Autoimmune Lymphoproliferative Syndrome Clinical Presentation

Updated: Jul 29, 2019
  • Author: Akaluck Thatayatikom, MD, RhMSUS; Chief Editor: Harumi Jyonouchi, MD  more...
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Presentation

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.

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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 synd 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.

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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 synd 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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