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Autoimmune Lymphoproliferative Syndrome Differential Diagnoses

  • Author: Luke M Webb, MD; Chief Editor: Harumi Jyonouchi, MD  more...
Updated: Aug 15, 2014

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 hematologic disorders (eg, sporadic acute idiopathic thrombocytopenic purpura [ITP]), clinicians must first rule out other, more immediate life-threatening conditions (eg, leukemia and lymphoma).

ALPS has distinguishing laboratory features that should be sought 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 important 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 in the differential diagnosis, 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)

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 as team leader and case manager.

Differential Diagnoses

Contributor Information and Disclosures

Luke M Webb, MD Staff Physician, Department of Allergy and Immunology, Evans Army Community Hospital

Luke M Webb, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology

Disclosure: Nothing to disclose.


David J Schwartz, MD Staff Physician, Department of Allergy and Immunology, Eisenhower Army Medical Center

David J Schwartz, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Allergy, Asthma and Immunology

Disclosure: Nothing to disclose.

V Koneti Rao, MD FRCPA, Staff Clinician, Lymphocyte Clinical Genomics Unit, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health

V Koneti Rao, MD is a member of the following medical societies: American Society of Hematology, American Society of Pediatric Hematology/Oncology

Disclosure: Nothing to disclose.

Chief Editor

Harumi Jyonouchi, MD Faculty, Division of Allergy/Immunology and Infectious Diseases, Department of Pediatrics, Saint Peter's University Hospital

Harumi Jyonouchi, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Medical Association, Clinical Immunology Society, New York Academy of Sciences, Society for Experimental Biology and Medicine, Society for Pediatric Research, Society for Mucosal Immunology

Disclosure: Nothing to disclose.


Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.


The authors acknowledge Drs Kip Hartman and Margaret Merino of the Pediatric Hematology and Oncology Department at the Walter Reed Army Medical Center for the use of their clinical expertise and patient photographs in this article. In addition, the authors thank Dr Scott Whitworth of the Department of Radiology at Walter Reed Army Medical Center for his assistance with positron emission tomography (PET) imaging. Finally, the authors also express thanks to the patients and parents who granted permission to use these photographs.

This research was supported by the Intramural Research Program of the National Institutes of Health. The views expressed in this article are those of the authors and do not reflect the official policy of the Department of Army, Department of Defense, or the US Government.

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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.
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