Two Brothers with Immunodeficiency: Mixed Clinical Findings with a Common Diagnosis

Activated phosphoinositide 3-kinase δ syndrome is novel autosomal-dominant primary immunodeficiency caused by a heterozygous gain-of-function mutation in the PIK3CD gene. We describe a case of two brothers with differing clinical presentations, both diagnosed with deleterious PIK3CD mutation. National Institutes of Health performed targeted capture of exons from a panel of immune related genes, followed by Sanger sequence of the suspect variant. Two brothers, ages 12 and 19, presented for evaluation of immune deficiency. The younger brother had a more severe presentation with history of hypogammaglobulinemia, bilateral otitis media with tympanic membrane perforations, sinusitis, pneumonia, bronchiectasis and delayed gastric emptying—requiring immunoglobulin therapy for symptom resolution. He had persistent lymphadenopathy, status post resection with biopsy results revealing follicular, interfollicular and monocytoid hyperplasia, without evidence of malignancy. The older brother had normal immunoglobulin levels, bilateral otitis media, sinusitis, pneumonia and bronchiectasis—not requiring immunoglobulin therapy for symptom management. There was concern that familial inheritance may be underlying the brothers’ clinical phenotype. Genetic testing confirmed the brothers heterozygosity for a deleterious mutation in PIK3CD, c.3061G>A— causing p.E1021K, consistent with their clinical phenotype. The younger brother is being considered for clinical trial with rapamycin therapy. The older brother is undergoing evaluation for mammalian target of rapamycin (mTOR) inhibitor trial. Their case illustrates the importance of identifying genetic conditions in familial immune deficiency, as the specific diagnosis has implications in therapeutic management beyond the supportive options of antibiotics and intravenous immunoglobulin. Individuals with PIK3CD mutation also warrant monitoring for development of autoimmunity and lymphoid malignancy.