History
The initial presentations of ALPS are often that of persistent lymphadenopathy (>95%) or splenomegaly (>90%) followed by autoimmunity (>70%) and hepatomegaly (50%) in an otherwise healthy child. [15, 16] Patients with germline FAS mutations typically present earlier than somatic FAS mutations; however, both mutations have the same clinical manifestations. [40]
The majority of patients develop lymphoproliferation at a young age (median age of 11.5 months) without associated constitutional symptoms. To meet the case definition of ALPS, a patient must have chronic, nonmalignant lymphadenopathy, or splenomegaly that lasts for 6 months or longer. The lymphoproliferation can wax and wane randomly before resolving in most patients after 20 years of age. [6]
Autoimmunity is the second most common clinical presentation, especially autoimmune cytopenias in one or more cell lineages. Autoimmune hemolytic anemia and autoimmune thrombocytopenia are more common than autoimmune neutropenia. The multilineage cytopenias often noticed in ALPS result from splenic sequestration, as well as from underlying autoimmune processes. [1] The symptoms related to cytopenia are pallor, petechiae, bleeding, icterus, fatigue, and recurrent infections. A family history of similar disorders may be noted; these are usually inherited in an autosomal dominant fashion. A thorough review of a patient’s extended family for a history of adenopathy, cytopenias, splenectomies, or lymphoma can provide clues in diagnosing ALPS.
Other autoimmune diseases occur in 10–20% of ALPS and can affect any organ system. The most common are skin rashes, immune-mediated pulmonary fibrosis, autoimmune thyroiditis, uveitis, Guillain-Barre syndrome, autoimmune hepatitis, nephristis, gastritis, pancreatitis, colitis, transverse myelitis, cerebellar ataxia, myocarditis, and arthritis. [6]
Careful attention to the development of systemic B symptoms (e.g., fever, drenching night sweats, pruritus, and weight loss) is essential for cancer surveillance in those at high-risk for B cell lymphoma.
Physical Examination
The lymphadenopathy and hepatosplenomegaly seen in patients with ALPS can often be remarkable, sometimes visibly distorting anatomic landmarks (see the image below). These findings can wax and wane.
Examples of an autoimmune lymphoproliferative syndrome (ALPS) in a patient with grade IV (visible) lymphadenopathy.
Areas most commonly affected by lymphadenopathy include the neck and axillary regions, but careful assessment of epitrochlear, femoral, inguinal, and other lymph node chains is essential in the assessment. Petechiae, pallor, icterus, and evidence of infections may be found in patients with characteristic cytopenias. Ongoing surveillance in these patients should include careful attention to the development of changes in lymph node size or the appearance of new focal or generalized lymphadenopathy and worsening splenomegaly.
Complications
Complications of ALPS include the development of lymphoma or other malignancy and the development of pneumococcal sepsis or other serious systemic infection (secondary to splenectomy, autoimmune neutropenia, or both; see the image below).
A patient with autoimmune lymphoproliferative syndrome (ALPS) who developed pneumococcal sepsis, a serious complication secondary to neutropenia and asplenia. Note the patient's cochlear implant; he has neurosensory hearing loss from prior episode of pneumococcal meningitis.
Patients with genetic mutations that affect the intracellular domain of the FAS protein have a more severe clinical manifestation from early childhood and are found to have a 51-fold higher risk of Hodgkin lymphoma and a 14-fold increased risk of non-Hodgkin lymphoma. A report on the largest cohort of ALPS patients worldwide showed an approximate 6% incidence of lymphoma in patients with ALPS overall, with a median age at presentation of 17 years. [41]
Lymphadenopathy in ALPS patients with lymphoma can be especially difficult to discern because persistent lymphadenopathy is common even as the patient progresses into adulthood. Like any sporadic lymphomas, however, ALPS-associated lymphomas are amenable to chemotherapy and should be managed accordingly. ALPS-associated lymphadenopathy and splenomegaly tend to become less prominent with age. In patients who have undergone splenectomy, asplenia-related sepsis is a significant lifelong cause of morbidity and mortality. [16] Long-term management with steroid-sparing medication and avoiding splenectomy are strongly recommended to preserve some antipolysaccharide response.
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Examples of an autoimmune lymphoproliferative syndrome (ALPS) in a patient with grade IV (visible) lymphadenopathy.
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Autoimmune lymphoproliferative syndrome (ALPS) and ALPS-related disorders classification:
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Primary and accessory diagnostic criteria for autoimmune lymphoproliferative syndrome (ALPS).
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A patient with autoimmune lymphoproliferative syndrome (ALPS) who developed pneumococcal sepsis, a serious complication secondary to neutropenia and asplenia. Note the patient's cochlear implant; he has neurosensory hearing loss from prior episode of pneumococcal meningitis.
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Positron emission tomography (PET) superimposed over a CT scan from a patient with autoimmune lymphoproliferative syndrome (ALPS). Note the massive cervical adenopathy. PET scans may be used as a screening tool in patients with autoimmune lymphoproliferative syndrome to decrease the number of lymph node biopsies used in screening for malignancy.
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The extrinsic pathway of apoptosis. Mutations have been identified in each of the genes coding for Fas, Fas-ligand (FasL), caspase-8, and caspase-10. This figure was previously published in Rao VK, Straus SE. Autoimmune Lymphoproliferative Syndrome. Clinical Hematology. 58;759. 2006: Elsevier.
