Hematopoietic Stem Cell Transplantation in a Patient With ICF2 Syndrome Presenting With EBV-Induced Hemophagocytic Lymphohystiocytosis

Expanding the mutation spectrum in ICF syndrome: Evidence for a gender bias in ICF2

“…With the identification of mutations in 12 ICF syndrome cases, a total of 77 genetically confirmed ICF patients have been reported . Fifty‐six percent of the ICF syndrome patients carry mutations in DNMT3B , 31% carry mutations in ZBTB24 , 6.5% carry mutations in CDCA7 , and 6.5% carry mutations in HELLS (Figure A).…”

“…Although humoral immunodeficiency is pronounced in patients with ICF syndrome, opportunistic infections observed in about 20% of the patients also suggest involvement of a T‐cell dysfunction . Currently, patients are most often treated by intravenous immunoglobulin therapy and few cases underwent successful hematopoietic stem cell transplantation . ICF syndrome patients present with a distinct but variable set of facial anomalies, including, but not limited to, hypertelorism, flat nasal bridge, and epicanthus …”

“…2 Currently, patients are most often treated by intravenous immunoglobulin therapy and few cases underwent successful hematopoietic stem cell transplantation. [1][2][3][4] ICF syndrome patients present with a distinct but variable set of facial anomalies, including, but not limited to, hypertelorism, flat nasal bridge, and epicanthus. 1,2 The cytogenetic hallmark of ICF syndrome is centromeric instability.…”

“…2,9 We and others have described mutations in the zinc finger and BTB (Broad-Complex, Tramtrack, and Bric a Brac) domain containing 24 (ZBTB24; ICF2) gene in some patients negative for mutations in DNMT3B. 2,4,[10][11][12][13][14] Most often, homozygous nonsense mutations were identified, which are predicted to lead to an absence of full-length protein in patients. In addition, a few ICF2 cases with homozygous or compound heterozygous missense mutations in ZBTB24 have been described.…”

“…With these new cases included, the total number of genetically confirmed ICF cases reported to date is 77 (including patient 2 from Franceschini et al 16 with ZBTB24 mutations [unpublished F. Licciardi]), of which 56% have mutations in DNMT3B, 31% have mutations in ZBTB24, and the remaining 13% have mutations in CDCA7 or HELLS. This study, combined with earlier mutation reports, 1,2,4,11,12,15,[17][18][19][20][21] also revealed a gender bias specific to the ICF2 population with 79% of all ICF2 patients being male. In summary, we expand the mutation spectrum for the 2 most common genetic causes of ICF, show that complete absence of the ZBTB24 locus is compatible with human life, and identify a gender bias in ICF2.…”