiops) as an experimental model for Trypanosoma brucei gambiense human African trypanosomiasis: a clinical, biological and pathological study.

It has long been known that the vervet monkey, Chlorocebus (C.) aethiops, can be infected with Trypanosoma rhodesiense, but this model has not been described for T. gambiense. In this study, we report the development of such a model for human African trypanosomiasis. Twelve vervet monkeys infected with T. gambiense developed chronic disease. The duration of the disease ranged between 23 and 612 days (median 89 days) in five untreated animals. Trypanosomes were detected in the blood within the first 10 days post-infection and in the cerebrospinal fluid, with a median delay of 120 days (n = 4, range 28-348 days). Clinical changes included loss of weight, adenopathy, and in some cases eyelid oedema and lethargy. Haematological alterations included decreases in haemoglobin level and transitory decreases in platelet count. Biological modifications included increased gamma globulins and total proteins and decreased albumin. Pathological features of the infection were presence of Mott's cells, inflammatory infiltration of either mononuclear cells or lymphocytes and plasma cells in the brain parenchyma, and astrocytosis. These observations indicate that the development of the disease in vervet monkeys is similar to human T. gambiense infection. We conclude that C. aethiops is a promising experimental primate model for the study of T. gambiense trypanosomiasis.

A report of a desmoplastic ganglioglioma in a 12-year-old girl with review of the literature.

Desmoplastic infantile ganglioglioma is a supratentorial tumor that typically occurs in infants below the age of 24 months. Rare tumors with the same radiological and histological characteristics have been described in older subjects. We report a case of desmoplastic ganglioglioma in a 12-year-old girl with a 13 years follow-up. The patient presented with an inaugural generalized seizure. CT scan demonstrated a large superficial parieto-occipital mass, attached to the dura with solid and cystic components. Surgical resection was macroscopically complete. No adjuvant treatment was given. Thirteen years after surgery, the patient is symptom free. Histological examination revealed a pleomorphic tumor involving the meningeal space and the cortex. Meningeal portion was made of neoplastic astrocytes enmeshed in a dense network of connective tissue. The cortical component showed abnormal neurons, tumoral astrocytes and small foci of poorly differentiated cells with rare mitoses. Our observation and the seven others found in the literature indicate that desmoplastic gangliogliomas can occur in children and even in young adults. Despite some worrisome radiological and histological features, these tumors should not be misdiagnosed as malignant glioma. Like infantile cases, non-infantile desmoplastic gangliogliomas seem to have a favorable prognosis without additional therapy, if a total surgical resection can be performed.

Detection of human cytomegalovirus genome and gene products in central nervous system tumours.

Human cytomegalovirus (HCMV) genome and related proteins have been reported in a great proportion of malignant gliomas. However, these results are unexpected since HCMV is not known as an oncogenic virus. By immunohistochemistry (with an anti-IE1 monoclonal antibody) and in situ hybridisation (with biotinylated DNA probes) on tissue microarrays and frozen sections, we investigated a French series of central nervous system (CNS) tumours, including 97 glioblastomas. In 10 cases of glioblastoma, rare astrocyte-like cells, admixed with tumour cells, stained positively for HCMV and in one case a doubtful staining of rare cells was noticed. This may indicate a reactivation of the virus under local immunosuppression but none of the cases of CNS tumours (n=132) contained HCMV genomes and/or proteins in a significant proportion of tumour cells. Our results strongly suggest that HCMV is unlikely to be implicated in the development of human malignant gliomas, at least in French cases.

[Adult laryngeal cavernous hemangioma: a case report]. / Malformation veineuse laryngée de l'adulte: à propos d'un cas.

We describe a case of laryngeal venous malformation, discovered by dysphonia. This malformation has a different histology and evolution compared to infant laryngeal hemangioma. The histological exam shows large and multiple vessels lined by regular endothelium. There is no spontaneous regression; this malformation can be stable or increase and induce a laryngeal obstruction. Although inconstant, a bluish colour, seen at endoscopy, suggests the presence of venous malformation. The diagnostic is confirmed by MRI, which shows local extension. We propose regular clinical and radiological supervision for asymptomatic venous malformations. Treatment is recommended only for symptomatic patients usually by laryngeal microsurgery or cervicotomy. Per cutaneous sclerosis is an interesting alternative therapy alone or prior to surgery. Regular follow-up is essential in order to detect frequent recurrences.