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Histiocytoses are rare disorders of unknown origin with highly heterogeneous prognosis. BRAF mutations have been observed in Langerhans cell histiocytosis (LCH). We investigated the frequency of BRAF mutations in several types of histiocytoses. Histology from 127 patients with histiocytoses were reviewed. Detection of BRAF(V600) mutations was performed by pyrosequencing of DNA extracted from paraffin embedded samples. Diagnoses of Erdheim-Chester disease (ECD), LCH, Rosai-Dorfman disease, juvenile xanthogranuloma, histiocytic sarcoma, xanthoma disseminatum, interdigitating dendritic cell sarcoma, and necrobiotic xanthogranuloma were performed in 46, 39, 23, 12, 3, 2, 1, and 1 patients, respectively. BRAF status was obtained in 93 cases. BRAF(V600E) mutations were detected in 13 of 24 (54%) ECD, 11 of 29 (38%) LCH, and none of the other histiocytoses. Four patients with ECD died of disease. The high frequency of BRAF(V600E) in LCH and ECD suggests a common origin of these diseases. Treatment with vemurafenib should be investigated in patients with malignant BRAF(V600E) histiocytosis.

Background: The purpose of this study was to report long-term results of rituximab induction monotherapy in patients with low-tumor-burden follicular lymphoma (LTBFL)., Patients and Methods: Of 49 first-line LTBFL patients who received weekly doses of rituximab (375 mg/m(2)), 46 have been followed with a long-term analysis of clinical and molecular responses., Results: Best clinical response (at any staging within a year following treatment) was 80%, 24 (52%) patients had complete or unconfirmed complete response, 13 (28%) had partial response and 9 (20%) had stable or progressive disease. Of 31 patients having a positive bcl2-JH rearrangement, 15 (48%) became negative following treatment. After 83.9 months of follow-up (95% confidence interval 6.4-92.8 months), the median progression-free survival is 23.5 months and overall survival (OS) is 91.7%. Five patients died (one progression, one myelodysplasia, one diffuse large B-cell lymphoma and two solid tumors). Seven patients (15%) are progression-free including five who are bcl2 informative. No unexpected long-term adverse event has been observed., Conclusion: A significant proportion of patients remain progression-free 7 years after a single 4-dose rituximab treatment in first-line LTBFL. The 7-year overall survivalOS is very high in this selected population of patients.

Enteropathy-associated T-cell lymphoma (EATL) is a rare non-Hodgkin lymphoma frequently associated with celiac disease. We report a case of EATL complicating adult autoimmune enteropathy (AIE). Analysis of phenotype, rearrangements in T-cell receptor genes, and chromosome alterations by high-resolution comparative genomic hybridization identified features distinct from those described for types I and II EATL. Furthermore, EATL arose from a single T-cell clone that had been present for several years in AIE-associated, oligoclonal, intestinal T-cell infiltrate. Emerging T-cell clones should be monitored in patients with AIE who receive long-term immunosuppressive therapy., (Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: To determine and list the clinical and pathological features of cutaneous hematologic diseases in childhood., Procedure: We retrospectively analyzed the data for 51 patients up to 15 years of age, who presented with primary cutaneous hematologic disorders according to the WHO-EORTC classification, at Necker-Enfants Malades Hospital, Paris, France, over a 17-year period. The cases were classified into the following diagnostic categories: CD30+ T-cell lymphoproliferative disorders (24) all consisting of lymphomatoid papulosis (LyP, 24), lymphoblastic lymphoma (LL, 7), acute leukemias (AL, 7), mycosis fungoides (MF, 5), Epstein-Barr virus-related lymphoproliferative disorders (EBV-related LPD, 5), T/NK-cell lymphoma, nasal type (1), γ/δ T-cell lymphoma (1), and panniculitis-like T-cell lymphoma (1)., Results: We encountered a majority of LyP. No secondary lymphoma was found in LyP patients with a median follow-up of 8 years. 29% and 80% of LyP and MF patients, respectively, presented with pityriasis lichenoides chronica (PLC) before onset of disease. Owing to a frequently misleading clinicopathological presentation, MF patients were first underdiagnosed. Clinicopathological features of LL and AL were highly stereotypical, leading to the diagnosis being suspected and confirmed more promptly. In the latter patients and in EBV-related LPD patients, skin lesions usually led to the discovery of systemic disease., Conclusion: Distribution of cutaneous hematologic diseases seems to be different in adults and in children aged <15-year old. PLC was strongly correlated with MF and LyP. Physicians must be made aware of the stereotypical clinical presentations of LL and AL to allow prompt diagnosis and treatment., (Copyright © 2011 Wiley Periodicals, Inc.)

Following the introduction of tacrolimus, intestinal transplantation is now a valid option for patients with chronic intestinalfailure. However, its outcome is undermined by the abundant lymphoid component of the graft and the septic nature of the procedure. The heavy immunosuppression necessitated by this transplant, and its non specific nature, creates a risk of infectious and tumoral complications. Several approaches are being tested to improve the immune tolerance of intestinal grafts, both in animals models and in the clinic. The most promising seek to induce specific tolerance while sparing antimicrobial and antitumoral immunity.

Background: Lymphoblastic lymphoma (LBL) is a rare malignant neoplasm usually occurring in the mediastinum of children and adolescents. The B-cell immunophenotype of LBL (B-LBL) accounts for less than 20% of all cases and may involve extramediastinal areas, such as the skin. Although highly aggressive, LBL is potentially curable if diagnosed early., Objective: We sought to describe the clinical and histopathologic features of B-LBL in children presenting with cutaneous lesions, and to highlight the specific features of this rare and serious disease., Methods: Seven children with a confirmed diagnosis of cutaneous B-LBL were identified by retrospective chart review. The clinical and histopathologic features were documented, analyzed, and compared with cases previously published in the literature., Results: Six children developed nodules on the head, and one child presented with lesions on the back and abdomen. Histopathology showed a diffuse dermal and subcutaneous monomorphous infiltrate made up of atypical cells with an immature B-cell phenotype. The average duration of the lesions before diagnosis was 3.2 months. A staging workup revealed extracutaneous disease in 5 patients, including bone-marrow involvement in 4 children., Limitations: This was a retrospective study with a small number of patients., Conclusion: The cutaneous lesions of B-LBL typically manifest as rapidly growing erythematous firm nodules located on the head. Awareness of these clinical features is important for the diagnosis to be reached rapidly and treatment started without delay., (Copyright © 2010 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)

