D1.329 - Late-Childhood Diagnosis of DNA Methyltransferase 3B Deficiency-ICF1 Syndrome

INTRODUCTION: Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is an autosomal recessive combined immunodeficiency. Here, we aimed to present the clinical and immunological features of a boy with a homozygous DNMT3B variant.

CASE: An eleven-year-old male patient, born of consanguineous parents, was referred to our clinic with a productive cough persisting for two months. His medical history revealed recurrent pneumonia since three months of age, surgery for osteomyelitis following a left leg fracture at six months of age, and a history of anal abscess at nine months of age. His sibling died of pneumonia at 1.5 years of age. He had hypertelorism, a broad and flat nasal bridge, low-set ears, retrognathia, and a flat, coarse facial appearance. Diffuse crackles were noted. Laboratory evaluation showed a normal complete blood count and selective IgA deficiency (IgG:920 mg/dL(642–2290), IgA:<6.28 mg/dL(32.6–262), IgM:10.2 mg/dL(37.4–213), and IgE:<17.5 IU/mL). There was no response to tetanus vaccination and isohemagglutinin titers were negative. Peripheral lymphocyte subset analysis showed normal percentages and absolute counts of T, B, and NK cells, as well as normal naive T-cell and recent thymic emigrant numbers. Total memory B cells and class-switched memory B cells were markedly reduced. Whole-exome sequencing revealed a homozygous DNMT3B variant, c.1936A>T(p.Ile646Phe) and the presence of centromeric instability in this patient supported its consistency with ICF syndrome spectrum.

CONCLUSION: This case highlights that ICF1 syndrome associated with DNMT3B variants may present with subtle findings in early childhood and should be considered in patients with treatment-refractory clinical findings.