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Autoimmune Lymphoproliferative Syndrome

July 07, 2017

Disease synonyms

Autoimmune lymphoproliferative syndrome (ALPS), Canale-Smith syndrome, FAS deficiency

Inheritance pattern

Autosomal recessive, autosomal dominant

Clinical features

Autoimmune lymphoproliferative syndrome (ALPS) is a rare, inherited disease caused by abnormal lymphocyte homeostasis. ALPS is characterized by non-malignant lymphoproliferation, splenomegaly, and autoimmune cytopenia. ALPS-affected patients have a lifelong increased risk of Hodgkin's and non-Hodgkin's lymphoma 1.

The diagnosis of autoimmune lymphoproliferative syndrome (ALPS) is based on a collection of clinical and laboratory findings and on identification of pathogenic variants in genes associated with FAS-related apoptosis 1. Thus, ALPS should be considered in individuals with the following signs and symptoms:

  • Chronic non-malignant lymphoproliferation signs that includes:
    • Chronic and/or recurrent lymphadenopathy
    • Splenomegaly with/without hypersplenism
    • Hepatomegaly
    • Lymphocytic interstitial pneumonia

  • Autoimmune diseases, including:
    • Cytopenia, particularly combinations of autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), and autoimmune neutropenia
    • Autoimmune hepatitis
    • Autoimmune glomerulonephritis
    • Autoimmune thyroiditis
    • Guillain-Barré syndrome

  • Lymphoma, both Hodgkin lymphoma and non-Hodgkin lymphoma
  • Skin rashes, often but not exclusively of an urticarial nature
  • Family history of ALPS or ALPS-like features

The prevalence of ALPS is unknown. It has been characterized in more than 500 patients to date and has been reported worldwide in various ethnic groups, without racial or ethnic preferences. In the largest world cohort (NIH cohort) investigated the likelihood of developing ALPS for males and females was 69% and 46%, respectively 2. The ratio of affected males to affected females was higher only in the French cohort (1:2.2), with 75% affected females compared to 51% affected males (the percentages refer to a patient with a FAS gene pathogenic variant) 1, 2.

The most common type of autoimmune lymphoproliferative syndrome is associated with heterozygous germline pathogenic variants in the FAS gene. FAS belongs to a death receptor family and encodes tumor necrosis factor receptor 6 (TNFRSF6), also known as Apoptosis antigen 1 (APO1) or CD95. Binding of FAS to FAS ligand on the cell surface activates the complex process of programmed cell death which regulates cell homeostasis in the immune system. Pathogenic variants in FASLG (previously known as FASL or TNFSF6), caspase family of genes (CASP10, CASP8), and other apoptosis related genes (FADD, ITK, KRAS, NRAS, PRKCD) have also been identified in some individuals with ALPS 1.

Heterozygous germline pathogenic variants in the FAS gene account for approximately 65-70% of all familial ALPS cases 3-9. Somatic FAS mutations were also reported in about 15-20% of ALPS cases 10. To date more than 130 different variants have been reported at HGMD (HGMD® Professional 2016.4). These variants are found throughout the entire gene, including missense, nonsense, splicing variants, small deletions/insertions, and a few large deletions.

Approximately 3-6% of ALPS cases are caused by mutations in the CASP10 gene 11. Of 6 variants identified in CASP10 to date, only 3 have been classified as disease-causing mutations: two missense variants, p.Leu285Phe 1, 13 and p.Ile406Leu 1, 13, and a large deletion of 13,4kb, including exons 6-9 14.

Less than 1% of ALPS-affected patients have a pathogenic variant in the FASLG gene12. So far only 3 different mutations have been reported in FASLG:

  • A missense mutation p.Arg156Gly shown to interfere with apoptosis 15
  • A homozygous pathogenic variant, p.Ala247Glu, linked to defective FasL-mediated apoptosis and defective Fas-dependent cytotoxic function 16
  • A heterozygous pathogenic variant leading to deletion of a single base pair, c.263delT 12

There is no cure for ALPS. In the absence of curative treatment, current management is focused on monitoring for and treatment of lymphoproliferation, hyperplensim, and lymphomas and management of refractory cytopenias and other autoimmune diseases1.

CENTOGENE offers the Autoimmune lymphoproliferative syndrome panel, including sequencing (genes: CASP10, CASP8, CTLA4, FADD, FAS, FASLG, ITK, KRAS, MAGT1, NRAS, and PRKCD) and deletion/duplication analysis of selected genes (FAS, FASLG). In addition, any of the genes in the Autoimmune lymphoproliferative syndrome panel can also be ordered individually, for sequencing and deletion/duplication analysis.

Differential diagnosis

The differential diagnosis of autoimmune lymphoproliferative syndrome-related disorders – depending on the major symptoms in the initial case – includes the following diseases:

  • Dianzani autoimmune lymphoproliferative disease (DALD)
  • Ras-associated autoimmune leukoproliferative disorder (RALD)
  • Fas-associated via death domain (FADD) deficiency
  • Caspase-8 deficiency state (CEDS)
  • Common variable immune deficiency (CVID)
  • Common variable immunodeficiency 9 (PRKCD deficiency)
  • X-linked lymphoproliferative disease (XLP)
  • Hyper IgM (HIGM) syndrome
  • WAS-related disorders (Wiskott-Aldrich syndrome, X-linked thrombocytopenia and X-linked congenital neutropenia)

Testing strategy

CENTOGENE offers advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on the PCR-free Whole Genome Sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and provides sequencing of entire gene at a more uniform coverage.

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for autoimmune lymphoproliferative syndrome using NGS Panel Genomic targeted towards this specific phenotype:

Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire genic region (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Autoimmune lymphoproliferative syndrome panel. Copy Number Variants analysis derived from NGS data is also included.

Step 2: If no mutation is identified after analysis of the Autoimmune lymphoproliferative syndrome panel, based on the approval and consent, we further recommend to continue the bioinformatics analysis of the data obtained by whole genome sequencing to cover genes that are either implicated in an overlapping phenotype or could be involved in a similar pathway but not strongly clinically implicated based on the current information in literature.

Referral reasons

The following individuals are candidates for Autoimmune lymphoproliferative syndrome panel testing:

  • Individuals with a family history of autoimmune lymphoproliferative syndrome and presentation of the most common symptoms
  • Individuals without a positive family history of autoimmune lymphoproliferative syndrome, but with symptoms resembling this disease
  • Individuals with a negative but suspected family history, in order to perform proper genetic counseling (prenatal analyses are recommended in families with affected individuals).

Test utility

Sequencing, deletion/duplication of this gene and related genes should be performed in all individuals suspected for autoimmune lymphoproliferative syndrome. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes.

Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management.

Genetic counseling can provide a patient and/or family with the natural history of the condition, identify at-risk family members, provide reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.