Welcome to the ESID 2022 Meeting Interactive Programme
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Introduction
FOXN1 Deficiency - An Expanding Phenotype
APECED - Advances in Clinical Management
A Dose-Dependent Effect of AIRE Causes a Diverse Clinical Picture
LONG-TERM OUTCOMES AFTER THYMUS TRANSPLANTATION IN COMPLETE DIGEORGE SYNDROME
Abstract
Background and Aims
Congenital athymia is most frequently associated with complete DiGeorge Syndrome (cDGS). More than 100 cDGS patients have been treated by thymus transplantation (TT)1,2, including at Great Ormond Street Hospital (GOSH) which offers the only European TT programme, with overall survival of 75-80%. Post-TT, absolute T-cell counts, including naïve T-cells, remain suboptimal. Nevertheless, typically sufficient immune reconstitution is achieved for clearance of pre-existing and acquired infections, as well as discontinuation of antibiotic prophylaxis and immunoglobulin replacement treatment (IgRT). We report long-term outcomes post-TT, including long-term quality of T-cell immunity, which have not previously been described in detail.
Methods
We analysed clinical and laboratory outcomes for cDGS patients with more than 3 years follow-up post-TT.
Results
24 cDGS patients treated between 2009-2018 were included, with a median follow up time of 6.7 years to date (3.4-13.1). No late deaths occurred. At last follow-up, median T-cell counts (/μL) were: CD3+ 720, CD4+ 500, naïve CD4+ 110, CD4+ recent thymic emigrants 92, CD8+ 180, naïve CD8+ 60. Diverse T-cell receptor repertoires persist over time. 19 patients successfully discontinued IgRT and started/completed immunisations. Chronic autoimmunity is common post-TT, with 12 patients suffering autoimmune thyroiditis and 1 autoimmune haemolytic anaemia (AIHA). 2 patients remain on long-term immunomodulatory treatments for either AIHA or inflammatory disease. All bar one patients >5 years of age attend school.
Conclusions
After successful TT in cDGS, satisfactory T-cell immunity is maintained for at least several years facilitating an improved quality of life.
References: 1Markert et al 2022; 2Davies et al 2017.
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.