Primary Adrenal Insufficiency, Complete Sex Reversal, and Unique Clinical Phenotype in a Patient with Severe CYP11A1 (P450scc) Deficiency-Case Report and Literature Overview

Overview

Journal Children (Basel)

Specialty Health Services

Date 2024 Oct 26

PMID 39457196

Authors

Zuzanna Nowak

Ewelina Preizner-Rzucidlo

Jakub Gawlik

Jerzy B Starzyk

Dominika Janus

Affiliations

Soon will be listed here.

Abstract

Background: Congenital adrenal hyperplasia (CAH) is a group of genetic disorders that lead to the dysfunction of the steroidogenesis pathway, resulting in steroid hormone deficiency of varied intensity. The cholesterol side-chain cleavage enzyme (P450scc), coded by the gene, is vital to the first step in the biosynthesis of steroid hormones, which is the conversion of cholesterol to pregnenolone. Therefore, its deficiency causes a general steroid hormone shortage.

Objective: We report a case of CAH caused by P450scc deficiency with complete 46, XY sex reversal, characteristic facial features (narrow middle section of the face, small ears with thick helix, fleshy upturned lobules), and dysmorphic macrocephaly along with shortened upper and lower extremities.

Results: Our patient carries a compound heterozygotic pathogenic variant of the gene, with two frameshift pathogenic variants NM_000781.3():c.358del (p.Arg120Aspfs*18) in exon 2 and NM_000781.3():c.835del (p.Ile279Tyrfs*10) in exon 5. To date, only around 50 cases with pathogenic variants have been reported worldwide. We believe this is the first described case of a newborn with severe, classic P450scc deficiency in Poland.

Conclusions: CYP11A1 (P450scc) deficiency is a rare and complex disorder that leads to primary adrenal insufficiency and may present with 46, XY disorders of sex development (DSD), phenotypic variations, and associated endocrinological abnormalities. This case, along with others cited, highlights the diverse presentations of DSD in individuals with pathogenic variants. Optimal management necessitates a multidisciplinary approach by a specialized DSD team. Gonadectomy is a key consideration to decrease the teratogenic risk associated with intra-abdominal gonadal tissue.

References

Buonocore F, Maharaj A, Qamar Y, Koehler K, Suntharalingham J, Chan L . Genetic Analysis of Pediatric Primary Adrenal Insufficiency of Unknown Etiology: 25 Years' Experience in the UK. J Endocr Soc. 2021; 5(8):bvab086. PMC: 8266051. DOI: 10.1210/jendso/bvab086. View

Pomahacova R, Sykora J, Zamboryova J, Paterova P, Varvarovska J, Subrt I . First case report of rare congenital adrenal insufficiency caused by mutations in the CYP11A1 gene in the Czech Republic. J Pediatr Endocrinol Metab. 2016; 29(6):749-52. DOI: 10.1515/jpem-2015-0255. View

Kim A, Fujimoto M, Hwa V, Backeljauw P, Dauber A . Adrenal Insufficiency, Sex Reversal, and Angelman Syndrome due to Uniparental Disomy Unmasking a Mutation in CYP11A1. Horm Res Paediatr. 2018; 89(3):205-210. PMC: 5906135. DOI: 10.1159/000487638. View

Sarathi V, Nagalingam C . Normal male external genitalia do not rule out CYP11A1 deficiency. BMJ Case Rep. 2019; 12(7). PMC: 6615807. DOI: 10.1136/bcr-2018-228235. View

Tajima T, Fujieda K, Kouda N, Nakae J, Miller W . Heterozygous mutation in the cholesterol side chain cleavage enzyme (p450scc) gene in a patient with 46,XY sex reversal and adrenal insufficiency. J Clin Endocrinol Metab. 2001; 86(8):3820-5. DOI: 10.1210/jcem.86.8.7748. View

Papadimitriou D, Bothou C, Zarganis D, Karantza M, Papadimitriou A . Heterozygous mutations in the cholesterol side-chain cleavage enzyme gene (CYP11A1) can cause transient adrenal insufficiency and life-threatening failure to thrive. Hormones (Athens). 2018; 17(3):419-421. DOI: 10.1007/s42000-018-0048-y. View

