“A non-X-linked syndrome with susceptibility to
severe Epstein-Barr virus infection”
A new perspective 20 years later
The Children’s Hospital of Philadelphia,
University of Pennsylvania School of
Medicine, and The Ohio State University
David LaRosa, Aharon Freud, Raquel Deering,
Kim Nichols, Michael Caligiuri, and Jordan Orange
• 46 y/o man, fatigue.
• Previous PID diagnosis, well without follow-up.
• Recurrent otitis and sinusitis, childhood and adolescence.
• Severe infectious mononucleosis age 22: hepatitis, multi-lobar
pneumonia, 3 months to recover.
• Full spectrum of antibodies to EBV in expected titer ranges.
• More recently: chronic rhinosinusitis s/p FESS x 2, pneumonia x 1.
• Occasional cough mildly productive of yellow sputum.
– Sinus CT: chronic pan-sinusitis.
– High-resolution chest CT: no active disease.
– Spirometry normal.
– Quantitative Ig normal.
• Brother 1: recurrent otitis, sinusitis, pneumonia, bronchiectasis, multiple
– Immunologic studies normal: quIg, sIgA, lymphocyte proliferation, CH50, NBT,
– Infectious mononucleosis age 16: anemia, thrombocytopenia, pneumonia,
hepatitis, myocarditis, nephritis, encephalitis. Died day 26 from multi-organ
• Sister: recurrent pneumonia, bronchiectasis, multiple hospitalizations.
– Similar immunologic evaluation to Brother 1: unrevealing.
– Infectious mononucleosis age 17: multi-lobar pneumonia.
– Recovered after 3 months.
– Severe herpetic gingivostomatitis age 18. Age 25 cervix neoplasia and
– Died age 38 from pulmonary disease (advanced bronchiectasis).
• Brother 2: usual childhood infection history.
– Infectious mononucleosis age 21, usual course, uncomplicated.
DDx for severe EBV-associated illness
• Primary diseases known to result in EBV-associated
hemophagocytic syndrome (HPS):
– X-linked lymphoproliferative syndrome (XLP)
– Diseases associated with defective perforin expression:
• Familial erythrophagocytic lymphohistiocytosis (FELH).
• Hemophagocytic ly