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LOSS OF HOXA3 CAUSES LARYNGEAL DYSMORPHIA, THYMIC APLASIA AND SEVERE COMBINED IMMUNODEFICIENCY (SCID)
Abstract
Background and Aims
Severe combined immunodeficiency (SCID) is due to genetic defects intrinsic to hematopoietic cells, or, less frequently, impaired thymic epithelium. Human thymic aplasia is reported for mutations in TBX1, TBX2, FOXI3, CHD7, FOXN1 or PAX1. For the first time, we present a case of complete HOXA3 deficiency and thymus aplasia. Homebox (HOX) genes pattern the embryonic anterior–posterior axis.
Methods
Disease phenotype and immunological characteristics were captured. Whole-exome and Sanger sequencing and segregation analysis were conducted.
Results
Thymic aplasia, laryngopharyngeal dysmorphia, resulting in dysphagia and apnoea, and dysmorphia of face, neck and ears characterize the disease. The immunological phenotype fulfills criteria of SCID (CD3+ T cells 10/μl, naive CD4+RA+CCR7+ T cells 4%, γ/δ+ T cells 20%, and absent lymphocyte transformation upon stimulation with PHA, all data from 5th day post natum). Levels of NK cells were normal. Humoral immunity was characterized by normal absolute B cells, and a hyper IgM phenotype (IgG 8.5 g/l, IgA < 0,1 g/l and IgM 0.45 g/l and 0,29 g/l after one month). Sequencing showed a biallelic nonsense mutation. The disorder is autosomal recessive.
Conclusions
Complete HOXA3-deficiency is the seventh genetic and third autosomal recessive immunodeficiency with thymus aplasia in humans. Derivatives of several pharyngeal arches and pouches are impaired, suggesting that the role of HOXA3 in embryogenesis is not restricted to the third pharyngeal arch, where the thymus originates. Compared to other conditions with thymic aplasia, our findings suggest that HOXA3 is downstream to TBX1, CHD7 and FOXI3 and upstream to FOXN1 in human thymus organogenesis.