Table 4.

Genes of Interest in the Differential Diagnosis of X-Linked Lymphoproliferative Disease

Gene(s)DisorderMOIClinical FeaturesComment
ADA2
CARD11
CTLA4
DEF6
IL12RB1
IL2RA
IL2RB
KRAS
NRAS
PIK3CD
PIK3R1
PRKCD
STAT1
STAT3
STK4
TET2
TNFAIP3
TNFRSF9
TPP2 		ALPS-like syndrome 1AD
AR		Benign & chronic lymphoproliferation, autoimmunity, & ↑ risk of lymphomaInherited gain- or loss-of-function pathogenic variants in these genes lead to immune regulatory disorders that phenocopy multiple features of XLP, incl hypogammaglobulinemia, inflammation, predisposition to infection, & lymphoma.
AP3B1 AP3B1-related Hermansky-Pudlak syndromeARStrong susceptibility to EBV infection, incl severe infection, & development of EBV-assoc Hodgkin & non-Hodgkin lymphomas 2XLP should be considered in persons presenting w/severe EBV infection.
BTK X-linked agammaglobulinemia XL↑ susceptibility to bacterial infectionXLP should be considered in males w/hypogammaglobulinemia identified in 1st decade of life.
CD19
CD81
CR2
ICOS
IKZF1
IL21
IRF2BP2
LRBA
MS4A1
NFKB1
NFKB2
TNFRSF13B
TNFRSF13C 		CVID (OMIM PS607594)AD
AR
  • Humoral immune deficiency w/age of onset most commonly between 16 & 20 yrs resulting in ↑ susceptibility to infections & ↓ responses to protein & polysaccharide vaccines
  • The most common infections are sinopulmonary.
  • Overall prevalence is approximately one in 20,000 to 50,000 live births.
  • Occurs equally in males & females. 3
  • The genetic etiology of most CVID is currently unknown.
  • XLP should be considered in males w/CVID & hypogammaglobulinemia identified during 1st decade of life, particularly in presence of other signs or positive family history.
  • Persons w/CVID occasionally present with HLH-like phenotype. 4
CD27
CD70
CORO1A
CTPS1
MAGT1
RASGRP1 		EBV-assoc lymphoproliferative disorders 5AR
XL		Strong susceptibility to EBV infection, incl severe infection, & development of EBV-assoc Hodgkin & non-Hodgkin lymphomasXLP should be considered in persons presenting w/severe EBV infection.
CDC42 CDC42-related HLH 2ADCytopenias, hepatosplenomegaly, ↑ transaminases, recurrent fevers, rashes, failure to thrive, & HLH 2XLP should be considered in males who meet criteria for HLH.
FAS
FASLG 		ALPS-FAS & ALPS-FASLG 6AD
AR 7		Accumulation of autoreactive lymphocytes leading to lymphadenopathy, hepatosplenomegaly, autoimmune cytopenias, & ↑ risk for lymphomaALPS phenocopies many features of XLP. XLP should be considered in males presenting w/benign or malignant lymphoproliferation.
ITK ITK deficiency (lymphoproliferative syndrome 1) (OMIM 613011)ARPresentation is quite variable in the few persons reported to date & incl fatal HLH, hypogammaglobulinemia, & autoimmune-mediated renal disease, often following EBV infection.In contrast to XLP1, 4/5 persons w/ITK deficiency developed Hodgkin lymphoma, as opposed to Burkitt lymphoma.
LYST Chediak-Higashi syndrome (CHS)AR
  • Partial oculocutaneous albinism, a mild bleeding tendency, & severe immunodeficiency
  • ~85% of persons w/classic CHS develop HLH.
CHS can be differentiated from XLP by the presence of huge secretory lysosomes in neutrophils & lymphocytes & giant melanosomes on skin biopsy in persons w/CHS.
MVK Hyper-IgD syndrome (OMIM 260920)ARHigh serum IgD levels w/assoc febrile episodes, lymphadenopathy, & abdominal painXLP shares clinical features w/hyper-IgD syndrome but can be differentiated by the presence of hypogammaglobulinemia.
NLRC4 NLRC4-related HLH 2ADEnterocolitis & HLH 2XLP should be considered in males who meet criteria for HLH.
PRF1
STX11
STXBP2
UNC13D 		Familial HLH (fHLH)AR 8
  • Excessive immune activation w/uncontrolled T lymphocyte & macrophage activation
  • Familial HLH may also be triggered by EBV infection
  • Familial HLH is lethal in childhood unless treated w/HSCT.
XLP should be considered in males who meet criteria for HLH. HLH in persons w/XLP commonly occurs in the setting of infection w/EBV, while an underlying infectious trigger is often not identified in persons w/fHLH.
RAB27A Griscelli syndrome type 2 (GS2) (OMIM 607624)AR
  • Disorder of cytotoxic T lymphocytes
  • Usually assoc w/ neurologic abnormalities in addition to partial albinism w/fair skin & silvery-gray hair
  • Many persons w/GS2 develop HLH.
Persons w/GS2 can present w/HLH, similar to persons w/XLP, but XLP is not assoc w/albinism or neurologic abnormalities.

AD = autosomal dominant; ALPS = autoimmune lymphoproliferative syndrome; AR = autosomal recessive; CVID = common variable immunodeficiency; EBV = Epstein-Barr virus; HLH = hemophagocytic lymphohistiocytosis; HSCT = hematopoietic stem cell transplant; Ig = immunoglobulin; MOI = mode of inheritance; XL = X-linked; XLP = X-linked lymphoproliferative disease

1.
2.
3.
4.
5.
6.

ALPS-FAS refers to autoimmune lymphoproliferative syndrome (ALPS) associated with biallelic or heterozygous germline pathogenic variants in FAS. ALPS-FASLG refers to ALPS associated with biallelic or heterozygous germline pathogenic variants in FASLG.

7.

In most individuals with ALPS-FAS and some individuals with ALPS-FASLG, inheritance is autosomal dominant. In most individuals with ALPS-FASLG and individuals with severe ALPS associated with biallelic FAS pathogenic variants, inheritance is autosomal recessive.

8.

Autosomal dominant inheritance of STXBP2-related fHLH has been suggested by rare reports of symptomatic individuals with heterozygous gain-of-function variants.

From: X-Linked Lymphoproliferative Disease

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