Adrenarche unmasks compound heterozygous 3β-hydroxysteroid dehydrogenase deficiency: c.244G>A (p.Ala82Thr) and the novel 931C>T (p.Gln311*) variant in a non-salt wasting, severely undervirilised 46XY
-
and
Abstract
3β-Hydroxysteroid dehydrogenase type II deficiency (3βHSD2) congenital adrenal hyperplasia is a rare cause of ambiguous genitalia, resulting in abnormal virilisation in both 46XY and 46XX. We describe a case of 46XY ambiguous genitalia that was misdiagnosed as androgen insensitivity syndrome. The correct diagnosis was made after adrenarche. Genotyping demonstrated compound heterozygosity in two alleles, the previously described c.244G>A (p.Ala82Thr), and a novel 931C>T(p.Gln311*) variant. We suggest that adrenarche unmasked the condition by driving cortisol production to rates that caused the mutant 3bHSD2 enzyme to become rate limiting for cortisol production. This case illustrates how markedly different the effects of this condition may be on androgen production compared with glucocorticoid and mineralocorticoid production. It also demonstrates how current guidelines based on urinary steroids and cortisol sufficiency may not arrive at the correct diagnosis, and underlines the importance of gene testing in the work-up of disorders of sexual differentiation.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) 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.
References
1. Rege J, Rainey WE. The steroid metabolome of adrenarche. J Endocrinol 2012;214:133–43.10.1530/JOE-12-0183Search in Google Scholar PubMed PubMed Central
2. Charmandari E, Brook CG, Hindmarsh PC. Why is management of patients with classical congenital adrenal hyperplasia more difficult at puberty? Arch Dis Child 2002;86:266–9.10.1136/adc.86.4.266Search in Google Scholar PubMed PubMed Central
3. Suzuki T, Sasano H, Takeyama J, Kaneko C, Freije WA, et al. Developmental changes in steroidogenic enzymes in human postnatal adrenal cortex: immunohistochemical studies. Clin Endocrinol (Oxf) 2000;53:739–47.10.1046/j.1365-2265.2000.01144.xSearch in Google Scholar PubMed
4. Nakamura Y, Gang HX, Suzuki T, Sasano H, Rainey WE. Adrenal changes associated with adrenarche. Rev Endocr Metab Disord 2009;10:19–26.10.1007/s11154-008-9092-2Search in Google Scholar PubMed PubMed Central
5. Miller WL, Auchus RJ. The molecular biology, biochemistry and physiology of human steroidogenesis and its disorders. Endocr Rev 2011;32:81–151.10.1210/er.2010-0013Search in Google Scholar PubMed PubMed Central
6. Moisan AM, Ricketts ML, Tardy V, Desrochers M, Barki F, et al. New Insight into the molecular basis of 3β-hydroxysteroid dehydrogenase deficiency: identification of eight mutations in the HSD3B2 gene in eleven patients from seven new families and comparison of the functional properties of twenty-five mutant enzymes. J Clin Endocrinol Metab 1999;8:4410–25.10.1210/jcem.84.12.6288Search in Google Scholar PubMed
7. Benkert AR, Young M, Robinson D, Hendrickson C, Lee PA, et al. Severe salt-losing 3beta-hydroxysteroid dehydrogenase deficiency: treatment and outcomes of HSD3B2 c.35G>A homozygotes. J Clin Endocrinol Metab 2015;100:E1105–15.10.1210/jc.2015-2098Search in Google Scholar PubMed
8. Juniarto, AZ, van der Zwan YG, Santosa A, Ariani MD, Eggers S, et al. Hormonal evaluation in relation to phenotype and genotype in 286 patients with a disorder of sex development from Indonesia. Clin Endocrinol 2016;85:247–57.10.1111/cen.13051Search in Google Scholar PubMed
9. Rabbani B, Mahdieh N, Haghi Ashtiani MT, Setondeh A, Rabbani A. In silico structural, functional and pathogenicity evaluation of a novel mutation: an overview of HSD3B2 gene mutations. Gene 2012;503:215–21.10.1016/j.gene.2012.04.080Search in Google Scholar PubMed
