Case#: Case 1, male

DiseaseAssertion: APDS

FamilyInfo: consanguineous Pakistani parents. During the preparation of this manuscript, two kindreds with loss-of-function (LOF) variants in PIK3CD were published, all of whom had hypogammaglobulinemia and recurrent sinopulmonary infections (Table E1).3,4

CaseHPOFreeText: The patient received the attenuated Bacillus Calmette-Guérin, polio, and measles vaccines without sequelae and was healthy until six years of age, when he presented with chronic diarrhea and polyarticular arthritis affecting his knees and ankles. He was empirically treated with steroids for two months, leading to complete resolution of his symptoms. Over the subsequent five years, he had episodes of colitis treated with prednisone, sulfasalazine, and methotrexate for presumed inflammatory bowel disease. Due to worsening colitis, he underwent an upper endoscopy and colonoscopy that revealed candida esophagitis as well as increased intraepithelial lymphocytes and moderate villous blunting in the duodenum. His laboratory evaluation was notable for leukocytosis, neutrophilia, mild monocytosis, and thrombocytosis (Table 1). He had normal numbers of T, B, and NK cells and normal percentages of T and B cell subsets. His serum levels of IgG and IgA were decreased. Ca2+ flux in response to anti-CD3 crosslinking on T cells was decreased (Fig. 1A), although proliferation to anti-CD3+CD28 stimulation was robust (Table 1). The patient was treated with immunoglobulin replacement therapy, antifungal prophylaxis, and prophylactic antibiotics, but died at the age of 14 years due to a severe pneumonia and sepsis shortly after the mutation was identified.

CasePreviousTesting: WES

GenotypingMethod: WES

Variant: Whole-exome sequencing of the patient revealed a novel homozygous frameshift mutation in PIK3CD (c.2558_2559delAT; p.Asp853Glyfs*20), disrupting exons 20 – 24 encoding 171 amino acids of the ATP binding site within the catalytic domain

CAID: CA2499214908

gnomAD: absent from gnomAD v2.1.1

SupplementalData: