Early-onset granulomatous arthritis, uveitis and skin rash: characterization of skin involvement in Blau syndrome.

BACKGROUND: Blau syndrome (BS) is a rare monogenic autoinflammatory disease caused by NOD2 mutations. BS classically presents in early childhood as a triad of granulomatous polyarthritis, uveitis and skin involvement. Joint and ocular involvement have been characterized by several cohort studies but only very little data are available on skin lesions. OBJECTIVES: We aimed to provide a detailed clinical and microscopic analysis of skin manifestations and to study whether they may contribute to an early diagnosis. METHODS: We conducted a retrospective multicentre study in a French cohort of 21 patients diagnosed with genetically confirmed BS. RESULTS: Skin involvement was the first clinical manifestation of BS in 15/16 patients with dermatological manifestations. The presence of skin lesions was associated with significant shorter age at diagnosis (P = 0.03) and diagnostic delay (P = 0.04). Dermatological assessment allowed an earlier diagnosis (P = 0.001) and reduces the diagnostic delay (P = 0.007). Early skin lesions had a homogeneous, stereotypical clinical presentation, namely non-confluent erythematous or pigmented millimetric papules in 13/14(93%) patients. In contrast, skin lesions occurring during later disease stages had a more heterogeneous clinical presentation, including ichthyosiform dermatosis, panniculitis, livedoid lesions and vasculitis. Whatever their time of occurrence and the clinical aspect, all biopsied showed histologically presence of granuloma. CONCLUSION: Skin involvement in BS is the earliest clinical manifestation of the BS in the large majority of patients. The recognition of dermatological manifestations as granulomatous skin lesions and early dermatological expertise are the key to an early diagnosis of BS. In view of our results, it seems reasonable to propose a simplified view of skin lesions of BS in which the granuloma is the key structure.

[Familial chilblain lupus: Four cases spanning three generations]. / Lupus-engelures familial : quatre cas sur trois générations.

BACKGROUND: Familial chilblain lupus is a hereditary form of cutaneous lupus erythematosus seen in young children. It shows autosomal dominant inheritance due to mutations in the TREX-1 gene, or, more rarely, SAMHD1 or TMEM173 (STING). It belongs to the type I interferonopathies, i.e. inflammatory diseases associated with excessive interferon production and characterized by a positive "interferon signature". This is a rare entity with fewer than 10 families described to date. We report a new family followed over several years. PATIENTS AND METHODS: The patients were four subjects from the same family and spanning three generations (a brother and sister aged 17 and 15 years, their 39-year-old mother, and their 60-year-old grandfather). The initial cutaneous lesions on the extremities were described as papular, erythematous, purplish, infiltrated, hyperkeratotic, pruritic and/or painful. They occurred in childhood, improved during summer and stabilized over time. Immunological abnormalities such as positive antinuclear antibodies were noted. The interferon signature was positive in all patients. Molecular analysis of TREX-1, SAMHD1 and STING genes in both children showed no evidence of mutation. DISCUSSION: The cutaneous involvement was classic except for absence of the scarring and mutilating progression, photosensitivity and vasculopathy reported in other families. There was no intrafamily variability other than unconstant immunological abnormalities. At the molecular level, no mutations in the known genes were identified. A complementary molecular analysis is in progress. CONCLUSION: We report a new case of familial LEF, thus adding to knowledge about this very rare form of lupus erythematosus.

[Pansclerotic morphea with a rapidly fatal outcome in an 11-year-old girl]. / Morphée pansclérotique d'évolution rapidement létale chez une jeune fille de 11ans.

