Version May 2024
INTRODUCTION — Autoimmune lymphoproliferative syndrome (ALPS) is characterized by dysregulation of the immune system due to an inability to regulate lymphocyte homeostasis through the process of lymphocyte apoptosis (a form of programmed cell death). The consequences of this include lymphoproliferative disease, manifested by lymphadenopathy, hepatomegaly, splenomegaly, and an increased risk of lymphoma, as well as autoimmune disease, typically involving blood cells.
Several genetic defects are associated with ALPS. ALPS-FAS and ALPS-sFAS are caused by germline and somatic variants, respectively, in the FAS gene. In rare cases, ALPS is caused by pathogenic variants in the genes encoding Fas ligand (ALPS-FASLG) or caspase 10 (ALPS-CASP10).
This topic reviews the epidemiology, genetics, and pathogenesis of ALPS. The clinical manifestations, laboratory findings, diagnosis, and management of ALPS are discussed separately. (See "Autoimmune lymphoproliferative syndrome (ALPS): Management and prognosis" and "Autoimmune lymphoproliferative syndrome (ALPS): Clinical features and diagnosis".)
EPIDEMIOLOGY — The incidence and prevalence of ALPS are unknown. Estimated cases of ALPS worldwide exceed several hundred, but that number has not reliably been confirmed. Cases of ALPS probably remain undiagnosed due to variable phenotypic expression and a constellation of symptoms that overlap with many other conditions, particularly Evans syndrome and other lymphoproliferative disorders [1,2]. (See "Autoimmune hemolytic anemia (AIHA) in children: Classification, clinical features, and diagnosis", section on 'Evans syndrome' and "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Evans syndrome'.)
ALPS is reported in various racial and ethnic backgrounds. A male predominance was previously suggested [3]. This sex inequality was confirmed in both the French ALPS cohort [4] and the National Institutes of Health (NIH) ALPS cohort [5]. In families with FAS pathogenic variants in the French cohort, the likelihood that a male with the FAS pathogenic variant would have symptomatic ALPS was approximately 75 percent compared with 51 percent for females. Similarly, in the NIH cohort, 69 percent of males versus 46 percent of females with FAS pathogenic variants developed overt features of ALPS. In addition, the ratio of male-to-female patients with ALPS was 2.2 in the French cohort and 1.6 in the NIH cohort.
GENETICS
Germline FAS variants — Approximately two-thirds of patients with ALPS have an identified genetic defect [6]. The majority of patients with ALPS have a germline pathogenic variant in the FAS gene (classified as ALPS-FAS, MIM #601859). FAS, also called tumor necrosis factor receptor superfamily member 6 (TNFRSF6), is located at chromosomal locus 10q24.1. Exons 1 and 2 encode a signal sequence that is cleaved off upon trafficking of the Fas protein to the cell surface. Exons 3, 4, and 5 encode three extracellular cysteine-rich domains (ECDs). Exon 6 encodes the transmembrane domain. The intracellular domains (ICDs) of Fas are encoded by exons 7 through 9. Exon 9 contains the death domain (ICD-DD) that interacts with an adaptor molecule, Fas-associated via death domain (FADD). FADD binding to ICD-DD leads to generation of the death-inducing signaling complex, ultimately resulting in cellular apoptosis [3].
ALPS-FAS is inherited in an autosomal dominant manner. In rare cases, homozygous or compound heterozygous pathogenic variants cause a severe form of ALPS [7-11]. De novo germline variants are rare. There is a broad spectrum of FAS pathogenic variants throughout the entire coding region and exon/intron boundaries, including deletions or insertions of one to a few nucleotides, single nucleotide substitutions, and splice-site abnormalities, but the majority of pathogenic variants are localized to the highly conserved ICD (66 and 73 percent in the French and National Institutes of Health [NIH] cohorts, respectively) [4,5]. These abnormal allele variants cause absence of functional proteins or result in truncated or misfolded proteins that cause disease by interfering with assembly of the trimeric Fas complex at the cell surface.
Somatic FAS variants — Approximately 15 to 20 percent of patients with ALPS have somatic pathogenic variants in FAS (ALPS-sFAS) that are limited to hematopoietic lineage cells, particularly T cells [4]. In these patients, somatic pathogenic variants may be found in only a subset of the alpha/beta double-negative T (DNT) cells or in fractions of other hematopoietic cell lineages, although this remains less well defined, but not in nonhematopoietic cells (eg, skin cells, germ cells) [12-15]. Thus far, the distribution and types of pathogenic variants seen in ALPS-sFAS are similar to germline-mutant ALPS-FAS [12,14,15].
