Skip to main content

Advertisement

SpringerLink
Log in

The mystery of transient pregnancy-induced cushing’s syndrome: a case report and literature review highlighting GNAS somatic mutations and LHCGR overexpression

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Purpose

Transient pregnancy-induced Cushing’s syndrome is a rare condition characterized by the manifestation of symptoms solely during pregnancy, which typically resolve spontaneously following delivery or miscarriage. While it has been established that GNAS is associated with adrenal tumors, its specific role in the pathogenesis of pregnancy-induced Cushing’s syndrome remains uncertain.This work aims to examine the association between GNAS mutation and pregnancy-induced Cushing’s syndrome.

Methods

DNA was extracted from patients’ peripheral blood and tumor tissues for whole-exome sequencing (WES) and Sanger sequencing. We used AlphaFold to predict the protein structure of wild-type and mutant GNAS and to make functional predictions, and immunohistochemistry was used to detect disease-associated protein expression. A review and summary of reported cases of transient pregnancy-induced Cushing’s syndrome induced by pregnancy was conducted.

Results

Using WES, we identified a somatic mutation in GNAS (NM_000516, c.C601T, p.R201C) that was predicted to have a deleterious effect using computational methods, such as AlphaFold. Human chorionic gonadotropin (hCG) stimulation tests had weakly positive results, and immunohistochemical staining of adrenal adenoma tissue also revealed positivity for luteinizing hormone/chorionic gonadotropin receptor (LHCGR) and cytochrome P450 family 11 subfamily B member 1 (CYP11B1). We reviewed 15 published cases of transient Cushing’s syndrome induced by pregnancy. Among these cases, immunohistochemical staining of the adrenal gland showed positive LHCGR expression in 3 case reports, similar to our findings.

Conclusion

Transient pregnancy-induced Cushing’s syndrome may be associated with somatic GNAS mutations and altered adrenal pathology due to abnormal activation of LHCGR.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Data availability

The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding author.

Abbreviations

WES:

whole-exome sequencing

CS:

Cushing’s syndrome

LHCGR:

luteinizing hormone/chorionic gonadotropin receptor

hCG:

human chorionic gonadotropin

CYP11B1:

cytochrome P450 family 11 subfamily B member 1

cAMP:

cyclic adenosine monophosphate

PKA:

protein kinase A

GPCRs:

G protein-coupled receptors

GDP:

guanosine diphosphate

GTP:

guanosine triphosphate

References

  1. A. Lacroix, R.A. Feelders, C.A. Stratakis, L.K. Nieman, Cushing’s syndrome. Lancet 386(9996), 913–927 (2015)

    Article  CAS  PubMed  Google Scholar 

  2. N. Younes, M. St-Jean, I. Bourdeau, A. Lacroix, Endogenous Cushing’s syndrome during pregnancy. Rev. Endocr. Metab. Disord. 24(1), 23–38 (2023)

    Article  CAS  PubMed  Google Scholar 

  3. J. Kero, M. Poutanen, F.P. Zhang et al. Elevated luteinizing hormone induces expression of its receptor and promotes steroidogenesis in the adrenal cortex. J. Clin. Invest 105(5), 633–641 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. U. Plöckinger, M. Chrusciel, M. Doroszko et al. Functional implications of LH/hCG receptors in pregnancy-induced cushing syndrome. J. Endocr. Soc. 1(1), 57–71 (2017)

    PubMed  PubMed Central  Google Scholar 

  5. J. Jumper, R. Evans, A. Pritzel et al. Highly accurate protein structure prediction with AlphaFold. Nature 596(7873), 583–589 (2021)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  6. P.C. Ng, S. Henikoff, SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res. 31(13), 3812–3814 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. B. Yariv, E. Yariv, A. Kessel et al. Using evolutionary data to make sense of macromolecules with a “face-lifted” ConSurf. Protein Sci. 32(3), e4582 (2023)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. I.A. Adzhubei, S. Schmidt, L. Peshkin et al. A method and server for predicting damaging missense mutations. Nat. Methods 7(4), 248–249 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. X. Liu, C. Li, C. Mou, Y. Dong, Y. Tu, dbNSFP v4: a comprehensive database of transcript-specific functional predictions and annotations for human nonsynonymous and splice-site SNVs. Genome Med 12(1), 103 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. D. Szklarczyk, R. Kirsch, M. Koutrouli et al. The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res 51(D1), D638–d646 (2023)

    Article  CAS  PubMed  Google Scholar 

  11. F. Caimari, E. Valassi, P. Garbayo et al. Cushing’s syndrome and pregnancy outcomes: a systematic review of published cases. Endocrine 55(2), 555–563 (2017)

    Article  CAS  PubMed  Google Scholar 

  12. S. Li, C. Yang, J. Fan et al. Pregnancy-induced Cushing’s syndrome with an adrenocortical adenoma overexpressing LH/hCG receptors: a case report. BMC Endocr. Disord. 20(1), 62 (2020)

    Article  PubMed  PubMed Central  Google Scholar 

  13. E. Reschini, G. Giustina, P.G. Crosignani, A. D’Alberton, Spontaneous remission of Cushing syndrome after termination of pregnancy. Obstet. Gynecol. 51(5), 598–602 (1978)

    Article  CAS  PubMed  Google Scholar 

  14. C.E. Andreescu, R.A. Alwani, J. Hofland et al. Adrenal Cushing’s syndrome during pregnancy. Eur. J. Endocrinol. 177(5), K13–k20 (2017)

    Article  CAS  PubMed  Google Scholar 

  15. C. Ruggiero, E. Lalli, Impact of ACTH signaling on transcriptional regulation of steroidogenic genes. Front Endocrinol. (Lausanne) 7, 24 (2016)