BACKGROUND: Pansclerotic morphea is a poorly described but extremely debilitating variant of localized scleroderma. We report a case with a rapidly fatal outcome in an 11-year-old girl. PATIENTS AND METHODS: An 11-year-old girl with a 2-year history of morphea presented at our institution in April 2012. The sclerosis had started on her trunk and progressed rapidly to involve her entire skin. Initial treatment with corticosteroids was ineffective and she presented extremely painful ulcerations of the lower limbs. The outcome was rapidly fatal, in early 2014, due to cachexia and sepsis after two amputations and several failed treatments including methotrexate. DISCUSSION: Pansclerotic morphea is characterized by rapidly progressing sclerosis involving the entire skin, trophic cutaneous ulcers, painful contraction and limited joint mobility. The prognosis is poor since the disease has an incapacitating and potentially fatal outcome. No reliably effective treatment has yet been established. CONCLUSION: Our case highlights the clinical characteristics of this uncommon form of localized scleroderma, the extremely severe prognosis, and the therapeutic challenge involved.

French recommendations for the management of non-infectious chronic uveitis.

This French National Diagnostic and Care Protocol (NDPC) includes both pediatric and adult patients with non-infectious chronic uveitis (NICU) or non-infectious recurrent uveitis (NIRU). NICU is defined as uveitis that persists for at least 3 months or with frequent relapses occurring less than 3 months after cessation of treatment. NIRU is repeated episodes of uveitis separated by periods of inactivity of at least 3 months in the absence of treatment. Some of these NICU and NIRU are isolated. Others are associated with diseases that may affect various organs, such as uveitis associated with certain types of juvenile idiopathic arthritis, adult spondyloarthropathies or systemic diseases in children and adults such as Behçet's disease, granulomatoses or multiple sclerosis. The differential diagnoses of pseudo-uveitis, sometimes related to neoplasia, and uveitis of infectious origin are discussed, as well as the different forms of uveitis according to their main anatomical location (anterior, intermediate, posterior or panuveitis). We also describe the symptoms, known physiopathological mechanisms, useful complementary ophthalmological and extra-ophthalmological examinations, therapeutic management, monitoring and useful information on the risks associated with the disease or treatment. Finally, this protocol presents more general information on the care pathway, the professionals involved, patient associations, adaptations in the school or professional environment and other measures that may be implemented to manage the repercussions of these chronic diseases. Because local or systemic corticosteroids are usually necessary, these treatments and the risks associated with their prolonged use are the subject of particular attention and specific recommendations. The same information is provided for systemic immunomodulatory treatments, immunosuppressive drugs, sometimes including anti-TNFα antibodies or other biotherapies. Certain particularly important recommendations for patient management are highlighted in summary tables.

Efficacy and tolerability of methotrexate in severe childhood alopecia areata.

BACKGROUND: Alopecia areata (AA) occurring in childhood is associated with a poorer prognosis than adult AA and may severely affect quality of life. The efficacy of methotrexate (MTX) was reported in adults with AA but there is little information about its use in children. OBJECTIVES: We aimed to assess the efficacy and safety of MTX in severe childhood AA. METHODS: We conducted a retrospective study including children with severe AA treated with MTX in the Departments of Paediatric Dermatology in France between November 2005 and December 2009. RESULTS: Fourteen children (eight girls and six boys) aged between 8 and 18 years (mean 14·7) were included. AA was present for a mean duration of 5·7 years (range 2 months-11 years 8 months). The treatment was administered once weekly, the mean maximal dose was 18·9 mg weekly (range 15-25) and the mean duration of treatment was 14·2 months (range 1-31). Thirteen children were assessable. Of these 13 children, MTX was considered as successful (regrowth >50% of hair) for five of them. The remaining eight children were considered treatment failures. No serious side-effects were reported. CONCLUSIONS: The efficacy of MTX in children with severe AA is variable. MTX may be considered for severe childhood AA in the absence of alternative effective treatments.

[Livedoid erythema of the lower back revealing thrombosed abdominal aortic aneurysm]. / Érythème lombaire livédoïde révélateur d'un anévrisme thrombosé de l'aorte abdominale.

