Autoimmune lymphoproliferative syndrome

Autoimmune lymphoproliferative syndrome (ALPS) is a condition in which pathogenic variants in specific genes (most commonly FAS – see table 1 below) cause immune cells to accumulate in the lymphatic system, leading to lymphadenopathy and chronic splenomegaly. Due to defective cell death processes, autoimmune diseases may also occur, particularly autoimmune cytopaenias (typically haemolytic anaemia and thrombocytopaenia), which can present early in childhood and can be life threatening. Patients are also at an increased risk of lymphoma.

Clinical features of ALPS include:

• chronic enlarged lymph nodes that should be present for >6 months without a malignant or infectious cause;
• splenomegaly;
• multi-lineage cytopaenias (most commonly haemolytic anaemia and thrombocytopaenia); and
• lymphoma.

Other less commonly encountered features include:

• hepatomegaly;
• autoimmune manifestations (such as thyroiditis or Addison disease);
• polyclonal hypergammaglobulinaemia (raised IgG); and
• elevated lymphocyte count.

Clinical features can be extremely variable, even between family members with the same genetic variant. Patients may have a family history of lymphoma or non-malignant lymphoproliferation.

ALPS typically presents during early childhood, but somatic (tumour) variants in FAS may present in adults. In some constitutional (germline) variants of FAS, symptoms often improve after adolescence.

ALPS is caused by pathogenic variants in a group of six genes.

Table 1: ALPS genes

Variants in FAS account for up to 75% of ALPS cases. Missense variants, nonsense variants, splice site variants, small indels, and larger insertions and deletions are all reported. The mechanism of action may be dominant negative (more typical ALPS), which occurs when a variant causes the protein produced to interfere with the normal protein function. Alternatively, it may be haploinsufficiency (may be associated with more variable penetrance), which occurs when only one functional copy of the gene (normally there are two) is not enough for correct protein function and leads to disease. Somatic FAS variants more typically arise in adulthood.

Non-FAS-related ALPS accounts for <20% of cases and variants in FASLG, CASP8, CASP10, PRKCK and FADD are less well characterised.

The majority of pathogenic FAS variants are heterozygous missense variants that affect the intracellular death domain of the FAS protein. The death domain interacts with downstream signalling enzymes, such as pro-caspase 8, pro-caspase 10 and receptors (FAS-associated death domain, or FADD) (figure 1). This forms the death-inducing signalling complex (DISC) to enable programmed apoptosis. Disruption of these protein-protein interactions through variations leads to the defective lymphocyte apoptosis characteristic of ALPS.

Protein kinase C delta (PRKCD) is a key protein in B-cell growth and proliferation. Loss of function of the protein kinase removes control on B-cell proliferation, leading to inappropriate B-cell accumulation. NK (natural killer) cell cytolytic activity also appears to be affected.

Several genetic conditions with overlapping features of ALPS are described, including:

• RAS-associated autoimmune lymphoproliferative disease caused by somatic gain-of-function variants in NRAS or KRAS;
• X-linked lymphoproliferative disease caused by SAP deficiency (SH2D1A); and
• CTLA4 haploinsufficiency.

A definitive diagnosis of ALPS is based on the presence of both required criteria (see below) plus one primary accessory criterion. A probable diagnosis is based on the presence of both required criteria plus one secondary accessory criterion.

The required diagnostic features are:

• chronic (>6 months) non-malignant, non-infectious lymphadenopathy and/or splenomegaly; and
• elevated CD3+ alpha-beta+ CD4- CD8- double-negative T cells (>1.8% of total lymphocytes or >2.5% of CD3+ lymphocytes).

The primary accessory criteria are:

• abnormal FAS-mediated apoptosis; and
• confirmed constitutional (germline) or somatic (tumour) pathogenic genetic variant in FAS, FASLG, FADD or CASP8.