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Suggested treatment algorithm for patients with autoimmune lymphoproliferative syndrome (ALPS). This schematic diagram is included only as a suggested guideline for managing children with autoimmune lymphoproliferative syndrome–associated autoimmune multilineage cytopenias. Use of granulocyte-colony stimulating factor (G-CSF) may be warranted for severe neutropenia associated with systemic infections. Similarly, use of other chemotherapeutic and immunosuppressive agents (eg, vincristine, methotrexate, mercaptopurine, azathioprine, cyclosporine, hydroxychloroquine, tacrolimus, sirolimus) besides mycophenolate mofetil (MMF) should be considered as a steroid-sparing measure or while avoiding or postponing surgical splenectomy at the discretion of the treating clinicians based on the circumstances of a specific patient.
Tables
| Disease | Mutation | Clinical Features |
|---|---|---|
| Caspase-8 deficiency state (CEDS) | Autosomal recessive/ LOF mutation in CASP8 gene (2q33.1) | Recurrent sinopulmonary infections, severe mucocutaneous herpes simplex viral infection with defects in activation of T, B and NK cells, hypogammaglobulinemia, low pneumococcal antibodies, low T cell function (lymphocyte mitogen stimulation), low NK function [18] |
| FADD deficiency | Autosomal recessive/ LOF mutation in FADD gene (11q13.3) | Susceptibility to bacterial and viral infections related to functional hyposplenism and impaired interferon immunity, congenital heart disease, recurrent fever, liver dysfunction, seizures [19] |
| Ras-associated autoimmune leukoproliferative disorder | Germline or somatic mutations/ GOF mutation in NRAS gene (1p13.2) and KRAS gene (12p12.1) | Lymphadenopathy, massive splenomegaly, increased circulating B cells, hypergammaglobulinemia, autoimmunity [20, 21, 22] |
| Dianzani autoimmune lymphoproliferative disease | N252S and A91B perforin gene variations, osteopontin polymorphism | No increased DNT, defective Fas, lymphadenopathy, splenomegaly, autoimmunity [23, 24] |
| Activated phosphoinositide 3-kinase δ syndrome (APDS) | Autosomal dominant/ gain of function mutations in PIK3CD (1p36.22), PIK3R1(5q13.1) | Combined immunodeficiency with recurrent sinopulmonary infections, lymphadenopathy, herpesvirus infection, autoinflammatory disease, lymphoma and neurodevelopmental delay [25] |
| Protein kinase C delta (PRKCD) deficiency | Autosomal recessive/ loss of function mutation in PRKCD gene (3p21.1) | Hypogammaglobinemia, recurrent infections, lymphadenopathy, hepatosplenomegaly, autoimmunity and NK cell dysfunction [26, 27] |
| Lipopolysaccharide responsive and beige like anchor protein (LABA) deficiency with autoantibodies, regulatory T cell defects, autoimmune infiltration and enteropathy (LATAIE) | Autosomal recessive/ loss of function mutation in LPS-responsive and beige-like anchor protein (LABA) gene (4q31.3) | Autoimmunity, chronic diarrhea, enteropathy or IBD–like disease, splenomegaly, pneumonia, reduction in number of regulatory T cell, CD4 T cells, class-switched memory B cell and hypogammaglobinemia [28] |
| CTLA4 haloinsufficiency with autoimmune infiltration (CHAI) | Autosomal dominant/ LOF in CTLA4 gene (2q33.2) | Hypogammaglobulinemia, lymphoproliferation, autoimmune cytopenia, and respiratory, gastrointestinal, or neurological symptoms [29] |
| GOF mutations in STAT1 | Autosomal dominant/ GOF mutation in STAT1 gene (2q32.2) | Recurrent infections including chronic mucocutaneous candidiasis (CMC), recurrent Staphylococcus aureus, recurrent herpes, Mycobacterium, autoimmunity, cytopenia and aneurysm [30] |
| GOF mutations in STAT3 | Autosomal dominant/ GOF mutation in STAT3 gene (17q21.2) |
Hypogammaglobulinemia, autoimmunity, cytopenia, lymphadenopathy, splenomegaly, enteropathy, interstitial lung disease, endocrinopathy, postnatal growth failure [31, 32] |
Deficiency of adenosine deaminase 2 (DADA2) |
Autosomal recessive adenosine deaminase-2 (ADA2) gene (22q11.1) | Recurrent fever, vasculitis, aneurysms, hypertension, ischemic or hemorrhagic stroke, livedo reticularis, lymphadenopathy, hepatosplenomegaly,hypogammaglobulinemia, cytopenia, lymphopenia [33, 34] |
| B cell expansion with NF-B and T cell anergy disease (BENTA) | Autosomal dominant, GOF mutation in CARD11 gene (7p22.2) | Lymphadenopathy, splenomegaly, autoimmunity, cytopenia, low antibodies, recurrent bacterial infections, chronic viral (EBV, molluscum) infections, B cell lymphoma [35, 36] |
Deregulation of Fas ligand expression caused by IL-12RB1 mutation |
Autosomal recess, LOF mutation in IL12RB1 gene (19p13.11) | Lymphadenopathy, splenomegaly, hepatomegaly, elevated numbers of double-negative T cells, autoimmune cytopenias, and increased levels of vitamin B12 and interleukin-10 [37] |
| X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia” (XMEN) | LOF mutation in MAGT1 gene (Xq21.1) | Persistent Epstein–Barr virus (EBV) viremia, history of EBV+ lymphoma, a CD4:CD8 T-cell ratio of 1 or less with a normal lymphocyte count or mild to moderate lymphopenia, recurrent sinopulmonary and viral infections, hypogammaglobulinemia, variable antibody response to vaccinations, neutropenia, autoimmunity [38, 39] |
