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1.
Br J Haematol ; 2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34312844

RESUMO

BRAF inhibitors are an effective treatment for BRAFV600E -mutated, risk-organ-positive Langerhans cell histiocytosis (RO+ LCH). However, cell-free BRAFV600E DNA often persists during therapy and recurrence frequently occurs after therapy discontinuation. To identify a pathological reservoir of BRAFV600E -mutated cells, we studied peripheral blood cells obtained from six infants with RO+ multisystem (MS) LCH that received targeted therapy. After cell sorting, the BRAFV600E mutation was detected in monocytes (n = 5), B lymphocytes (n = 3), T lymphocytes (n = 2), and myeloid and plasmacytoid dendritic cells (n = 2 each). This biomarker may offer an interesting tool for monitoring the effectiveness of new therapeutic approaches for weaning children with RO+ LCH from targeted therapy.

2.
Pediatr Blood Cancer ; 68(9): e29140, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34109735

RESUMO

BACKGROUND: The somatic BRAFV600E mutation occurs in 38-64% of pediatric cases of Langerhans cell histiocytosis (LCH). Vemurafenib (VMF), a BRAF inhibitor, was approved for refractory BRAFV600E mutated LCH. In adults, VMF causes frequent cutaneous adverse events (CAE) including skin tumors (squamous cell carcinomas, melanomas), but little is known in children. The objective of this study was to evaluate the frequency, clinical spectrum, and severity of CAEs in children treated with VMF for LCH. In addition, a correlation between CAE occurrence and VMF dose, residual plasma levels (RPLs), and efficacy was searched for. PROCEDURE: Multicentric retrospective observational study including patients <18 years treated with VMF alone for refractory BRAFV600E mutated LCH in 13 countries between October 1, 2013 and December 31, 2018. RESULTS: Fifty-seven patients: 56% female, median age 2.1 years (0.2-14.6), median treatment duration 4.1 months (1.4-29.7). Forty-one patients (72%) had at least one CAE: photosensitivity (40%), keratosis pilaris (32%), rash (26%), xerosis (21%), and neutrophilic panniculitis (16%). No skin tumor was observed. Five percent of CAEs were grade 3. None were grade 4 or led to permanent VMF discontinuation. Dose reduction was necessary for 12% of patients, temporary treatment discontinuation for 16%, none leading to loss of efficacy. VMF dose, median RPL, and efficacy were not correlated with CAE occurrence. CONCLUSIONS: At doses used for pediatric LCH, CAEs are frequent but rarely severe and have little impact on the continuation of treatment when managed appropriately. Regular dermatological follow-up is essential to manage CAEs and screen for possible induced skin tumors.

3.
J Pediatr ; 2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34146548

RESUMO

OBJECTIVE: To evaluate the prognostic impact of gastrointestinal involvement on the survival of children with Langerhans cell histiocytosis (GI-LCH) registered with the international clinical trials of the Histiocyte Society. STUDY DESIGN: This was a retrospective analysis of 2414 pediatric patients registered onto the consecutive trials DAL-HX 83, DAL-HX 90, LCH-I, LCH-II, and LCH-III. RESULTS: Among the 1289 patients with single-system LCH, there was no single case confined to the GI tract; 114 of 1125 (10%) patients with multisystem LCH (MS-LCH) had GI-LCH at initial presentation. GI-LCH was significantly more common in children aged <2 years at diagnosis (13% vs 6% in those aged >2 years; P < .001) and in those with risk organ involvement (15% vs 6% in those without risk organ involvement; P < .001). The 5-year overall survival (OS) in patients without risk organ involvement was excellent irrespective of GI disease (98% vs 97% in patients with GI-LCH; P = .789). In patients with risk organ involvement, the 5-year OS was 51% in 70 patients with GI-LCH vs 72% in 394 patients without GI-LCH (P < .001). CONCLUSIONS: GI-LCH has an additive unfavorable prognostic impact in children with MS-LCH and risk organ involvement. The emerding need for more intensive or alternative treatments mandates prospective evaluation.