Germline variants in other genes — Germline variants in the genes encoding FAS ligand (FASL, TNFSF6) [16-20] and CASP10 [21] are reported in rare cases of patients with ALPS who do not have a FAS pathogenic variant (ALPS-FASLG and ALPS-CASP10, respectively). However, results from a subsequent publication add further evidence against a previously proposed autosomal dominant pathogenic role of heterozygous FASL mutations in ALPS [22]. In this report, the dominant-negative effects of previously published variants could not be confirmed, suggesting that heterozygous mutations may be better tolerated for ALPS-FASLG than ALPS-FAS. It thus appears that ALPS-FASLG is inherited in an autosomal recessive manner and has features distinctly different from typical ALPS due to FAS variants with respect to normal Fas-induced apoptosis in ALPD-FASL but has abnormal activation-induced cell death (AICD) and cytotoxic T lymphocyte (CTL) function [11,20,22,23].
No somatic variants in FASL and CASP10 in DNT cells have been reported.
A germline pathogenic variant in tumor necrosis factor alpha-induced protein 3 (TNFAIP3) causing haploinsufficiency of TNFAIP3 has been reported in a single Japanese patient [24]. This patient showed evidence of autoinflammation, in addition to more typical ALPS-associated manifestations.
Genotype-phenotype correlations — An important aspect of genetics concerns the relationship between genetic defects (genotypes) and clinical manifestations (disease phenotypes). In ALPS, there are relationships between genotype and phenotype as well as between genotype and penetrance (see 'Penetrance (ALPS-FAS only)' below). The death domain (the ICD of Fas that connects cell surface-expressed Fas to the intracellular [death] signal transduction pathway) is a mutational hotspot. However, genotypes resulting from pathogenic variants in any domain of Fas can lead to the same clinical lymphoproliferative and autoimmune phenotype of ALPS. In contrast, thus far, lymphomas have been associated only with pathogenic variants affecting the ICDs of Fas [5,25]. In vitro Fas-mediated apoptosis is less defective in persons with pathogenic variants affecting extracellular domains than in those with pathogenic variants affecting ICDs, despite the similar clinical phenotype [26].
In the majority of affected persons, heterozygous FAS pathogenic variants cause ALPS-FAS by the mechanism of dominant-negative interference (the mutated protein inhibits the action of the normal protein). However, the proposed mechanism for certain variants affecting extracellular domain is haploinsufficiency (the single functional allele does not produce enough of the protein). In the latter case, it appears that the ALPS clinical phenotype is less severe [27,28], although an insufficient number of patients with proven haploinsufficiency have been studied to independently confirm this observation. Patients with homozygous or biallelic FAS pathogenic variants thus far appear to have a severe clinical phenotype [7-10]. Genotype-phenotype correlations have not been established for FASLG and CASP10 variants, due to the rarity of cases.
Penetrance (ALPS-FAS only) — Penetrance is the fraction of cases with overt clinical findings. Reduced penetrance indicates that genetic or environmental factors play a role in determining whether disease occurs in addition to the particular gene variants that are present. There is a difference between the penetrance of the cellular phenotype (defective Fas-mediated apoptosis) and the penetrance of the clinical phenotype (ie, ALPS). Family studies to date show that penetrance for the cellular phenotype is complete or approximates 100 percent (ie, every person heterozygous for an inherited [germline] ALPS-causing variant has defective apoptosis in vitro), whereas the penetrance for the clinical phenotype is reduced (ie, a significant proportion of relatives heterozygous for the disease-causing variant have no clinical findings of ALPS). (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Penetrance and expressivity'.)
The factors that determine the penetrance of clinical ALPS are not entirely understood. It appears that penetrance is determined by the location and type of variant; however, further study and independent confirmation are needed [26,29-32]. The highest penetrance for clinical phenotype is reported for missense variants affecting the ICDs followed by variants leading to truncation of the ICDs [30]. The penetrance for the clinical phenotype in the presence of an extracellular variant is lower. In the original NIH study, penetrance for missense ICD variants, truncation ICD variants, and ECD variants was approximately 90, 70, and 30 percent, respectively, whereas penetrance in the French cohort was 52 percent for ECD variants and 63 percent for ICD variants (73 percent for missense variants affecting the ICD-DD) if all ALPS patients were counted [4,30]. Excluding the index cases, penetrance was 28, 40, and 56 percent for ECD, ICD, and ICD-DD variants, respectively.
