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Severe Combined Immunodeficiency (SCID) caused by thymic aplasia due to a mutation in TBX1

Severe Combined Immunodeficiency (SCID) caused by thymic aplasia due to a mutation in TBX1 content piece image
Complete thymic aplasia is a rare cause of SCID but increasingly recognized with SCID newborn screening. Tbox transcription factor 1 (TBX1) is important in thympoiesis; heterozygous mutation in TBX1 are a rare cause of velocardiofacial syndrome but not a common cause of complete thymic aplasia in humans.

Case Presentation:
A 10 day old term female with 0 TRECs on newborn screen was identified. Evaluation revealed severe T cell lymphopenia (CD3 XX cells/ul), normal B and NK cell populations, absent proliferation to PHA, and no thymus on CXR. Complete sensorineural deafness was present in the patient’s mother, maternal grandfather, and maternal great grandmother. A presumptive diagnosis of SCID was made and HSCT pursued. A 20 base pair heterozygous duplication was found in TBX1 c.1176_1195dup20; the same heterozygous mutation is suspected in the mother and maternal great grandmother. HSCT was abandoned and thymic transplantation pursued.

We report one of the first cases of TBX1 haploinsufficiency causing complete thymic aplasia and SCID. By case in this family, mutations in TBX1 have variable penetrance. The genetic diagnosis of this patient drastically changed management arguing that waiting on a genetic diagnosis in some presentations of SCID may be warranted.