Background: Chronic allograft injury, the primary cause of late allograft failure in renal transplantation, can be diagnosed early at a preclinical stage by histopathological changes such as interstitial fibrosis (IF). Currently, assessed by semiquantitative analysis in the Banff classification, IF quantification is limited by pathologist's subjective interpretation., Methods: We have designed algorithms dedicated to quantify IF by computerized color image analysis. This innovative and objective software automatically extracts the green areas characteristic of IF in Masson's trichrome based on color image segmentation followed by removal of nonspecific IF staining (capsula, sclerosis glomeruli and normal glomeruli, normal basement membrane) and computes an index. It also counts automatically the number of glomeruli. Sixty-seven Masson stained renal transplant biopsies at various IF stages were imaged using a digital color camera mounted on a microscope. We tested the robustness of the method against varying acquisition parameters., Results: We demonstrated that the parameters do not have an impact on this quantification and that the algorithm is able to handle biopsy color variations. The intra- and interobserver reproducibility was good (P<0.003). The kappa coefficient that was performed on another set of 90 biopsies to evaluate the concordance of our method with an expert Banff quantification was 0.68, indicating a substantial agreement. Finally, the computerized IF correlated with renal function., Conclusion: This study demonstrates that computerized color image analysis is a reliable and reproducible method to evaluate renal IF in routine practice and in multi-centric studies.

Retiform hemangioendothelioma (RH) is a rare low-grade malignancy angiosarcoma, with a high rate of local recurrence and a low metastatic risk. A 6 year-old girl with a large cervical cystic lymphangioma diagnosed by ultrasound and Doppler ultrasound, which showed a large multiloculated anechoic cyst with no flow. The lymphangioma was treated with injections of Picibanil (OK-432). The tumor regressed, but after a year, she developed a poorly limited infiltrated plaque spreading out regularly over her chest, back, and shoulder. The biopsy showed a poorly limited dermal and subcutaneous vascular proliferation composed of elongated arborising vessels lined with ovoid endothelial cells in a hobnail pattern. In addition, the deep part of the lesion showed typical features of a papillary intralymphatic angioendothelioma pattern (PILA) or Dabska tumor. The endothelial cells strongly expressed podoplanin (D2-40). A diagnosis of RH with focal areas of PILA was reached. The girl died 8 months after surgery of hypovolemic shock in a context of diffuse lymphangiomatosis with pulmonary localization. To our knowledge, RH has hardly ever been described in children. This entity exhibits a continuum with the PILA, sharing not only morphological and immunohistochemical similarities but also its ability to develop in a context of a vascular anomaly, particularly a lymphangioma. The role of Picibanil in the development of this tumor can be discussed.

Aims: To describe the histopathological features of heterotopic cutaneous meningeal tissue., Methods and Results: Nineteen cases were collected between 1993 and 2010. Immunohistochemistry for epithelial membrane antigen (EMA), neuron specific enolase (NSE), S100, glial fibrillary acid protein (GFAP), progesterone receptor (PR), CD31, glucose transporter-1 (Glut-1), podoplanin and NKI-C3 was performed. Lesions were congenital (100%) and presented as aplasia cutis with alopecia (63%) or lumps (37%), on the scalp (18 of 19) and sacral region. Resonance magnetic imaging revealed four underlying anomalies of the neuraxis. Histopathological analysis showed meningeal tissue arranged in four variably associated architectural patterns: fibrous (100%), pseudovascular (100%), cellular (68%) and pseudomyxoid (32%). Other features included collagen bodies (58%), calcifications (26%) and dermal melanocytes (32%). Heterotopic brain tissue or heterotopic ependymal cyst was associated in two cases. Arachnoidal cells expressed EMA and NSE, but not S100 protein, CD31 or GFAP. They expressed podoplanin (93%), especially in pseudovascular areas, NKI-C3 (79%), and less frequently Glut-1 (46%) and PR (30%)., Conclusions: Histopathological features of cutaneous meningeal heterotopias are various and sometimes misleading. Fibrous lesions should not be misdiagnosed as aplasia cutis. Podoplanin-positive pseudovascular spaces represent the main pitfall and should not be diagnosed as lymphangioma. Correct diagnosis is confirmed by EMA and NSE coexpression within the lesion., (© 2011 Blackwell Publishing Limited.)

In human B-acute lymphoblastic leukemia (B-ALL), RAG1-induced genomic alterations are important for disease progression. However, given that biallelic loss of the RAG1 locus is observed in a subset of cases, RAG1's role in the development of B-ALL remains unclear. We chose a p19Arf(-/-)Rag1(-/-) mouse model to confirm the previously published results concerning the contribution of CDKN2A (p19ARF /INK4a) and RAG1 copy number alterations in precursor B cells to the initiation and/or progression to B-acute lymphoblastic leukemia (B-ALL). In this murine model, we identified a new, Rag1-independent leukemia-initiating mechanism originating from a Sca1(+)CD19(+) precursor cell population and showed that Notch1 expression accelerates the cells' self-renewal capacity in vitro. In human RAG1-deficient BM, a similar CD34(+)CD19(+) population expressed p19ARF. These findings suggest that combined loss of p19Arf and Rag1 results in B-cell precursor leukemia in mice and may contribute to the progression of precursor B-ALL in humans.

Mutations of the EPCAM gene have been recently identified in Congenital Tufting Enteropathy (CTE), a severe autosomal recessive gastrointestinal insufficiency of childhood requiring parenteral nutrition and occasionally intestinal transplantation. Studying seven multiplex consanguineous families from the Arabic peninsula (Kuwait and Qatar) we found that most patients were homozygote for a c.498insC mutation in exon 5. The others carried a novel mutation IVS4-2A→G. Both mutations were predicted to truncate the C-terminal domain necessary to anchorage of EPCAM at the intercellular membrane. Consistently, immunohistochemistry of intestinal biopsies failed to detect the EPCAM protein at the intercellular membrane level. The c.498insC mutation was found on the background of a minimal common haplotype of 473kb suggesting a very old founder effect (5000-6000 yrs)., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

A child with plexiform fibrohistiocytic tumor is presented, in whom a superficial biopsy was misdiagnosed as an inflammatory granuloma. Cytogenetic analysis revealed a 46,X,del(X)(q13)[3]/46,XX[23] karyotype. However, fluorescence in situ hybridization (FISH) and array-comparative genomic hybridization (CGH) analysis failed to detect any numerical or quantitative genomic anomaly. Because of lack of specific chromosomal hallmarks, a molecular diagnosis of plexiform fibrohistiocytic tumor with the currently available tools is not reliable., (© 2011 Wiley Periodicals, Inc.)