PATHOGENESIS — The phenotype of ALPS results from defective apoptosis of lymphocytes mediated through the Fas/Fas ligand (FasL) pathway. This pathway normally limits the size of the lymphocyte compartment by eliminating autoreactive lymphocytes. As a consequence, defects in the Fas apoptosis pathway lead to persistence and expansion of antigen-specific lymphocyte populations. Fas also appears to play a role in suppression of malignant transformation of lymphocytes, although it is not firmly established whether this involves the Fas/FasL pathway in a similar way. The pathogenesis of ALPS remains an ongoing topic of research.
In most patients, heterozygous pathogenic variants cause defective apoptosis and clinical ALPS through the mechanism of dominant-negative interference (see 'Genotype-phenotype correlations' above). In in vitro transfection studies, mutant and wild type Fas were coexpressed on the surface of a Fas-negative cell line to simulate the heterozygous defect present in the ALPS patients. Functional studies of these co-transfected cells demonstrated that the mutation-bearing Fas proteins were able to interfere with Fas-mediated apoptosis when mixed with normal (wild type) proteins. Fas (and FasL) protein molecules form homotrimers. Thus, in the presence of a heterozygous Fas death domain variant, only one out of eight possible Fas trimer configurations is composed of three normal units, assuming equal amounts of mutant and wild type Fas are expressed [33-35].
In other patients, such as those with extracellular defects, mutant Fas causes disease through haploinsufficiency, particularly if mutant Fas prohibits formation of the homotrimer (which is preassembled prior to engagement of Fas with its ligand) [27,28,34].
The variable penetrance for ALPS suggests that one or more additional pathogenic factors interact with defective Fas-mediated apoptosis to cause the clinical phenotypes of ALPS. A lesser deficiency in apoptosis is seen in patients with Fas defects due to haploinsufficiency than to dominant-negative interference, suggesting that additional pathogenic factors are more likely to play a role in patients with the former type of defect [26]. On the other hand, the high penetrance for the clinical phenotype in families associated with missense variants affecting the death domain of FAS casts doubt on that assumption, indicating that an appropriate FAS genotype is sufficient to cause ALPS [29,30,32].
These observations and considerations led to the discovery of accumulation of secondary somatic defects of the second FAS allele in persons known to have inherited a heterozygous Fas defect. In a series of seven patients, clinical disease appeared to develop as a consequence of the combination of an inherited (germline) heterozygous FAS pathogenic variant in one allele and a somatic genetic event in the second FAS allele that involved either a somatic missense or nonsense variant; the second event, thought to occur in a single lymphocyte or progenitor, produced loss of heterozygosity by telomeric uniparental disomy of chromosome 10 [36]. The failure of the resulting cells to undergo apoptosis led to their accumulation and to the symptomatic ALPS features of autoimmune blood cytopenias, adenopathy, and splenomegaly.
Connecting this observation back to penetrance, persons in those families with both the germline variant affecting the extracellular domains of Fas and the (secondary) somatic variant in double-negative T (DNT) cells acquired the clinical ALPS phenotype, whereas persons carrying only the germline variant did not. It remains unclear if the second somatic variant occurred during embryogenesis or was acquired after birth. From a disease pathogenesis standpoint, the possibility that somatic genetic events can be acquired during life has far-reaching ramifications [4].
Somatic FAS variants are of particular interest in better understanding the pathogenesis of ALPS because they may help identify the impact of the FAS variant relative to other potential pathogenic factors or the sequence of events in the pathogenesis of ALPS, keeping in mind that approximately 15 to 20 percent of ALPS patients are defined solely by a somatic FAS pathogenic variant (ALPS-sFAS). (See 'Genetics' above.)
The somatic variants are mostly confined to DNT cells and typically are not found in large proportions in other lymphocyte subsets, such as B cells, indicating that DNT cells may not be merely a byproduct of disease pathogenesis but a major contributor to the development of ALPS [37].
SUMMARY
●Definition – Autoimmune lymphoproliferative syndrome (ALPS) is a rare disorder of lymphocyte apoptosis characterized by dysregulation of the immune system. (See 'Introduction' above and 'Epidemiology' above.)
●Genetics – ALPS-FAS and ALPS-sFAS are the most common types of ALPS and are caused by germline and somatic variants, respectively, in the FAS gene. In rare cases, ALPS is caused by pathogenic variants in the genes encoding Fas ligand (ALPS-FASLG) or caspase 10 (ALPS-CASP10). (See 'Genetics' above.)
●Pathogenesis – The phenotype of ALPS results from an inability to regulate lymphocyte homeostasis due to defective apoptosis of lymphocytes mediated through the Fas/Fas ligand (FasL) pathway. Defects in this pathway lead to expansion of antigen-specific lymphocyte populations. Fas also appears to play a role in suppression of malignant transformation of lymphocytes. (See 'Pathogenesis' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.
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