P053 Activated PI3K-Delta Syndrome (APDS): A Monogenic Cause of VEO-IBD That Impacts on Treatment
Authors: Lindoso Livia , Deboni Mariana , Barros Dorna Mayra , Moschione Castro Ana Paula , Pastorino Antonio Carlos , Toma Ricardo 
Published: December 2019

BACKGROUND:
An increasing spectrum of monogenic disorders has been associated to VEO-IBD. Genetic diagnosis may have direct implications in the treatment. We report three patients with mutations in the PI3KCD gene with classical clinical phenoptype of APDS: lymphoproliferation, recurrent sinopulmonary infections, autoimmune cytopenias and VEO-IBD.

METHODS:
Retrospective evaluation of medical records and description of clinical features, genetic analysis, immunological and radiological findings. Genetic studies were performed using whole exome sequencing for two patients and a genetic panel that included PI3KCD gene analysis for one patient.

RESULTS:
In our center we have 140 IBD patients and 36 of them have VEO-IBD. Genetic evaluation for monogenic causes is performed for refractory cases. Mutation in PI3KCD gene was identified in three patients. All of them presented the same c.3061G>A:p.Glu1021Lys pathogenic mutation that causes APDS. Patient were male and one was female and their ages vary from 8 months to 11 years. The age of onset of the IBD range from 2 months to 8 years. Their parents are non-consanguineous and healthy. Patient 3 had an older sister that died of pneumonia at the age of 1 year. The patients were from distinctive ethical groups: one was Asian descent and the others were Caucasian. Patient 1 and 2 presented with progressive hepatosplenomegaly and recurrent episodes of pneumonia with encapsulated bacteria, resulting in bronchiectasis and sinusitis. Those patients evolved with thrombocytopenia, hemolytic anemia, chronic diarrhea and failure to thrive. One of them developed lytic lesions in ischium and splenic nodules. Patient 3 presented with bloody diarrhea, anemia, cervical abscess and failure to thrive. This patient developed recurrent wheezing, anemia, eczema and had one hospitalization due to pneumonia. For immunological function, patient 1 and 2 exhibited reduced CD4 ratios and immunoglobulin A and G below the 3rd percentile. In the other hand, patient 3 had an increased immunoglobulin M, normal immunoglobulin A and G and CD 4 ratio. Endoscopy and histology identified pancolitis with an inflammatory chronic process, with cryptite and microabcess of crypts, histicocyte aggregates and eosinophilia in patients 1 and 2. Patient 3 were treated with antibiotic prophylaxis, obtaining complete resolution of the diarrhea and eczema. Patient 1 and 2 were treated with immunoglobulin replacement therapy and Sirolimus. Patient 2 developed an allergic reaction to the immunoglobulin replacement. Sirolimus help improve immunological markers and reducing the hepatosplenomegaly in both patients. Patient 1 and 3 are in full remission of the symptoms and patient 2 have a flare with diarrhea due to an intestinal cryptococcus infection.

CONCLUSION:
Children presenting with IBD, especially those with VEO, refractory disease, family history or recurrent infections may benefit from immunological and genetic evaluation. The identification of PI3KCD gene mutation guided the choice of a more targeted IBD treatment since Sirolimus is an inhibitor of the mTOR pathway that is the excessively activated in those patients. Targeted therapies are of great importance, since they can modulate the defects that cause the symptoms of the disease, minimizing unnecessary immunosuppression and other adverse effects of the treatment in an already immunodeficient patient.