BACKGROUND: We report the case of a patient presenting a very painful livedo of the lower back as well as paraparesis revealing a complicated abdominal aortic aneurysm. PATIENTS AND METHODS: A 61-year-old man was referred to our emergency unit for sudden lower back pain and weakness of the lower limbs. He had a large and very painful livedo racemosa on the lower back as well as partial neurological deficit of the lower limbs. Abdominal CAT revealed a bulky thrombosed infrarenal aortic aneurysm. Despite surgery, ischaemia worsened, leading to cutaneous then muscular and visceral necrosis, followed by death. DISCUSSION: Livedo racemosa of the lower limbs may be the consequence of thrombosis or embolism resulting from an abdominal aortic aneurysm. Livedo racemosa on other skin areas is uncommon but may be due to the same physiopathology. Neurological deficit is occasionally associated with a complicated abdominal aortic aneurysm or with surgical treatment thereof. However, to our knowledge, livedo on the back associated with neurological deficit has not yet been reported. Such an association should prompt practitioners to screen for a thrombosed aortic aneurysm. Furthermore, this condition is also likely to carry a poor prognosis because of the proximal secondary location of the thrombotic phenomenon, involving the lumbar arteries, which supply the medullar, cutaneous and muscular arteries.

[Malignant acanthosis nigricans associated with cholangiocarcinoma]. / Acanthosis nigricans malin révélant un cholangiocarcinome.

INTRODUCTION: Acanthosis nigricans is a dermatosis characterized by the presence of a hyperpigmented, velvety cutaneous thickening in the flexural areas, especially axillary and inguinal fossas, and lateral faces of the neck. AN is usually a benign condition but can sometimes reveal an internal malignancy corresponds to a cutaneous paraneoplasic syndrome. Literature shows a predominant association with gastric adenocarcinoma. Here, we report a rare association between AN and cholangiocarcinoma. CASE REPORT: We report a 43-year-old woman who presented an extensive AN associated to a tripe palms syndrome and florid cutaneous papillomatosis. She consulted in dermatology because of the itchiness of the lesions as well as for esthetics reasons. Complementary investigations enabled to diagnose a cholangiocarcinoma without visceral metastasis and she was treated by tumor resection and chemotherapy. Consequently, a slight improvement of the skin condition and the disappearance of pruritus were observed. CONCLUSION: AN should be considered as cutaneous sign either of malignancy or endocrinopathy and therefore requires further investigations. The existence of extensive lesions, pruritus, tripe palms syndrome, florid cutaneous papillomatosis or mucous lesions, associated to an AN is a sign of malignancy should be investigated urgently the early diagnosis of which can lead to a better prognosis.

[Two cases of papular elastorrhexis]. / Elastorrhexie papuleuse : deux cas.

BACKGROUND: Papular elastorrhexis is a rare dermatosis characterized by asymptomatic papules on the trunk and the upper extremities. Histological examination shows loss and fragmentation of elastic fibres as well as thickening of collagen bundles. PATIENTS AND METHODS: Case 1: a 46-year-old man was examined with asymptomatic papular lesions for 20 years. Firm and clearly delineated papules ranging from few millimetres to 2cm in diameter became wrinkled at their surface. They were located on the back and symmetrically on the upper limbs. The oldest of them were 15cm wide. Histological examination showed thickened collagen bundles with almost complete loss of dermal elastic fibres, fragmentation of elastic fibres around the lesion and mucin deposits. Standard laboratory tests and bone X-rays were normal. Case 2: a 34-year-old man consulted for clearly delineated asymptomatic papules on the back present for four years. Histological examination was similar to the previous patient and the laboratory tests were normal. He developed Hodgkin's lymphoma. DISCUSSION: We report these two cases because of their particularities as well as the rarity of papular elastorrhexix. The first exhibited large lesions and mucin deposits while the second was associated with Hodgkin's disease. Differential diagnosis of papular elastorrhexis includes Buschke-Ollendorff syndrome, eruptive collagenoma and elastic tissue disorders: macular anetoderma, mid-dermal elastolysis, nevus anelasticus, acne scars and pseudoxanthoma elasticum. The aetiology is unknown. There are no extracutaneous signs.

[Granuloma annulare of the eyelid in a child: an atypical localization]. / Granulome annulaire des paupières: une localisation atypique.

