C Hage1, E Sabini2, H Alsharhan3,4, J A Fahrner3, A Beckers5, A Daly5, R Salvatori6,7. 1. Division of Endocrinology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 2. Deparment of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 3. McKusick-Nathans Institute of Genetic Medicine and Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 4. Children's Hospital of Philadelphia, Philadelphia, PA, USA. 5. Department of Endocrinology, Centre Hospitalier Universitaire de Liège, Liège, Belgium. 6. Division of Endocrinology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. salvator@jhmi.edu. 7. Division of Endocrinology, Diabetes and Metabolism, Johns Hopkins University, 1830 East Monument Street #333, Baltimore, MD, 21287, USA. salvator@jhmi.edu.
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.
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.
Authors: Outi Vierimaa; Marianthi Georgitsi; Rainer Lehtonen; Pia Vahteristo; Antti Kokko; Anniina Raitila; Karoliina Tuppurainen; Tapani M L Ebeling; Pasi I Salmela; Ralf Paschke; Sadi Gündogdu; Ernesto De Menis; Markus J Mäkinen; Virpi Launonen; Auli Karhu; Lauri A Aaltonen Journal: Science Date: 2006-05-26 Impact factor: 47.728
Authors: Wei Shen; Jennifer M Heeley; Colleen M Carlston; Rocio Acuna-Hidalgo; Willy M Nillesen; Karin M Dent; Ganka V Douglas; Kara L Levine; Pinar Bayrak-Toydemir; Carlo L Marcelis; Marwan Shinawi; John C Carey Journal: Am J Med Genet A Date: 2017-09-21 Impact factor: 2.802
Authors: B Xin; T Cruz Marino; J Szekely; J Leblanc; K Cechner; V Sency; C Wensel; M Barabas; V Therriault; H Wang Journal: Clin Genet Date: 2017-01-22 Impact factor: 4.438
Authors: Silvia Vandeva; Marie-Lise Jaffrain-Rea; Adrian F Daly; Maria Tichomirowa; Sabina Zacharieva; Albert Beckers Journal: Best Pract Res Clin Endocrinol Metab Date: 2010-06 Impact factor: 4.690
Authors: Margaret A Ferris; Amanda M Smith; Sharon E Heath; Eric J Duncavage; Matthew Oberley; David Freyer; Robert Wynn; Sofia Douzgou; John M Maris; Anne F Reilly; Melinda D Wu; Florence Choo; Roel B Fiets; Saskia Koene; David H Spencer; Christopher A Miller; Marwan Shinawi; Timothy J Ley Journal: Blood Date: 2022-01-20 Impact factor: 22.113
Authors: Alana C Cecchi; Amier Haidar; Isabella Marin; Callie S Kwartler; Siddharth K Prakash; Dianna M Milewicz Journal: Am J Med Genet A Date: 2021-10-13 Impact factor: 2.578
Authors: Amanda M Smith; Taylor A LaValle; Marwan Shinawi; Sai M Ramakrishnan; Haley J Abel; Cheryl A Hill; Nicole M Kirkland; Michael P Rettig; Nichole M Helton; Sharon E Heath; Francesca Ferraro; David Y Chen; Sangeeta Adak; Clay F Semenkovich; Diana L Christian; Jenna R Martin; Harrison W Gabel; Christopher A Miller; Timothy J Ley Journal: Nat Commun Date: 2021-07-27 Impact factor: 14.919