Cytophagic histiocytic panniculitis: is it a macrophage activation syndrome in situ?

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Clinical spectrum of MTOR-related hypomelanosis of Ito with neurodevelopmental abnormalities

PURPOSE: Hypomelanosis of Ito (HI) is a skin marker of somatic mosaicism. Mosaic MTOR pathogenic variants have been reported in HI with brain overgrowth. We sought to delineate further the pigmentary skin phenotype and clinical spectrum of neurodevelopmental manifestations of MTOR-related HI. METHODS: From two cohorts totaling 71 patients with pigmentary mosaicism, we identified 14 patients with Blaschko-linear and one with flag-like pigmentation abnormalities, psychomotor impairment or seizures, and a postzygotic MTOR variant in skin. Patient records, including brain magnetic resonance image (MRI) were reviewed. Immunostaining (n = 3) for melanocyte markers and ultrastructural studies (n = 2) were performed on skin biopsies. RESULTS: MTOR variants were present in skin, but absent from blood in half of cases. In a patient (p.[Glu2419Lys] variant), phosphorylation of p70S6K was constitutively increased. In hypopigmented skin of two patients, we found a decrease in stage 4 melanosomes in melanocytes and keratinocytes. Most patients (80%) had macrocephaly or (hemi)megalencephaly on MRI. CONCLUSION: MTOR-related HI is a recognizable neurocutaneous phenotype of patterned dyspigmentation, epilepsy, intellectual deficiency, and brain overgrowth, and a distinct subtype of hypomelanosis related to somatic mosaicism. Hypopigmentation may be due to a defect in melanogenesis, through mTORC1 activation, similar to hypochromic patches in tuberous sclerosis complex

A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity.

Heterozygosity for human () dominant-negative (DN) mutations underlies an autosomal dominant form of hyper-immunoglobulin E syndrome (HIES). We describe patients with an autosomal recessive form of HIES due to loss-of-function mutations of a previously uncharacterized gene, ZNF341 is a transcription factor that resides in the nucleus, where it binds a specific DNA motif present in various genes, including the promoter. The patients\u27 cells have low basal levels of STAT3 mRNA and protein. The autoinduction of STAT3 production, activation, and function by STAT3-activating cytokines is strongly impaired. Like patients with DN mutations, ZNF341-deficient patients lack T helper 17 (T17) cells, have an excess of T2 cells, and have low memory B cells due to the tight dependence of STAT3 activity on ZNF341 in lymphocytes. Their milder extra-hematopoietic manifestations and stronger inflammatory responses reflect the lower ZNF341 dependence of STAT3 activity in other cell types. Human ZNF341 is essential for the transcription-dependent autoinduction and sustained activity of STAT3

ALK-positive histiocytosis: a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition

ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in three infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailed clinicopathologic data of 39 cases, including 37 cases with confirmed ALKrearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (seven and twelve from Groups 1B and 2, respectively). Histology included classic xanthogranuloma features in almost one third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated-ERK, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, while CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, ten with neurologic involvement. This study presents the existing clinicopathologic and molecular landscape of ALK-positive histiocytosis, and provides guidance for the clinical management of this emerging histiocytic entity.Molecular tumour pathology - and tumour genetic

Fedotozine in Functional Dyspepsia: Results of a six week placebo-controlled multicentre trial

Efficacy and safety of fedotozine (FZ), a peripheral K agonist, were compared to that of placebo (PL) in patients with functional dyspepsia. Methods. A phase Ill, double blind, parallel group trial was carried out in UK and Eire by 25 hospital or general practice centers. The entry criteria were: presence of 2 or more post-prandial dyspeptic symptoms occurring at least 3 times a week in the previous 3 months; the symptoms included epigastric pain, early satiety, epigastric fullness or distension, nausea or vomiting, feeling of slow digestion. Each patient had negative gastroduodenoscopy, upper abdominal ultrasound and routine blood tests. Patients completed a diary card daily and rated the overall intensity of their symptoms (main criterion) as well as the intensity of each dyspeptic symptom using a 5 point scale. 333 patients entered the trial. At the end of the run-in period lasting 7 to 14 days, patients with a low symptomatic score were excluded. 271 patients (139 F/132 M, aged 42 ± 14 yrs, m ± SD) were randomized to receive either oral FZ, 30 mg tid (n = 140) or PL tid (n = 131) for 6 weeks. Intent-totreat analysis was performed comparing the mean over the 6wk treatment adjusted for the baseline value (ancova). Results. FZ and PL groups were comparable before treatment. During treatment, the improvement for the overall intensity of dyspeptic symptoms was significantly higher (treatment effect: 0.180; 95% Cl: 0.07 to 0.29; p = 0.002) on FZ group than on PL. So too were epigastric pain (p = 0.004) and nausea (p = 0.01). The difference for sensation of fullness was of borderline statistical significance (p = 0.052). The patient global score, average of the five individual symptoms, was significantly improved in the FZ group (p = 0.021). There was no significant difference in the incidence of adverse events. The number of withdrawals associated with adverse events was comparable on FZ (n = 13) and on PL (n = 10). Biological tolerance was similar for both groups