Key Points Some 10.1% of adults with non–Langerhans cell histiocytosis have a concomitant myeloid neoplasm with each often harboring distinct mutations. The presence of distinct kinase mutations in histiocytosis and myeloid neoplasms resulted in discordant responses to targeted therapy.
Congenital erythropoietic porphyria (CEP) is a rare disease characterized by erosive photosensitivity and chronic hemolysis due to a defect of the enzyme uroporphyrinogen-III-synthase (UROS). To date, hematopoietic stem cell transplantation (HSCT) is the only curative therapy for the devastating early and severe form of the disease. We describe 6 patients with CEP treated with HSCT (3 of them twice after failure of a first graft) between 1994 and 2016 in our center, including 2 of the very first living patients treated more than 20 years ago. Four patients are doing well at 6 to 25 years post-HSCT, with near-normal biochemical parameters of porphyrin metabolism without the cutaneous or hematologic features of CEP. One patient died within the first year after HSCT from severe graft-versus-host disease (GVHD), and 1 child died of unexplained acute hepatic failure at 1 year after HSCT, despite full donor chimerism. Retrospectively, it appears that all but 1 child had increased transaminase activity with onset from the early postnatal period, which was significantly more marked in the child who died of liver failure. In contrast, liver function values progressively normalized after engraftment in all other children. Liver pathology before HSCT for 3 patients revealed varying degrees of portal, centrilobular, and perisinusoidal fibrosis; clarification of hepatocytes; and cytosolic porphyrin deposits. The liver porphyrin content in biopsy specimens was >60 times the normal values. Despite difficult engraftment, the long-term efficacy of HSCT in CEP appears to be favorable and reinforces its benefits for the severe form of CEP. Hepatic involvement requires careful evaluation before and after HSCT and further investigation into its pathophysiology and care.
Juvenile dermatomyositis (JDM) is a rare and heterogeneous pediatric-onset idiopathic inflammatory myopathy. Gastrointestinal (GI) involvement occurs in 22% to 37% of JDM patients but has only been described in case reports. In this retrospective, single-center, observational study, we aimed to assess the causes and management of severe GI manifestations in JDM patients. We studied a cohort of 9 patients among 110 JDM patients followed during the study period (8.3%). The GI complications were related to JDM in most cases (17/19), with digestive tract involvement (n = 10), acute pancreatitis (n = 4), and hepatitis (n = 3). Three patients died from refractory JDM 2.9 years (2–3.6) after the JDM diagnosis. We highlight the need to consider pancreatitis as a main diagnostic factor in JDM patients with severe GI manifestations and the requirement of early aggressive treatment for these patients.
ObjectiveTo describe the clinical and radiologic neurologic characteristics of patients with cytotoxic T-lymphocyte antigen-4 (CTLA4) haploinsufficiency.MethodsThree patients from 2 families had neurologic manifestations in the context of CTLA4 haploinsufficiency. Their clinical and MRI findings are presented.ResultsA 16-year-old boy with a previous diagnosis of combined immunodeficiency presented with severe recurrent episodes of headaches, motor deficit, and seizures associated with waxing and waning gadolinium-enhancing FLAIR cortical/juxtacortical hyperintensities. His sister, who also had combined immunodeficiency, had a brain MRI when she was aged 13 years due to recent headaches and transient right hemianopsia. It revealed a gadolinium-enhancing left occipital white matter hyperintensity. Another 49-year-old woman had progressive visual loss and cerebellar ataxia in the context of recurrent pulmonary infections. All 3 patients were found to have inherited CTLA4 haploinsufficiency. Patient 1's general condition and neurologic manifestations were completely controlled with abatacept (CTLA4-Ig).ConclusionsThese cases suggest that in addition to the variable clinical penetrance and wide spectrum of CTLA4 haploinsufficiency, its neurologic spectrum is broad, ranging from recurrent tumefactive lesions to progressive deficits including cerebellar ataxia and optic atrophy with leukoencephalopathy. These phenotypes must be recognized, and should lead to a complete immunologic workup, because potentially effective targeted immunotherapy exists.