10. Simard J, Rickets M, Gingras S, Soucy P, Feltus FA, et al. Molecular biology of the 3β-hydroxy-steroid dehydrogenase/δ5-δ4 isomerase gene family. Endoc Rev 2005;26:525–82.10.1210/er.2002-0050Search in Google Scholar PubMed
11. Mebarki F, Sanchez R, Rheaume E, Laflamme N, Simard J, et al. Nonsalt-Losing male pseudohermaphroditism due to the novel homozygous NIOOS mutation in the type II 3β-hydroxysteroid dehydrogenase gene*. J Clin Endocrinol Metab 1995;80:2127–34.Search in Google Scholar
12. Zhang L, Sakkal-Alkaddour H, Chang YT, Yang X, Pang S. A new compound heterozygous frameshift mutation in type II 3β-hydroxysteroid dehydrogenase (3bHSD) gene causing salt-wasting 3βHSD deficiency congenital adrenal hyperplasia. J Clin Endocrinol Metab 1996;81:291–5.Search in Google Scholar
13. Burckhardt MA, Udhane SS, Marti N, Schnyder I, Tapia C, et al. Human 3beta hydroxysteroid dehydrogenase deficiency seems to affect fertility but may not harbor a tumor risk: lesson from an experiment of nature. Eur J Endocrinol 2015;173:K1–12.10.1530/EJE-15-0599Search in Google Scholar
14. Johannssen TH, Mallet D, Dige-Petersen H, Müller J, Main KM, et al. Delayed diagnosis of congenital adrenal hyperplasia with salt wasting due to type II 3beta-hydroxysteroid dehydrogenase deficiency. J Clin Endocrinol Metab 2005;90:2076–80.10.1210/jc.2004-1374Search in Google Scholar
15. Flück CE, Pandey AV. Steroidogenesis of the testis – new genes and pathways. Ann Endocrinol (Paris) 2014;75:40–7.10.1016/j.ando.2014.03.002Search in Google Scholar
16. Luu-The V. Assessment of steroidogenesis and steroidogenic enzyme functions. J Steroid Biochemmolec Biol 2013;137: 176–82.10.1016/j.jsbmb.2013.05.017Search in Google Scholar
17. Ahmed SF, Achermann JC, Arlt W, Balen AH, Conway G, et al. UK guidance on the initial evaluation of an infant or an adolescent with a suspected disorder of sex development. Clin Endocrinol (Oxf) 2011;75:12–26.10.1111/j.1365-2265.2011.04076.xSearch in Google Scholar
18. Lutfallah C, Wang W, Mason JI, Chang YT, Haider A, et al. Newly proposed hormonal criteria via genotypica proof for type II 3β-hydroxysteroid dehydrogenase deficiency. J Clin Endocrinol Metab 2002;87:2611–22.Search in Google Scholar
19. Mermejo LM, Elias LL, Marui S, Moreira AC, Mendonca BB, et al. Refining hormonal diagnosis of type II 3β-hydroxysteroid dehydrogenase deficiency in patients with premature pubarche and hirsutism based on HSD3B2 genotyping. J Clin Endocrinol Metab 2005;90:1287–93.10.1210/jc.2004-1552Search in Google Scholar
20. Caulfield MP, Lynn T, Gottschalk ME, Jones KL, Taylor NF, et al. The diagnosis of congenital adrenal hyperplasia in the newborn by gas chromatography/mass spectrometry analysis of random urine specimens. J Clin Endocrinol Metab 2000;87:3682–90.10.1210/jcem.87.8.8712Search in Google Scholar
21. Dhayata NA, Freya AC, Freya BM, d’Uscioa CH, Vogta B, et al. Estimation of reference curves for the urinary steroid metabolome in the first year of life in healthy children: tracing the complexity of human postnatal steroidogenesis. J Steroid Biochem Molec Biol 2015;154:226–36.10.1016/j.jsbmb.2015.07.024Search in Google Scholar
22. Stark MJ, Wright IM, Clifton VL. Sex-specific alterations in placental 11-hydroxysteroid dehydrogenase 2 activity and early postnatal clinical course following antenatal beta methasone. Am J Physiol Regul Integr Comp Physiol 2009;297:R510–14.10.1152/ajpregu.00175.2009Search in Google Scholar
23. Toscano V, Balducci R, Adamo MV, Mangiantini A, Cives C, et al. Changes in steroid pattern following acute and chronic adrenocorticotropin administration in premature adrenarche. J Steroid Biochem 1989;32:321–6.10.1016/0022-4731(89)90271-9Search in Google Scholar
24. Lee YS, Kirk JM, Stanhope RG, Johnston DI, Harland S, et al. Phenotypic variability in 17β-hydroxysteroid dehydrogenase-3 deficiency and diagnostic pitfalls. Clin Endocrinol 2007;67:20–8.10.1111/j.1365-2265.2007.02829.xSearch in Google Scholar PubMed