BACKGROUND: Granuloma annulare is a common form of dermatosis in children and young adults. Lesions are typically found on the hands, the feet and the extensor surfaces of the limbs, and occasionally on the trunk. We report a case original in terms of its palpebral localization. CASE-REPORT: A 5 year-old girl consulted for papular lesions on the eyelids. The clinical examination revealed papules on the right lower eyelid measuring 8 mm, on the left lower eyelid measuring 5 mm and on the right upper eyelid measuring 3 mm. Laboratory tests including serum glucose, lipids and calcium as well as a complete blood count proved normal. Biopsy showed granulomatous lesions: a region of central necrosis surrounded by a palisade of inflammatory cells confirmed the diagnosis of granuloma annulare. The lesions disappeared in a few weeks without treatment. DISCUSSION: To our knowledge, 44 cases of granuloma annulare of the periorbital area have been reported, of which 19 concerned children. This presentation represents an atypical localization of granuloma annulare which must not be confused with many other palpebral disorders. Biopsy is necessary to confirm the diagnosis.

Histone acetylation-mediated chromatin compaction during mouse spermatogenesis.

One of the most dramatic chromatin remodelling events takes place during mammalian spermatogenesis involving massive incorporation of somatic and testis-specific histone variants, as well as generalized histone modifications before their replacement by new DNA packaging proteins. Our data suggest that the induced histone acetylation occurring after meiosis may direct the first steps of genome compaction. Indeed, a double bromodomain-containing protein expressed in postmeiotic cells, Brdt, shows the extraordinary capacity to specifically condense acetylated chromatin in vivo and in vitro. In elongating spermatids, Brdt widely co-localizes with acetylated histones before accumulating in condensed chromatin domains. These domains preferentially maintain their acetylation status until late spermatogenesis. Based on these data, we propose that Brdt mediates a general histone acetylation-induced chromatin compaction and also maintains differential acetylation of specific regions, and is therefore involved in organizing the spermatozoon's genome.

[Babywalker use (baby-trot, youpala): an unsafe practice]. / Utilisation du trotteur (baby-trot, youpala): une conduite à risque.

AIM: Epidemiological analysis of accidents related to babywalker use admitted to a pediatric emergency department. METHODS: Retrospective, descriptive study of injuries related to babywalkers admitted to the pediatric emergency department between January 1st, 2003 and December 31st, 2005. RESULTS: One hundred and seventy-eight children were admitted due to an accident related to babywalker use. The sex ratio was 1.7 with a male prevalence. Mean age was 11+/-4 months. Seventy-eight percent of babywalker-related injuries were attributable to fall down a flight of stairs. The mean number of steps that a child fell down was 7 (range 1-20 steps). The repartition of accidents was bimodal: during the year, 1 peak in May and 1 in October; during the week: 54% of the cases occurred on Thursday or on the weekend; during the day (1 peak between 10 a.m. and 1 p.m. and 1 peak between 4 p.m. and 7 p.m.). Non-severe head traumas represented the most frequent injury (72%). Twenty-one children were hospitalised for concussion (N=15), cranial fractures (N=3), forearm fracture (N=1), dental subluxation (N=1) and extradural hematoma (N=1). A social problem (families with unsafe domestic practices) was identified in 26 children (15%), 16 of these situations were recognized due to the retrospective character of the study and the analysis of hospital admissions after the first accident. CONCLUSION: Stairway related falls associated with babywalker use and fall down in the stairs are very frequent in children less than 1 year-old. This resulted in babywalkers being prohibited in Canada since 2004. In several countries, advocates are working to ban babywalkers. Active or passive prevention methods have shown their limits. This unsafe and dangerous practice should be banned in France.

Complex regional pain syndrome type I in children. Clinical description and quality of life.