4.
Blood ; 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34115842

RESUMO

Severe congenital neutropenia (SCN) is an inborn disorder of granulopoiesis. Approximately one-third of cases do not have a known genetic cause. Exome sequencing of 104 persons with congenital neutropenia identified heterozygous missense variants of CLPB (caseinolytic peptidase B) in 5 SCN cases, with 5 more cases identified through additional sequencing efforts or clinical sequencing. CLPB encodes an adenosine triphosphatase (ATPase) implicated in protein folding and mitochondrial function. Prior studies showed that biallelic mutations of CLPB are associated with a syndrome of 3-methylglutaconic aciduria, cataracts, neurologic disease, and variable neutropenia. However, 3-methylglutaconic aciduria was not observed and, other than neutropenia, these clinical features were uncommon in our series. Moreover, the CLPB variants are distinct, consisting of heterozygous variants that cluster near the ATP-binding pocket. Both genetic loss of CLPB and expression of CLPB variants results in impaired granulocytic differentiation of human hematopoietic progenitors and increased apoptosis. These CLPB variants associate with wildtype CLPB and inhibit its ATPase and disaggregase activity in a dominant-negative fashion. Finally, expression of CLPB variants is associated with impaired mitochondrial function but does not render cells more sensitive to endoplasmic reticulum stress. Together, these data show that heterozygous CLPB variants are a new and relatively common cause of congenital neutropenia and should be considered in the evaluation of patients with congenital neutropenia.

5.
Artigo em Inglês | MEDLINE | ID: mdl-34020934

RESUMO

OBJECTIVE: Peritoneal or mesenteric tumours may correspond to several tumour types or tumour-like conditions, some of them being represented by histiocytosis. This rare condition often poses diagnostic difficulties that can lead to important time delay in targeted therapies. Our aim was to describe main features of histiocytoses with mesenteric localisation that can improve the diagnostic process. DESIGN: We performed a retrospective study on 22 patients, whose peritoneal/mesenteric biopsies were infiltrated by histiocytes. RESULTS: Abdominal pain was the revealing symptom in 10 cases, and 19 patients underwent surgical biopsies. The diagnosis of histiocytosis was proposed by initial pathologists in 41% of patients. The other initial diagnoses were inflammation (n=7), sclerosing mesenteritis (n=4) and liposarcoma (n=1). The CD163/CD68+CD1a- histiocytes infiltrated subserosa and/or deeper adipose tissues in 16 and 14 cases, respectively. A BRAF V600E mutation was detected within the biopsies in 11 cases, and two others were MAP2K1 mutated. The final diagnosis was histiocytosis in 18 patients, 15 of whom had Erdheim-Chester disease. The median diagnostic delay of histiocytosis was 9 months. Patients treated with BRAF or MEK inhibitors showed a partial response or a stable disease. One patient died soon after surgery, and five died by the progression of the disease. CONCLUSION: Diagnosis of masses arising in the mesentery should be carefully explored as one of the possibilities in histiocytosis. This diagnosis is frequently missed on mesenteric biopsies. Molecular biology for detecting the mutations in BRAF or in genes of the MAP kinase pathway is a critical diagnostic tool.

6.
Lancet ; 398(10295): 157-170, 2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-33901419

RESUMO

Histiocytoses constitute a heterogeneous group of rare disorders, characterised by infiltration of almost any organ by myeloid cells with diverse macrophage or dendritic cell phenotypes. Histiocytoses can start at any age. Diagnosis is based on histology in combination with appropriate clinical and radiological findings. The low incidence and broad spectrum of clinical manifestations often leads to diagnostic delay, especially for adults. In most cases, biopsy specimens infiltrated by histiocytes have somatic mutations in genes activating the MAP kinase cell-signalling pathway. These mutations might also be present in blood cells and haematopoietic progenitors of patients with multisystem disease. A comprehensive range of investigations and molecular typing are essential to accurately predict prognosis, which can vary from spontaneous resolution to life-threatening disseminated disease. Targeted therapies with BRAF or MEK inhibitors have revolutionised salvage treatment. However, the type and duration of treatment are still debated, and the prevention of neurological sequelae remains a crucial issue.

