LETTER TO EDITOR EBV-Related Hodgkin Lymphoma in an ICF2 Patient: Is EBV Susceptibility a Hallmark of This ICF Subtype? Francesco Licciardi 1 & Marlinde van den Boogaard 2 & Marta Delle Piane 1 & Pier Angelo Tovo 1 & Davide Montin 1 Received: 11 December 2018 / Accepted: 22 January 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 To the Editor, Immunodeficiency, centromeric region instability, and fa- cial anomalies syndrome (ICF) is a rare autosomal recessive disorder caused by defective DNA methylation. So far, ap- proximately 70 cases have been reported: 56% have mutations in DNMT3B (ICF1), 31% in ZBTB24 (ICF2), and the remain- ing 13% in CDCA7 (ICF3) or HELLS (ICF4) [1]. Regardless of ICF subtype, the main clinical manifestations are recurrent and severe infections due to the underlying im- munodeficiency, in particular T cell lymphocytopenia and/or hypo/agammaglobulinemia and facial abnormalities, such as epicanthus, low-set ears, hypertelorism, flat nasal bridge, telecanthus, and a round face. We describe the history of an ICF2 patient who had a chronic EBV infection and developed aggressive Hodgkin lymphoma (HL). The clinical history and the revision of liter- ature reveal that ICF2 patients have a predisposition to EBV infection with severe complications. Case Report The patient was born from Italian, non-consanguineous parents. At 7 years of age, he underwent immunological investigations because of recurrent stomatitis and bronchopneumonias (3/year). Laboratory tests revealed hypogammaglobulinemia (IgG 425 mg/dl, IgA 147 mg/dl, IgM 27 mg/dl) and T cell alterations (CD3 + 82%, CD4 + 34%, CD8 + 61%, CD19 + 5%) with normal lymphocyte count (2200/mm 3 ). He had mild facial abnormalities, including mild dolichocephaly, high forehead, hypertelorism/telecanthus, downslanting palpebral fissures, and cryptorchidism. Cytogenetic analy- sis showed peculiar centromeric alterations on chromo- somes 1, 9, and 16. Hence, the patient was diagnosed as affected by ICF syndrome [ 2 ]. Genetic testing for DNMT3B was negative, while recent ZBTB24 sequencing showed two heterozygous mutations: a nonsense mutation (c.909 dup, p. Lys304X) and a missense mutation in the BTB domain of ZBTB24 (c.175A > G, p.S59G). Regular intravenous immunoglobulin substitution therapy (400 mg/kg every 4 weeks) was started. At follow-up, no major infectious events were observed, but chronic sinusi- tis and rare upper respiratory tract infections successfully treated with antibiotic therapy. At 19 years of age during routine analyses, an increase in liver enzyme levels (AST 50–98 U/l; ALT 58–183 U/l; GGT 228–443 U/l) was noticed. Ultrasound elastography demon- strated a mild, progressive fibrosis. HCV-PCR, HbsAg, CMV- PCR, ANA, ASMA, anti-LKM, ANCA, anti-endomysial, and tissue transglutaminase antibodies were all negative. Screening for cryptosporidium in stools, 24-h urinary copper, urine PBG, and dALA were also negative. From then on, EBV-DNA was constantly detected in PBMCs ranging from 5808 to 9983 copies/ml. Given the persistence of biochemical signs of hepatitis, although without evidence of progression at 24 years of age, a hepatic biopsy (initially refused as well as any immunosuppressive therapy) was performed, demonstrat- ing a chronic cholangitis with marked portal inflammation and T lymphocyte infiltiration of biliary ductules. Multiplex/ heteroduplex PCR analysis of TCRγ revealed the monoclonal nature of T lymphocyte that was not found in peripheral blood. No significant clinical disturbances were reported until 27 years of age, when he developed persistent fever unrespon- sive to antibiotic therapy, weight loss, and asthenia. * Francesco Licciardi francesco.licciardi@gmail.com 1 Division of Pediatric Immunology and Rheumatology, Department of Public Health and Pediatrics, BRegina Margherita^ Children Hospital, University of Turin, P.zza Polonia 94, 10126 Turin, Italy 2 Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands Journal of Clinical Immunology https://doi.org/10.1007/s10875-019-00596-6