INTRODUCTION: Complex regional pain syndrome type 1 (CRPS I) in children differs from its adult counterpart and relevant literature is scarce. Our aim was to investigate potential risk factors and to assess midterm outcome and quality of life. MATERIAL AND METHODS: Medical records of patients diagnosed with CRPS I between 2004 and 2012 were analyzed. Patients and parents were called for a phone interview including the PEDS Quality of Life 4-0 questionnaire. Results were compared to a control group matched for age, gender and socio-economic status. RESULTS: Seventy-three patients were included (64 girls, 9 boys). Mean age at diagnosis was 11.5 years and mean time to diagnosis was 14.2 months. The lower limb was affected in 89% of cases. Allodynia, coldness and cyanosis were noted in 95%, 81% and of 74% of cases, respectively. Forty-nine percent of patients reported a physical injury. Multivariate analysis showed a strong association with being anxious (OR = 44.9, 95% CI [7.4-273]), presence of an atopic background (OR = 25.0, 95% CI: [4.6-135]), being good to excellent school performers (OR = 8.4 95% CI [1.3-52.1]), and having trouble falling asleep (OR = 5.3, 95% CI [1.6-17.0]). At a mean 37 months' follow-up (12-102), PEDS QL 4-0 score was significantly lower in CRPS patients compared to controls. Fifty-seven percent of patients acknowledged healing and 55% had presented a relapse. CONCLUSION: Childhood onset CRPS I affects predominantly preadolescent girls at the ankle. The present study highlights the relatively poor outcome, especially its physical and emotional aspects and the large role of psychology. LEVEL OF EVIDENCE: IV.

A large national cohort of French patients with chronic recurrent multifocal osteitis.

OBJECTIVE: To document more fully the characteristics of chronic recurrent multifocal osteomyelitis (CRMO) in pediatric patients, to collect data on the outcomes and management of the disease, and to define prognostic factors. METHODS: One hundred seventy-eight patients were included (123 female patients and 55 male patients), with a mean ± SD age at diagnosis of 10.9 ± 2.9 years. Inclusion criteria were a diagnosis of CRMO, evidence of at least one lesion of osteitis confirmed by imaging, and development of the syndrome before age 18 years. RESULTS: Longitudinal clinical and imaging studies revealed that only 12 of 178 CRMO patients (7%) had unifocal lesions at the last medical visit. We were able to apply the clinical chronic nonbacterial osteomyelitis score to 110 of 178 patients (62%), which indicated that bone biopsy could have been avoided in 27 cases (25%). At the last medical visit, disease was in remission in only 73 of 171 patients (43%) (41% receiving therapy) after a mean ± SD of 47.9 ± 38.9 months; 44 of 171 patients (26%) experienced sequelae. Using cluster analysis, the CRMO cohort was separated into 3 homogeneous phenotypes (severe, mild, and intermediate). Patients with the severe phenotype had the worst prognosis. This group was entirely composed of male patients, most of whom had the multifocal form of CRMO and inflammatory syndrome. Patients with the mild phenotype had the best prognosis. This group was primarily composed of female patients with a unifocal form of CRMO and infrequent clavicle involvement and inflammatory syndrome. Patients with the intermediate phenotype had a good prognosis but greater reliance on treatment. This group primarily included female patients with multifocal lesions and inflammatory syndrome. CONCLUSION: This is the largest CRMO cohort described in the literature to date. Clinical evolution and imaging investigations confirmed the multifocal pattern of the disease. Three distinct subgroups of CRMO patients were distinguished, with very different prognoses.

Regulated hyperacetylation of core histones during mouse spermatogenesis: involvement of histone deacetylases.

Here we report a detailed analysis of waves of histone acetylation that occurs throughout spermatogenesis in mouse. Our data showed that spermatogonia and preleptotene spermatocytes contained acetylated core histones H2A, H2B and H4, whereas no acetylated histones were observed throughout meiosis in leptotene or pachytene spermatocytes. Histones remained unacetylated in most round spermatids. Acetylated forms of H2A and H2B, H3 and H4 reappeared in step 9 to 11 elongating spermatids, and disappeared later in condensing spermatids. The spatial distribution pattern of acetylated H4 within the spermatids nuclei, analyzed in 3D by immunofluorescence combined with confocal microscopy, showed a spatial sequence of events tightly associated with chromatin condensation. In order to gain an insight into mechanisms controlling histone hyperacetylation during spermiogenesis, we treated spermatogenic cells with a histone deacetylase inhibitor, trichostatin A (TSA), which showed a spectacular increase of histone acetylation in round spermatids. This observation suggests that deacetylases are responsible for maintaining a deacetylated state of histones in these cells. TSA treatment could not induce histone acetylation in condensing spermatids, suggesting that acetylated core histones are replaced by transition proteins without being previously deacetylated. Moreover, our data showed a dramatic decrease in histone deacetylases in condensing spermatids. Therefore, the regulation of histone deacetylase activity/concentration appears to play a major role in controling histone hyperacetylation and probably histone replacement during spermiogenesis.

