Age: 14.0
Sex: M
Vaccine: PPV
Symptoms: Clostridium test negative, Cytogenetic analysis normal, Death, Haematocrit normal, Immunoglobulin therapy
Clinical narrative: Information has been received from the authors in a published letter to the editor, regarding a 14 year old male patient who did not respond to repeated vaccinations of PNEUMOVAX and PREVNAR. The patient presented at 3 years of age with recurrent otitis media and sinusitis. He had normal lymphocyte and monocyte counts, platelet numbers, and hematocrit levels. He had IgG2 and IgA deficiency and absent tetanus and low PRP (52 ng/mL) antibody titers. Tetanus and Haemophilus influenzae type b (Hib) vaccine boosters resulted in protective tetanus (0.4 IU/mL) and PRP (>1200 ng/mL) titers. Two years later, his tetanus titer was undetectable, his polyribosylribitol phosphate (PRP) titer decreased to 1S5 ng/mL, and his IgG level was decreased at 444 mg/dL, prompting intravenous immunoglobulin (IVIG) initiation. At 10 years of age, IVIG was discontinued to reassess his antibody response. His tetanus titer increased from 0.14 to 0.27 IU/mL after a booster but waned within 1 year to 0.03 IU/mL. At 14 years of age, his PRP titer increased significantly after the Hib vaccine, but he did not respond to repeated vaccinations of PNEUMOVAX and PREVNAR; additionally, his IgG level was low, and his IgA level was undetectable. He had pneumonia and pansinusitis in the setting of absent B cells and CD4+ T-cell lymphopenia, and therefore IVIG was restarted. He had absent tonsils, which had been barely visible on previous examinations. No mutations were found in the TACJ, PNP, ADA, BTK, or SH2DJA genes. At 16 years of age, he had persistent warts on his hands and severe bronchiectasis. Sputum cultures were positive for Mycobacterium kansasii. Lymphocyte proliferation to mitogens and antigens was normal, but NK cell, monocyte, and platelet counts were low. Progressive respiratory decline led to his death at 22 years of age. Whole-exome sequencing on both patients identified a heterozygous mutation in GATA2 (c. C1061T) that was confirmed by means of Sanger sequencing. The mutation results in amino acid change from threonine to methionine at position 354 (T354M) in the second zinc finger domain9 and is predicted to be damaging to protein function by using both the PolyPhen (score 0.997) and SIFT (score 0) tools. The T354M mutation does not affect GATA2 expression or nuclear localization, but significantly impairs GATA2 binding to DNA and to the transcription factor PU.l, resulting in a dominant negative effect on transcriptional activation. The phenotypes associated with the T354M mutation autosomal dominant MDS/acute myeloid leukemia, MDS with pancytopenia, multilineage cytopenias, and opportunistic infections. One patient with this mutation had 1 episode of parainfluenza and Mycoplasma infection with normal immunoglobulin levels, another had pneumonias limited to childhood, and 3 others had mycobacterial and viral infections. Four subjects were healthy into adulthood. The patient presented with IgG2 and IgA deficiencies and an abnormal vaccine response, which has not been previously reported in patients with GATA2 mutations. No additional mutations were found through whole-exome sequencing that would account for the hypogammaglobulinemia seen in both patients. This report highlighted the importance of considering mutations in GATA2 in patients with hypogammaglobulinemia, particularly in the setting of abnormal lymphocyte subsets and monocyte counts. Additional information has been requested.