Abstract
Objectives
3β-Hydroxysteroid dehydrogenase (3β-HSD) deficiency is a rare type of congenital adrenal hyperplasia caused by recessive loss-of-function mutations in HSD3B2 gene.
Case presentation
We report an 8.5-year-old, 46XY, Roma boy with advanced adrenarche signs born to consanguineous parents. He was born at term with ambiguous genitalia. At 15 days of age, he underwent replacement therapy with hydrocortisone and fludrocortisone due to a salt wasting (SW) crisis and adrenal insufficiency. At 3.5 years, he was admitted again with SW crisis attributed to the low – unadjusted to body surface area – hydrocortisone dose and presented with bilateral gynecomastia and adrenarche. At 8.5 years, his bone age was four years more advanced than his chronological age and he was prepubertal, with very high testosterone levels. Gas chromatography-mass spectrometry (GC-MS) urinary steroid metabolome analysis revealed the typical steroid metabolic fingerprint of 3β-HSD deficiency. Sequencing of the HSD3B2 gene identified in homozygosity the novel p.Lys36Ter nonsense mutation. Furthermore, this patient was found to be heterozygous for p.Val281Leu in the CYP21A2 gene. Both parents were identified as carriers of the p.Lys36Ter in HSD3B2.
Conclusions
A novel nonsense p.Lys36Ter mutation in HSD3B2 was identified in a male patient with hypospadias. 3β-HSD deficiency due to mutations in the HSD3B2 gene is extremely rare and the finding of a patient with this rare type of disorders of sex development (DSD) is one of the very few reported to date. The complexity of such diseases requires a multidisciplinary team approach regarding the diagnosis and follow-up.
Funding source: A.G. Leventis Foundation
Research funding: This work was funded by the A.G. Leventis Foundation to Prof. Leonidas A Phylactou.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved the submission.
Competing interests: The funding organization played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
Ethical approval: Informed consent was obtained from the parents of the patient, and all tests were completed in agreement with the pertinent guidelines and regulations. All procedures involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
References
1. Simard, J, Durocher, F, Mebarki, F, Turgeon, C, Sanchez, R, Labrie, Y, et al.. Molecular biology and genetics of the 3 beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase gene family. J Endocrinol 1996;150:S189–207.Search in Google Scholar
2. Rheaume, E, Simard, J, Morel, Y, Mebarki, F, Zachmann, M, Forest, MG, et al.. Congenital adrenal hyperplasia due to point mutations in the type II 3 beta-hydroxysteroid dehydrogenase gene. Nat Genet 1992;1:239–45. https://doi.org/10.1038/ng0792-239.Search in Google Scholar
3. Pang, SY, Lerner, AJ, Stoner, E, Levine, LS, Engel, IV, Oberfield, SE, et al.. Late-onset adrenal steroid 3 beta-hydroxysteroid dehydrogenase deficiency. I. A cause of hirsutism in pubertal and postpubertal women. J Clin Endocrinol Metab 1985;60:428–39. https://doi.org/10.1210/jcem-60-3-428.Search in Google Scholar
4. Al Alawi, AM, Nordenstrom, A, Falhammar, H. Clinical perspectives in congenital adrenal hyperplasia due to 3beta-hydroxysteroid dehydrogenase type 2 deficiency. Endocrine 2019;63:407–21. https://doi.org/10.1007/s12020-018-01835-3.Search in Google Scholar
5. El-Maouche, D, Arlt, W, Merke, DP. Congenital adrenal hyperplasia. Lancet 2017;390:2194–210. https://doi.org/10.1016/s0140-6736(17)31431-9.Search in Google Scholar
6. Hamed, SA, Metwalley, KA, Farghaly, HS. Cognitive function in children with classic congenital adrenal hyperplasia. Eur J Pediatr 2018;177:1633–40. https://doi.org/10.1007/s00431-018-3226-7.Search in Google Scholar PubMed
7. Wudy, SA, Schuler, G, Sanchez-Guijo, A, Hartmann, MF. The art of measuring steroids: principles and practice of current hormonal steroid analysis. J Steroid Biochem Mol Biol 2018;179:88–103. https://doi.org/10.1016/j.jsbmb.2017.09.003.Search in Google Scholar PubMed
8. Neocleous, V, Fanis, P, Toumba, M, Stylianou, C, Picolos, M, Andreou, E, et al.. The spectrum of genetic defects in congenital adrenal hyperplasia in the population of Cyprus: a retrospective analysis. Horm Metab Res 2019;51:586–94. https://doi.org/10.1055/a-0957-3297.Search in Google Scholar PubMed
9. Finkielstain, GP, Chen, W, Mehta, SP, Fujimura, FK, Hanna, RM, Van, Ryzin C, et al.. Comprehensive genetic analysis of 182 unrelated families with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 2011;96:E161–72. https://doi.org/10.1210/jc.2010-0319.Search in Google Scholar PubMed PubMed Central
10. Neocleous, V, Byrou, S, Toumba, M, Costi, C, Shammas, C, Kyriakou, C, et al.. Evidence of digenic inheritance in autoinflammation-associated genes. J Genet 2016;95:761–6. https://doi.org/10.1007/s12041-016-0691-5.Search in Google Scholar PubMed
11. Bizzarri, C, Massimi, A, Federici, L, Cualbu, A, Loche, S, Bellincampi, L, et al.. A new homozygous frameshift mutation in the HSD3B2 gene in an apparently nonconsanguineous Italian family. Horm Res Paediatr 2016;86:53–61. https://doi.org/10.1159/000444712.Search in Google Scholar PubMed
12. Kulle, A, Krone, N, Holterhus, PM, Schuler, G, Greaves, RF, Juul, A, et al.. Steroid hormone analysis in diagnosis and treatment of DSD: position paper of EU COST Action BM 1303 ’DSDnet’. Eur J Endocrinol 2017;176:1–9. https://doi.org/10.1530/eje-16-0953.Search in Google Scholar
© 2020 Walter de Gruyter GmbH, Berlin/Boston
