LAUSR

To the Editor: Immunodeficiency, centromeric instability, facial anomalies syndrome (ICF) is a rare autosomal recessive disorder and is one of the few heritable human diseases caused by mutations in a DNA methyltransferase [1]. The majority of patients with ICF syndrome have a defect in either the DNMT3B or ZBTB24 gene, classified as ICF1 and ICF2, respectively [2]. DNMT3B, in conjunction with DNMT3A and the catalytically inactive stimulatory factor DNMT3L, is responsible for de novo DNA methylation during embryogenesis and early development [3]. DNMT3A and DNMT3B are responsible for methylating unique genomic targets, with DNMT3B being solely responsible for methylating cytosine residues of CpG dinucleotides in highly repetitive satellite 2 and 3 DNA of pericentromeric heterochromatin [3]. Patients with biallelic pathogenic variants in DNMT3B show hypomethylation and characteristic aberrations of the pericentromeric regions of chromosomes 1, 9, and 16 in mitogen-stimulated lymphocytes. The most common clinical observations in ICF1 syndrome are hypogammaglobulinemia, intrinsic T cell defects leading to increased risk of opportunistic infections, neurologic abnormalities, and characteristic facial features including epicanthal folds, hypertelorism, flattened nasal bridge, low set ears, micrognathia, and macroglossia. Many patients with ICF1 die by early adulthood due to infectious diseases [2]. Here we describe a 14-month-old Caucasian female born full term to nonconsanguineous parents with no facial dysmorphism. She was well until 3 months of age when she began having increased work of breathing and failure to thrive with diarrhea. At 4 months, she developed rhinovirus and enterovirus infection necessitating hospitalization in the intensive care unit. At 5 months of age, she developed enteroviral meningitis, prompting an immune evaluation that demonstrated agammaglobulinemia with normal numbers of total T and B cells (Supplemental Table I). She was successfully treated with high-dose immune globulin and the investigational antiviral drug pocapavir, after which she was continued on immune globulin replacement. However, she continued to have unexplained diarrhea, and at 6 months of age developed Pneumocystis jiroveci pneumonia. She was successfully treated and maintained thereafter on trimethoprimsulfamethoxazole prophylaxis. Although she did not develop any additional serious infections, she continued to have diarrhea, poor feeding, and poor weight gain, resulting in gastrostomy tube placement at 7 months. In addition, she experienced a developmental delay in her milestones most notably unable to walk any steps by 14 months or say any words. Genetic testing revealed two heterozygous missense variants which were reported as variants of uncertain clinical significance in the DNMT3B gene (NM_006892.3), c.2177T>G and c.2281G>C, in this patient. Parental studies confirmed they are in the compound heterozygous state (i.e., in trans). The first missense variant (c.2177T>G) occurs in exon 20 and results in a substitution of glycine for valine at codon 726 Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10875-019-00704-6) contains supplementary material, which is available to authorized users.