The distinction between Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL), two types of mature aggressive B-cell lymphomas that require distinct treatments, can be difficult because of forms showing features intermediate between DLBCL and BL (here called BL/DLBCL). They can be discriminated by the presence of c-myc translocations characteristic of BL. However, these are not exclusive of BL and when present in DLBCL are associated with lower survival. In this study, we show that Epstein-Barr virus-induced gene 3 (EBI3) is differentially expressed among BL and DLBCL. Analysis of gene expression data from 502 cases of aggressive mature B-cell lymphomas available on Gene Expression Omnibus and immunohistochemical analysis of 184 cases of BL, BL/DLBCL or DLBCL, showed that EBI3 was not expressed in EBV-positive or -negative BL cases, whereas it was expressed by over 30% of tumoral cells in nearly 80% of DLBCL cases, independently of their subtypes. In addition, we show that c-myc overexpression represses EBI3 expression, and that DLBCL or BL/DLBCL cases with c-myc translocations have lower expression of EBI3. Thus, EBI3 immunohistochemistry could be useful to discriminate BL from DLBCL, and to identify cases of BL/DLBCL or DLBCL with potential c-myc translocations.

Introduction: Enteropathy-associated T-cell lymphoma (EATL) is a rare complication of celiac disease (<1% of lymphomas) and has a poor prognosis., Methods: International literature review with PubMed search (up to January 2009) of pathophysiological, clinical and therapeutic data., Results: EATL is found in patients with a mean age of 59 years, often with a complication that signals its diagnosis. Refractory celiac disease (RCD), equivalent to low-grade intraepithelial T-cell lymphoma, could be an intermediary between celiac disease and high-grade invasive T-cell lymphoma. The median survival is 7 months, with no significant difference between stages; the cumulative 5-year survival is less than 20%. The poor prognosis is determined by disease that has often spread before it is diagnosed (50%), multifocal involvement of the small bowel (50%), poor general health status and undernutrition, and recurrence of complications (infections, perforations, gastrointestinal haemorrhages, occlusions), thus delaying the chemotherapy and contributing to frequent chemotherapy resistance. There is currently no effective and consensual treatment: preventive surgery for complications is controversial, and the results of chemotherapy are disappointing. The classic CHOP protocol (combination of doxorubicin-cyclophosphamide-vincristine-prednisone) does not have satisfactory results and survival remains poor, especially in patients with underlying RCD. High-dose chemotherapy with autotransplantion seems to only improve the prognosis in localised forms. Allogeneic bone marrow transplantation was not evaluated. In all, 1/3 of patients, being unfit for treatment, die before 3 months and half of treated patients stop chemotherapy prematurely due to inefficacy, intolerance and/or complications., Conclusion: Improvement of the prognosis requires collaboration in order to compose a national cohort, to evaluate new diagnostic and therapeutic strategies and to define prognostic factors., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

Anorectal Hodgkin lymphoma (HL) is rare, mainly described in human immunodeficiency virus (HIV) patients with exceptional cases reported in immunocompetents. We report the case of a middle age HIV male, presenting with intestinal occlusion. Rectosigmoidoscopy showed multiple anorectal nodular and ulceronecrotic masses. The biopsy specimens revealed a diffuse polymorphous inflammatory infiltrate in the lamina propria, associated with CD30, CD20, CD3, CD15, and ALK1 scattered large Hodgkin and/or Reed Sternberg -like cells stained by LMP1 antibody and EBER. A diagnosis of EBV-associated atypical lymphoproliferative disease mimicking HL was made. These lesions remained stable for 2 years without treatment then disappeared leaving a mucosal scar. A later control biopsy showed a condylomatous lesion, without lymphoid lesion, suggesting a sexually acquired infection. Eight years later, the complete resolution of the lesion without any treatment is a strong argument against a malignant lymphoid process and raises doubts as to the reality of isolated anorectal HL in immunocompetent participants.

There is a causal association between Helicobacter pylori (Hp) gastric infection and the development of gastric MALT lymphoma. In contrast, the link between Hp gastric infection and the development of extragastric lymphoma has not been thoroughly investigated. We, therefore, studied the prevalence of gastric Hp infection at initial diagnosis of ophthalmologic and nonophthalmologic extragastric lymphoma patients. Three cohorts of patients were studied: a first one of 83 patients with OAL, a second one of 101 patients with extraophthalmologic extragastric lymphoma, and a third one of 156 control individuals (control) without malignant lymphoma. Gastric Hp infection was investigated by histopathological analysis and Hp-specific PCR assay on gastric biopsy tissue samples. We found gastric Hp infection in 37 OAL patients (45%), in 25 extraophthalmologic extragastric lymphoma cases (25%), and in 18 controls individuals (12%) (P < 0.0001 OAL/C and P < 0.01 OAL/extra-OAL cases). Gastritis was found in 51% and 9% of Hp-positive and Hp-negative lymphoma patients, respectively (P < 10(-4)). Gastric Hp infection only correlated with MALT/LPL lymphoma (P = 0.03). There is a significant association between gastric Hp infection and MALT/LPL OAL. This suggests a novel mechanism of indirect infection-associated lymphomagenesis whereby chronic local antigen stimulation would lead to the emergence of ectopic B-cell lymphoma., (© 2010 Wiley-Liss, Inc.)

Angioimmunoblastic T-cell lymphoma (AITL) is the most frequent nodal T-cell lymphoma and is characterized by a polymorphic lymph node infiltrate, various dysimmune disorders, and a poor prognosis. Regulatory T-cells (Treg) play an emerging role in the prognosis of non-Hodgkin B-cell lymphoma and mediate significant autoreactive T-cell suppression. In this report, we demonstrate that numbers of Treg are significantly decreased in AITL lymph nodes [n = 30, 91 (40-195) per high power fields] compared with follicular lymphoma [n = 19, 179 (86-355)] and reactive lymph nodes [n = 8, 186 (140-265)]. Moreover, the few Treg in lymph nodes of AITL are resting Treg (rTreg) and have a naive CD45RA+, PD1-, and ICOS- phenotype [n = 5, 57% of Treg are CD45RA+ (16-96)], in contrast to the Treg in follicular lymphomas [n = 5, 7.4% (1-13)] or reactive lymph nodes [n = 7, 18.6% (6-48)]. Interestingly, Treg depletion was not observed in AITL peripheral blood at diagnosis. Altogether, these data suggest that Treg depletion could contribute to the nodal neoplastic T(FH) expansion and dysimmune symptoms in AITL.

