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Blood, Vol. 94 No. 8 (October 15), 1999:
pp. 2575-2582
Lymphoproliferative Syndrome With Autoimmunity: A Possible Genetic
Basis for Dominant Expression of the Clinical Manifestations
Frédéric Rieux-Laucat,
Séverine Blachère,
Sylvia Danielan,
Jean Pierre De Villartay,
Mathias Oleastro,
Eric Solary,
Brigitte Bader-Meunier,
Peter Arkwright,
Corinne Pondaré,
Françoise Bernaudin,
Helen Chapel,
Susan Nielsen,
Mohamed Berrah,
Alain Fischer, and
Françoise Le Deist
From the Department of Pediatric Immunology, Unit INSERM U429,
Hôpital Necker-Enfants-Malades, Paris, France; the Department of
Pediatric Immunology, Hospital Garrahan, Buenos-Aires, Argentina; the
Department of Clinical Hematology, CHRU de Dijon, Dijon, France; the
Department of Pediatrics, Hôpital de Bicêtre, Le Kremlin
Bicêtre, France; the Department of Pediatric Immunology,
Newcastle General Hospital, Newcastle upon Tyne, UK; the Department of
Pediatric Immunology, Hôpital Debrousse, Lyon, France; the
Department of Pediatric Hematology, Hôpital Intercommunal,
Créteil, France; the Department of Clinical Immunology, Oxford
Radcliffe Hospital, Headington, Oxford, UK; The Juliane Marie Center,
Copenhagen, Denmark; and the Department of Pediatrics, Central Army
Hospital, Alger, Algeria.
Fas (CD95/Apo-1) mutations were previously reported as the genetic
defect responsible for human lymphoproliferative syndrome associated
with autoimmune manifestations (also known as autoimmune lymphoproliferative syndrome or Canale-Smith syndrome). We have identified 14 new heterozygous Fas mutations. Analysis of patients and
families allow us to further dissect this syndrome with regards to the
relationship between Fas mutations, inheritance pattern, and phenotype
as observed on long-term follow-up. In vitro studies show that
lymphocytes from all Fas mutant carriers exhibit a
Fas-antibody-induced apoptosis defect. However, among the 8 inherited
mutations, 4 of 4 Fas missense mutations were associated with high
clinical penetrance, whereas 3 of 4 mutations leading to a truncated
Fas product were associated with variable clinical penetrance. This suggests that a second defect, in another yet undefined factor involved
in apoptosis and/or lymphoproliferation control, is necessary to induce
full clinical expression of the disease. These results also indicate
that the currently available antibody-mediated in vitro apoptosis assay
does not necessarily reflect the in vivo ability of abnormal Fas
molecules to trigger lymphocyte death. In addition, we found that
lymphoproliferative manifestations resolved with age, whereas
immunological disorders [ie, hypergammaglobulinemia and detection of
TcR   (+) CD4( ) CD8() lymphocytes] persisted. This
observation suggests that Fas-mediated apoptosis plays a more important
role in lymphocyte homeostasis in early childhood than later on in life.
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