Casitas B-lineage lymphoma Gene Mutation Ocular Phenotype.

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.

Two neurologic facets of CTLA4-related haploinsufficiency.

OBJECTIVE: To describe the clinical and radiologic neurologic characteristics of patients with cytotoxic T-lymphocyte antigen-4 (CTLA4) haploinsufficiency. METHODS: Three patients from 2 families had neurologic manifestations in the context of CTLA4 haploinsufficiency. Their clinical and MRI findings are presented. RESULTS: A 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). CONCLUSIONS: These 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.

Severe Abdominal Manifestations in Juvenile Dermatomyositis.

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.

Bone Marrow Transplantation in Congenital Erythropoietic Porphyria: Sustained Efficacy but Unexpected Liver Dysfunction.

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.

Pediatric-onset Evans syndrome: Heterogeneous presentation and high frequency of monogenic disorders including LRBA and CTLA4 mutations.

Evans syndrome (ES) is defined by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. Clinical presentation includes manifestations of immune dysregulation, found in primary immune deficiencies, autoimmune lymphoproliferative syndrome with FAS (ALPS-FAS), Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) and Lipopolysaccharide-Responsive vesicle trafficking Beige-like and Anchor protein (LRBA) defects. We report the clinical history and genetic results of 18 children with ES after excluding ALPS-FAS. Thirteen had organomegaly, five lymphocytic infiltration of non-lymphoid organs, nine hypogammaglobulinemia and fifteen anomalies in lymphocyte phenotyping. Seven patients had genetic defects: three CTLA4 mutations (c.151C>T; c.109+1092_568-512del; c.110-2A>G) identified by Sanger sequencing and four revealed by Next Generation Sequencing: LRBA (c.2450+1C>T), STAT3 gain-of-function (c.2147C>T; c.2144C>T) and KRAS (c.37G>T). No feature emerged to distinguish patients with or without genetic diagnosis. Our data on pediatric-onset ES should prompt physicians to perform extensive screening for mutations in the growing pool of genes involved in primary immune deficiencies with autoimmunity.

High prevalence of myeloid neoplasms in adults with non-Langerhans cell histiocytosis.

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis that most commonly affects adults and is driven by a high frequency of mutations in BRAF, MAP2K1, and kinases promoting MAPK signaling. Because of the relative rarity of ECD, key clinical features of the disease may not be well defined. Across a multi-institutional cohort of 189 patients with ECD and ECD overlapping with Langerhans cell histiocytosis (so-called mixed histiocytosis [MH]), we identified an unexpected and heretofore undescribed frequent occurrence of myeloid neoplasms among patients with ECD and MH. Some 10.1% (19/189) of patients with ECD have an overlapping myeloid neoplasm, most commonly occurring as a myeloproliferative neoplasm (MPN), myelodysplastic syndrome (MDS), or mixed MDS/MPN overlap syndrome (including chronic myelomonocytic leukemia). Consistent with this, molecular analysis frequently detected hallmark driver mutations of myeloid neoplasms (such as JAK2V617F and CALR mutations) coexisting with those characteristic of histiocytosis (such as BRAFV600E and MAP2K1 mutations). Histiocytosis patients diagnosed with a concomitant myeloid malignancy were significantly older at diagnosis and more commonly presented with MH than those without a myeloid malignancy. In some cases, the presence of distinct kinase mutations in the histiocytosis and myeloid neoplasm resulted in discordant and adverse responses to kinase-directed targeted therapies. These data highlight the clinical importance of evaluating adults with histiocytosis for a concomitant myeloid neoplasm.