Autoimmune Lymphoproliferative Syndrome Differential Diagnoses

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