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Background: Autoimmune thyroid diseases (AITD) tend to occur in a polyautoimmune context, the presence of more than one autoimmune disease in the same patient. The etiology of (poly)autoimmunity (PAI) is thought to be a complex interaction between multiple genetic variants, each frequent and of little effect, but relevant in conjunction with certain environmental factors. Monogenetic variants causing PAI have been identified as well, yet only in the context of primary immunodeficiencies. Objective: In this paper, we evaluate whether a single highly penetrant genetic variant in patients with AITD would be responsible for their PAI. Method: We used data of a cohort of patients with multiple autoimmune diseases (n=500) collected in the context of a doctoral thesis at KU Leuven. Patients with AITD and two or more autoimmune diseases were characterized by gene sequencing and immunological testing with T cell receptor excision circles (TREC) and Kappa-deleting recombination excision circles (KREC) as screening tools. The patients were also checked among others for familial history and organ-specific autoantibodies. We selected those patients with candidate variants and collected additional interesting laboratory results. Results: Six out of 500 patients showed AITD with two or more autoimmune diseases. Sequencing confirmed two candidate variants in two different patients. One patient showed a heterozygous mutation p.R471C in the autoimmune regulator (AIRE) gene with elevated TREC and normal KREC. The other had a p.P41A mutation in GATA2 with normal TREC, absent KREC, slightly elevated Fms-like tyrosine kinase 3 ligand and a mild hypogammaglobulinemia. Family history for autoimmune diseases as well as autoantibodies against type I interferon were negative in both cases. Conclusion: With this paper, we could not prove the association of p.R471C in AIRE and p.P41A in GATA2 to be a causal factor of PAI in the context of AITD. P.R471C in AIRE is a low-frequency variant with a strong intermediate effect and p.P41A in GATA2 is a common variant of which the effect size is still unknown. Our patients fit the concept of AITD with PAI to be a complex disease with multiple genetic risk factors rather than a Mendelian inherited monogenic disorder. Larger population-based studies investigating the role of genome sequencing in patients with undiagnosed rare diseases are required to reveal knew monogenetic-phenotypical associations.

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Background: The thyroid gland is a common unintended target during and after cancer treatment in childhood cancer survivors. However, only a limited number of studies has assessed the thyroid adverse events of newer and more selective anticancer drugs. The main objective of this review was to conduct a literature overview of thyroid disorders in children, treated with 131 I-metaiodobenzylguanidine (131 I-MIBG), tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs), and to provide practical guidance. Methods: We performed a systematic review using Medline, Embase, Cochrane and clinicaltrials.org by means of the PRISMA guidelines. Fifty-four studies were included, of which only three clinical trials describing the effect of TKIs and ICIs on the pediatric thyroid. Results: Overall, hypothyroidism was the most frequent thyroid disorder with an incidence ranging from 35 to 81% for 131 I-MIBG. Thyrotoxicosis was usually a transient phase of thyroiditis, related to TKIs and ICIs. ICI-treated children were more sensitive for central hypothyroidism and 131 I-MIBG was associated with highest incidences of thyroid nodules. In general, time of onset was longer for 131 I-MIBG (years) compared with TKIs and ICIs (weeks to months). Conclusion: Despite the limited data, thyroid disorders appear to occur frequently in childhood cancer survivors treated with 131 I-MIBG, TKIs or ICIs. Strict follow-up with lifelong surveillance is therefore recommended. However, further research is essential to analyze long-term thyroid effects of 131 I-MIBG and thyroid sequelae related to TKIs and ICIs in children.

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Inleiding Schildklierhormonen spelen een belangrijke rol in de regulatie van vele biologische processen. Een toenemend aantal studies heeft zich gericht op impact van een gestoorde schildklierfunctie op de gonadale as en de daarmee gepaarde seksuele disfuncties. Echter ontbreekt er nog veel kennis omtrent de interactie tussen het schildkliermetabolisme en de gonadale as, inclusief bindingseiwitten zoals SHBG, oestradiol en de gonadotrofines alsook prolactine. Methode Onze studie had als doel verder te onderzoeken op welk niveau hyper- en hypothyreoïdie interfereren met de gonadale as, inclusief bindingseiwitten zoals SHBG, oestradiol en de gonadotrofines alsook prolactine door een prospectieve klinische cohort studie uit te voeren. De korte termijn veranderingen in de hypothalamus-hypofyse-gonadale as (HPG-as) bij hyper- en hypothyreoïde mannen voor en na behandeling werden geanalyseerd. Bloedstalen werden afgenomen bij aanvang (visite 1) en op de vervolgafspraak (visite 2). Voor de statistische analyse werden gepaarde t-testen of Wilcoxon matched-pairs signed rank toetsen uitgevoerd. Resultaten Achttien patiënten met hyperthyreoïdie en 13 patiënten met hypothyreoïdie werden geïncludeerd. De mediane opvolgduur bij hyperthyreoïdie was 1.27 maanden [bereik 0.66- 11.96] en bij hypothyreoïdie 3.66 maanden [bereik 1.56- 5.76]. Bij de hyperthyreoïde groep waren totaal testosteron (p = 0.0063) en sekshormoonbindend globuline (SHBG) (p = 0.0006) significant hoger voor behandeling. Er was geen goede correlatie tussen wijziging in thyroxine (T4) (totaal of vrij) en wijziging in testosteron (T) (totaal of vrij) bij de hyperthyreoïde groep. Bij de hypothyreoïde groep was SHBG (p = 0.0014) significant lager voor behandeling. In deze groep zag men ook een significante wijziging van luteïniserend hormoon (LH) (p = 0.0293) en follikelstimulerend hormoon (FSH) (p = 0.0020). In de hypothyreoïde groep was er een goede correlatie tussen wijziging in totaal thyroxine (ΔTT4) en wijziging in T (totaal of vrij) (respectievelijk 0.8571, 0.8214). Discussie De verhoogde schildklierhormonen bij hyperthyreoïdie leiden tot hogere concentraties van SHBG, wat op zijn beurt de balans van geslachtshormonen kan beïnvloeden. Zo bleek uit deze prospectieve klinische cohort studie dat totaal testosteron significant gestegen was bij hyperthyreoïdie, terwijl men geen wijzigingen zag bij vrij T en E2. Het omgekeerde werd gezien bij hypothyreoïdie. Het grootste effect situeert zich dus op niveau van SHBG. Echter, grotere langetermijn studies zijn nodig om de precieze mechanismen en klinische implicaties van de relatie tussen een gestoorde HPT-as en de gonadale as verder te begrijpen.