25. Hughes IA, Houk C, Ahmed SF, Lee PA, Wilkins L. Pediatric Endocrine Society/European Society forPaediatric Endocrinology Consensus G. Consensus statement on management of intersex disorders. J Pediatr Urol 2006;2:148–62.10.1016/j.jpurol.2006.03.004Search in Google Scholar PubMed
©2017 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Review
- Adrenocortical neoplasms in adulthood and childhood: distinct presentation. Review of the clinical, pathological and imaging characteristics
- Original Articles
- Assessment of health-related quality of life in Egyptian adolescents with type 1 diabetes: DEMPU survey
- Non-HDL-cholesterol and C-reactive protein in children and adolescents with type 1 diabetes
- Nutritional status and metabolic profile in neurologically impaired pediatric surgical patients
- Vascular risk factors are associated with retinal arteriolar narrowing and venular widening in children and adolescents with type 1 diabetes
- Are aromatase inhibitors in boys with predicted short stature and/or rapidly advancing bone age effective and safe?
- Increased prevalence of bicuspid aortic valve in Turner syndrome links with karyotype: the crucial importance of detailed cardiovascular screening
- Resting energy expenditure in girls with Turner syndrome
- AMH levels in girls with various pubertal problems
- Bone age in unilateral spastic cerebral palsy: is there a correlation with hand function and limb length?
- Novel germline mutation (Leu512Met) in the thyrotropin receptor gene (TSHR) leading to sporadic non-autoimmune hyperthyroidism
- A novel DAX-1 mutation in two male siblings presenting with precocious puberty and late-onset hypogonadotropic hypogonadism
- Case Reports
- Adrenarche unmasks compound heterozygous 3β-hydroxysteroid dehydrogenase deficiency: c.244G>A (p.Ala82Thr) and the novel 931C>T (p.Gln311*) variant in a non-salt wasting, severely undervirilised 46XY
- Three cases of Gordon syndrome with dominant KLHL3 mutations
- Unexplained cyanosis caused by hepatopulmonary syndrome in a girl with APECED syndrome
Articles in the same Issue
- Frontmatter
- Review
- Adrenocortical neoplasms in adulthood and childhood: distinct presentation. Review of the clinical, pathological and imaging characteristics
- Original Articles
- Assessment of health-related quality of life in Egyptian adolescents with type 1 diabetes: DEMPU survey
- Non-HDL-cholesterol and C-reactive protein in children and adolescents with type 1 diabetes
- Nutritional status and metabolic profile in neurologically impaired pediatric surgical patients
- Vascular risk factors are associated with retinal arteriolar narrowing and venular widening in children and adolescents with type 1 diabetes
- Are aromatase inhibitors in boys with predicted short stature and/or rapidly advancing bone age effective and safe?
- Increased prevalence of bicuspid aortic valve in Turner syndrome links with karyotype: the crucial importance of detailed cardiovascular screening
- Resting energy expenditure in girls with Turner syndrome
- AMH levels in girls with various pubertal problems
- Bone age in unilateral spastic cerebral palsy: is there a correlation with hand function and limb length?
- Novel germline mutation (Leu512Met) in the thyrotropin receptor gene (TSHR) leading to sporadic non-autoimmune hyperthyroidism
- A novel DAX-1 mutation in two male siblings presenting with precocious puberty and late-onset hypogonadotropic hypogonadism
- Case Reports
- Adrenarche unmasks compound heterozygous 3β-hydroxysteroid dehydrogenase deficiency: c.244G>A (p.Ala82Thr) and the novel 931C>T (p.Gln311*) variant in a non-salt wasting, severely undervirilised 46XY
- Three cases of Gordon syndrome with dominant KLHL3 mutations
- Unexplained cyanosis caused by hepatopulmonary syndrome in a girl with APECED syndrome
