Review on X-linked lymphoproliferative disease (XLP), with data on clinics, and the genes involved

Bassiri, H

Nichols, KE

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Cancer Prone Disease Section 
Review 
 
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(9)  685 
INIST-CNRS 
 
OPEN ACCESS JOURNAL 
Atlas of Genetics and Cytogenetics 
in Oncology and Haematology 
X-linked lymphoproliferative disease (XLP) 
Hamid Bassiri, Kim E Nichols 
Division of Infectious Diseases, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA (HB), 
Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, United States (KEN) 
 
Published in Atlas Database: April 2012 
Online updated version : http://AtlasGeneticsOncology.org/Kprones/XlinkedlymphoproliferID10028.html 
DOI: 10.4267/2042/47545 
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. 
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology 
 
Identity 
Note 
Two subtypes of XLP have been idenitified to date.  
XLP type 1, (also known as Duncan disease, Purtilo 
syndrome) is a rare primary immunodeficiency, first 
described by Purtilo (Purtilo et al., 1974), in which 
patients develop dysgammaglobulinemia (most 
commonly hypogammaglobulinemia of one or more 
immunoglobulin subclasses), fulminant mononucleosis 
following infection with Epstein Barr virus (EBV), and 
B-cell lymphoma.  
XLP1 is caused by mutations in SH2D1A (formerly 
DSHP; SAP), which encodes the cytoplasmic adaptor 
protein Signaling Lymphocytic Activation Molecule 
(SLAM)-associated protein (SAP) (Coffey et al., 1998; 
Sayos et al., 1998). 
XLP type 2, (Rigaud et al., 2006) is a clinically similar 
disorder that predisposes primarily to hemophagocytic 
lymphohistiocytosis (HLH), which often presents in the 
setting of primary EBV infection.  
Patients with XLP2 may also exhibit splenomegaly, 
hypogammaglobulinemia and hemorrhagic colitis 
(Marsh et al., 2010). To date, no patient with XLP2 has 
been reported to develop abnormal B-
lymphoproliferation or lymphoma. XLP2 is caused by 
mutations in XIAP (BIRC4), the gene encoding the X-
linked inhibitor of apoptosis protein. 
Inheritance 
XLP1 and -2 are transmitted in an X-linked fashion and 
do not have a known ethnic or racial predilection. The 
causative genes are located in proximity to one another 
at Xq25.  
Mutations in SH2D1A or XIAP are identified in 83-
97% of XLP1 and 12% of XLP2 patients, respectively 
(Filipovich et al., 2011).  
Mutations include insertions, deletions of one or more 
exons and nucleotide substitutions that result in 
reduced or absent expression of the encoded proteins. 
De novo mutations in either gene are rare. Female 
SH2D1A or XIAP mutation carriers are clinically 
unaffected yet at risk to transmit the mutant allele to 
50% of male offspring, who will have XLP. Female 
offspring of XLP carriers are at 50% risk to inherit a 
mutant allele and thus be carriers of XLP. 
Clinics 
Note 
XLP is estimated to affect 1-3 per million male 
individuals, although the incidence may be higher as 
the condition may go undetected. Nonetheless, any 
male individual presenting with severe or fatal EBV 
infection, or HLH as a result of EBV exposure should 
be evaluated for XLP, especially if there is a family 
history of maternally related males with 
dysgammaglobulinemia, lymphoma or EBV-induced 
HLH. Early diagnosis of XLP is paramount, as the 
mean ages of death of individuals with XLP1 and 
XLP2 are 11 and 16 years, respectively (Pachlopnik 
Schmid et al., 2011). 
Phenotype and clinics 
XLP1 patients usually present with fulminant FIM (a 
hyperinflammatory condition resembling HLH that is 
induced by EBV infection and typified by the 
dysregulated expansion of EBV-infected B cells and 
cytotoxic T cells, and the abnormal activation 
of macrophages), dysgammaglobulinemia and B cell 
lymphoma. Less commonly, XLP1 manifests as 
lymphocytic vasculitis (usually involving the lungs or 
central nervous sytem [CNS]), aplastic anemia or 
lymphatoid granulomatosis (Gaspar et al., 2002). The
manifestations of XLP1 can occur in the absence of 
EBV infection. 
XLP2 commonly presents with splenomegaly and 
recurrent episodes of HLH, often in response to EBV 
X-linked lymphoproliferative disease (XLP) Bassiri H, Nichols KE 
 
 
 
 
 
