Minimally Invasive Follicular Thyroid Carcinoma Developed in Dyshormonogenetic Multinodular Goiter Due to Thyroid Peroxidase Gene Mutation
ABSTRACT The occurrence of thyroid carcinoma in patients with congenital hypothyroidism (CH) caused by dyshormonogenesis is very rare, and has only been reported in one patient harboring mutations in the thyroid peroxidase (TPO) gene.
We report on a 29-year follow-up of two consanguineous siblings with CH due to total iodide organification defect who also had sensorineural hearing loss. Molecular analysis revealed a novel biallelic mutation of the TPO gene in which phenylalanine substitutes serine at codon 292 (c.875C>T, p.S292F) in exon 8. Despite early initiation, adequate doses of levothyroxine treatment and consequently normal thyrotropin (TSH) levels, the proposita developed a huge multinodular goiter (MNG) and underwent total thyroidectomy due to tracheal compression. Pathological examination revealed a unifocal follicular thyroid carcinoma without vascular invasion in the left lobe of the thyroid gland.
Our finding of follicular thyroid carcinoma arising from dyshormonogenetic MNG in a patient without elevated serum TSH levels indicates that genetic and environmental factors other than TSH level might be involved in the development of thyroid carcinoma in dyshormonogenetic MNG.
Despite the rare occurrence of thyroid carcinoma in dyshormonogenetic MNG, we recommend long-term follow-up and regular neck ultrasound imaging to prevent delayed diagnosis of thyroid carcinoma.
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ABSTRACT: The c.2268dup mutation in the thyroid peroxidase (TPO) gene is the most common TPO alteration reported in Taiwanese patients with thyroid dyshormonogenesis. The ancestors of these patients are believed to originate from the southern province of China. Our previous study showed that this mutation leads to reduced abundance of the TPO protein and loss of TPO enzyme activity in a Malaysian-Chinese family with goitrous hypothyroidism. The aim of our study was to provide further data on the incidence of the c.2268dup mutation in a cohort of Malaysian-Chinese and its possible phenotypic effects. Cohort study. Twelve biologically unrelated Malaysian-Chinese patients with congenital hypothyroidism were recruited in this study. All patients showed high thyrotropin and low free thyroxine levels at the time of diagnosis with proven presence of a thyroid gland. Screening of the c.2268dup mutation in the TPO gene in all patients was carried out using a PCR-direct DNA sequencing method. Further screening for mutations in other exonic regions of the TPO gene was carried out if the patient was a carrier of the c.2268dup mutation. The c.2268dup mutation was detected in 4 of the 12 patients. Apart from the c.2268dup and a previously documented mutation (c.2647C>T), two novel TPO alterations, c.670_672del and c.1186C>T, were also detected in our patients. In silico analyses predicted that the novel alterations affect the structure/function of the TPO protein. The c.2268dup mutation was detected in approximately one-third of the Malaysian-Chinese patients with thyroid dyshormonogenesis. The detection of the novel c.670_672del and c.1186C>T alterations expand the mutation spectrum of TPO associated with thyroid dyshormonogenesis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.BMJ Open 01/2015; 5(1):e006121. DOI:10.1136/bmjopen-2014-006121 · 2.06 Impact Factor
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ABSTRACT: Thyroid hormone biosynthetic defects are rare causes of congenital hypothyroidism. Although, initial presentations are usually diffuse goiter and hypothyroidism, subsequently they may develop thyroid nodules and or thyroid cancer. We describe a case of hypothyroidism due to dyshormonogenesis whose one of the previously solid nodules degenerates into a large cyst. A 22-year-old male was referred to our clinic for evaluation of enlarging thyroid nodule. Hypothyroidism was diagnosed in infancy, however due to poor compliance to treatment TSH values were elevated most of the times. When he was fifteen the first nodule was detected which was a solid cold nodule. Fine needle aspiration was in favor of benign follicular nodule. Seven years later we found a large multi nodular thyroid with a predominant large cyst corresponding to the previously detected solid nodule. 21cc straw colored fluid was aspirated. Cytology was reported as benign cystic nodule. The patient underwent thyroidectomy and pathology confirmed a benign thyroid cyst. Although underreported thyroid dyshormonogenesis may progress to cystic degeneration. Taking into account the risk of malignancy and eventually cyst formation, we recommend more frequent evaluation in the face of nodule formation in these patients. Arq Bras Endocrinol Metab. 2014;58(9):958-61.Arquivos Brasileiros de Endocrinologia & Metabologia 12/2014; 58(9):958-61. DOI:10.1590/0004-2730000003287 · 0.68 Impact Factor
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ABSTRACT: Background: Defects in the thyroid peroxidase (TPO) gene have been associated with goitrous congenital hypothyroidism (CH). Case Report: In this study, we report 3 siblings possessing a homozygous mutation, c.1159G>A, but exhibiting different clinical phenotypes in a Malaysian-Malay family. The index patient was diagnosed with CH during a routine neonatal screening but the other 2 siblings appeared to be asymptomatic until the ages of 19 and 12.5, respectively, when they started to develop goiter. Results and Conclusion: The mutation was predicted to interrupt the correct splicing of pre-mRNA and also lead to structural alterations in the functional sites of the mutant TPO. The current results suggest the association of goiter development with a homozygous c.1159G>A mutation, but the CH in the index patient could be triggered by other genetic and epigenetic factors distinct from the c.1159G>A mutation. © 2014 S. Karger AG, Basel.Hormone Research in Paediatrics 04/2014; 81(5). DOI:10.1159/000359922 · 1.71 Impact Factor