7.
Pediatr Blood Cancer ; 68(7): e29071, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33871916

RESUMO

Shwachman-Diamond syndrome with Shwachman-Bodian-Diamond syndrome (SBDS) biallelic variants is a rare disorder that predisposes the carrier to malignant hemopathies but solid-cancer predisposition is poorly known. Among 155 cases entered in the French Registry for Severe Chronic Neutropenia, three were identified with malignant solid tumors (ovary, breast, and esophagus). All cancers occurred during the fifth decade and, despite being localized at diagnosis, were rapidly fatal thereafter. No cancer was observed post transplantation in the 14 HSCT survivors. Based on the literature and our patient data, we can merely advance that this complication is predominantly diagnosed in adults.

9.
Blood ; 137(20): 2770-2784, 2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-33512478

RESUMO

Dendritic cells (DCs) encompass several cell subsets that collaborate to initiate and regulate immune responses. Proper DC localization determines their function and requires the tightly controlled action of chemokine receptors. All DC subsets express CXCR4, but the genuine contribution of this receptor to their biology has been overlooked. We addressed this question using natural CXCR4 mutants resistant to CXCL12-induced desensitization and harboring a gain of function that cause the warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (WS), a rare immunodeficiency associated with high susceptibility to the pathogenesis of human papillomavirus (HPV). We report a reduction in the number of circulating plasmacytoid DCs (pDCs) in WHIM patients, whereas that of conventional DCs is preserved. This pattern was reproduced in an original mouse model of WS, enabling us to show that the circulating pDC defect can be corrected upon CXCR4 blockade and that pDC differentiation and function are preserved, despite CXCR4 dysfunction. We further identified proper CXCR4 signaling as a critical checkpoint for Langerhans cell and DC migration from the skin to lymph nodes, with corollary alterations of their activation state and tissue inflammation in a model of HPV-induced dysplasia. Beyond providing new hypotheses to explain the susceptibility of WHIM patients to HPV pathogenesis, this study shows that proper CXCR4 signaling establishes a migration threshold that controls DC egress from CXCL12-containing environments and highlights the critical and subset-specific contribution of CXCR4 signal termination to DC biology.

10.
J Clin Immunol ; 41(3): 639-657, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33417088

RESUMO

PURPOSE: Germline heterozygous mutations of GATA2 underlie a variety of hematological and clinical phenotypes. The genetic, immunological, and clinical features of GATA2-deficient patients with mycobacterial diseases in the familial context remain largely unknown. METHODS: We enrolled 15 GATA2 index cases referred for mycobacterial disease. We describe their genetic and clinical features including their relatives. RESULTS: We identified 12 heterozygous GATA2 mutations, two of which had not been reported. Eight of these mutations were loss-of-function, and four were hypomorphic. None was dominant-negative in vitro, and the GATA2 locus was found to be subject to purifying selection, strongly suggesting a mechanism of haploinsufficiency. Three relatives of index cases had mycobacterial disease and were also heterozygous, resulting in 18 patients in total. Mycobacterial infection was the first clinical manifestation in 11 patients, at a mean age of 22.5 years (range: 12 to 42 years). Most patients also suffered from other infections, monocytopenia, or myelodysplasia. Strikingly, the clinical penetrance was incomplete (32.9% by age 40 years), as 16 heterozygous relatives aged between 6 and 78 years, including 4 older than 60 years, were completely asymptomatic. CONCLUSION: Clinical penetrance for mycobacterial disease was found to be similar to other GATA2 deficiency-related manifestations. These observations suggest that other mechanisms contribute to the phenotypic expression of GATA2 deficiency. A diagnosis of autosomal dominant GATA2 deficiency should be considered in patients with mycobacterial infections and/or other GATA2 deficiency-related phenotypes at any age in life. Moreover, all direct relatives should be genotyped at the GATA2 locus.

