LAUSR

To the Editor: Phosphoglucomutase 3 (PGM3) is an enzyme converting Nacetyl-glucosamine-6-phosphate to N-acetylglucosamine-1phosphate, a sugar nucleotide critical for glycosylation pathways. PGM3 defects have been reported in 41 patients of 16 families with immunodeficiency [1–8]. Mutations in PGM3 were first reported in 17 patients with hyper-IgE syndrome (HIES) [1, 2]. Subsequently, patients with PGM3 mutations were found to have varying degrees of immunological abnormalities including T-B-severe combined immunodeficiency [4–6], diminished T cell function with high immunoglobulins including IgE [7, 8], and normal IgE with mild immunodeficiency [3]. Herein, we report the clinical course and detailed laboratory investigations of a Thai patient carrying novel mutations in PGM3. The boy was born at term to non-consanguineous Thai parents. He was the second child, and his older brother was healthy. His parents were both healthy with no histories of immunodeficiency or infantile death in their families. The patient presented with severe atopic dermatitis at the age of 2 months. During infancy, he had chronic diarrhea, recurrent otitis media, recurrent pneumonia, salmonella and candida septicemia, a severe varicella infection, and multiple food allergies. At the age of 2 years, he was referred to our hospital for further immunological evaluation. Investigations revealed increased IgE (13,877 IU/mL; normal range 2–97 IU/mL) and IgG (1320 mg/dL; normal range 453–916 mg/dL) but normal IgA (30 mg/dL; normal range 20–100 mg/dL) and IgM (50 mg/dL; normal range 19–146 mg/dL) levels. Lymphocyte phenotype showed low CD3 (730 cells/μL; normal range 2100–6200 cells/μL), CD4 (300 cells/μL; normal range 1300–3400 cells/μL), CD8 (430 cells/μL; normal range 620–2000 cells/μL), and CD4:CD8 ratio (0.69), with very low CD 19/20 (30 cells/μL; normal range 720–2600 cells/μL). PHA lymphocyte proliferation testing was within the normal range. He had protective tetanus antibody titers but inadequate responses to the 23-valent pneumococcal polysaccharide vaccine. The patient underwent molecular testing using Sanger sequencing of STAT3, DOCK8, and TYK2, which showed no pathogenic variants. Therefore, exome sequencing (ES) of the boy and his parents was performed. The Agilent SureSelect Human All Exon kits version 4 were used for exon capturing, exome enrichment, and library preparation followed by sequencing of the post-captured libraries on the Illumina HiSeq 4000 Sequencer. Filtering criteria for candidate variants include the allele frequencies of less than 1% in our 2166 inhouse Thai exomes, The Genome Aggregation Database (gnomAD, https://gnomad.broadinstitute.org) and 1000G databases. Prediction software including SIFT, Polyphen, and MCAP was used [9]. Trio ES revealed that the patient was compound heterozygous for the novel c.1003A>G (p.Thr335Ala) missense in exon 8 and c.1443delC (p.Asn482Metfs*4) frameshift mutations in exon 12 (NM_015599.2). Both mutations were Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10875-019-00693-6) contains supplementary material, which is available to authorized users.