Chronic disseminated candidiasis is a complication of the intensive therapies of hematological malignancies revealed during hematopoietic recovery, a context reminiscent of the immune restoration inflammatory syndrome in human immunodeficiency virus patients receiving antiretroviral therapy. We report a case of severe exacerbation of chronic disseminated candidiasis after pegylated granulocyte-colony stimulating factor administration. We emphasize the major inflammatory substrate of the disease and suggest that immune-modulating strategies such as hematopoietic growth factors, should be used cautiously in such patients., (Copyright (c) 2010 Taiwan Society of Microbiology. Published by Elsevier B.V. All rights reserved.)

Purpose: To study the value of conjunctival biopsy in congenital tufting enteropathy diagnosis., Design: Case-comparative study., Methods: Between January 2000 and June 2007, all children seeking treatment with an early onset of intractable diarrhea were examined in the ophthalmology department of Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, France. Children underwent complete ophthalmologic examination with concurrent conjunctival and intestinal biopsies. Main outcome measures were age at diagnosis, associated disorders, parenteral nutrition, and ophthalmologic symptoms. Conjunctival biopsies support diagnosis in the presence of specific alteration., Results: Twenty patients were included. The mean age of the population was 30.2 months. Congenital tufting enteropathy was diagnosed in 15 cases. In the congenital tufting enteropathy group, 10 children exhibited ophthalmic functional disorders since the first months of life, with superficial punctate keratitis and conjunctivitis and in addition alacrima and cataract in 1 case, respectively, whereas 5 children had asymptomatic conjunctival hyperemia at presentation. Conjunctival biopsies showed epithelial parakeratosis, hyperplasia, basal cells hyperplasia, and tufts. In some cases, the lamina propria contained inflammatory cells or fibrosis, and the density of goblet cells then was abnormal. In the comparison group of 5 children with early-onset intractable diarrhea but without congenital tufting enteropathy diagnosis, no tuft occurrence was observed., Conclusions: In cases of intractable diarrhea in infancy, even without ocular symptoms, a systematic ophthalmologic examination should be performed. It also should be associated with the pathologic examination of both the conjunctival and the intestine mucosae, which helps to diagnose congenital tufting enteropathy (adhesion molecules disease). Specific conjunctival findings allow affirmation of congenital tufting enteropathy before the genetic confirmation of an EpCAM gene mutation., (2010 Elsevier Inc. All rights reserved.)

Enteropathy-associated T cell lymphoma is a severe complication of celiac disease (CD). One mechanism suggested to underlie its development is chronic exposure of intraepithelial lymphocytes (IELs) to potent antiapoptotic signals initiated by IL-15, a cytokine overexpressed in the enterocytes of individuals with CD. However, the signaling pathway by which IL-15 transmits these antiapoptotic signals has not been firmly established. Here we show that the survival signals delivered by IL-15 to freshly isolated human IELs and to human IEL cell lines derived from CD patients with type II refractory CD (RCDII) - a clinicopathological entity considered an intermediary step between CD and enteropathy-associated T cell lymphoma - depend on the antiapoptotic factors Bcl-2 and/or Bcl-xL. The signals also required IL-15Rbeta, Jak3, and STAT5, but were independent of PI3K, ERK, and STAT3. Consistent with these data, IELs from patients with active CD and RCDII contained increased amounts of Bcl-xL, phospho-Jak3, and phospho-STAT5. Furthermore, incubation of patient duodenal biopsies with a fully humanized human IL-15-specific Ab effectively blocked Jak3 and STAT5 phosphorylation. In addition, treatment with this Ab induced IEL apoptosis and wiped out the massive IEL accumulation in mice overexpressing human IL-15 in their gut epithelium. Together, our results delineate the IL-15-driven survival pathway in human IELs and demonstrate that IL-15 and its downstream effectors are meaningful therapeutic targets in RCDII.

Background: Fibroblastic rheumatism is a unique fibro-proliferative disease affecting the skin and joints. It is characterized by distinctive clinical and histological features related to benign spindle-shaped cells proliferation. Pediatric reports are scarce in the literature., Objective: We describe here a new case in a 10-year-old boy and discuss the potential origin of the cell proliferation., Methods: Clinical findings, radiology, microscopic examination and outcome are reviewed. Histopathology and immunochemistry studies were performed on skin biospies using CD68, CD163, desmin, factor XIIIa, CD34, smooth muscle actin, PS100, epithelial membrane antigen, and calponin., Results: Histological sections disclosed a rather circumscribed nonencapsulated nodular infiltrate, invading the dermis and the upper subcutaneous tissue, consisted of a proliferation of spindle or stellate-shaped cells and thickened collagen fibers. Orcein staining showed disappearance of the elastic network. Aponeurosis and muscle were normal. A mild perivascular lymphohistiocytic infiltrate was noted. Calponin-staining was less strongly expressed as SMA, and some of them but not all were CD68 positive, as well. On the other hand, all were CD34, CD163, FXIIIa, PS100, EMA and desmin-negative., Conclusion: The true origin of these cells remains unclear. Some authors have speculated a histiocytic origin. However, immuno-chemical staining in our case failed to confirm this hypothesis and instead supported a fibroblastic/myofibroblastic origin. Given the clinical course and the histological and immunohistochemical results, we suggest that FR should be added to the group of fibromatoses.

Autosomal recessive microvillus inclusion disease (MVID) is characterized by an intractable diarrhea starting within the first few weeks of life. The hallmarks of MVID are a lack of microvilli on the surface of villous enterocytes, occurrence of intracellular vacuoles lined by microvilli (microvillus inclusions), and the cytoplasmic accumulation of periodic acid-Schiff (PAS)-positive vesicles in enterocytes. Recently, we identified mutations in MYO5B, encoding the unconventional type Vb myosin motor protein, in a first cohort of nine MVID patients. In this study, we identified 15 novel nonsense and missense mutations in MYO5B in 11 unrelated MVID patients. Fluorescence microscopy, Western blotting, and electron microscopy were applied to analyze the effects of MYO5B siRNA knock-down in polarized, brush border possessing CaCo-2 cells. Loss of surface microvilli, increased formation of microvillus inclusions, and subapical enrichment of PAS-positive endomembrane compartments were induced in polarized, filter-grown CaCo-2 cells, following MYO5B knock-down. Our data indicate that MYO5B mutations are a major cause of microvillus inclusion disease and that MYO5B knock-down recapitulates most of the cellular phenotype in vitro, thus independently showing loss of MYO5B function as the cause of microvillus inclusion disease., ((c) 2010 Wiley-Liss, Inc.)

