{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T20:35:10Z","timestamp":1769632510178,"version":"3.49.0"},"reference-count":25,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T00:00:00Z","timestamp":1685491200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Congenital adrenal hyperplasia (CAH) owing to 21-hydroxylase deficiency (21-OHD) is a rare autosomal recessive disorder caused by pathological variants in the <jats:italic>CYP21A2<\/jats:italic> gene. After a high prevalence of classic 21-OHD CAH in the Romani population was reported in the Republic of North Macedonia, we decided to estimate the prevalence of 21-OHD in Croatia and, if high, assess the possible causes and estimate the frequency of particular <jats:italic>CYP21A2<\/jats:italic> variants.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design<\/jats:title><jats:p>Cross-sectional study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Data from a Croatian 21-OHD genetic database was reviewed, and only Romani patients were included in the study. <jats:italic>CYP21A2<\/jats:italic> genotyping was performed using allele-specific PCR, MLPA, and Sanger sequencing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>According to a survey conducted in 2017, Croatia had 22,500 Romani people and six of them had a salt-wasting (SW) form of 21-OHD. All were homozygous for the c.IVS2-13A\/C-G pathological variant in intron 2 and descended from consanguineous families belonging to different Romani tribes. The calculated prevalence of 21-OHD in Croatian Romani is 1:3,750, while in the Croatian general population, it is 1:18,000. Three of the six Romani patients originated from two neighboring villages in North-western Croatia (Slavonia County), as well as the seventh patient who is of mixed Romani\/Croatian descent and heterozygous for the c.IVS2-13A\/C-G pathological variant (not included in the prevalence calculation).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>A high prevalence of SW 21-OHD in the Croatian Romani population caused by the homozygous cIVS2-13A\/C-G pathological variant was found. In addition to isolation and consanguinity, other possible reasons could be the heterozygous advantage of the <jats:italic>CYP21A2<\/jats:italic> gene pathological variant and the bottleneck effect as a result of the Romani Holocaust in World War II.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2023.1170449","type":"journal-article","created":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T13:43:00Z","timestamp":1685540580000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["The prevalence and genotype of 21-hydroxylase deficiency in the Croatian Romani population"],"prefix":"10.3389","volume":"14","author":[{"given":"Katja K.","family":"Dumic","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zorana","family":"Grubic","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vesna","family":"Kusec","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Duje","family":"Braovac","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristina","family":"Gotovac","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maja","family":"Vinkovic","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maja","family":"Vucinic","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miroslav","family":"Dumic","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,5,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1210\/endrev\/bnab016","article-title":"Congenital adrenal hyperplasia-current insights in pathophysiology, diagnostics, and management","volume":"43","author":"Claahsen-van der Grinten","year":"2022","journal-title":"Endocr Rev"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1300057110","article-title":"Genotype-phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency","volume":"110","author":"New","year":"2013","journal-title":"Proc Natl Acad Sci USA."},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/s0022-5347(17)42164-1","article-title":"Worldwide experience in newborn screening for classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency","volume":"81","author":"Pang","year":"1988","journal-title":"Pediatrics"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1159\/000526401","article-title":"Ethnic and national differences in congenital adrenal hyperplasia incidence: a systematic review and meta-analysis","author":"Navarro-Zambrana","year":"2022","journal-title":"Horm Res Paediatr"},{"key":"B5","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1186\/1471-2350-2-5","article-title":"Genetic studies of the Roma (Gypsies): a review","volume":"2","author":"Kalaydjieva","year":"2001","journal-title":"BMC Med Genet"},{"key":"B6","article-title":"The Roma in Croatia: from migration to intercultural relations","volume":"20","author":"Hrvatic","year":"2004","journal-title":"J Migration Ethnic Themes"},{"key":"B7","first-page":"264 p","volume-title":"The gypsies during the second world war: final