13.
Blood ; 137(4): 485-492, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33067622

RESUMO

Erdheim-Chester disease (ECD) is a clonal hematopoietic disorder characterized by the accumulation of foamy histiocytes within organs (in particular, frequent retroperitoneal involvement) and a high frequency of BRAFV600E mutations. Although ECD is not commonly recognized to have overt peripheral blood (PB) or bone marrow (BM) disease, we recently identified that ECD patients have a high frequency of a concomitant myeloid malignancy. We thus conducted a systematic clinical and molecular analysis of the BM from 120 ECD patients. Surprisingly, 42.5% of ECD patients (51 of 120) had clonal hematopoiesis whereas 15.8% of patients (19 of 120) developed an overt hematologic malignancy (nearly all of which were a myeloid neoplasm). The most frequently mutated genes in BM were TET2, ASXL1, DNMT3A, and NRAS. ECD patients with clonal hematopoiesis were more likely to be older (P < .0001), have retroperitoneal involvement (P = .02), and harbor a BRAFV600E mutation (P = .049) than those without clonal hematopoiesis. The presence of the TET2 mutation was associated with a BRAFV600E mutation in tissue ECD lesions (P = .0006) and TET2-mutant ECD patients were more likely to have vascular involvement than TET2 wild-type ECD patients. Clonal hematopoiesis mutations in ECD were detected in cells derived from CD34+CD38- BM progenitors and PB monocytes but less frequently present in PB B and T lymphocytes. These data identify a heretofore unrecognized high frequency of clonal hematopoiesis in ECD patients, reaffirm the development of additional high risk of myeloid neoplasms in ECD, and provide evidence of a BM-based precursor cell of origin for many patients with ECD.


Assuntos
Hematopoiese Clonal , Doença de Erdheim-Chester/fisiopatologia , Cariótipo Anormal , Adulto , Fatores Etários , Idoso , Medula Óssea/patologia , Transformação Celular Neoplásica/genética , Hematopoiese Clonal/genética , Proteínas de Ligação a DNA/genética , Progressão da Doença , Doença de Erdheim-Chester/genética , Éxons/genética , Feminino , Genes Neoplásicos , Humanos , Leucemia Mieloide/genética , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Mutação , Síndromes Mielodisplásicas/genética , Proteínas de Neoplasias/genética , Células-Tronco Neoplásicas/patologia , Especificidade de Órgãos , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas B-raf/genética
15.
Orphanet J Rare Dis ; 15(1): 241, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32907615

RESUMO

BACKGROUND: Lung involvement in childhood Langerhans cell histiocytosis (LCH) is infrequent and rarely life threatening, but occasionally, severe presentations are observed. METHODS: Among 1482 children (< 15 years) registered in the French LCH registry (1994-2018), 111 (7.4%) had lung involvement. This retrospective study included data for 17 (1.1%) patients that required one or more intensive care unit (ICU) admissions for respiratory failure. RESULTS: The median age was 1.3 years at the first ICU hospitalization. Of the 17 patients, 14 presented with lung involvement at the LCH diagnosis, and 7 patients (41%) had concomitant involvement of risk-organ (hematologic, spleen, or liver). Thirty-five ICU hospitalizations were analysed. Among these, 22 (63%) were secondary to a pneumothorax, 5 (14%) were associated with important cystic lesions without pneumothorax, and 8 (23%) included a diffuse micronodular lung infiltration in the context of multisystem disease. First-line vinblastine-corticosteroid combination therapy was administered to 16 patients; 12 patients required a second-line therapy (cladribine: n = 7; etoposide-aracytine: n = 3; targeted therapy n = 2). A total of 6 children (35%) died (repeated pneumothorax: n = 3; diffuse micronodular lung infiltration in the context of multisystem disease: n = 2; following lung transplantation: n = 1). For survivors, the median follow-up after ICU was 11.2 years. Among these, 9 patients remain asymptomatic despite abnormal chest imaging. CONCLUSIONS: Severe lung involvement is unusual in childhood LCH, but it is associated with high mortality. Treatment guidelines should be improved for this group of patients: viral infection prophylaxis and early administration of a new LCH therapy, such as targeted therapy.