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(9)  686 
infection. XLP2 patients also display 
dysgammaglobulinemias, and a proportion of affected 
individuals develop hepatitis and/or colitis. 
There is no known correlation between SH2D1A or 
XIAP genotype and phenotype in XLP1 or XLP2. 
Affected members of the same family may exhibit 
significant variability in presentation.  
Diagnosis is generally suspected based on clinical 
history. Screening tests can be performed to assess for 
protein levels of SAP or XIAP in lymphocytes via flow 
cytometry, and the diagnosis confirmed by genetic 
analysis of the associated genes. In rare instances, 
genetic analysis fails to identify an abnormality in 
SH2D1A or XIAP in a host presenting with signs and 
symptoms consistent with XLP. 
Neoplastic risk 
The risk for development of lymphomas in XLP1 
approaches 25-30%, with a mortality rate of 9% (Booth 
et al., 2011). The lymphomas are typically high grade 
non-Hodgkins type B cell lymphomas. Lymphomas 
tend to be extranodal and involve the intestines, 
although they can also be found in liver, kidneys and 
CNS. Histologically, they are classified as Burkitt's, 
immunoblastic, small cleaved B cell lymphomas or 
mixed cell lymphomas. Not all lymphomas carry 
evidence of EBV genome. It remains poorly understood 
why patients with XLP1 develop lymphoma; however, 
absence of invariant natural killer T (NKT) cells and 
defects in T and NK cell cytotoxic function may 
contribute to lymphoma formation. 
Treatment 
The therapy of choice for XLP patients is 
hematopoietic cell transplantation (HCT). HCT is the 
only known curative treatment and has the best chance 
of success if performed as early as possible - before the 
onset of other disease manifestations. Other therapies 
directed at treating the manifestations of XLP may be 
necessary before HCT is attempted. Although HCT 
carries its own risk of complications and mortality, 
without it only 50% of XLP1 patients reach adulthood. 
The majority perish secondary to HLH (70%), 
lymphoma (12%) or myelodysplasia (6%) (Booth et al., 
2011; Pachlopnik Schmid et al., 2011). The prognosis 
is similarly poor for XLP2 without HCT, in which 
mortality is attributed to HLH (30%), colitis (23%), 
liver failure (8%), and infectious causes (8%) 
(Pachlopnik Schmid et al., 2011). 
HLH is generally treated with corticosteroids, 
cyclosporine, and etoposide. Rituximab has been used
successfully to prevent EBV-induced FIM in XLP1  
(Milone et al., 2005), and should be considered in any
XLP1 or -2 patient who experiences primary EBV 
infection.  
Lymphomas can be effectively treated with standard 
chemotherpateutic regimens; however, patients should 
be carefully monitored for the development of EBV 
and other infections, which can be difficult to manage 
due to underlying immune defects.  
Patients with hypogammaglobulinemia are treated with
monthly immunoglobulin replacement.  
Asymptomatic patients with XLP should be 
periodically monitored for immunoglobulin levels, 
evidence for EBV exposure, and signs of development 
of other manifestations of disease. 
Genes involved and proteins 
SH2D1A 
Note 
XLP1. SH2D1A consists of 4 exons spanning 25 kb of 
genomic DNA and encodes a 128 amino acid protein 
comprised primarily of a Src Homology 2 (SH2) 
domain. Over 70 disease-associated mutations have 
been identified (Filipovich et al., 2011). 
Protein 
Note 
SH2D1A encodes the SLAM (Signaling Lymphocytic 
Activation Molecule)-associated protein (SAP), which 
is required for signaling through the SLAM family of 
receptors (SLAM, 2B4, CD84, Ly108/NTB-A, Ly9). 
Loss of SAP expression and/or function results in 
immune cell defects, including reduced T and NK cell
cytotoxicity, impaired follicular T helper cell function 
resulting in poor germinal center formation, decreased 
restimulation-induced T cell death, altered Th2-type 
cytokine production and abrogation in NKT cell 
development (Rezaei et al., 2010; and references 
therein). 
XIAP 
Note 
XLP2. XIAP consists of 6 exons spanning 42 kb and 
encodes a 497 amino acid protein. The XIAP protein 
contains 3 Baculovirus IAP Repeat domains and a C-
terminal Ring domain with E3 ubiquitin ligase activity. 
XIAP binds the tumor necrosis factor receptor-
associated factors TRAF1 and TRAF2 and inhibits 
apoptosis through interactions with caspases 3, 
caspases 7, and caspases 9. It is still unclear how 
mutations in XIAP and the resulting disinhibition of
apoptosis result in the manifestations of XLP2. 
X-linked lymphoproliferative disease (XLP) Bassiri H, Nichols KE 
 
 
 
 
 
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(9)  687 
 
 
Schematic representing the putative mechanism of SAP-mediated signaling. (A) In the absence of SAP, signaling from the SLAM 
family receptors is impaired due to the binding of inhibitory phosphatases, such as SHP-1, SHP-2 or SHIP. Via a unique portion of its 
SH2 domain, SAP binds to the Src family tyrosine kinase Fyn, which leads to the activation of Fyn's kinase activity. (B) Engagement of 
SLAM family receptors via homotypic or heterotypic interactions with similar receptors on neighboring cells leads to a conformational 
change in the SLAM receptor tails, thereby facilitating the binding and SAP and Fyn. (C) Fyn then phosphorylates specific tyrosines 
within the SLAM receptors, which form docking sites for additional signaling proteins, and allow the transmission of signals required for 
cell functions, such as Th2 type cytokine production, cytotoxicity and natural killer T cell development. 
 
X-linked lymphoproliferative disease (XLP) Bassiri H, Nichols KE 
 
 
 
 
 
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(9)  688 
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This article should be referenced as such: 
Bassiri H, Nichols KE. X-linked lymphoproliferative disease 
(XLP). Atlas Genet Cytogenet Oncol Haematol. 2012; 
16(9):685-688. 


X-linked lymphoproliferative disease (XLP)

H Bassiri

KE Nichols

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http://documents.irevues.inist.fr/bitstream/2042/47545/3/04-2012-XlinkedlymphoproliferID10028.pdf

X-linked lymphoproliferative disease (XLP)

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