PURPOSE First-line treatment for patients with newly diagnosed follicular lymphoma (FL) still remains debated, even in the rituximab-based combination therapy era. Few studies have addressed the question whether complete remission (CR) translates into better survival. The aim of this study was to assess the long-term follow-up of prospectively treated patients with FL and the potential correlation between response quality to first-line treatment and overall survival (OS). PATIENTS AND METHODS Data from 536 patients with FL with low (n = 193) or high (n = 343) tumor burden enrolled from October 1986 to May 1995 in the French and Belgian GELF86 studies were analyzed. Data from these trials have been previously reported for low-tumor burden and high-tumor burden patients. Results Median follow-up was 14.9 years, and median OS was 9.8 years. Treated patients who achieved a complete response (CR; n = 194; 45%) had a significant longer OS than those only reaching a partial response (PR; n = 168; 39%) throughout treatment (hazard ratio [HR], 0.55; 95% CI, 0.42 to 0.72; P < .001) in an univariate time-dependent Cox model. Similar findings were found when response to treatment (CR v PR) was adjusted for potentially confounding factors in a multivariate model (HR, 0.53; 95% CI, 0.38 to 0.73; P < .001). CONCLUSION These data provide a long follow-up of these patients' cohorts and indicate that a better response to first-line treatment translates into an improved survival for patients with FL. Therefore, response-adapted therapy aiming to achieve a CR should be considered as first-line treatment.

Objectives: To describe clinical and immunohistochemical findings in patients with cutaneous Langerhans cell histiocytosis (LCH) beginning in the first 3 months of life and to define predictors of disease evolution., Design: Observational retrospective survey from July 15, 1989, to April 30, 2007., Setting: Referral center in pediatric dermatology., Patients: Thirty-one patients with a diagnosis of cutaneous LCH in the first 3 months of life and no previous visceral LCH., Main Outcome Measures: Cutaneous lesion characteristics, regulatory T-lymphocyte density, and E-cadherin expression were assessed. Data were compared between the patient groups with self-regressive vs non-self-regressive forms of cutaneous LCH. Pathologic analysis was performed blinded to patient group., Results: Self-regressive cutaneous LCH was found in 21 patients and non-self-regressive cutaneous LCH in 10 patients. Monolesional forms, necrotic lesions, hypopigmented macules at presentation, and distal topography of limb lesions were seen only in patients with self-regressive cutaneous LCH. Regulatory T-lymphocyte density correlated with interleukin 10 expression in lesions (r = 0.77, P = .003) but was not predictive of disease evolution. E-cadherin expression by Langerhans cells was found in 7 patients with disease limited to the skin whether self-regressive or not. One patient with secondary disseminated disease showed loss of E-cadherin expression in Langerhans cells., Conclusions: Some morphologic traits of skin lesions can orient the diagnosis to a self-regressive form of cutaneous LCH. Regulatory T-lymphocyte density does not seem to be predictive of disease evolution. E-cadherin expression seems to be an indicator of limited skin disease but not of disease regression. Additional immunohistochemical study is required to confirm these data.

Calcinosis of the cutis and the subcutis is a rare complication of calcium-containing heparin cutaneous injections, mostly occurring in a context of severe renal failure. We report 2 cases. The first patient developed firm erythematous nodules on his thighs and right arm, in a context of disseminated tuberculosis and acute severe renal failure related to human immunodeficiency virus nephropathy. Cutaneous location of tuberculosis was suspected. Histological features allowed to establish the diagnosis of calcinosis of the cutis and the subcutis, showing violaceous and crackled von Kossa-positive calcium deposits in the whole reticular dermis and in thin collagenous septa of subcutaneous tissue. A retrospective inquiry confirmed that subcutaneous injections of calcium-containing heparin had been performed on the sites where lesions occurred. The second patient developed similar lesions at injection sites of calcium-containing heparin, in a context of non-Hodgkin lymphoma and end-stage renal failure. Similar histological features were observed. Calcinosis of the cutis and the subcutis after subcutaneous injections of calcium-containing heparin is rare. It always occurs in a context of elevated calcium-phosphate product, a situation mostly encountered in severe renal failure. Early cutaneous lesions do not bear specific clinical features.

Background: Richter's syndrome (RS) corresponds to the transformation of chronic lymphocytic leukemia (CLL) into high-grade lymphoma. RS can involve extranodal sites including the gastrointestinal tract, lungs and skin. Cutaneous RS is rare, we describe 4 cases with clinical manifestations, histological and immunohistological patterns, and outcome., Methods: Clinical data were analyzed and all patients' skin biopsy samples stained with HE for the CD20, CD5, CD3 and CD30 antigens. Epstein-Barr-virus (EBV)-encoded early RNA and clonal rearrangements were also analyzed., Results: The patients' mean age at CLL diagnosis was 57 years (53-62 years), with a male/female sex ratio of 3:1. The transformation to cutaneous RS occurred between 8 and 75 months after initial diagnosis and progressed to a fatal systemic disease in 3 cases, between 24 and 129 months. Cutaneous CLL was associated with earlier transformation in our series and could not be distinguished from RS on clinical grounds alone. All patients had a large-cell infiltrate and clonal rearrangements., Conclusions: The precise mechanism of RS is unclear, but a role of EBV has been suggested in fludarabine-treated CLL. For all our patients, the diagnosis of transformation was made on the basis of cutaneous localizations and led to intensified CLL treatment., (2010 S. Karger AG, Basel.)

Background: Chronic granulomatous disease (CGD) is a rare inherited disease of the phagocyte NADPH oxidase system that causes defective production of toxic oxygen metabolites, impaired bacterial and fungal killing, and recurrent life-threatening infections, mostly by catalase-producing organisms. We report for the first time, to our knowledge, chronic infections with Actinomyces species in 10 patients with CGD. Actinomycosis is a chronic granulomatous condition that commonly manifests as cervicofacial, pulmonary, or abdominal disease, caused by slowly progressive infection with oral and gastrointestinal commensal Actinomyces species. Treatment of actinomycosis is usually simple in immunocompetent individuals, requiring long-term, high-dose intravenous penicillin, but is more complicated in those with CGD because of delayed diagnosis and an increased risk of chronic invasive or debilitating disease., Methods: Actinomyces was identified by culture, staining, 16S ribosomal DNA polymerase chain reaction, and/or a complement fixation test in 10 patients with CGD., Results: All 10 patients presented with a history of fever and elevated inflammatory signs without evident focus. Diagnosis was delayed and clinical course severe and protracted despite high-dose intravenous antibiotic therapy and/or surgery. These results suggest an unrecognized and unanticipated susceptibility to weakly pathogenic Actinomyces species in patients with CGD because these are catalase-negative organisms previously thought to be nonpathogenic in CGD., Conclusions: Actinomycosis should be vigorously sought and promptly treated in patients with CGD presenting with uncommon and prolonged clinical signs of infection. Actinomycosis is a catalase-negative infection important to consider in CGD.

