Autoimmune Lymphoproliferative Syndrome (ALPS) in a Child from Consanguineous Parents: A Dominant or Recessive Disease?

Abstract

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by autoimmune features and lymphoproliferations and is generally caused by defective Fas-mediated apoptosis. This report describes a child with clinical features of ALPS without detectable Fas expression on freshly isolated blood leukocytes. Detection of FAS transcripts via real-time quantitative PCR made a severe transcriptional defect unlikely. Sequencing of the FAS gene revealed a 20-nucleotide duplication in the last exon affecting the cytoplasmic signaling domain. The patient was homozygous for this mutation, whereas the consanguineous parents and the siblings were heterozygous. The patient reported here is a human homologue of the Fas-null mouse, inasmuch as she carries an autosomal homozygous mutation in the FAS gene and she shows the severe and accelerated ALPS phenotype. The heterozygous family members did not have the ALPS phenotype, indicating that the disease-causing FAS mutation in this family is autosomal recessive. Ϫ TCR␣␤ ϩ T cells, and several autoimmune features, such as autoantibody production and autoimmune hemolytic anemia (1). It is caused by a defect in apoptosis mediated by Fas (also designated CD95, Apo1, or Apt1). ALPS features are highly comparable to the phenotype of mice with lpr or gld mutations, which carry an autosomal recessive mutations in the FAS gene or in the gene encoding Fas ligand (FASL), respectively, causing autoimmunity, lymphoproliferations and accumulation of CD4 Ϫ CD8 Ϫ TCR␣␤ ϩ T cells (2-4). There are three mouse strains carrying different FAS mutations i.e. the lpr, the lpr cg and the Fas-null strains (2,5). Although these mice have a similar phenotype, there are differences in severity and the time of development of the symptoms (6).Both FasL and Fas are transmembrane proteins, which belong to the tumor necrosis factor and tumor necrosis factor receptor family, respectively (7,8). Fas is expressed as a trimer on peripheral activated lymphocytes and also in tissues such as liver, lung, heart, and ovary. The intracellular part of the Fas protein contains a death domain, which is essential for the induction of apoptosis on interaction of Fas and FasL trimers (9). Fas-mediated apoptosis is needed for the elimination of autoreactive T lymphocytes that escaped thymic selection, but seems not to be involved in negative selection of immature cells in the thymus (10 -12). The Fas-FasL interaction also appears to be important in B cell homeostasis and is involved in the control of immune responses (13,14 (1, 19 -24). We herein present a new patient in whom Fas protein expression studies were followed by extensive molecular analysis of the FAS gene of the patient as well as her parents and siblings. The unique genotype and phenotype of this patient are discussed in the context of previously described patients with ALPS and the different mouse strains with distinct FAS gene mutations. METHODSClinical report. The patient is a girl from consanguineous parents. She has three healthy siblings, but two other siblings...

Autoimmune lymphoproliferative syndromes: genetic defects of apoptosis pathways

“…20,21 Outcome of the phenotype was strikingly similar, with prenatal onset, very severe lymphoproliferation accompanied by lung infiltration and leading to death in one case. 21 …”

“…Since such mutations were inherited from healthy parents (carrying the mutation at the heterozygous state), it was proposed that these mutations were recessive. 21 However, another unpublished case of family with ALPS 0 patient is not in support with this conclusion. In that kindred, whereas the mother is healthy and carries the heterozygous mutation, the father, with the same genotype, presented with symptoms of classical ALPS Ia (Rieux-Laucat et al, unpublished observations).…”

“…Three cases of homozygous mutations were reported. 15,20,21 In one case, a stop codon in the ECD was predicted to lead to a complete expression defect. In contrast, in the two other cases mutations are localized in the intracytoplasmic domain (ICD), affecting the DD-encoding exon 9.…”

Autoimmune Lymphoproliferative Syndrome

“…The relationship between hematological diseases and autoimmune processes is bi-directional (1,2). The autoimmune lymphoproliferative syndrome (ALPS) was first described by Canale and Smith in 1967.…”

Residual CD95-Pathway Function in Children With Autoimmune Lymphoproliferative Syndrome Is Independent From Clinical State and Genotype of CD95 Mutation

“…Mutations in the extracellular domain of CD95 were linked to low-penetrance whereas death domain mutations were linked to high-penetrance. The patients with a homozygous mutation described so far suffered from a more extended disease leading to early death and even hydrops fetalis (23)(24)(25). The less severe disease in heterozygotes substantiates that the wild-type allele might be functional and ameliorates disease manifestation.…”