chapter","author":"Kenrick","year":"2006"},{"key":"B8","volume-title":"Census of population, households and dwellings 2011","year":"2013"},{"key":"B9","volume-title":"Roma Inclusion in the Croatian society: a baseline data study","author":"Kunac","year":"2018"},{"key":"B10","volume-title":"Roma Inclusion in the Croatian society: identity, social distance and the experience of discrimination","author":"Rasic","year":"2020"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3390\/ijns3030025","article-title":"The first results of extended newborn screening in Slovakia - differences between the majority and the Roma ethnic group","volume":"3","author":"Dluholucky","year":"2017","journal-title":"Int J Neonatal Screen"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1007\/s00431-003-1311-y","article-title":"Twenty years\u2019 experience in rapid identification of congenital adrenal hyperplasia in Hungary","volume":"162","author":"Torok","year":"2003","journal-title":"Eur J Pediatr"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1007\/s00431-011-1656-6","article-title":"Lessons learned from 5 years of newborn screening for congenital adrenal hyperplasia in the Czech republic: 17-hydroxyprogesterone, genotypes, and screening performance","volume":"171","author":"Votava","year":"2012","journal-title":"Eur J Pediatr"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1111\/cen.14447","article-title":"First insights into the genetics of 21-hydroxylase deficiency in the Roma population","volume":"95","author":"Kocova","year":"2021","journal-title":"Clin Endocrinol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2016.03.035","article-title":"Molecular genetic analysis in 93 patients and 193 family members with classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency in Croatia","volume":"165","author":"Dumic","year":"2017","journal-title":"J Steroid Biochem Mol Biol"},{"key":"B16","article-title":"Multiplex ligation-dependent probe amplification assay for diagnosis of congenital adrenal hyperplasia","volume":"41","author":"Jang","year":"2011","journal-title":"Ann Clin Lab Sci"},{"key":"B17","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1111\/j.1399-0004.1979.tb02022.x","article-title":"Genetic structure of the Greek gypsies","volume":"15","author":"Bartsocas","year":"1979","journal-title":"Clin Genet"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2006.12.005","article-title":"Ethnic-specific distribution of mutations in 716 patients with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency","volume":"90","author":"Wilson","year":"2007","journal-title":"Mol Genet Metab"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1159\/000245933","article-title":"Classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency in Croatia between 1995 and 2006","volume":"72","author":"Dumic","year":"2009","journal-title":"Horm Res"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.788812","article-title":"Characteristics of In2G variant in congenital adrenal hyperplasia due to 21-hydroxylase deficiency","volume":"12","author":"Kocova","year":"2022","journal-title":"Front Endocrinol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.82.7.4086","article-title":"Evidence for a heterozygote advantage in congenital adrenal hyperplasia due to 21-hydroxylase deficiency","volume":"82","author":"Witchel","year":"1997","journal-title":"J Clin Endocrinol Metab"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2019-01199","article-title":"Carriers of a classic CYP21A2 mutation have reduced mortality: a population-based national cohort study","volume":"104","author":"Nordenstr\u00f6m","year":"2019","journal-title":"J Clin Endocrinol Metab"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1111\/cen.13242","article-title":"Are carriers of CYP21A2 mutations less vulnerable to psychological stress? a population-based national cohort study","volume":"86","author":"Nordenstr\u00f6m","year":"2017","journal-title":"Clin Endocrinol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1159\/000249161","article-title":"A favorable metabolic and antiatherogenic profile in carriers of CYP21A2 gene mutations supports the theory of a survival advantage in this population","volume":"72","author":"Livadas","year":"2009","journal-title":"Horm Res"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.15291\/geoadria.2877","article-title":"Projekcije kretanja romske populacije u medimurju-put od manjine ka vecini","volume":"24","author":"Slezak","year":"2019","journal-title":"Geoadria"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2023.1170449\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T13:43:03Z","timestamp":1685540583000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2023.1170449\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,31]]},"references-count":25,"alternative-id":["10.3389\/fendo.2023.1170449"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2023.1170449","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,31]]},"article-number":"1170449"}}