Nathalie Aladjidi, France
Bordeaux University Hospital Pediatric oncologyPresenter of 2 Presentations
GAIN-OF-FUNCTION ACTIVATING STAT3 MUTATIONS : FROM AUTO-IMMUNITY TO LEUKEMIA.
Abstract
Background and Aims
Germline gain-of-function STAT3 mutations are identified in early-onset multiorgan autoimmune diseases. Somatic STAT3 mutations are associated with 40% of adult T-cell large granular lymphocytic (LGL) leukemia. The two phenotypes are thought to be distinct.
Methods
We describe a child with Evans syndrome who developed in the young adult age a T-cell LGL leukemia.
Results
The patient was born from non-consanguineous healthy parents. From the age of 2, he suffered of pyogenic infections, autoimmune neutropenia, unexplained splenomegaly and hypergammaglobulinemia. At the age of 9, he presented tri-lineage autoimmunity.
At the pediatric age, whole exome sequencing identified a de novo activating p.Y640F STAT3 mutation in blood but not in fibroblasts. He had recurrent mouth ulcers, persistent splenomegaly and severe neutropenia. He received immunoglobulins or steroid pulses and preventive sequential G-CSF. Repeated blood and marrow smears showed no leukemia.
At the age of 21, splenomegaly and neutropenia worsened and a clonal proliferation of large granular lymphocytes CD3+ CD5+ CD7+ CD8+ TiA1+, granzyme B+ perforine+ CD57+ was identified on blood smears, marrow aspirate and biopsy. Ruxolitinib was initiated: 3 months later, the spleen regressed, neutrophil count improved and G-CSF was stopped.
Conclusions
The mutation identified in this patient with early-onset Evans syndrome belongs to the hotspots associated with LGL leukemia. G-CSF use should be limited in this context. The JAK-STAT3 pathway is involved in various germline or somatic diseases. New avenues on pathophysiology, natural history and targeted therapies are opened. Those rare patients require specific care by specialized teams wit a special attention for the transition period.
FULMINANT GASTRIC ADENOCARCINOMA IN A TEENAGER WITH X-LINKED AGAMMAGLOBULINEMIA: LESSONS FROM RARE DISEASES
Abstract
Background and Aims
In national PID registries, the incidence of malignancies in X-linked agammaglobulinemia (XLA) seems lower than in other primitive immune deficiencies.
Methods
We describe a teenager with XLA who developed a fulminant gastric adenocarcinoma.
Results
A boy was diagnosed from birth with XLA (mutation of BTK exon 9) and received from early infancy adapted immunoglobulin replacement. He suffered of recurrent Campylobacter colitis, megaloblastic anemia and B12 deficiency. From the age of 8, he presented a recurrent Helicobacter pylori (Hp) gastritis finally eradicated at the age of 14 (mutation for macrolide resistance, repeated courses of high doses proton pump inhibitor, clarithromycin, amoxicillin, metronidazole, and finally bismuth). At the age of 16, he consulted with abdominal pain, weight loss and abundant ascitis. Tomodensitometry identified a voluminous gastric tumor, peritoneal carcinomatosis, liver and bone metastatic spread. Gastroduodenoscopy confirmed a muco-secretant adenocarcinoma HER2/Neu+++. Absence of CDH1 mutation. The tumor rapidly progressed and the patient died 2 months after the diagnosis. Retrospectively, the gastric biopsies showed atrophic gastritis of fundus, intestinal metaplasia and focal dysplasia for at least 5 years.
Conclusions
Genetic causes may be responsible of rare cancers in young patients. In humoral deficiencies, chronic Hp infection is the main factor involved in gastric carcinogenesis, and in case of symptoms, it should be early detected and eradicated. The improvement of outcome for those cancers is based on pathologic and molecular survey of any potentially precancerous lesion. Another major challenge is the multidisciplinary follow-up of those rare patients with a special attention for the transition period.