[Treatment of chemotherapy induced emesis in children]. / Traitement des vomissements induits par la chimiothérapie des cancers chez l'enfant.

In recent years, the management of chemotherapy-induced emesis in children has been greatly modified by the introduction of a new therapeutic class: serotonin antagonists. Based on a better knowledge of mechanisms, the treatment now uses combinations of different drugs. These treatments need to be carefully adapted to the patient and to the emetic risk of the chemotherapy, also taking into account the minimal cost. A gradual treatment proposal in five steps is described.

[Noninfectious febrile inflammatory syndromes in children: diagnosis and usefulness of diagnostic procedures]. / Syndromes inflammatoires fébriles non infectieux de l'enfant: diagnostic, contribution des examens complémentaires.

OBJECTIVE: To determine the causes and to quantify the benefits obtained from further diagnostic investigations in children presenting with a non infectious inflammatory fever. METHODS: The records of 62 children aged from two-months to 15 years (median: four years) admitted to a paediatric department between 1990 and 2000 for the evaluation of a fever associated to an inflammatory syndrome, defined as temperature over 38 degrees C with an increase of the erythrocyte sedimentation rate (ESR) more than 20 mm/h and/or a serum C-reactive protein level (CRP) > 20 mg/L, and excluding overt infectious diseases, were retrospectively reviewed. RESULTS: Of these patients, 79% children (49 cases) had inflammatory systemic disease, 3.2% (two cases) had malignancy, and 17.8% (11 cases) had undiagnosed disorders. The most frequent disease was Kawasaki disease (22 children), especially in young children. Increase of ESR above 100 mm/h and of CRP above 100 mg/L was present in 59% of Kawasaki disease, 71% of idiopathic juvenile arthritis, 100% of malignancies and 7% of unknown diagnoses. Increase of ESR below 50 mm/h and of CRP below 50 mg/L was present in 75% of hemophagocytic syndromes and 46% of unknown diagnosis. The polymorphonuclear count, hepatic function evaluation, triglycerides levels, abdominal ultrasound, abdominal computed tomography, echocardiography, biopsies were useful diagnosis tools. Technetium scintigraphy was helpful only when abnormalities were found on physical examination. CONCLUSION: The diagnosis of Kawasaki disease must be quickly suspected in febrile young children with inflammatory syndrome without infection. ESR and CRP values, abdominal ultrasound and echocardiography are helpful tools for the diagnostic procedure.

[Atypical onset of Churg and Strauss syndrome in a child]. / Révélation atypique d'un syndrome de Churg et Strauss chez l'enfant.

We report the case of a 13-year-old boy who had been treated since the age of 6 for moderate asthma. Except asthma, his past medical history was uneventful. The patient was referred for the sudden onset of bilateral leg edemas with peripheral purpuric lesions. Blood tests showed increased blood eosinophilia (9000/mm(3)) with no fever. The antineutrophil cytoplasmic antibodies (ANCA) were negative. The skin biopsy showed extensive ischemic subcutaneous necrosis related to necrotizing vasculitis. The general secondary symptoms occurred with multiorgan involvement (pulmonary infiltrates, peripheral neuropathy, gastrointestinal tract symptoms, and arthralgia). Genital infiltration was also noted. The child's general health was preserved. Neither cardiac nor renal involvement were found. The patient showed favorable clinical progression after oral prednisone therapy.