This case report characterizes the first human patient with autosomal recessive HOXA3 deficiency, evaluating its clinical, immunological, and molecular phenotype, including response to thymus transplantation.
A homozygous nonsense variant in HOXA3 produced a truncated protein with cytoplasmic retention and reduced transcriptional activity, causing thymus aplasia (congenital athymia), severe laryngopharyngeal malformation with epiglottic hypoplasia, craniofacial/cervical anomalies, and central breathing disorder; T-cell maturation was restored after thymus transplantation, confirming a non-hematopoietic defect.
Single patient (n=1) limits generalizability; human HOXA3 phenotype differs from murine Hoxa3 (parathyroid and thyroid glands appear unaffected in this patient, unlike in mice), suggesting possible species-specific redundancy that is not yet fully understood.
HOXA3 should be added to genetic panels for patients with a SCID phenotype, especially when epiglottic hypoplasia or laryngeal malformation is present as a co-morbidity; thymus transplantation is a viable, life-saving intervention for this condition.
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