Displaying One Session

Parallel Session
Room
Copper
Date
20.09.2019, Friday
Session Time
11:00 - 12:30
Parallel Session No Topic Needed

LCH GENERAL OVERVIEW

Lecture Time
11:00 - 11:25
Room
Copper
Date
20.09.2019, Friday
Session Time
11:00 - 12:30
Presentation Topic
No Topic Needed

Abstract

Abstract Body

Langerhans cell histiocytosis (LCH) is a rare disease of the monocyte, macrophage, and dendritic cell lineage, but still the most common entity among the histiocytoses. Its clinical manifestations, severity, and clinical course are diverse and make diagnosis and management challenges. More than a century after its first description, LCH remains an intriguing disease. The disease results from somatic mutations leading to constitutive activation of the MAPK pathway. The most common causative mutation is the BRAF V600E, accounting for around 50-60% of the cases. Current experimental data suggest that LCH is myeloid neoplasia with inflammatory properties, yet the exact pathophysiology remains incompletely understood. The management concepts changed over time, closely reflecting the changing view on the nature of the disease process. Patients with single-system LCH (involvement of one organ system) generally have a favorable prognosis. The course of multisystem LCH is unpredictable upon diagnosis and requires systemic therapy. The international Histiocyte Society conducted three prospective clinical studies since the early 1990s. The standard front-line treatment for patients with multisystem LCH treated outside of controlled clinical trials consists of 6-12 weeks of initial therapy (daily oral steroids and weekly vinblastine injections), followed by pulses of prednisolone/vinblastine every three weeks, for a total treatment duration of 12 months. A currently ongoing study (LCH-IV) with a complex design (5 interventional and 2 observational strata) targets further reduction of mortality and morbidity by tailoring treatment intensity depending on expected risk. Accumulating knowledge on LCH pathobiology opens chances for molecular markers and targeted therapy.

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Parallel Session No Topic Needed

BRAF INHIBITORS AND LCH

Lecture Time
11:25 - 11:50
Room
Copper
Date
20.09.2019, Friday
Session Time
11:00 - 12:30
Presentation Topic
No Topic Needed
Parallel Session No Topic Needed

PANNICULITIS-LIKE T CELL LYMPHOMA AND HAVCR2 MUTATIONS

Lecture Time
11:50 - 12:15
Room
Copper
Date
20.09.2019, Friday
Session Time
11:00 - 12:30
Presentation Topic
No Topic Needed
Parallel Session Innate Immunity

MYCOBACTERIAL DISEASE MIMICKING LANGERHANS HISTIOCYTOSIS IN A PATIENT WITH A NOVEL FORM OF INHERITED JAK1 DEFICIENCY

Lecture Time
12:15 - 12:25
Room
Copper
Date
20.09.2019, Friday
Session Time
11:00 - 12:30
Presentation Topic
Innate Immunity

Abstract

Background and Aims

Human JAK1 is involved in multiple cytokine responsive pathways, including type I and II IFN signalling pathways. Homozygosity for a rare germline hypomorphic mutation in JAK1 was previously described in a 22-year-old Pakistani patient with mycobacterial and viral infections, as well as early onset bladder malignancy.

Methods

By whole-exome sequencing, we investigated a 6-year-old Algerian patient with mycobacterial infections mimicking Langerhans histiocytiosis.

Results

The patient is compound heterozygous for a missense (p.C657S) and a splice mutation (c.2108_2115+15del) in JAK1. The splice mutant allele encodes three alternative transcripts (c.1756_2115del, c.1900_2115del, and c.1988_2115del). Upon overexpression, the missense protein impairs but does not abolish responses to IFN-γ, while it does not even impair responses to IFN-α2b. In contrast, the products of the three splice variants are loss-of-function for both IFN-γ and IFN-α2b stimulation. Moreover, EBV-B cells from the patient respond poorly to IFN-γ, a phenotype that is rescued by retrotransduction with a WT JAK1 cDNA. Response to IFN-α2b is normal in EBV-B cells from patient. In contrast, the patient’s fibroblasts respond normally to both IFN-γ and IFN-α2b.

Conclusions

We thus describe a second patient with a novel partial form of autosomal recessive JAK1 deficiency, manifesting as isolated MSMD due to an apparently selective impairment of the IFN-γ responsive pathway.

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