Hematopoietic Stem Cell Transplantation in an Infant with Immunodeficiency, Centromeric Instability, and Facial Anomaly Syndrome

Abstract

Immunodeficiency, centromeric instability, and facial anomaly (ICF) syndrome is a rare autosomal recessive genetic condition with severe immunodeficiency, which leads to lethal infections if not recognized and treated in early childhood. Up-to-date treatment regimens consist of prophylactic and supportive treatment of the recurrent infections. Here, we report the case of a 1-year-old boy of Moroccan consanguineous parents, who was diagnosed at 4 months of age with ICF syndrome with a homozygous missense mutation in the DNMT3B gene. He was initially admitted to the hospital with recurrent pulmonary infections from the opportunistic pathogen Pneumocystis jirovecii (PJ). Further immunological workup revealed agammaglobulinemia in the presence of B cells. After successful recovery from the PJ pneumonia, he underwent hematopoietic stem cell transplantation (HSCT) from the HLA-matched healthy sister using a chemotherapeutic conditioning regimen consisting of treosulfan, fludarabine, and thiotepa. Other than acute chemotherapy-associated side effects, no serious adverse events occurred. Six months after HSCT immune-reconstitution, he had a stable chimerism with 2.9% autologous portion in the peripheral blood and a normal differential blood cell count, including all immunoglobulin subtypes. This is one of the first cases of successful HSCT in ICF syndrome. Early diagnosis and subsequent HSCT can prevent severe opportunistic infections and cure the immunodeficiency. Centromeric instability and facial anomaly remain unaffected. Although the long-term patient outcome and the neurological development remain to be seen, this curative therapy for immunodeficiency improves life expectancy and quality of life. This case is meant to raise physicians awareness for ICF syndrome and highlight the consideration for HSCT in ICF syndrome early on.

Epigenetic Regulation of Genomic Stability by Vitamin C

“…(C) DNA hypermethylation is associated with: aberrant silencing of tumor suppressors from increased DNMT activity or loss of TET function; an increased frequency of C > T transitions due to enhanced mutagenicity and deamination of 5mC; loss of CTCF/cohesin binding leading to gene mis-regulation; and telomere shortening and altered sister chromatid cohesion. upregulated gene expression at these loci, chromosome breaks, and rearrangements in radial structures that are detectable in stimulated lymphocytes and increase the risk of hematological malignancies (Brown et al, 1995;Kaya et al, 2011;Gossling et al, 2017).…”

“…ICF is a rare disease showing symptoms in early childhood of recurrent gastrointestinal and pulmonary infections as a result of agammaglobulinemia ( Ehrlich et al, 2008 ; Hagleitner et al, 2008 ). ICF patients display evident decondensation of heterochromatin caused by DNA hypomethylation at pericentromeric regions in chromosomes 1, 9, and 16, causing upregulated gene expression at these loci, chromosome breaks, and rearrangements in radial structures that are detectable in stimulated lymphocytes and increase the risk of hematological malignancies ( Brown et al, 1995 ; Kaya et al, 2011 ; Gossling et al, 2017 ).…”

Chromatin Imbalance as the Vertex Between Fetal Valproate Syndrome and Chromatinopathies

“…FIGURE 1 | Facies of fetal valproate spectrum disorders (FVSD) and related overlapping chromatinopathies. Distinctive facial phenotypes of patients affected by FVSD (Schorry et al, 2005), KLEFS (Willemsen et al, 2012), KS (Makrythanasis et al, 2013), CHARGE (Hefner and Fassi, 2017), MRD1 (Talkowski et al, 2011), ARTHS (Kennedy et al, 2019), and ICF1 (Gössling et al, 2017).…”

Immune Reconstitution after Hematopoietic Stem Cell Transplantation in Immunodeficiency–Centromeric Instability–Facial Anomalies Syndrome Type 1

“…Treatment for the immunologic manifestations of ICF1 includes early immunoglobulin replacement and prophylaxis for opportunistic organisms; however, recurrent infections frequently lead to shortened lifespan, with affected patients rarely surviving beyond the second decade [4]. The only curative option for the immunodeficiency associated with ICF1 is hematopoietic cell transplant (HCT), which has been reported in less than 10 cases of ICF1 worldwide [3,[6][7][8]. All previously reported patients seemingly had successful correction of their hypogammaglobulinemia and reported full donor chimerism following either myeloablative or reduced intensity conditioning (RIC); however, data regarding long-term follow up after transplant is limited.…”

“…There are very few reports of HCT for ICF1 in the literature. Five cases from Europe have reported HCT for patients with DNMT3B mutations using either RIC (three patients) or fully myeloablative conditioning (two patients), all of whom had immune reconstitution, and were able to discontinue immunoglobulin replacement [3,6,8]. Additional reports of transplant for ICF in the literature for unclear subtype include: two patients with ICFX (now classified as ICF3 or ICF4), one patient for unspecified ICF [12] and a patient transplanted for MDS with a history of ICF [1].…”