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J . Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015; 17(5):405-24. PMC: 4544753. DOI: 10.1038/gim.2015.30. View

Kaur J, Rice A, OConnor E, Piya A, Buckler B, Bose H . Novel SCC mutation in a patient of Mexican descent with sex reversal, salt-losing crisis and adrenal failure. Endocrinol Diabetes Metab Case Rep. 2016; 2016. PMC: 5093401. DOI: 10.1530/EDM-16-0059. View

Tee M, Abramsohn M, Loewenthal N, Harris M, Siwach S, Kaplinsky A . Varied clinical presentations of seven patients with mutations in CYP11A1 encoding the cholesterol side-chain cleavage enzyme, P450scc. J Clin Endocrinol Metab. 2013; 98(2):713-20. PMC: 3565115. DOI: 10.1210/jc.2012-2828. View

10.

Auton A, Brooks L, Durbin R, Garrison E, Kang H, Korbel J . A global reference for human genetic variation. Nature. 2015; 526(7571):68-74. PMC: 4750478. DOI: 10.1038/nature15393. View

11.

Miller W, Bose H . Early steps in steroidogenesis: intracellular cholesterol trafficking. J Lipid Res. 2011; 52(12):2111-2135. PMC: 3283258. DOI: 10.1194/jlr.R016675. View

12.

Katsumata N, Ohtake M, Hojo T, Ogawa E, Hara T, Sato N . Compound heterozygous mutations in the cholesterol side-chain cleavage enzyme gene (CYP11A) cause congenital adrenal insufficiency in humans. J Clin Endocrinol Metab. 2002; 87(8):3808-13. DOI: 10.1210/jcem.87.8.8763. View

13.

Lara-Velazquez M, Perdomo-Pantoja A, Blackburn P, Gass J, Caulfield T, Atwal P . A novel splice site variant in CYP11A1 in trans with the p.E314K variant in a male patient with congenital adrenal insufficiency. Mol Genet Genomic Med. 2017; 5(6):781-787. PMC: 5702577. DOI: 10.1002/mgg3.322. View

14.

Metherell L, Naville D, Halaby G, Begeot M, Huebner A, Nurnberg G . Nonclassic lipoid congenital adrenal hyperplasia masquerading as familial glucocorticoid deficiency. J Clin Endocrinol Metab. 2009; 94(10):3865-71. PMC: 2860769. DOI: 10.1210/jc.2009-0467. View

15.

Al Kandari H, Katsumata N, Alexander S, Rasoul M . Homozygous mutation of P450 side-chain cleavage enzyme gene (CYP11A1) in 46, XY patient with adrenal insufficiency, complete sex reversal, and agenesis of corpus callosum. J Clin Endocrinol Metab. 2006; 91(8):2821-6. DOI: 10.1210/jc.2005-2230. View

16.

Li H, Durbin R . Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009; 25(14):1754-60. PMC: 2705234. DOI: 10.1093/bioinformatics/btp324. View

17.

Kim C . Congenital lipoid adrenal hyperplasia. Ann Pediatr Endocrinol Metab. 2015; 19(4):179-83. PMC: 4316413. DOI: 10.6065/apem.2014.19.4.179. View

18.

Kolli V, Kim H, Torky A, Lao Q, Tatsi C, Mallappa A . Characterization of the CYP11A1 Nonsynonymous Variant p.E314K in Children Presenting With Adrenal Insufficiency. J Clin Endocrinol Metab. 2018; 104(2):269-276. PMC: 6607962. DOI: 10.1210/jc.2018-01661. View

19.

Matusik P, Gach A, Zajdel-Cwynar O, Pinkier I, Kudela G, Gawlik A . A Novel Intronic Splice-Site Mutation of the Gene Linked to Adrenal Insufficiency with 46,XY Disorder of Sex Development. Int J Environ Res Public Health. 2021; 18(13). PMC: 8295740. DOI: 10.3390/ijerph18137186. View

20.

Balsamo A, Baronio F, Ortolano R, Menabo S, Baldazzi L, Di Natale V . Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant. Front Pediatr. 2021; 8:593315. PMC: 7783414. DOI: 10.3389/fped.2020.593315. View