Autoimmune lymphoproliferative syndrome (ALPS): Clinical features and diagnosis
- Jack JH Bleesing, MD, PhD
Jack JH Bleesing, MD, PhD
- Professor of Pediatrics
- Cincinnati Children's Hospital Medical Center
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.
This topic reviews the clinical features and diagnosis of ALPS. The epidemiology, genetics, pathogenesis, management, and prognosis of ALPS are discussed separately. (See "Autoimmune lymphoproliferative syndrome (ALPS): Epidemiology and pathogenesis" and "Autoimmune lymphoproliferative syndrome (ALPS): Management and prognosis".)
In the two largest cohorts of patients with ALPS, the French cohort and National Institutes of Health (NIH) cohort, disease onset was most commonly marked by lymphoproliferation with generalized adenopathy and hepatosplenomegaly at a median age of 2.7 to 3 years [1,2]. Patients with later disease onset often presented with autoimmune manifestations rather than lymphoproliferative disease.
ALPS due to mutations in the FAS gene that encodes an apoptosis-associated antigen (ALPS-FAS) is the most common and best-characterized type of ALPS, although it is nonetheless a rare condition. The following are the main consequences of perturbed lymphocyte homeostasis in ALPS-FAS.
Chronic nonmalignant lymphoproliferation — Expansion and persistence of lymphocyte populations that are not eliminated through apoptosis affect the lymphoid compartment, resulting in chronic lymphadenopathy, splenomegaly with or without premature destruction of blood cells (hypersplenism), and, less frequently, hepatomegaly. The lymphoproliferation typically manifests in the first years of life in individuals with ALPS-FAS. In some individuals, splenomegaly is the predominant or only manifestation of lymphoproliferation [3,4].
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- CLINICAL MANIFESTATIONS
- Chronic nonmalignant lymphoproliferation
- Other findings
- Other ALPS genotypes
- LABORATORY FINDINGS
- Diagnostic criteria
- - Required criteria
- - Primary accessory criteria
- - Secondary accessory criteria
- Testing and classification strategy
- Inheritance and prenatal diagnosis
- Additional testing and diagnostic considerations
- DIFFERENTIAL DIAGNOSIS
- Common variable immunodeficiency disease
- Hyperimmunoglobulin M syndrome
- X-linked lymphoproliferative syndrome
- Wiskott-Aldrich syndrome
- CTLA-4 haploinsufficiency with autoimmune infiltration (CHAI) disease
- STAT3 gain-of-function mutations causing autoimmune disease
- LRBA deficiency disease
- Other rare disorders