Skip to main content

Advertisement

SpringerLink
Log in

Acromegaly in the setting of Tatton-Brown-Rahman Syndrome

  • Published:
Pituitary Aims and scope Submit manuscript

Abstract

Purpose

Tatton-Brown-Rahman syndrome (TBRS) is a newly defined genetic entity characterized by overgrowth and intellectual disability, resulting from germline mutations in the gene encoding DNA methyltransferase 3 alpha (DNMT3A). Affected individuals with benign and malignant tumors have been reported; to our knowledge pituitary adenomas (and other tumors identified in our patient) have not yet been described in this syndrome.

Case

We report the case of a 34-year-old woman with TBRS who developed a GH-secreting pituitary macroadenoma and other benign tumors and cystic lesions involving diverse organ systems. Whole-exome sequencing revealed a heterozygous, likely pathogenic variant (c.700_709 del10, p. Gly234ArgfsX79) in exon7 of DNMT3A, and a heterozygous variant of uncertain significance (c.25 C>T, p.Arg9Trp) in exon 1 of the gene encoding aryl hydrocarbon receptor-interacting protein (AIP). The patient failed somatostatin analog treatment, and underwent surgery. The tumor retained AIP expression, and analysis of tumor DNA indicated the presence of both AIP alleles, consistent with no loss of heterozygosity. These findings suggest that the AIP variant was not the primary driver of pituitary adenoma development.

Conclusion

Our case suggests that TBRS might be associated with pituitary adenoma and a broader spectrum of tumors than previously thought, making long-term follow up of these patients crucial to identify tumors early, and to elucidate the clinical spectrum of the disorder for optimization of management.

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

Similar content being viewed by others

References

  1. Tatton-Brown K, Seal S, Ruark E et al (2014) Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability. Nat Genet 46(4):385–388

    Article  CAS  Google Scholar 

  2. Tatton-Brown K, Zachariou A, Loveday C et al (2018) The Tatton-Brown-Rahman syndrome: a clinical study of 55 individuals with de novo constitutive DNMT3A variants. Wellcome Open Res 3:46

    Article  Google Scholar 

  3. Tenorio J, Alarcón P, Arias P, et al (2019) Further delineation of neuropsychiatric findings in Tatton-Brown-Rahman syndrome due to disease-causing variants in DNMT3A: seven new patients. Eur J Hum Genet. https://doi.org/10.1038/s41431-019-0485-3

    Article  PubMed  Google Scholar 

  4. Kosaki R, Terashima H, Kubota M, Kosaki K (2017) Acute myeloid leukemia-associated DNMT3A p.Arg882His mutation in a patient with Tatton-Brown-Rahman overgrowth syndrome as a constitutional mutation. Am J Med Genet 173(1):250–253

    Article  CAS  Google Scholar 

  5. Shen W, Heeley JM, Carlston CM et al (2017) The spectrum of DNMT3A variants in Tatton-Brown-Rahman syndrome overlaps with that in hematologic malignancies. Am J Med Genet 173(11):3022–3028

    Article  CAS  Google Scholar 

  6. Xin B, Cruz Marino T, Szekely J et al (2017) Novel DNMT3A germline mutations are associated with inherited Tatton-Brown-Rahman syndrome. Clin Genet 91(4):623–628

    Article  Google Scholar 

  7. Lemire G, Gauthier J, Soucy J, Delrue M (2017) A case of familial transmission of the newly described DNMT3A-Overgrowth syndrome. Am J Med Genet Part A 173(7):1887–1890

    Article  CAS  Google Scholar 

  8. Vandeva S, Jaffrain-Rea M, Daly AF, Tichomirowa M, Zacharieva S, Beckers A (2010) The genetics of pituitary adenomas. Best Pract Res Clin Endocrinol Metab 24(3):461–476

    Article  CAS  Google Scholar 

  9. Jaffrain-Rea ML, Angelini M, Gargano D et al (2009) Expression of aryl hydrocarbon receptor (AHR) and AHR-interacting protein in pituitary adenomas: pathological and clinical implications. Endocr Relat Cancer 16:1029–1043

    Article  CAS  Google Scholar 

  10. Jaffrain-Rea ML, Rotondi S, Turchi A et al (2013) Somatostatin analogues increase AIP expression in somatotropinomas, irrespective of Gsp mutations. Endocr Relat Cancer. 20(5):753–766

    Article  CAS  Google Scholar 

  11. Vierimaa O, Georgitsi M, Lehtonen R et al (2006) Pituitary adenoma predisposition caused by germline mutations in the AIP gene. Science 312(5777):1228–1230

    Article  CAS  Google Scholar 

  12. Caimari F, Hernández-Ramírez LC, Dang MN et al (2018) Risk category system to identify pituitary adenoma patients with AIP mutations. J Med Genet 55(4):254–260

    Article  CAS  Google Scholar 

  13. Ma HS, Wang EL, Xu WF et al (2018) Overexpression of DNA (cytosine-5)-methyltransferase 1 (DNMT1) And DNA (cytosine-5)-methyltransferase 3A (DNMT3A) is associated with aggressive behavior and hypermethylation of tumor suppressor genes in human pituitary adenomas. Med Sci Monit. 13(24):4841–4850

    Article  Google Scholar 

  14. Lavrentaki A, Paluzzi A, Wass J, Karavitaki N (2017) Epidemiology of acromegaly: review of population studies. Pituitary. 20(1):4–9

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Endocrinology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    C. Hage & R. Salvatori

  2. Deparment of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    E. Sabini

  3. McKusick-Nathans Institute of Genetic Medicine and Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    H. Alsharhan & J. A. Fahrner

  4. Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    H. Alsharhan

  5. Department of Endocrinology, Centre Hospitalier Universitaire de Liège, Liège, Belgium

    A. Beckers & A. Daly

  6. Division of Endocrinology, Diabetes and Metabolism, Johns Hopkins University, 1830 East Monument Street #333, Baltimore, MD, 21287, USA

    R. Salvatori

Authors
  1. C. Hage
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E. Sabini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H. Alsharhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. A. Fahrner
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A. Beckers
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A. Daly
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R. Salvatori
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception, design and approved the final manuscript.

Corresponding author

Correspondence to R. Salvatori.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Informed consent

Written informed consent was obtained from the guardian of the patient included in the study.

Additional information

Publisher's Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hage, C., Sabini, E., Alsharhan, H. et al. Acromegaly in the setting of Tatton-Brown-Rahman Syndrome. Pituitary 23, 167–170 (2020). https://doi.org/10.1007/s11102-019-01019-w

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11102-019-01019-w

Keywords

Search

Navigation