Background: Reports of an increased risk of lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease are controversial. We assessed this risk in a prospective observational cohort study., Methods: 19,486 patients with inflammatory bowel disease, of whom 11,759 (60.3%) had Crohn's disease and 7727 (39.7%) had ulcerative colitis or unclassified inflammatory bowel disease, were enrolled in a nationwide French cohort by 680 gastroenterologists, who reported details of immunosuppressive therapy during the observation period, cases of cancer, and deaths. The risk of lymphoproliferative disorder was assessed according to thiopurine exposure. Median follow-up was 35 months (IQR 29-40)., Findings: At baseline, 5867 (30.1%) of patients were receiving, 2809 (14.4%) had discontinued, and 10,810 (55.5%) had never received thiopurines. 23 new cases of lymphoproliferative disorder were diagnosed, consisting of one case of Hodgkin's lymphoma and 22 cases of non-Hodgkin lymphoproliferative disorder. The incidence rates of lymphoproliferative disorder were 0.90 per 1000 (95% CI 0.50-1.49) patient-years in those receiving, 0.20/1000 (0.02-0.72) patient-years in those who had discontinued, and 0.26/1000 (0.10-0.57) patient-years in those who had never received thiopurines (p=0.0054). The multivariate-adjusted hazard ratio of lymphoproliferative disorder between patients receiving thiopurines and those who had never received the drugs was 5.28 (2.01-13.9, p=0.0007). Most cases associated with thiopurine exposure matched the pathological range of post-transplant disease., Interpretation: Patients receiving thiopurines for inflammatory bowel disease have an increased risk of developing lymphoproliferative disorders., Funding: Programme Hospitalier de Recherche Clinique National (AOM05157), Association François Aupetit, Délégation Inter-régionale de la Recherche clinique Ile de France-Assistance Publique Hôpitaux de Paris (AP-HP), Ligue contre le Cancer, and Fonds de Recherche de la Société Nationale Française de Gastro-entérologie.

Background: Hypochromic streaks can be the only cutaneous sign of incontinentia pigmenti (IP) in adulthood (stage IV). Discovery of such lesions in an adult female with no family history of IP is essential for appropriate genetic counselling., Objective: To describe and to validate the histological features of residual skin lesions in adult IP., Methods: The analysis and comparison of skin biopsies of 26 women affected with molecularly confirmed IP., Results: Most biopsies showed slight atrophy and some scattered apoptotic cells in the epidermis, epidermal hypopigmentation and reduced melanocyte number. The dermis appeared thickened and homogeneous and revealed a complete absence of hair follicles (23/26) and sweat glands (22/26). There was no melanin incontinence or inflammatory cells, and the elastic network was normal., Conclusion: These features lead unequivocally to the diagnosis of a stage IV IP skin lesion. Consequently, histology is a major confirmatory criterion for diagnoses of these mild clinical forms of IP. It is therefore a useful tool in genetic counselling and prenatal diagnosis. Moreover, the observations described here may contribute to understanding the physiopathology of the late stages of IP.

Although most classical Hodgkin lymphoma patients are cured, a significant minority fail after primary therapy and may die as result of their disease. To date, there is no consensus on biological markers that add value to usual parameters (which comprise the International Prognostic Score) used at diagnosis to predict outcome. We evaluated 59 patients (18 with primary refractory or early relapse disease and 41 responders) for bcl2, Ki67, CD20, TiA1 and c-kit expression by semi-quantitative immunohistochemical study and correlated the results with the response to treatment.The results showed that expression of bcl2 and CD20 in Hodgkin and Reed Sternberg cells, and expression of TiA1 in micro-environmental lymphocytes, and c-kit positive mast cells in microenvironment, were independent prognostic markers. These novel cHL markers could be used in association with clinical parameters to identify newly diagnosed patients with favorable or unfavorable prognosis and to better tailor treatment for different risk groups.

Background & Aims: Refractory celiac disease (RCD) was recently subdivided into 2 subtypes (RCD I and II) based on a normal or abnormal phenotype of intraepithelial lymphocytes (IELs), respectively. It is not clear, however, if these 2 entities differ in their presentation at diagnosis or long-term outcome. We compared the clinical and biological characteristics of RCD I and RCD II at diagnosis, the risk of developing an overt lymphoma, and the predictive factors of survival., Methods: Medical files of 14 patients with RCD I and 43 with RCD II were analyzed retrospectively. Predictive factors of overt lymphoma and survival were studied in univariate and multivariate analyses., Results: At diagnosis, malnutrition, ulcerative jejunitis, and lymphocytic gastritis were more common in patients with RCD II than RCD I (P< .05). Overt lymphomas occurred in 2 patients with RCD I and 16 with RCD II. In the univariate analysis, abnormal IEL phenotype and increased age at diagnosis of RCD were predictive factors for overt lymphoma. Abnormal IEL phenotype (P< .01), clonality (P= .01), and overt lymphoma (P= .001) predicted short survival time. Only abnormal IEL phenotype (P= .03) and overt lymphoma (P= .04) were predictive in the multivariate analysis. The 5-year survival rate was 93% in patients with RCD I and 44% with RCD II., Conclusions: RCD II has a much more severe presentation and prognosis than patients with RCD I; <44% of patients with RCD II survive 5 years after diagnosis. Abnormal IEL phenotype is a predictive factor but not a necessary condition for the development of overt lymphoma.

Immunodysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX) syndrome is a well recognized and particularly severe form of autoimmune enteropathy. It has an X-linked recessive transmission, and is caused by mutations in the FOXP3 gene. We studied the intestinal morphological changes characterizing IPEX syndrome in a series of 12 children with a molecularly confirmed diagnosis. Histological examination of duodenal, gastric and colonic biopsies were retrospectively reviewed and compared by two independent experienced pathologists. In parallel, the presence of circulating anti-enterocyte antibodies was analysed using an indirect immunofluorescence technique and a quantitative radioligand assay against the 75-kDa autoantigen. The morphology of the inflammatory gut lesions could be categorized into three different entities, namely graft-vs-host disease-like changes (9/12 patients), a coeliac disease-like pattern (2/12) and an enteropathy with a complete depletion of goblet cells (1/12). Our results do not suggest any phenotype-genotype correlation. Circulating antibodies were detected in all 12 patients, with an anti-brush border pattern (11/12) and anti-goblet cell antibodies (1/12), as well as by a radioligand assay. The histological presentation of autoimmune enteropathy is rather variable. However, a graft-vs-host disease-like pattern associated with positive anti-enterocyte antibodies is the most frequent intestinal presentation of IPEX syndrome, and constitutes a very valuable tool for pathologists to suspect this diagnosis.

