Sébastien Héritier

Diverse and Targetable Kinase Alterations Drive Histiocytic Neoplasms

UNLABELLED Histiocytic neoplasms are clonal, hematopoietic disorders characterized by an accumulation of abnormal, monocyte-derived dendritic cells or macrophages in Langerhans cell histiocytosis (LCH) and non-Langerhans cell histiocytosis (non-LCH), respectively. The discovery of BRAF(V600E) mutations in approximately 50% of these patients provided the first molecular therapeutic target in histiocytosis. However, recurrent driving mutations in the majority of patients with BRAF(V600E)-wild-type non-LCH are unknown, and recurrent cooperating mutations in non-MAP kinase pathways are undefined for the histiocytic neoplasms. Through combined whole-exome and transcriptome sequencing, we identified recurrent kinase fusions involving BRAF, ALK, and NTRK1, as well as recurrent, activating MAP2K1 and ARAF mutations in patients with BRAF(V600E)-wild-type non-LCH. In addition to MAP kinase pathway lesions, recurrently altered genes involving diverse cellular pathways were identified. Treatment of patients with MAP2K1- and ARAF-mutated non-LCH using MEK and RAF inhibitors, respectively, resulted in clinical efficacy, demonstrating the importance of detecting and targeting diverse kinase alterations in these disorders. SIGNIFICANCE We provide the first description of kinase fusions in systemic histiocytic neoplasms and activating ARAF and MAP2K1 mutations in non-Langerhans histiocytic neoplasms. Refractory patients with MAP2K1- and ARAF-mutant histiocytoses had clinical responses to MEK inhibition and sorafenib, respectively, highlighting the importance of comprehensive genomic analysis of these disorders.

Primary T-cell immunodeficiency with immunodysregulation caused by autosomal recessive LCK deficiency.

BACKGROUND Signals emanating from the antigen T-cell receptor (TCR) are required for T-cell development and function. The T lymphocyte-specific protein tyrosine kinase (Lck) is a key component of the TCR signaling machinery. On the basis of its function, we considered LCK a candidate gene in patients with combined immunodeficiency. OBJECTIVE We identify and describe a child with a T-cell immunodeficiency caused by a homozygous missense mutation of the LCK gene (c.1022T>C) resulting from uniparental disomy. METHODS Genetic, molecular, and functional analyses were performed to characterize the Lck deficiency, and the associated clinical and immunologic phenotypes are reported. RESULTS The mutant LCK protein (p.L341P) was weakly expressed with no kinase activity and failed to reconstitute TCR signaling in LCK-deficient T cells. The patient presented with recurrent respiratory tract infections together with predominant early-onset inflammatory and autoimmune manifestations. The patient displayed CD4(+) T-cell lymphopenia and low levels of CD4 and CD8 expression on the T-cell surface. The residual T lymphocytes had an oligoclonal T-cell repertoire and exhibited a profound TCR signaling defect, with only weak tyrosine phosphorylation signals and no Ca(2+) mobilization in response to TCR stimulation. CONCLUSION We report a new form of T-cell immunodeficiency caused by a LCK gene defect, highlighting the essential role of Lck in human T-cell development and responses. Our results also point out that defects in the TCR signaling cascade often result in abnormal T-cell differentiation and functions, leading to an important risk factor for inflammation and autoimmunity.

Vemurafenib Use in an Infant for High-Risk Langerhans Cell Histiocytosis

Vemurafenib Use in an Infant for High-Risk Langerhans Cell Histiocytosis Langerhans cell histiocytosis (LCH) is a clonal disorder characterized by lesions containing pathological CD207+ dendritic cells. Refractory high-risk LCH is a life-threatening disease that affects mostly infants. Patients with a Disease Activity Score (DAS) higher than 6, in whom vinblastine sulfate– steroid treatment had failed, have a greater than 50% risk of death, which mostly concerns children younger than 2 years.1 Because somatic BRAF V600E mutation plays an important role in LCH pathophysiology,2 BRAF inhibitors could offer a new therapeutic approach3 but, to our knowledge, have never been proposed as a treatment in infants.

BRAF Mutation Correlates With High-Risk Langerhans Cell Histiocytosis and Increased Resistance to First-Line Therapy

PURPOSE Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia with a broad spectrum of clinical manifestations and outcomes in children. The somatic BRAF(V600E) mutation occurs frequently, but clinical significance remains to be determined. PATIENTS AND METHODS BRAF(V600E) mutation was investigated in a French LCH cohort. We analyzed associations between mutation status and clinical presentation, extent of disease, reactivation rate, response to therapy, and long-term permanent sequelae. RESULTS Among 315 patients with successfully determined BRAF status, 173 (54.6%) carried a BRAF(V600E) mutation. Patients with BRAF(V600E) manifested more severe disease than did those with wild-type BRAF. Patients with BRAF(V600E) comprised 87.8% of patients (43 of 49) with multisystem LCH with risk organ involvement (liver, spleen, hematology), 68.6% of patients (35 of 51) with multisystem LCH without risk organ involvement, 43.9% of patients (86 of 196) with single-system LCH, and 42.1% of patients (8 of 19) with lung-involved LCH (P < .001). BRAF(V600E) mutation was also associated with organ involvement that could lead to permanent, irreversible damage, such as neurologic (75%) and pituitary (72.9%) injuries. Compared with patients with wild-type BRAF, patients with BRAF(V600E) more commonly displayed resistance to combined vinblastine and corticosteroid therapy (21.9% v 3.3%; P = .001), showed a higher reactivation rate (5-year reactivation rate, 42.8% v 28.1%; P = .006), and had more permanent, long-term consequences from disease or treatment (27.9% v 12.6%; P = .001). CONCLUSION In children with LCH, BRAF(V600E) mutation was associated with high-risk features, permanent injury, and poor short-term response to chemotherapy. Further population-based studies should be undertaken to confirm our observations and to assess the impact of BRAF inhibitors for this subgroup of patients who may benefit from targeted therapy.

