ESPE Abstracts (2022) 95 P1-201

ESPE2022 Poster Category 1 Adrenals and HPA Axis (52 abstracts)

Gene Chimeras Involving CYP21A2 and TNXB Genes in Spanish Patients with Congenital Adrenal Hyperplasia (CAH)

Laura Martínez Figueras 1,2 , Arancha Escribano Muñoz 3 , Atilano Carcavilla 4 , Laura Berthold 5 , Elena Llorente Martín 6 , María Arriba Domènech 6,7 & Begoña Ezquieta Zubicaray 6,7

1Laboratorio Diagnóstico Molecular. Bioquímica. Hospital General Universitario Gregorio Marañón, Madrid, Spain; 2Instituto Investigación Sanitaria Gregorio Marañón, Madrid, Spain; 3Endocrinología Pediátrica. Hospital Virgen de la Arrixaca (HVA), Murcia, Spain; 4Endocrinología Pediátrica. Hospital Universitario La Paz (HLP), Madrid, Spain; 5Endocrinología Pediátrica. Hospital Universitario Marqués de Valdecilla (HMV), Santander, Spain; 6Laboratorio Diagnóstico Molecular. Bioquímica. Hospital General Universitario Gregorio Marañón., Madrid, Spain; 7Instituto Investigación Sanitaria Gregorio Marañón., Madrid, Spain

Background-Aim: Gene rearrangements between CYP21A2, TNXB and their homologous pseudogenes (CYP21A1P,TNXA) result in chimeric genes, responsible for the CAHX syndrome. CAHX patients show CAH and Ehlers-Danlos syndrome (EDS) symptoms. Three CAHX chimeras with different clinical severity are described: CH1 (including 120bp deletion in exon 35), CH2 and CH3. The small size and few series reported so far warrant further studies in other populations.

Aim: To learn about the number of CAH Spanish patients at risk of having CAHX chimeras, their distribution, and clinical manifestations in three tertiary hospitals.

Methods: Molecular analysis: 1. CYP21A2 chimeras junction-site determination: intra or downstream to the gene 2. Multiplex Ligation Probe Amplification (MLPA) to detect CH1-chimeras 3. Heterodimers detection after TNXB (ex34-ex37)-PCR and electrophoresis to detect CH1 in retrospective samples 4. Sequencing of TNXB exons 40,41,43 for CH2, CH3-chimeras Medical history review and clinical evaluation were performed in 20 patients.

Results: CAH patients carrying alleles “at risk” of CAHX chimeras Among the 4284 CAH patients (classical, nonclassical and hyperandrogenism) analyzed in our laboratory since 1995, 404 were carrying, at least, one CYP21A2 deletion allele. In 185, junction-site was located before CYP21A2-exon 6. In 219 (54.2%) deletion extended downstream and may involve TNXB. MLPA performed in 114 patients revealed 27 (23.7%) CH1-chimeras. Heterodimers detection approach performed in 36 samples detected four CH1-chimeras. Sequencing of TNXB exons detected 20 CH2 and five CH3-chimeras. - CAHX chimeras distribution and clinical evaluation HVA (6/6): Intragenic CYP21A2 chimeras were more frequent (71%, P<0.05) in this area. Only one CH2 patient with no clinical symptoms was detected. HLP (7/10 revised): CAHX chimeras were detected in four patients (2 CH1 and 2 CH2). A CH2 patient showed EDS-related clinical symptoms without hypermobility (Beighton score:2/9). One patient with EDS manifestations was negative. HMV (7/7): five chimeras were detected. Three patients carried CH1 (two with clinical signs -luxations and cronic artralgy-) and two carried CH2, one with EDS signs, the other with Perthes disease.

Conclusions: CAHX chimeras distribution is different in our population (CH1: 21.8% vs 39%, CH2: 15% vs 32%, CH3: 3.8% vs 1.5%). A not homogeneous geographic distribution was observed, as well (1.8%, 7.4% and 9.3% in different areas). As a dominant disease CAHX should be also considered in carriers and nonclassical forms. MLPA, first approach allowing the systematic search of CAHX chimeras, only detects CH1. TNXB sequencing must be performed to discard CAHX. A heterodimer approach to detect CH1 chimeras was useful to investigate retrspective DNA samples.

Volume 95

60th Annual ESPE (ESPE 2022)

Rome, Italy
15 Sep 2022 - 17 Sep 2022

European Society for Paediatric Endocrinology 

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