Diagnostic Considerations
With its classic presenting clinical triad of generalized lymphadenopathy, splenomegaly, and cytopenias in childhood, autoimmune lymphoproliferative syndrome (ALPS) can present a significant diagnostic challenge for clinicians. Because ALPS is rare and has clinical and laboratory features that can overlap those of other common pediatric rheumatologic or hematologic disorders (eg, sporadic acute idiopathic thrombocytopenic purpura [ITP]), clinicians must first rule out other, more immediate life-threatening conditions (eg, leukemia, lymphoma), and HLH.
ALPS has distinguishing laboratory features that should be obtained during evaluation (see Workup) to help differentiate this condition from other clinically similar conditions and thereby help keep the patient from undergoing unnecessary diagnostic and therapeutic interventions. Its rarity notwithstanding, ALPS should be considered in the differential diagnosis of any child who presents with chronic nonmalignant lymphadenopathy and splenomegaly, particularly when a family history of a similar disease is elicited.
Establishing a specific diagnosis is essential for prognosis and treatment. In the past, patients not uncommonly experienced a delayed diagnosis or misdiagnosis that led to unnecessary surgical procedures (including repeated lymph nodes biopsies and unwarranted splenectomy) or even courses of chemotherapy.
In addition to the conditions listed and the differential diagnosis below, other problems to be considered include the following:
-
Hyper IgM (HIGM) syndrome
-
Interleukin (IL)–2 receptor alpha-chain deficiency
-
Leukemia
-
Lymphoma (Hodgkin and non-Hodgkin)
-
Mycobacterial disease
-
Rosai-Dorfman disease
-
X-lined lymphoproliferative syndrome (XLP)
-
ALPS-related syndrome or ALPS-like disorders (Table 1)
Issues of misdiagnosis (often with malignancy or chronic infection) and obtaining informed consent for therapies like bone marrow transplantation (leading to wrongful death litigation) constitute the major medicolegal pitfalls in the management of ALPS. Accordingly, the participation of experienced specialists is essential to the diagnosis and treatment of patients with this syndrome. These patients require a treatment team with a pediatric hematologist or immunologist as a team leader and case manager.
Differential Diagnoses
-
Immunodysregulation Polyendocrinopathy Enteropathy X-Linked Syndrome (IPEX)
-
Examples of an autoimmune lymphoproliferative syndrome (ALPS) in a patient with grade IV (visible) lymphadenopathy.
-
Autoimmune lymphoproliferative syndrome (ALPS) and ALPS-related disorders classification:
-
Primary and accessory diagnostic criteria for autoimmune lymphoproliferative syndrome (ALPS).
-
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.
-
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.
-
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.
-
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] |
