Autoimmune lymphoproliferative syndrome (ALPS) is characterised by autoimmune features and lymphoproliferations, and is generally caused by defective Fas-mediated apoptosis (Rieux-Laucat et al, 1995). Previously described haematologic manifestations of the disease consist of autoimmune peripheral cytopenia(s) (Rieux-Laucat et al, 1999), and, less frequently, dyserythropoiesis (Bader-Meunier et al, 2000). We report three patients diagnosed with ALPS, who presented with Coombs’ negative haemolytic anaemia associated with mild splenomegaly as the first manifestation of the disease when aged 3 months, 4 months and 3 years respectively. All of them had increased reticulocyte count, undetectable serum haptoglobin, and repeatedly negative direct antiglobulin tests (DAGT) (Table I). Haemoglobin electrophoresis, glucose-6-phosphate dehydrogenase and pyruvate kinase activities and ektacytometric profile were normal. Additionally, an isotopic study disclosed a markedly reduced half-life for Cr-labelled autologous erythrocytes of 5 d (normal, 26–33 d), with prominent splenic sequestration in one patient. The association of splenomegaly with unexplained autoimmune haemolytic anaemia led to investigations for ALPS. Monoclonal antibodies were used in immunofluorescence studies, and cells were analysed on a FACScan flow cytometer (Becton, Dickinson, Pont-de-Claix, France) (Rieux-Laucat et al, 1999); apoptosis was assessed in activated T cells that were incubated with a monoclonal antibody to Fas (anti-Apo1.3) (Rieux-Laucat et al, 1999); DNA samples were prepared from activated lymphocytes, and amplification of genomic DNA segments and direct DNA products sequencing was performed as previously described (Rieux-Laucat et al, 1999). Fas apoptosis deficiency was evidenced in three patients by the demonstration of an increased number of CD4 CD8 TCRab T cells, a decreased apoptotic response of activated T lymphocytes to anti-Apo 1-3 monoclonal antibody and the presence of a heterozygous mutation of the Fas receptor gene (Table I). Heterozygous mutation of the Fas receptor gene was also demonstrated in the mother of patients 1 and 2, and the father of patient 3. The DAGT became positive at the age of 5 and 10 years in patients 1 and 2, respectively, and remained persistently negative in the youngest child, aged 2.5 years. In patients with ALPS, autoimmune manifestations are inconstant and cannot be related to any other features of the disease. Our report suggests that haemolytic anaemia is not only mediated by autoantibodies in Fas-deficient conditions. A direct cell-mediated cytotoxicity, mediated by natural-killer cells, has been already reported as a non-phagocytic mechanism of erythrocyte destruction in haemolytic anaemia with negative DAGT (Gilsanz et al, 1996) and may be hypothetically incriminated in our patients. In conclusion, this report emphasises that the association of Coombs’ negative haemolytic anaemia of unknown aetiology with splenomegaly must prompt investigations for ALPS.
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Aug 1, 2008
Natasha Savage + 3
Open Access
