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Late diagnosis of 3β-Hydroxysteroid dehydrogenase deficiency: the pivotal role of gas chromatography-mass spectrometry urinary steroid metabolome analysis and a novel homozygous nonsense mutation in the HSD3B2 gene

Pavlos Fanis, Vassos Neocleous ORCID logo, Konstantina Kosta, Aristea Karipiadou, Michaela F. Hartmann, Stefan A. Wudy, Nikolaos Karantaglis, Dimitrios T. Papadimitriou, Nicos Skordis, Georgios Tsikopoulos, Leonidas A. Phylactou, Emmanouil Roilides and Maria Papagianni



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.


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.

Corresponding authors: Vassos Neocleous, PhD, Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus; and Cyprus School of Molecular Medicine, Nicosia, Cyprus, E-mail:; and Maria Papagianni, MD, PhD, Unit of Endocrinology, Diabetes and Metabolism 3rd Department of Pediatrics, Aristotle University School of Health Sciences, Hippokration Hospital of Thessaloniki, Thessaloniki, Greece, E-mail:

Funding source: A.G. Leventis Foundation

  1. Research funding: This work was funded by the A.G. Leventis Foundation to Prof. Leonidas A Phylactou.

  2. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved the submission.

  3. 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.

  4. 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.


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Received: 2020-05-06
Accepted: 2020-08-28
Published Online: 2020-11-11
Published in Print: 2021-01-27

© 2020 Walter de Gruyter GmbH, Berlin/Boston

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