Desmoplastic small round cell tumor (DSRCT) is a rare tumor, seen both in children and young adults with a marked predilection for the peritoneal cavity. Histology showed a small round cell tumor with a fibromyxoïd stroma and immunohistochemistry indicated neural and mesenchymal differentiation, and diagnosis was made by molecular detection of the EWS-WT1 fusion gene product. DSRCT should be considered in the differential diagnosis of intracranial small round cell tumors., ((c) 2008 Wiley-Liss, Inc.)

Previously, several individuals with X-linked SCID (SCID-X1) were treated by gene therapy to restore the missing IL-2 receptor gamma (IL2RG) gene to CD34+ BM precursor cells using gammaretroviral vectors. While 9 of 10 patients were successfully treated, 4 of the 9 developed T cell leukemia 31-68 months after gene therapy. In 2 of these cases, blast cells contained activating vector insertions near the LIM domain-only 2 (LMO2) proto-oncogene. Here, we report data on the 2 most recent adverse events, which occurred in patients 7 and 10. In patient 10, blast cells contained an integrated vector near LMO2 and a second integrated vector near the proto-oncogene BMI1. In patient 7, blast cells contained an integrated vector near a third proto-oncogene,CCND2. Additional genetic abnormalities in the patients' blast cells included chromosomal translocations, gain-of-function mutations activating NOTCH1, and copy number changes, including deletion of tumor suppressor gene CDKN2A, 6q interstitial losses, and SIL-TAL1 rearrangement. These findings functionally specify a genetic network that controls growth in T cell progenitors. Chemotherapy led to sustained remission in 3 of the 4 cases of T cell leukemia, but failed in the fourth. Successful chemotherapy was associated with restoration of polyclonal transduced T cell populations. As a result, the treated patients continued to benefit from therapeutic gene transfer.

Background: Nodular fasciitis rarely affects children. To date, apart from isolated cases, only two series comprising respectively 15 and six children have been reported., Patients and Methods: We carried out a retrospective study of the clinical and pathological aspects of 10 cases of nodular fasciitis involving children under 15 years of age diagnosed at the pathology laboratory of the Necker Children's Hospital (Paris, France) between 1992 and 2006., Results: In comparison with previously reported data, our study highlights four new factors: (1) nodular fasciitis affected girls more often than boys; (2) it occurred predominantly on the trunk; (3) follow-up showed a high recurrence rate (22%) after surgical removal; (4) immunohistochemical analysis revealed a high level of expression of p53 by tumour cells; this was much higher than in adults., Discussion: The high expression of p53 in nodular fasciitis, which has never been described in children, seems to point towards its preneoplastic rather than reactive nature.

Patients with mutations in the Artemis gene display a complete absence of T- and B lymphocytes, together with increased cellular radiosensitivity; this leads to a radiosensitive severe combined immunodeficiency (RS-SCID). Allogenic hematopoietic stem-cell (HSC) transplantation is only partially successful in the absence of an human leukocyte antigen-genoidentical donor, and this has prompted a search for alternative therapeutic approaches such as gene therapy. In this study, a self-inactivated lentiviral vector expressing Artemis was used to complement the Artemis knockout mouse (Art(-/-)). Transplantation of Artemis-transduced HSCs into irradiated Art(-/-) mice restored a stable (over a 15-month period of follow-up) and functional T- and cell repertoire that was comparable to that of control mice. The success of secondary transplantations demonstrated that the HSCs had been transduced. One of thirteen mice developed a thymoma 6 months after gene therapy. Although thymic cells were seen to be carrying two lentiviral integration sites, there was no evidence of lentivirus-driven oncogene activation. The Art(-/-) mice were found to be prone to develop T-cell lymphomas, either spontaneously or after irradiation. These data indicate that the observed lymphoproliferation was probably the consequence of the chromosomal instability associated with the Artemis-deficient background. As a whole, our work provides a basis for supporting the gene therapy approach in Artemis-deficient SCID.

Chronic allograft nephropathy accounts for the loss of approximately 40% of allografts at 10 yr. Currently, no biomarker is available to detect interstitial fibrosis and tubular atrophy in the renal graft at an early stage, when intervention may be beneficial. Because tubular epithelial cells have been shown to exhibit phenotypic changes suggestive of epithelial-to-mesenchymal transition, we studied whether these changes predict the progression of fibrosis in the allograft. Eighty-three kidney transplant recipients who had undergone a protocol graft biopsy at both 3 and 12 mo after transplantation were enrolled. De novo vimentin expression and translocation of beta-catenin into the cytoplasm of tubular cells were detected on the first biopsy by immunohistochemistry. Patients with expression of these markers in >or=10% of tubules at 3 mo had a higher interstitial fibrosis score at 1 yr and a greater progression of this score between 3 and 12 mo. The intensity of these phenotypic changes positively and significantly correlated with the progression of fibrosis, and multivariate analysis showed that their presence was an independent risk factor for this progression. In addition, the presence of early phenotypic changes was associated with poorer graft function 18 mo after transplantation. In conclusion, early phenotypic changes indicative of epithelial-to-mesenchymal transition predict the progression toward interstitial fibrosis in human renal allografts.

Immunopathology of acute graft-versus-host disease (aGVHD) involves secretion of proinflammatory cytokines with subsequent expression of danger signals by injured host tissues. This explanation, however, does not explain the cluster of aGVHD target organs (skin, gut, and liver). NKG2D ligands (MICA/B and ULBP1-3 proteins) are stress-induced molecules that act as danger signals to alert NK and alphabeta or gammadelta CD8 T cells through engagement of the activating NKG2D receptor. We observed a strong and reversible induction of MICA/B expression in skin and liver sections during aGVHD. Tumor necrosis factor-alpha and gamma-radiation up-regulated expression of MICA/B and ULBP proteins in vitro on skin and intestine epithelial cell lines and ex vivo in normal skin explants. This NKG2D-ligand induction was regulated by a complex interplay between NFkB and JNK activation pathways. Our data suggest that NKG2D ligand induction might participate in the amplification loop that leads to tissue damage during aGVHD.

