Elsevier

The Lancet

Volume 348, Issue 9029, 14 September 1996, Pages 719-723
The Lancet

Early Report
Clinical, immunological, and pathological consequences of Fas-deficient conditions

https://doi.org/10.1016/S0140-6736(96)02293-3Get rights and content

Summary

Background

The surface molecule named Fas/CD95, which is expressed on activated lymphocytes, can trigger cell death following interaction with its ligand (Fas L). This Fas-Fas-L interaction is thought to be a major regulatory mechanism for controlling the life span of peripheral lymphocytes, and therefore autoimmunity.

Methods

We assessed clinical, immunological and pathological features in three children who inherited mutations of the Fas-encoding gene. One infant had a genomic homozygous deletion, while two siblings had a heterozygous mutation in the fas gene.

Findings

The patient with a complete lack of Fas protein expression had prenatal onset of massive lymphoproliferation, which involved the spleen, the liver, and the intrathoracic and abdominal lymph nodes. Lymphoproliferation mainly involved T cells negative for the CD4 and CD8 receptors. These cells, which had a high mitotic index, were essentially found in the T cell zones of lymphoid organs. Active cell division was indicated by a rapid rise in the lymphocyte count following a chemotherapy-induced reduction in the lymphocyte burden. Despite the total Fas protein deficiency, limited autoimmunity was found in this child at age 1 year. A lymphoproliferative syndrome with similar characteristics–but less intense than in the patient with complete Fas deficiency–also occurred from a young age in the siblings with a fas gene mutation on one allele only. One sibling developed neutropoenia, autoimmune haemolytic anaemia, and severe recurrent thrombo-cytopoenia.

Interpretation

Fas-deficiency causes a non-malignant syndrome characterised by the accumulation of dividing lymphocytes. Severity of disease is probably related to the degree of functional Fas deficiency. Heterozygous fas gene mutations, like homozygous deletions, can also be expressed in various cells and tissues and may predispose towards autoimmune disorders. Fas deficiency should be considered in children with enlarged peripheral lymphoid organs and hyperimmunoglobulinaemia, and sometimes the occurrence of autoimmune manifestations towards blood cells.

Introduction

The Fas/CD 95/Apo-1 molecule, originally described with two monoclonal antibodies (anti-Fas, anti-APO-1) that were found to be cytolytic for various human cell lines,1, 2 is a cell surface protein belonging to the family of receptors for tumour necrosis factor (TNF). Its expression on lymphocytes is triggered by cell activation. Prolonged activation makes Fas-expressing cells sensitive to death by apoptosis once the Fas ligand (Fas-L), also expressed by activated T-lymphocytes, has interacted with Fas.1, 3 Fas/Fas-L interaction can occur in a cis or trans cell mechanism inducing suicide or cell killing, respectively,2, 4 through the activation of proteases of the interleukin converting enzyme (ICE) family.1 Fas-L/Fas interactions control the peripheral lymphocyte life span and thereby participate in peripheral elimination of autoreactive lymphocytes.5 The latter conclusion was mainly drawn from observations of Murphy/Roth (MRL) mouse strains with Fas-encoding lymphoproliferation gene mutations (1pr and 1prc-g that develop a syndrome associated with variable autoimmune manifestations (including a lupus-like syndrome and glomerulonephritis).6 We reported that homozygous and heterozygous mutations of the human Fas-encoding gene, located on chromosome 10, also cause lymphoproliferation.7 Similar findings in the case of heterozygous mutations were independently reported in five patients8 following an earlier description of children with a phenotype of lymphoproliferation resembling that of 1pr mice.9 Here we provide an in-depth description of the clinical, immunological and pathological manifestations associated with homozygous or heterozygous fas mutations in one and two patients, respectively. The outcome of treatment for lymphoproliferation and autoimmunity is also reported.

Section snippets

Patients and methods

We have previously reported fas gene mutations in three patients.7 Fas deficiency was related to a homozygous deletion in the Fas-encoding gene, resulting in loss of the last 29 aminoacid residues and the presence of six additional residues in the Fas protein in patient 1, while a heterozygous two-base pair (bp) nucleotide deletion was found at genomic position 1005 in two siblings (patients 2 and 3), and in their healthy mother. This deletion resulted in a reading frame shift which generated a

Complete Fas expression deficiency

Lymphoproliferation–Patient 1 was born, at 34–35 weeks of gestation, to second-cousin parents originating from the Middle East, from a polyhydramniotic uterine environment. Two older brothers were healthy. Hydrops and hepatosplenomegaly were noted at birth, with anaemia (9 g/dL) and thrombocytopoenia (50 000/μL). Splenectomy was done at age 3 months for persistent massive splenomegaly with hypersplenism. At age 5 months she developed tachypnoea with widespread pulmonary infiltrates, mild

Discussion

We describe the clinical, pathological and immunological manifestations associated with complete and partial Fas protein deficiencies in three patients from two families, together with responses to treatment of lymphoproliferation and autoimmunity. Complete absence of Fas expression resulted in prenatal onset of a major lymphocyte proliferative syndrome. There were no extra-lymphocyte manifestations, despite the known expression of Fas by liver cells and some heart cells.13 Absence of

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