    Article  PubMed  Google Scholar 

  16. D. Goricanec, R. Stehle, P. Egloff et al. Conformational dynamics of a G-protein α subunit is tightly regulated by nucleotide binding. Proc. Natl. Acad. Sci. USA 113(26), E3629–E3638 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. M. Lodish, C.A. Stratakis, A genetic and molecular update on adrenocortical causes of Cushing syndrome. Nat. Rev. Endocrinol. 12(5), 255–262 (2016)

    Article  CAS  PubMed  Google Scholar 

  18. L.S. Weinstein, A. Shenker, P.V. Gejman et al. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N. Engl. J. Med 325(24), 1688–1695 (1991)

    Article  CAS  PubMed  Google Scholar 

  19. M. Kometani, T. Yoneda, M. Demura et al. Cortisol overproduction results from DNA methylation of CYP11B1 in hypercortisolemia. Sci. Rep. 7(1), 11205 (2017)

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  20. J. Rege, J. Hoxie, C.J. Liu et al. Targeted mutational analysis of cortisol-producing adenomas. J. Clin. Endocrinol. Metab. 107(2), e594–e603 (2022)

    Article  PubMed  Google Scholar 

  21. K. Takedani, M. Yamamoto, S. Tanaka et al. ACTH-independent Cushing’s syndrome due to ectopic endocrinologically functional adrenal tissue caused by a GNAS heterozygous mutation: a rare case of McCune-Albright syndrome accompanied by central amenorrhea and hypothyroidism: a case report and literature review. Front Endocrinol. (Lausanne) 13, 934748 (2022)

    Article  PubMed  Google Scholar 

  22. M.C. Fragoso, S. Domenice, A.C. Latronico et al. Cushing’s syndrome secondary to adrenocorticotropin-independent macronodular adrenocortical hyperplasia due to activating mutations of GNAS1 gene. J. Clin. Endocrinol. Metab. 88(5), 2147–2151 (2003)

    Article  CAS  PubMed  Google Scholar 

  23. Q. Hu, K.M. Shokat, Disease-causing mutations in the G protein Gαs subvert the roles of GDP and GTP. Cell 173(5), 1254–1264.e1211 (2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. C. Nwabuobi, S. Arlier, F. Schatz et al. hCG: Biological functions and clinical applications. Int J. Mol. Sci. 18(10), 2037 (2017)

    Article  PubMed  PubMed Central  Google Scholar 

  25. J.E. Pabon, X. Li, Z.M. Lei et al. Novel presence of luteinizing hormone/chorionic gonadotropin receptors in human adrenal glands. J. Clin. Endocrinol. Metab. 81(6), 2397–2400 (1996)

    CAS  PubMed  Google Scholar 

  26. O. Hatano, A. Takakusu, M. Nomura, K. Morohashi, Identical origin of adrenal cortex and gonad revealed by expression profiles of Ad4BP/SF-1. Genes Cells 1(7), 663–671 (1996)

    Article  CAS  PubMed  Google Scholar 

  27. A.E. Teo, S. Garg, L.H. Shaikh et al. Pregnancy, primary aldosteronism, and adrenal CTNNB1 mutations. N. Engl. J. Med. 373(15), 1429–1436 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. J. Zhou, E.A.B. Azizan, C.P. Cabrera et al. Somatic mutations of GNA11 and GNAQ in CTNNB1-mutant aldosterone-producing adenomas presenting in puberty, pregnancy or menopause. Nat. Genet 53(9), 1360–1372 (2021)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. P. Konstantakou, G. Mastorakos, N. Vrachnis, J.W. Tomlinson, G. Valsamakis, Dysregulation of 11beta-hydroxysteroid dehydrogenases: implications during pregnancy and beyond. J. Matern Fetal Neonatal Med 30(3), 284–293 (2017)

    Article  CAS  PubMed  Google Scholar 

  30. Younes N., St-Jean M., Bourdeau I., Lacroix A. Endogenous Cushing’s syndrome during pregnancy. Rev. Endocr. Metab. Disord. 2022 https://doi.org/10.1007/s11154-022-09731-y.

Download references

Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (82260159,81060220).

Author contributions

Y.L. and J.L. designed the study and participated in data collection. Y.L. performed the systematic review and drafted the manuscript. Z.L. edited and reviewed the manuscript. S.F., L.L., Z.H., H.Y., X.L., Y.Q., J.Z., and D.L. partially conceived the research idea. All authors contributed to the article and approved the submitted version.

Author information

Authors and Affiliations

  1. Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, P. R. China

    Yufei Li, Jianfan Lin, Shien Fu, Li Li, Zhenxing Huang, Haiyan Yang, Xinghuan Liang, Yingfen Qin, Jia Zhou & Zuojie Luo

  2. Department of Urology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, P. R. China

    Deyun Liu

Authors
  1. Yufei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jianfan Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shien Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Li Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhenxing Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Haiyan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xinghuan Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yingfen Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jia Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Deyun Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Zuojie Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zuojie Luo.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Ethics approval

The studies involving human participants were reviewed and approved by The First Affiliated Hospital of Guangxi Medical University.

Consent to participate

No identifying information of participants was included in the article and verbal consent was obtained from the participants. Written informed consent was not required, as approved by the ethics committee.

Consent to publish

Verbal informed consent was obtained from the participant and this article does not contain any personal details, images or videos.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

These authors contributed equally: Yufei Li, Jianfan Lin

Supplementary informations

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, Y., Lin, J., Fu, S. et al. The mystery of transient pregnancy-induced cushing’s syndrome: a case report and literature review highlighting GNAS somatic mutations and LHCGR overexpression. Endocrine 83, 473–482 (2024). https://doi.org/10.1007/s12020-023-03549-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-023-03549-7

Keywords

Search

Navigation