Light Microscopic, Immunophenotypic, and Molecular Genetic Study of Autoimmune Lymphoproliferative Syndrome Caused by fas Mutation MADELEINE D. KRAUS, 1 *SHALINI SHENOY , 2 T ALAL CHATILA, 3 AND JAY L. HESS 1 1 Lauren V. Ackerman Laboratory of Surgical Pathology, Washington University Medical Center, 660 South Euclid Avenue, St. Louis, MO 63110, USA 2 Division of Pediatric Hematology–Oncology, Washington University Medical Center, 660 South Euclid Avenue, St. Louis, MO 63110, USA 3 Division of Immunology–Rheumatology, Washington University Medical Center, 660 South Euclid Avenue, St. Louis, MO 63110, USA Received January 22, 1999; accepted April 7, 1999. ABSTRACT This case provides a complete light microscopic, immu- nophenotypic, and molecular genetic analysis of autoim- mune lymphoproliferative syndrome (ALPS), a rare be- nign cause of dramatic lymphadenopathy with atypical histology and phenotype that may be mistaken for malig- nancy. The patient is 3-year-old child who was first clinically evaluated at the age of 16 months because of marked generalized lymphadenopathy and hepatospleno- megaly. Histologic sections of a cervical lymph node demonstrated a marked paracortical proliferation of occasional small and intermediate-sized lymphocytes and numerous large immunoblasts, the majority of which displayed a CD3 + , CD43 + , CD45RO - (OPD4, UCHL1) CD4 - , CD8 - phenotype on paraffin sections, and which had a CD2 + , CD3 + , CD5 + , CD56 - ,T1 - , [CD4 - , CD8 - ] double negative profile on flow cytometric analysis. Southern blot analysis did not identify a clonal T or B cell population, and sequencing of the fas gene identified a mutation that caused a single amino acid substitution in the intracytoplasmic death domain of this protein. An enriched population of CD45RO-negative naive T cells in the paracortex may explain the atypical histologic and immunophenotypic features of this case. Greater aware- ness of this heritable lymphoproliferative disorder will facilitate its recognition and minimize the possibility of misdiagnosis. Key words: fas, apoptosis, autoimmune, lymphoprolifer- ative, congenital INTRODUCTION The distinctive clinical profile of autoimmune lymphoproliferative syndrome (ALPS) has been recognized for 30 years [1], but its molecular basis has remained obscure until recently. These chil- dren present in early childhood with massive lymph- adenopathy and splenomegaly, and many have autoimmune complications. Several groups have demonstrated mutations in the fas gene [2–6], and additional studies have demonstrated a loss of fas-mediated apoptotic cell death via in vitro stud- ies [7]. Clinical manifestations of this disease de- rive from an inability of the mutated fas protein to induce apoptotic cell death in lymphocytes and the consequent failure to terminate exuberant alloim- mune responses and inappropriate autoimmune responses. Although most of the patients reported to date have undergone lymph node biopsy and/or splenectomy, few reports demonstrate the patho- logic findings or discuss in detail the differential diagnoses that the abnormal morphology and im- *Corresponding author, at Department of Pathology, Box 8118, Washing- ton University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA. Pediatric and Developmental Pathology 3, 101–109, 2000 Pediatric and Developmental Pathology DOI: 10.1007/s100249910014  2000 Society for Pediatric Pathology