The secondary accessory criteria are:

• elevated plasma sFAS-ligand levels (>200pg/ml);
• elevated plasma IL-10 levels (>20pg/ml);
• elevated serum or plasma vitamin B12 levels (>1500 pg/ml);
• autoimmune cytopaenia with elevated polyclonal IgG levels;
• positive family history of ALPS; and
• typical immunohistologic features, such as lymph node pathology.

Please contact the laboratory to check whether lymphocyte assays and biomarker assays are available prior to sending.

For information on genomic testing, see ‘Child with suspected autoimmune lymphoproliferative syndrome‘.

ALPS is mostly caused by pathogenic genetic variants in the FAS gene. Both autosomal dominant and autosomal recessive inheritance are described. Somatic FAS variants in affected haematopoietic cells may be found sporadically. With these, there is no risk of inheritance to future children.

As with FAS variants, variants in FASLG may also have autosomal dominant and recessive inheritance. CASP8, PRKCD and FADD variants have autosomal recessive inheritance, while autosomal dominant inheritance is described in CASP10 variants.

A family history should be taken, and careful consideration should be given to the possibility that other family members may be affected. Early diagnosis is important as there are significant management implications that may affect morbidity and mortality.

• If both parents are carriers of an autosomal recessive condition, with each pregnancy there is a:
  • 1 in 4 (25%) chance of a child inheriting both gene copies with the pathogenic variant and therefore being affected.
  • 1 in 2 (50%) chance of a child inheriting one copy of the gene with the pathogenic variant and one normal copy, and therefore being a healthy carrier themselves; and
  • 1 in 4 (25%) chance of a child inheriting both normal copies and being neither affected nor a carrier.
• Individuals affected by an autosomal dominant condition have one working copy of the gene, and one with a pathogenic variant.
  • The chance of a child inheriting the gene with the variant from an affected parent is 1 in 2 (50%).
  • Incomplete penetrance has been found in all ALPS variants (that is, not everyone who has the variant develops the disease).

Reproductive options are available for those at risk of having an affected child and genetic counselling is recommended.

ALPS management centres on the control of autoimmune features, mainly by immunosuppressive agents. Cytopaenias are particularly prevalent in ALPS and can be difficult to manage due to frequent recurrence. Initially, cases may be responsive to prednisolone treatment, but steroid-sparing approaches are preferred for chronic management. These include mycophenolate mofetil and sirolimus.

Other autoimmune manifestations, such as autoimmune hepatitis and uveitis, can be treated with immunosuppressants. Splenectomy may be necessary in very rare cases, although many patients may still have cytopaenias despite surgical intervention. Splenectomy also increases the risk of infection.

Lymphoma surveillance is a key aspect of management, and new or enlarged lymphadenopathy should be investigated for malignant change.

Haematopoietic stem cell transplantation has been used as a curative treatment for patients with severe clinical manifestations of ALPS due to biallelic pathogenic FAS variants.

ALPS is a rare, complex condition that is best managed by a tertiary immunology service. Patients may also require specialist input from haematologists due to autoimmune cytopaenias.

Further information about management can be found through the resources section below.

For clinicians

• OMIM: 601859 Autoimmune lymphoproliferative syndrome

References:

• Oliveira JB, Bleesing JJ, Dianzani U and others. ‘Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop‘. Blood 2010: volume 116, issue 14, pages e35-e40. DOI: 10.1182/blood-2010-04-280347
• Rao VK and Oliveira JB. ‘How I treat autoimmune lymphoproliferative syndrome‘. Blood 2011: volume 118, issue 22, pages 5,741–5,751. DOI: 10.1182/blood-2011-07-325217
• Xu X, Denton J, Wu Y and others. ‘Genetic testing in patients with autoimmune lymphoproliferative syndrome: Experience of 802 patients at Cincinnati Children’s Hospital Medical Center’. Journal of Clinical Immunology 2024: volume 44, article number 166. DOI: 10.1007/s10875-024-01772-z

For patients

• Immunodeficiency UK: Autoimmune lymphoproliferative syndrome
• Great Ormond Street Hospital for Children NHS Foundation Trust: Autoimmune lymphoproliferative syndrome