THROMBOCYTOPENIA, HYPOGAMMAGLOBULINEMIA, AND POOR VACCINE RESPONSE IN A PATIENT WITH TAKENOUCHI-KOSAKI SYNDROME

Abstract

<h3>Introduction</h3> Takenouchi-Kosaki Syndrome (TKS) is a rare congenital developmental disorder characterized by thrombocytopenia, facial abnormalities, and varied multisystemic anomalies including immunodeficiency. Heterozygous deficiency of CDC42, an intracellular signaling GTPase, has been found in all TKS patients described to date. The immunological phenotypes of TKS patients are heterogeneous: recurrent infections have been noted in some patient series but with variable penetrance. Herein we describe a case of TKS causing hypogammaglobulinemia, B-cell lymphopenia, and poor vaccine response. <h3>Case Description</h3> A fifteen-year-old girl with history of developmental delay, multiple congenital defects, and lymphedema was referred to the immunology clinic for evaluation of recurrent ear infections that began at 3 months of age requiring tympanostomy tube placement at 18 months. Her physical exam was notable for abnormal facies, scoliosis, strabismus, abnormal thumbs, and unilateral lymphedema. Her laboratory evaluation revealed macrothrombocytopenia, mild leukopenia with low T-cells and markedly low B-cells by flow cytometry, and notably low IgA (11.7, RR 69 – 309) and IgG (423, RR 613 – 1295). She had a poor response to a full course of PCV7 with PPSV23 booster (9 of 23 > 1.3). Whole exome sequencing identified a heterozygous p.Y64C mutation in CDC42 consistent with TKS. <h3>Discussion</h3> The Y64C mutation in CDC42 is a TKS Group I lesion causing ineffective intracellular signaling, resulting in <i>in vitro</i> defects including abnormal cellular proliferation and disruption of cell polarity. Actin remodeling disorders such as Wiskott-Aldrich Syndrome and TKS should be considered in patients with immunodeficiency and congenital thrombocytopenia.