Common cancer-associated PIK3CA activating mutations rarely occur in Langerhans cell histiocytosis

To the editor: Langerhans cell histiocytosis (LCH) can be a multisystem disease with an unpredictable outcome, from autoregressive to vital organ damage and sometimes fatal evolution. In 2010, Badalian-Very et al reported the BRAF V600E somatic activating mutation was present in 57% of LCH cases

Langerhans cell histiocytosis: therapeutic strategy and outcome in a 30‐year nationwide cohort of 1478 patients under 18 years of age

The French national cohort of children with Langerhans cell histiocytosis (LCH) has included 1478 patients since it was established in 1983. LCH therapeutic strategies substantially changed in 1998, so we have divided the cohort into two 15‐year periods. Starting in 1998, therapy duration increased from 6 to 12 months, repeated induction therapy was performed in cases showing a poor response to the first induction with vinblastine and steroids, and refractory disease in a risk organ (RO+) was treated with cladribine and cytarabine. A total of 483 (33%) patients were enrolled before 1998, and 995 (67%) after 1998. Five‐year survival was 96·6% (95% confidence interval: 95·4–97·5%) overall, improving from 92% pre‐1998 to 99% post‐1998 (P < 0·001 adjusted to disease extent). This change was supported by an increase in 5‐year survival from 60% to 92% in the RO+ group. Survival was particularly associated with cladribine and cytarabine among refractory RO+ patients. Disease reactivation was slightly less frequent after 1998, due to better enrolment of single‐system patients, extended therapy duration, and more efficient second‐line therapy. The crude rates of endocrine and neurological sequelae (the most frequent sequelae) appeared to improve over time, but this difference was not observed when the analysis was stratified by disease extent.

Temporal and Spatial Compartmentalization of Drug-Resistant Cytomegalovirus (CMV) in a Child with CMV Meningoencephalitis: Implications for Sampling in Molecular Diagnosis

ABSTRACT We describe a case of antiviral-resistant cytomegalovirus meningoencephalitis occurring after hematopoietic stem cell transplantation. Antiviral-resistant cytomegalovirus was identified in blood 16 months earlier. However, wild-type cytomegalovirus was evidenced in blood when the meningoencephalitis was diagnosed. Treatment of meningoencephalitis should be adapted to all previously identified resistance mutations in any compartment.

Retrospective French nationwide survey of childhood aggressive vascular anomalies of bone, 1988-2009

ObjectiveTo document the epidemiological, clinical, histological and radiological characteristics of aggressive vascular abnormalities of bone in children.Study designCorrespondents of the French Society of Childhood Malignancies were asked to notify all cases of aggressive vascular abnormalities of bone diagnosed between January 1988 and September 2009.Results21 cases were identified; 62% of the patients were boys. No familial cases were observed, and the disease appeared to be sporadic. Mean age at diagnosis was 8.0 years [0.8-16.9 years]. Median follow-up was 3 years [0.3-17 years]. The main presenting signs were bone fracture (n = 4) and respiratory distress (n = 7), but more indolent onset was observed in 8 cases. Lung involvement, with lymphangiectasies and pleural effusion, was the most frequent form of extraosseous involvement (10/21). Bisphosphonates, alpha interferon and radiotherapy were used as potentially curative treatments. High-dose radiotherapy appeared to be effective on pleural effusion but caused major late sequelae, whereas antiangiogenic drugs like alpha interferon and zoledrenate have had a limited impact on the course of pulmonary complications. The impact of bisphosphonates and alpha interferon on bone lesions was also difficult to assess, owing to insufficient follow-up in most cases, but it was occasionally positive. Six deaths were observed and the overall 10-year mortality rate was about 30%. The prognosis depended mainly on pulmonary and spinal complications.ConclusionAggressive vascular abnormalities of bone are extremely rare in childhood but are lifethreatening. The impact of anti-angiogenic drugs on pulmonary complications seems to be limited, but they may improve bone lesions.

Massive expansion of maternal T cells in response to EBV infection in a patient with SCID-Xl

To the editor: X-linked severe combined immunodeficiency (SCID-Xl) is caused by defects in IL2RG , the gene encoding the IL-2 receptor γ chain. Accounting for 50% to 60% of cases of SCID,[1][1] it SCID-XI is typically characterized by an absence of mature T and natural killer (NK) lymphocytes,

Disseminated Bacillus Calmette-Guérin Osteomyelitis in Twin Sisters Related to STAT1 Gene Deficiency

Mendelian susceptibility to mycobacterial disease is a rare syndrome characterized by severe clinical infections usually caused by weakly virulent mycobacterial species such as Bacillus Calmette-Guérin vaccines and environmental nontuberculous mycobacteria or more virulent mycobacteria as mycobacterium tuberculosis. Since 1996, 9 genes including 7 autosomal (STAT1, IFNGR1, IFNGR2, IL12B, IL12RB1, ISG15, and IRF8) and 2 X-linked genes (NEMO and CYBB) have been identified. Allelic heterogeneity leaded to recognize about 18 genetic diseases with variable clinical phenotypes, but sharing a same physiological mechanism represented by a defect in human IL-12-dependant-INF-γ-mediated immunity. We report here a case of multifocal Bacillus Calmette-Guérin osteomyelitis in a context Mendelian susceptibility to mycobacterial disease mimicking a metastatic neuroblastoma in a child presenting with delayed growth. The investigation of her twin sister showed the same disease. A heterozygous mutation in exon 22 of STAT1 gene was found in both sisters, another sister and the father being healthy and heterozygous for the same mutation.