Table 5.

X-Linked Proliferative Disease: Recommended Evaluations Following Initial Diagnosis 1

System/ConcernEvaluationComment
Gastroenterology
/Hepatology 		Physical exam to assess for hepatosplenomegaly
  • Consider liver imaging if there is hepatomegaly w/abnormal serum transaminases or bilirubin.
  • Consider MR cholangiopancreatography if there is concern for cholangitis in those w/XLP2 (XIAP-related XLP) & colitis. 2
Serum transaminases, bilirubin, triglycerides, lactate dehydrogenase, prothrombin time, PTT, fibrinogenTo assess for liver dysfunction/failure & coagulopathy
Serum triglyceride levelsTo evaluate for HLH
Assess for signs & symptoms of colitis & cholangitis (rare) 2In persons w/XLP2; consider referral to gastroenterologist.
Hematology / Spleen / Lymph nodes / Oncology Physical exam to assess for hepatosplenomegaly & lymphadenopathy
  • Splenomegaly can be seen in setting of HLH or incomplete HLH (fever & cytopenias only).
  • Splenomegaly & lymphadenopathy should prompt further investigation for lymphoma in those w/XLP1 (SH2D1A-related XLP).
  • In persons w/XLP2, transient splenomegaly can be seen after vaccinations.
CBC, lactate dehydrogenase, uric acidTo assess for anemia, thrombocytopenia, neutropenia, & ↑ cell turnover
Consider bone marrow biopsy in those w/cytopenias.To assess for bone marrow dysfunction/failure (such as aplastic anemia) & evidence of hemophagocytosis &/or malignancy
Assess for signs & symptoms of lymphoma.In those w/XLP1
Immunologic Lymphocyte subset analysis (T cell, B cell, NK cell) & serum concentrations of IgG, IgM, & IgATo assess immune function & for evidence of dysgammaglobulinemia
Measurement of serum concentrations of ferritin, soluble IL2RA, & other cytokines if concerns for HLHTo evaluate for evidence & severity of inflammation
Infection Assessment of previous infectious disease history
  • To evaluate for history of recurrent bacterial infections to aid in decisions for Ig replacement therapy, if needed
  • To evaluate for history of previous viral infections, such as EBV
  • Identification of possible active infections (esp viral infection or reactivation such as EBV, CMV, HSV, adenovirus, HHV6) that would require specific treatment
  • Eval of infection status of EBV & other infections 3
To determine active viral infection, viral blood PCR is recommended.
Neurologic Neurologic eval to assess for presence of infection, inflammation, vasculitis, CNS HLH, &/or CNS lymphoma
  • If abnormal neurologic exam or symptoms: evaluate CSF cell count w/differential, glucose, protein, culture (& meningitis PCR panel if available), & cytology. Consider CNS imaging w/MRI of brain w/ & w/o contrast (± MR angiography if concern for vasculitis).
  • Elevation of CSF mononuclear cells, often w/assoc elevation of protein, is sufficient to determine CNS involvement of HLH w/o need to demonstrate hemophagocytosis.
  • CNS lymphoma & vasculitis can be seen in persons w/XLP1.
Respiratory Assess for cough, shortness of breath, & signs/symptoms of pulmonary hemorrhage.To screen for possible lymphoid granulomatosis in those w/XLP1.
Genetic counseling By genetics professionals 4To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of XLP to facilitate medical & personal decision making
Family support
& resources 		By clinicians, wider care team, & family support organizationsAssessment of family & social structure to determine need for:

CBC = complete blood count; CMV = cytomegalovirus; CNS = central nervous system; CSF = cerebrospinal fluid; EBV = Epstein-Barr virus; FIM = fulminant infectious mononucleosis; HLH = hemophagocytic lymphohistiocytosis; HHV6 = human herpes virus 6; HSV = herpes simplex virus; Ig = immunoglobulin; IL2RA = interleukin-2 receptor alpha; MOI = mode of inheritance; MR = magnetic resonance; PCR = polymerase chain reaction; PTT = partial thromboplastin time; XLP = X-linked lymphoproliferative disease

1.

Unless otherwise specified, all recommendations listed in this table pertain to individuals diagnosed with either XLP1 or XLP2.

2.

Those with XLP1 generally do not develop cholitis.

3.

Consider evaluation of CMV, HSV, varicella, hepatitis B virus, and hepatitis C virus infection status.

4.

Medical geneticist, certified genetic counselor, certified advanced genetic nurse

From: X-Linked Lymphoproliferative Disease

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