Background and Aims: While severe villous atrophy (SVA) is the most typical histological feature in adult celiac disease (ACD), partial villous atrophy (PVA) is now also frequently found. So far, the impact of the severity of villous atrophy on the clinical presentation of ACD has been scarcely investigated. We aimed to compare the clinical, biological and immune features and outcomes in ACD patients presenting with PVA at diagnosis versus patients with SVA., Patients and Methods: Medical files of 48 patients with ACD diagnosed between 1992 and 2003 were retrospectively studied. The diagnosis was based on the presence of intestinal villous atrophy, with increases in intraepithelial lymphocytes and circulating celiac specific antibodies. Villous atrophy was classified as severe (subtotal and total) or partial. Symptoms, biological signs of malabsorption, immune markers, bone mineral density at diagnosis and response to gluten-free diet were recorded., Results: At diagnosis, ten patients (four M/six F) had PVA and 38 patients (five M/33 F) had SVA, with a median age of 54 and 33 years, respectively (p<0.05). Positivity for specific antibodies, HLA typing and frequency of autoimmune disease at diagnosis were similar in both PVA and SVA patients, as was their response to gluten-free diet. Diarrhea, malabsorption syndrome and osteopenia were independent of the degree of villous atrophy., Conclusion: PVA was observed in 21% of patients with ACD. Except for their older age at diagnosis, patients with PVA presented with similar clinical, biological and immune characteristics and outcomes as did patients with SVA.

Background/aims: Whether a life-long gluten-free diet (GFD) is necessary in all children with diagnosed coeliac disease (CD) remains debated. To address this question, a retrospective analysis of the clinical and biological status of adult coeliac patients diagnosed in childhood, who remained on a normal diet after gluten challenge and were clinically silent, was carried out., Methods: Patients aged 18-65 years with CD diagnosed in childhood were included. Clinical status, gluten intake, biological parameters of malabsorption, bone mineral density, human leucocyte antigen (HLA) genotype, serological markers of CD, and histological and immunohistochemical parameters in duodenal biopsies were recorded., Results: Sixty-one patients had resumed a normal diet and were asymptomatic. Forty-eight showed different degrees of villous atrophy (silent CD), while 13 had no detectable atrophy (latent CD) on duodenal biopsies. Latent CD patients had significantly less osteopenia/osteoporosis (1/9 (11%) vs 23/33 (70%), p<0.001)), and lower T cell receptor (TCR) alphabeta+ intraepithelial T cell counts (38+/-20 vs 55+/-15, p<0.01) than silent CD patients. The mean age at diagnosis and first GFD was lower in latent than in silent patients (14.4+/-5 vs 40.1+/-47 months, p<0.05). Latent patients did not differ significantly from the seven control patients on a long-term GFD, except for a higher frequency of CD-specific serum antibodies. However, two latent patients relapsed clinically and histologically during subsequent follow-up., Conclusions: Long-term latency developed in about 20% of CD patients who remained symptom free after gluten reintroduction. This latency can be transient and thus a regular follow-up is mandatory. In silent patients, the increased risk of osteoporosis substantiates the need for a GFD.

Gastrointestinal symptoms are common and often reveal primary immunodeficiency. Although they mimic gastrointestinal diseases observed in immunocompetent patients, there have diagnostic and therapeutic specificities that should be known for optimal management of these patients. This review describes the gastrointestinal diseases found in primary immunodeficiency and proposes some diagnostic and therapeutic strategies.

Most renal tumors of the adult are carcinomas. Their treatment is surgical, consisting of limited excision or nephrectomy. In some instances, biopsy of the tumor can be performed in order to adapt treatment. We report the case of a 45 year-old woman presenting with renal tumor. A biopsy of the mass showed a metanephric adenoma. No surgical excision was performed because of the benignity of this tumor. Here we develop the interest of immunohistochemistry for differential diagnosis of metanephric adenoma and other "basophilic small cell tumors" of the kidney. We also put the stress on the growing role of biopsy of renal tumor allowing optimal treatment.

We investigated, for the first time, the expression of I- and L-FABP in two very rare hereditary lipid malabsorption syndromes as compared with normal subjects. Abetalipoproteinemia (ABL) and Anderson's disease (AD) are characterized by an inability to export alimentary lipids as chylomicrons that result in fat loading of enterocytes. Duodeno-jejunal biopsies were obtained from 14 fasted normal subjects, and from four patients with ABL and from six with AD. Intestinal FABP expression was investigated by immuno-histochemistry, western blot, ELISA and Northern blot analysis. In contrast to normal subjects, the cellular immunostaining for both FABPs was clearly decreased in patients, as the enterocytes became fat-laden. In patients with ABL, the intestinal contents of I- (60.7 +/- 13.38 ng/mg protein) and L-FABP (750.3 +/- 121.3 ng/mg protein) are significantly reduced (50 and 35%, P < 0.05, respectively) as compared to normal subjects (I-135.3 +/- 11.1 ng, L-1211 +/- 110 ng/mg protein). In AD, the patients also exhibited decreased expression (50%, P < 0.05; I-59 +/- 11.88 ng, L-618.2 +/- 104.6 ng/mg protein). Decreased FABP expression was not associated with decreased mRNA levels. The results suggest that enterocytes might regulate intracellular FABP content in response to intracellular fatty acids, which we speculate may act as lipid sensors to prevent their intracellular transport.

Background: Wilms tumor, aniridia, genitourinary anomalies, and mental retardation (WAGR) syndrome is a genetic disorder caused by a deletion of band 11p13, which results in the loss of 1 allele of the Wilms tumor suppressor gene (WT1). It is not classically associated with nephropathies, but increased rates of renal failure are reported. Denys-Drash syndrome (DDS), caused by mutations in the WT1 gene affecting the third or second zinc finger, is characterized by a triad of glomerulopathy progressing rapidly to end-stage renal disease, male hermaphroditism, and Wilms tumor. In patients with DDS, small glomeruli were observed., Methods: We reviewed histological findings of nontumoral kidney samples of 7 patients with WAGR syndrome at the time of tumor surgery., Results: Median glomerular diameter was 110 +/- 37 microm in patients with WAGR syndrome versus 125 +/- 18.5 microm in controls (P < 0.0001)., Conclusion: The presence of small glomeruli in patients with WAGR syndrome, as in those with DDS, suggests a specific defect of WT1 function in development and a specific role of WT1 allele loss in the development of renal failure in these patients.