PTEN-LOF AND PI3K GOF– BETWEEN A ROCK AND A HARD PLACE

Abstract

Introduction Cowden syndrome is a genetically-mediated tumor syndrome caused by PTEN loss-of-function (PTEN-LOF) which results in, a recently recognized, paradoxical gain of function of PI-3-kinase (PI3K GOF) leading to an auto-inflammatory/immunodeficiency syndrome. We report a case manifesting with this syndrome. Case Description A 23-year old female presents to the immunodeficiency clinic for evaluation. She was healthy until age 6, when she developed recurrent uveitis, multiple polyps on EGD/colonoscopy and a deep left frontal para-sagittal brain tumor. At age 14, patient had genetic testing with whole exome sequencing revealing PTEN-LOF. Later, patient developed chronic rhinosinusitis requiring frequent antibiotics and sinus surgeries. Subsequently, patient was diagnosed with medullary carcinoma of thyroid and multiple lipomas. Immune workup revealed poor pneumococcal vaccine response, low CD3+ count, undetectable IgA, low IgG (489), and elevated CRP. IgG supplementation was initiated. Discussion Cowden syndrome is a rare, autosomal dominant disease affecting 1:200,000 individuals characterized by PTEN-LOF that begins with mucocutaneous then thyroid, colon and brain involvement in the form of hamartomas/malignancies. The PI3K pathway of cell growth, proliferation, survival, and metabolism is controlled by PI3K and PTEN, which are positive and negative regulators respectively. PTEN-LOF releases the negative regulation on PI3K/AKT/mTOR activation resulting in immune dysregulation, tumorigenesis, and immunodeficiency via an activated phosphatidylinositol-3-kinase δ syndrome (APDS)- like deficiency with impaired B cell differentiation and function. The patient we present had chronic sinusitis, hypogammaglobinemia, and the characteristic CD4 lymphopenia, and exemplifies the importance of recognizing Cowden syndrome manifesting as an immunodeficiency. Cowden syndrome is a genetically-mediated tumor syndrome caused by PTEN loss-of-function (PTEN-LOF) which results in, a recently recognized, paradoxical gain of function of PI-3-kinase (PI3K GOF) leading to an auto-inflammatory/immunodeficiency syndrome. We report a case manifesting with this syndrome. A 23-year old female presents to the immunodeficiency clinic for evaluation. She was healthy until age 6, when she developed recurrent uveitis, multiple polyps on EGD/colonoscopy and a deep left frontal para-sagittal brain tumor. At age 14, patient had genetic testing with whole exome sequencing revealing PTEN-LOF. Later, patient developed chronic rhinosinusitis requiring frequent antibiotics and sinus surgeries. Subsequently, patient was diagnosed with medullary carcinoma of thyroid and multiple lipomas. Immune workup revealed poor pneumococcal vaccine response, low CD3+ count, undetectable IgA, low IgG (489), and elevated CRP. IgG supplementation was initiated. Cowden syndrome is a rare, autosomal dominant disease affecting 1:200,000 individuals characterized by PTEN-LOF that begins with mucocutaneous then thyroid, colon and brain involvement in the form of hamartomas/malignancies. The PI3K pathway of cell growth, proliferation, survival, and metabolism is controlled by PI3K and PTEN, which are positive and negative regulators respectively. PTEN-LOF releases the negative regulation on PI3K/AKT/mTOR activation resulting in immune dysregulation, tumorigenesis, and immunodeficiency via an activated phosphatidylinositol-3-kinase δ syndrome (APDS)- like deficiency with impaired B cell differentiation and function. The patient we present had chronic sinusitis, hypogammaglobinemia, and the characteristic CD4 lymphopenia, and exemplifies the importance of recognizing Cowden syndrome manifesting as an immunodeficiency.