Abstract
Dyshormonogenesis (DG) is the failure of thyroid hormone production due to a defect in thyroid hormonogenesis. Loss-of-function mutations in the thyroglobulin (TG) gene are a cause of DG, leading to gland stimulation by thyroid-stimulating hormone (TSH), resulting in goiter. We report a mitotically active follicular nodule in an 11-year-old female with a novel mutation in the TG gene. The patient had been under follow-up for congenital hypothyroidism (CH) since the neonatal period, and she had normal TSH levels on replacement therapy. Genetic test revealed a novel compound heterogeneous mutation [c.2149C>T (p.R717*) (P.Arg717Ter) / c.5361_5362delCCinsG (p.H1787Qfs*3) (p.His1787GlnfsTer3)] in the TG gene. She underwent total thyroidectomy for a thyroid nodule that was reported as Bethesda IV on fine needle aspiration biopsy (FNAB) and noted as suspicious for noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Pathological examination revealed a 16 mm, well-demarcated follicular nodule with a solid/insular pattern. Mitotic activity and Ki67 proliferation index were unusually high (10 mitoses/mm2 and 10%, respectively). Marked cellular pleomorphism and nuclear atypia are well-known diagnostic pitfalls in patients with dyshormonogenetic goiter. However, high mitotic activity is a feature that is less commonly reported in dyshormonogenetic goiter and may raise suspicion of poorly differentiated carcinoma when observed together with a solid pattern. The absence of signs of invasion, history of CH, and awareness of the presence of mutations compatible with dyshormonogenetic goiter can prevent the overinterpretation of such lesions. The risk of cancer development in the dyshormonogenetic thyroid gland is possible in childhood. The close follow-up is life-saving and prevents morbidities and possible mortality.
Keywords: Congenital hypothyroidism, thyroglobulin synthesis defect, thyroglobulin (TG)
Read the full text
3 sections · 1 table · PDF
Create your free account to read the full text.
- Full text with figures and tables
- PDF and supplementary files
- Access on every Galenos journal
One Galenos account works on every Galenos journal site.
References
Francis GL, Waguespack SG, Bauer AJ, Angelos P, Benvenga S, Cerutti JM, Dinauer CA, Hamilton J, Hay ID, Luster M, Parisi MT, Rachmiel M, Thompson GB, Yamashita S; American Thyroid Association Guidelines Task Force. Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2015;25:716-759.
Penna G, Rubio IGS, Brust ES, Cazarin J, Hecht F, Alkmim NR, Rajão KMAB, Ramos HE. Congenital hypothyroidism and thyroid cancer. Endocr Relat Cancer. 2021;28:217-230.
Siffo S, Adrover E, Citterio CE, Miras MB, Balbi VA, Chiesa A, Weill J, Sobrero G, González VG, Papendieck P, Martinez EB, Gonzalez-Sarmiento R, Rivolta CM, Targovnik HM. Molecular analysis of thyroglobulin mutations found in patients with goiter and hypothyroidism. Mol Cell Endocrinol. 2018;473:1-16. Epub 2017 Dec 22
Targovnik HM, Citterio CE, Rivolta CM. Thyroglobulin gene mutations in congenital hypothyroidism. Horm Res Paediatr. 2011;75:311-321. Epub 2011 Mar 3
Ieiri T, Cochaux P, Targovnik HM, Suzuki M, Shimoda S, Perret J, Vassart G. A 3’ splice site mutation in the thyroglobulin gene responsible for congenital goiter with hypothyroidism. J Clin Invest. 1991;88:1901-1905.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-423. Epub 2015 Mar 5
Baloch ZW, Asa SL, Barletta JA, Ghossein RA, Juhlin CC, Jung CK, LiVolsi VA, Papotti MG, Sobrinho-Simões M, Tallini G, Mete O. Overview of the 2022 WHO Classification of Thyroid Neoplasms. Endocr Pathol. 2022;33:27-63. Epub 2022 Mar 14
Ghossein RA, Rosai J, Heffess C. Dyshormonogenetic Goiter: A Clinicopathologic Study of 56 Cases. Endocr Pathol. 1997;8:283-292.
Yoon JH, Hong AR, Kim HK, Kang HC. Anaplastic Thyroid Cancer Arising from Dyshormonogenetic Goiter: c.3070T>C and Novel c.7070T>C Mutation in the Thyroglobulin Gene. Thyroid. 2020;30:1676-1680. Epub 2020 Jul 6
Aydıner Ö, Karakoç Aydıner E, Akpınar İ, Turan S, Bereket A. Normative Data of Thyroid Volume-Ultrasonographic Evaluation of 422 Subjects Aged 0-55 Years. J Clin Res Pediatr Endocrinol. 2015;7:98-101.
Demir K, Konakçı E, Özkaya G, Kasap Demir B, Özen S, Aydın M, Darendeliler F. New Features for Child Metrics: Further Growth References and Blood Pressure Calculations. J Clin Res Pediatr Endocrinol. 2020;12:125-129. Epub 2019 Sep 2
