Recurrent bacterial infections, mendelian susceptibility to mycobacterial diseases (MSMD), and pancytopenia in adolescent cousins reveal family segregation of new heterozygous deleted variant in GATA2

Introduction: GATA2 deficiency is an inborn error of immunity (IEI) resulting from autosomal dominant (AD) heterozygous germline variants with various degrees of haploinsufficiency. Clinical manifestations include familial myelodysplastic syndrome (MDS), leukemias, monocytopenia and infectious diseases including mycobacterial infections and papillomavirus, among others.
Presentation of cases: The index case is a 13-year-old female patient born from apparently non-consanguineous parents, with a history of recurrent invasive infections from an early age. She was hospitalized at age 11 for MDS and prolonged febrile syndrome, associated with bacteremia (S. marcescens) and diarrhea (C. difficile). She developed organomegaly and retroperitoneal adenomegaly due to M. abscessus. Bone marrow (BM) aspirates revealed excess blasts, and the karyotype revealed monosomy of chr 7 and other cytogenetic abnormalities. Chemotherapy was initiated to induce pre-transplant remission. In the meantime, Whole exome sequencing (WES) from gDNA revealed a novel heterozygous variant in exon 4 in GATA2 (p.Glu294SerfsTer32), classified as probably pathogenic. The patient was successfully transplanted, and complete hematologic recovery was confirmed 7 months later. The history of infectious episodes in other members of the maternal family led to investigate for other affected individuals. In the meantime, a previously healthy 12-year-old male cousin consulted to a local hospital for cough and fever that rapidly progressed to respiratory distress syndrome with hypoxemia. He was diagnosed with multilobar SARS-CoV2 pneumonia, and pancytopenia became evident, and the BM aspirate confirmed MDS. The family history of MDS in her cousin strongly suggested segregation of the variant in the family. Sanger sequencing in several individuals is in progress.
Discussion: GATA2 deficiency should be considered in patients with mycobacterial infections and/or other GATA2 deficiency-related phenotypes at any age in life, and relatives should be genotyped at the GATA2 locus.

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