{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:54:57Z","timestamp":1790837697278,"version":"4.1.0"},"reference-count":11,"publisher":"The Endocrine Society","issue":"11","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"vor","delay-in-days":6,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Primary amenorrhea may be the first clinical presentation of an underlying 46,XY disorder of sex development (DSD). We report 2 siblings assigned female at birth; the index case presented with primary amenorrhea and the younger sibling was identified through family screening. Both had female external genitalia with minimal virilization, absent Mullerian structures, and testes located in the inguinal\/labioscrotal region on imaging. Hormonal evaluation showed impaired androgen synthesis with very low testosterone and markedly elevated 17-hydroxyprogesterone:androstenedione ratios, suggestive of isolated 17,20-lyase deficiency. Whole-exome sequencing identified a novel homozygous missense variant in exon 2 of the CYB5A gene (c.140G&amp;gt;T; p.Gly47Val) in both siblings, and segregation analysis confirmed the same variant in both parents as heterozygous carriers. Subsequently, methemoglobin levels were found to be above the normal reference range in both siblings despite the absence of clinical symptoms. Multidisciplinary evaluation confirmed female gender identity in both siblings without any gender incongruence and advised continuation of the assigned female gender role. Gonadectomy and vaginoplasty were planned after 18 years of age. These cases highlight cytochrome b5 deficiency due to a novel variant as a rare cause of 46,XY DSD and the importance of recognizing methemoglobinemia in a DSD.<\/jats:p>","DOI":"10.1210\/jcemcr\/luag299","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T11:19:28Z","timestamp":1789384768000},"source":"Crossref","is-referenced-by-count":0,"title":["Familial 46,XY disorder of sex development due to a novel\n                    <i>CYB5A<\/i>\n                    variant: a rare cause of isolated 17,20-lyase deficiency"],"prefix":"10.1210","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-5325-7370","authenticated-orcid":false,"given":"Aravind Kumar","family":"Muthu","sequence":"first","affiliation":[{"name":"Madurai Medical College and Government Rajaji Hospital Department of Endocrinology, , Madurai, Tamil N\u0101du 625 020 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5451-0848","authenticated-orcid":false,"given":"Subbiah","family":"Sridhar","sequence":"additional","affiliation":[{"name":"Madurai Medical College and Government Rajaji Hospital Department of Endocrinology, , Madurai, Tamil N\u0101du 625 020 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kumaravel","family":"Velayutham","sequence":"additional","affiliation":[{"name":"Alpha Hospital and Research Centre Department of Endocrinology, , Madurai, Tamil N\u0101du 625 009 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aruna","family":"Chelliah","sequence":"additional","affiliation":[{"name":"Alpha Hospital and Research Centre Department of Endocrinology, , Madurai, Tamil N\u0101du 625 009 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8829-3742","authenticated-orcid":false,"given":"Dhivyalakshmi Thiruppathi","family":"Venkatasamy","sequence":"additional","affiliation":[{"name":"Madurai Medical College and Government Rajaji Hospital Department of Endocrinology, , Madurai, Tamil N\u0101du 625 020 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7249-849X","authenticated-orcid":false,"given":"Shanmugam","family":"Dhivya","sequence":"additional","affiliation":[{"name":"Madurai Medical College and Government Rajaji Hospital Department of Endocrinology, , Madurai, Tamil N\u0101du 625 020 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"issue":"5","key":"2026100101590346800_luag299-B1","doi-asserted-by":"crossref","first-page":"392","DOI":"10.4103\/ijem.ijem_179_21","article-title":"Congruency the ART of being real\u201d\u201446XY DSD due to 5 \u03b1 reductase deficiency\u2014challenges in decision making","volume":"25","author":"Subbiah","year":"2021","journal-title":"Indian J Endocrinol Metab"},{"issue":"6","key":"2026100101590346800_luag299-B2","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1515\/jpem-2024-0613","article-title":"Two families, two pathways: a case series of 46, XY DSD with 17\u03b1-hydroxylase deficiency and isolated 17,20-lyase deficiency due to novel CYB5A variant","volume":"38","author":"Garg","year":"2025","journal-title":"J Pediatr Endocrinol Metab"},{"issue":"2","key":"2026100101590346800_luag299-B3","doi-asserted-by":"crossref","DOI":"10.1210\/jendso\/bvz016","article-title":"Isolated 17,20-lyase deficiency in a CYB5A mutated female with normal sexual development and fertility","volume":"4","author":"Leung","year":"2019","journal-title":"J Endocr Soc"},{"issue":"3","key":"2026100101590346800_luag299-B4","doi-asserted-by":"crossref","first-page":"E465","DOI":"10.1210\/jc.2011-2413","article-title":"A missense mutation in the human cytochrome b5 gene causes 46,XY disorder of sex development due to true isolated 17,20 lyase deficiency","volume":"97","author":"Idkowiak","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"2026100101590346800_luag299-B5","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1515\/jpem-2022-0515","article-title":"Diagnostic approach in 46, XY DSD: an Endocrine Society of Bengal (ESB) consensus statement","volume":"36","author":"Baidya","year":"2022","journal-title":"J Pediatr Endocrinol Metab"},{"issue":"3","key":"2026100101590346800_luag299-B6","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1210\/jc.2008-1745","article-title":"Isolated 17,20-lyase deficiency due to the cytochrome b5 mutation W27X","volume":"95","author":"Kok","year":"2010","journal-title":"J Clin Endocrinol Metab"},{"issue":"3","key":"2026100101590346800_luag299-B7","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1515\/jpem-2025-0549","article-title":"Rare phenotypic spectrum of 17\u03b2-hydroxysteroid dehydrogenase 3 deficiency: case series from infancy to adolescence","volume":"39","author":"Sridhar","year":"2026","journal-title":"J Pediatr Endocrinol Metab"},{"issue":"11","key":"2026100101590346800_luag299-B8","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1507\/endocrj.EJ24-0715","article-title":"46,XY 17 alpha-hydroxylase\/17,20 lyase deficiency with breast development: a case report and literature review","volume":"72","author":"Kawashima","year":"2025","journal-title":"Endocr J"},{"issue":"14","key":"2026100101590346800_luag299-B9","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1056\/NEJM198610023151415","article-title":"Congenital methemoglobinemia with cytochrome b5 deficiency","volume":"315","year":"1986","journal-title":"N Engl J Med"},{"issue":"4","key":"2026100101590346800_luag299-B10","doi-asserted-by":"crossref","first-page":"427","DOI":"10.4103\/0019-5049.118525","article-title":"Methemoglobinemia: what the anaesthetist must know","volume":"57","author":"Tandale","year":"2013","journal-title":"Indian J Anaesth"},{"issue":"7-8","key":"2026100101590346800_luag299-B11","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1159\/000512372","article-title":"Isolated 17, 20 lyase deficiency secondary to a novel CYB5A variant: comparison of steroid metabolomic findings with published cases provides diagnostic guidelines and greater insight into its biological 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