This article describes the ocular phenotype associated with the identified Casitas B-lineage lymphoma (CBL) gene mutation and reviews the current literature. This work also includes the longitudinal follow-up of five unrelated cases of unexplained fundus lesions with visual loss associated with a history of hepatosplenomegaly. Wide repeated workup was made to rule out infections, inflammatory diseases, and lysosomal diseases. No variants in genes associated with retinitis pigmentosa, cone–rod dystrophy, and inherited optic neuropathy were found. Molecular analysis was made using next-generation sequencing (NGS) and whole-exome sequencing (WES). The results included two cases sharing ophthalmological signs including chronic macular edema, vascular leakage, visual field narrowing, and electroretinography alteration. Two other cases showed damage to the optic nerve head and a fifth young patient exhibited bilateral complicated vitreoretinal traction and carried a heterozygous mutation in the CBL gene associated with a mutation in the IKAROS gene. Ruxolitinib as a treatment for RASopathy did not improve eye conditions, whereas systemic lesions were resolved in one patient. Mutations in the CBL gene were found in all five cases. In conclusion, a detailed description may pave the way for the CBL mutation ocular phenotype. Genetic analysis using whole-exome sequencing could be useful in the diagnosis of unusual clinical features.
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BackgroundJuvenile dermatomyositis (JDM) is a rare and heterogeneous children-onset idiopathic inflammatory myopathy. It primarily affects skeletal muscle and skin, but also pulmonary, cardiac and gastrointestinal systems in a subset of patients. Gastrointestinal (GI) involvement occurs in 22 to 37% of JDM patients and have been described only in a few case reports.ObjectivesTo describe causes of severe abdominal manifestations in JDM patients.MethodsRetrospective monocentric study. Inclusion criteria were (i) diagnosis of JDM according to the modified Bohan and Peter criteria before 16 years of age, (ii) occurrence of severe involvement of any intra-abdominal organ, (iii) follow-up at Necker Hospital from 2005 to 2018. Severe abdominal manifestation was defined as a potential life-threatening abdominal organ event, need for abdominal surgery and/or parenteral nutrition. Gastrointestinal (GI) involvement was defined by severe abdominal pain, dysphagia, digestive hemorrhage, obstruction, ulceration and/or perforation. Severe hepatitis was defined by an elevation of liver enzymes exceeding five times the upper limit associated with an elevation of γ-glutamyl transferase (γGT) activity and/or liver failure. Abdominal manifestations were classified as certain or probable primary JDM involvement, therapy-related event or infection-related event.ResultsNine patients with 19 abdominal complications were identified among 110 JDM patients followed during the study period (8,3%). Diagnosis of JDM was made at a median age of 10.7 years-old [range, 3.7 – 14.4], with a median CMAS of 7 [range, 2 – 48], median MMT of 47 [range, 38 – 76], a median creatine kinase level of 3 812 UI/L [range, 170 – 14 054], and a median follow-up of 3 years [range, 0.4 – 6.3]. Seven patients were positive for either anti-NXP2 (n = 4), anti-TIF1-γ (n = 2) or anti-MDA5 (n = 1) antibodies. JDM-related abdominal disease comprised GI involvement (n = 10), acute pancreatitis (n = 4) and hepatitis (n = 3). The revealing symptom for GI involvement and acute pancreatitis was abdominal pain. Five patients with severe abdominal pain, vomiting and/or obstruction, underwent abdominal imaging revealing thickening of colon (n = 2) and/or ileum mucosa (n = 2). Hepatitis was found in 3 patients with an uncommon extensive steatosis with moderate inflammation and perisinusoidal fibrosis (n = 2). Treatment-related complications were considered certain for methotrexate-induced liver toxicity (1 patient) and possible for duodenal perforations (1 patient) 3 days after a methylprednisolone pulse. At last visit, JDM was clinically inactive in four patients. Three patients died from refractory JDM, 2.9 years [range, 2 – 3.6] after the JDM diagnosis, among the 9 patients identified in this study versus only 1/92 of the other JDM patients from our cohort.ConclusionPrimary JDM involvement was the main cause of severe abdominal manifestations and associated to a high mortality rate. We highlight for the first time that pancreatitis should be considered as a main diagnosis in J...
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