Assuntos
Histiocitose de Células de Langerhans , Criança , Estudos de Coortes , Histiocitose de Células de Langerhans/tratamento farmacológico , Humanos , Lactente , Pulmão , Estudos Retrospectivos , Vimblastina
16.
Neurology ; 95(20): e2746-e2754, 2020 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-32887776

RESUMO

OBJECTIVE: CNS involvement in Erdheim-Chester disease (ECD) leads to substantial morbidity and mortality. To assess CNS manifestations in a French cohort of 253 patients with ECD, we determined clinical characteristics and outcomes, including those under targeted therapies. METHODS: This was a retrospective longitudinal study. CNS manifestations were determined by clinical examination and brain or spine MRI. Targeted therapy efficacy was assessed using global assessment from a physician and a radiologist. The study was approved by the ethics committee Comité de Protection des Personnes Ile de France III. RESULTS: Ninety-seven of 253 patients (38%) with ECD had CNS involvement. CNS involvement was significantly associated with a younger age at diagnosis (mean 55.5 years) and at symptom onset (mean 50.5 years), as well as with the presence of the BRAF V600E mutation (in 77% of cases), xanthelasma (34%), and diabetes insipidus (36%). Median survival among patients with CNS involvement was significantly lower than that of patients with ECD without CNS involvement (124 months vs 146 months, p = 0.03). Seventy-four CNS MRIs were centrally reviewed, which showed 3 patterns: tumoral in 66%, pseudo-degenerative in 50%, and vascular in 18%. Targeted therapy (BRAF or MEK inhibitors) was associated with improved symptoms in 43% of patients and MRI improvement in 45%. CONCLUSIONS: CNS manifestations are typically associated with poor prognosis in patients with ECD. Three distinct patterns can be recognized: tumoral, pseudodegenerative, and vascular. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that targeted therapy leads to clinical or imaging improvement in almost 50% of patients.


Assuntos
Tronco Encefálico/patologia , Córtex Cerebral/patologia , Doença de Erdheim-Chester/tratamento farmacológico , Doença de Erdheim-Chester/patologia , Inibidores de Proteínas Quinases/farmacologia , Medula Espinal/patologia , Adulto , Fatores Etários , Idoso , Atrofia/patologia , Tronco Encefálico/diagnóstico por imagem , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Córtex Cerebral/diagnóstico por imagem , Diabetes Insípido/etiologia , Doença de Erdheim-Chester/complicações , Doença de Erdheim-Chester/genética , Feminino , França , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Estudos Retrospectivos , Medula Espinal/diagnóstico por imagem , Resultado do Tratamento
17.
Pediatr Blood Cancer ; 67(10): e28496, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32710685

RESUMO

OBJECTIVE: This study was undertaken to describe the spectrum of lung computed-tomography (CT) findings in children with pulmonary Langerhans cell histiocytosis (PLCH) and to evaluate for this population the CT-scan nodule and cyst scores proposed by adult pulmonologists at diagnosis and during follow-up. METHODS: Among 175 children with PLCH identified in the French national population-based Langerhans cell histiocytosis cohort, 60 were retrospectively selected by the availability of CT for a central review by three pediatric radiologists. These 60 patients are representative of childhood PLCH for almost all clinical aspects, except a lower percentage of risk organ involvement (38% vs 54%; P = 0.05). RESULTS: The 60 children's chest CT scans (n = 218) were reviewed. At diagnosis, 63% of them had nodules, 53% had cysts, and 29% had both. The percentages of patients with nodules or cysts increased from diagnosis to peak disease activity, respectively, from 63% to 73% and from 53% to 66%. The costophrenic angle was involved in 71%. Patients with pneumothorax (25%) had a higher median cyst score. Alveolar consolidation was observed in 34%. Patients with low CT-scan nodule and cyst scores had no long-term pulmonary sequelae. CONCLUSIONS: Well-known characteristics of adult PLCH (nodules and cysts) were observed in children. The chest CT scores proposed by adult pulmonologists could easily be applied to childhood PLCH. Lesions in children, unlike those in adults, are frequently located near the costophrenic angles. Alveolar consolidation might be considered an atypical feature of childhood PLCH.


