Childhood Kaposi Sarcoma — A Rare Genetic Predisposition Explained

Kenneth Y. Tsai, MD, PhD

Inherited human OX40 deficiency underlies classic Kaposi sarcoma of childhood

An ethnogeographic predisposition to classic Kaposi sarcoma (KS) is well established in people of Mediterranean descent. Until now, an autosomal recessive predisposition has also been suspected (but not established) in otherwise-healthy individuals with the exceptionally rare condition of childhood-onset KS unrelated to immunodeficiency.

Byun and colleagues have identified an underlying cause of genetic predisposition to KS in an HIV-negative Turkish woman born to consanguineous parents who presented with classic KS at age 14. Unlike patients with childhood KS related to Wiskott-Aldrich syndrome or IFN-γ receptor 1 deficiency, she had no history of primary immunodeficiency. Comparative whole exome sequencing of her, her parents, and an unaffected sibling revealed a R65C mutation in OX40 (TNFRSF4) — a receptor found on activated T cells. The mutant allele is expressed poorly in T cells and causes a complete loss of function in signaling. Though she had normal lymphocyte counts and antibody titers, she had low numbers of memory T and B cells and defective memory T-cell recall responses. Interestingly, KS expresses OX40 ligand strongly, suggesting that interaction with T cells through OX40 may be relevant for immune responses against KS.

Citation(s):

Byun M et al. Inherited human OX40 deficiency underlying classic Kaposi sarcoma of childhood. J Exp Med 2013 Aug 26; 210:1743.