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Autoimmune Lymphoproliferative Syndrome Clinical Presentation

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

History

The initial presentation of autoimmune lymphoproliferative syndrome (ALPS) is often that of persistent lymphadenopathy or splenomegaly followed by an autoimmune disease such as idiopathic thrombocytopenic purpura (ITP) or hemolytic anemia in an otherwise healthy child.[12] To meet the case definition of ALPS, a patient must have chronic, nonmalignant lymphadenopathy or splenomegaly that lasts for 6 months or longer.

Associated multilineage cytopenias due to autoantibodies or splenic sequestration can lead to petechiae, bleeding, pallor, icterus, fatigue, and recurrent infections; the latter are mostly due to neutropenia. 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 helpful information and clues in diagnosing ALPS.

Careful attention to the development of systemic B symptoms (eg, fever, drenching night sweats, pruritus, and weight loss) is important for cancer surveillance in those at high-risk for B cell lymphoma. Some of the patients also develop autoimmune diseases that affect other organs (eg, autoimmune hepatitis, glomerulonephritis, uveitis, and Guillain-Barre syndrome).

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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).

Examples of an autoimmune lymphoproliferative synd Examples of an autoimmune lymphoproliferative syndrome (ALPS) in a patient with grade IV (visible) lymphadenopathy.

In as many as 50% of children with ALPS, splenectomy is eventually performed, usually due to refractory cytopenias. Many of these patients are diagnosed long after splenectomy has been performed and therefore do not have associated splenomegaly at the time when ALPS is diagnosed.

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 important 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.[7]

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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 asplenia, 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.[10]

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.[7]

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Contributor Information and Disclosures
Author

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.

Coauthor(s)

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.

Acknowledgements

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.

Acknowledgments

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.

References
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  8. Oliveira JB, Bidere N, Niemela JE, et al. NRAS mutation causes a human autoimmune lymphoproliferative syndrome. Proc Natl Acad Sci U S A. 2007 May 22. 104(21):8953-8. [Medline].

  9. Oliveira JB, Bleesing JJ, Dianzani U, Fleisher TA, Jaffe ES, Lenardo MJ, et al. Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop. Blood. 2010 Oct 7. 116(14):e35-40. [Medline]. [Full Text].

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  11. Bristeau-Leprince A, Mateo V, Lim A, Magerus-Chatinet A, Solary E, Fischer A. Human TCR alpha/beta+ CD4-CD8- double-negative T cells in patients with autoimmune lymphoproliferative syndrome express restricted Vbeta TCR diversity and are clonally related to CD8+ T cells. J Immunol. 2008 Jul 1. 181(1):440-8. [Medline].

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  17. Rao VK, Dowdell KC, Dale JK, Dugan F, Pesnicak L, Bi LL. Pyrimethamine treatment does not ameliorate lymphoproliferation or autoimmune disease in MRL/lpr-/- mice or in patients with autoimmune lymphoproliferative syndrome. Am J Hematol. 2007 Dec. 82(12):1049-55. [Medline].

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  19. Rao VK, Dugan F, Dale JK, Davis J, Tretler J, Hurley JK. Use of mycophenolate mofetil for chronic, refractory immune cytopenias in children with autoimmune lymphoproliferative syndrome. Br J Haematol. 2005 May. 129(4):534-8. [Medline].

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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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