Assuntos
Cistos/diagnóstico , Histiocitose de Células de Langerhans/diagnóstico , Pneumopatias/diagnóstico , Radiografia Torácica/métodos , Tomografia Computadorizada por Raios X/métodos , Criança , Pré-Escolar , Cistos/diagnóstico por imagem , Feminino , Seguimentos , Histiocitose de Células de Langerhans/diagnóstico por imagem , Humanos , Lactente , Pneumopatias/diagnóstico por imagem , Masculino , Prognóstico , Estudos Retrospectivos
18.
Br J Haematol ; 191(5): 825-834, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32700439

RESUMO

The nucleoside analogue, 2-chlorodeoxyadenosine (2CDA), was reported to be an active treatment for childhood Langerhans cell histiocytosis (LCH) without risk organ (RO-) involvement. However, we lack data on long-term effects of 2CDA treatment, including the disease reactivation rate, permanent sequelae and long-term tolerance. This study included 44 children from the French LCH registry, treated for a RO- LCH with 2CDA monotherapy (median number of six courses). The median age at the beginning of 2CDA was 3·6 years (range, 0·3-19·7 years) and the median follow-up after was 5·4 years (range, 0·6-15·1 years). Objective response to 2CDA was observed in 25 patients (56·8%), while six patients (13·6%) had stable disease and 13 patients (29·5%) exhibited progressive disease. Among patients without progression, only two experienced disease reactivation after 2CDA discontinuation. The five-year cumulative incidence of disease progression or reactivation after 2CDA therapy initiation was 34·3%. The lymphopenia reported in all cases [72% below absolute lymphocyte count (ALC) of 0·5 G/l], was addressed with appropriate prophylactic measures. Other toxicities above grade 2 were uncommon, and no second malignant neoplasm or neuropathy was reported. The five-year overall survival was 97·7%. In conclusion, we could confirm that 2CDA monotherapy was a beneficial long-term therapy for treating patients with RO- LCH. Appropriate management of induced immune deficiency is mandatory.


Assuntos
Cladribina/administração & dosagem , Histiocitose de Células de Langerhans/tratamento farmacológico , Histiocitose de Células de Langerhans/mortalidade , Sistema de Registros , Adolescente , Criança , Pré-Escolar , Cladribina/efeitos adversos , Intervalo Livre de Doença , Feminino , Seguimentos , França , Histiocitose de Células de Langerhans/sangue , Humanos , Lactente , Contagem de Linfócitos , Masculino , Taxa de Sobrevida
20.
Mol Genet Metab Rep ; 23: 100581, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32300528

RESUMO

Glycogenosis type Ib (GSD1B) causes not only hypoglycemia but also infections and "Crohn's disease like" inflammatory bowel disease (IBD) that can significantly impair patient's quality of life. We retrospectively evaluated infectious and digestive complications in 9 French patients (3 girls, 6 boys) diagnosed at 0.8 years on average, with a mean follow-up of 19.1 years. Infections occurred earlier than IBD, at mean ages of 1.7 and 3.8 years, respectively. The number of acute hospitalizations was 0.7/year due to infectious (0.4/year) or digestive symptoms (0.4/year). Clinical presentations allowed separating patients into mild (n = 5) and severe (n = 4) intestinal involvement. Patients in the severe group had more serious digestive symptoms but also earlier neutropenia (median 0.3 vs. 1.5 years, p =0 .046) with a tendency to a lower neutrophil count (NC) during follow-up, and a higher number of acute hospitalizations (median 1.3/year vs. 0.2/year, p =0 .014) due to digestive symptoms (median 0.6/year vs. 0.05/year, p = 0,012) and infections (median 0.8/year vs. 0.2/year, p =0 .014). Treatments included G-CSF and cotrimoxazole (n = 7), 5-aminosalicylic acid (n = 2), and a polymeric solution enriched in the anti-inflammatory cytokine TGF-ß (n = 4, "severe" group), and immunomodulatory treatment (n = 1). In conclusion, infections and IBD are rare but severe complications in GSD1B. Neutropenia tended to be more prevalent in the severe IBD group than in the mild IBD group. Dietetic treatment with specific anti-inflammatory solutions seems particularly appropriate in these patients.

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