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The Journal of Clinical Investigation Mar 2020BACKGROUNDDICER1 is the only miRNA biogenesis component associated with an inherited tumor syndrome, featuring multinodular goiter (MNG) and rare pediatric-onset... (Clinical Trial)
Clinical Trial
BACKGROUNDDICER1 is the only miRNA biogenesis component associated with an inherited tumor syndrome, featuring multinodular goiter (MNG) and rare pediatric-onset lesions. Other susceptibility genes for familial forms of MNG likely exist.METHODSWhole-exome sequencing of a kindred with early-onset MNG and schwannomatosis was followed by investigation of germline pathogenic variants that fully segregated with the disease. Genome-wide analyses were performed on 13 tissue samples from familial and nonfamilial DGCR8-E518K-positive tumors, including MNG, schwannomas, papillary thyroid cancers (PTCs), and Wilms tumors. miRNA profiles of 4 tissue types were compared, and sequencing of miRNA, pre-miRNA, and mRNA was performed in a subset of 9 schwannomas, 4 of which harbor DGCR8-E518K.RESULTSWe identified c.1552G>A;p.E518K in DGCR8, a microprocessor component located in 22q, in the kindred. The variant identified is a somatic hotspot in Wilms tumors and has been identified in 2 PTCs. Copy number loss of chromosome 22q, leading to loss of heterozygosity at the DGCR8 locus, was found in all 13 samples harboring c.1552G>A;p.E518K. miRNA profiling of PTCs, MNG, schwannomas, and Wilms tumors revealed a common profile among E518K hemizygous tumors. In vitro cleavage demonstrated improper processing of pre-miRNA by DGCR8-E518K. MicroRNA and RNA profiling show that this variant disrupts precursor microRNA production, impacting populations of canonical microRNAs and mirtrons.CONCLUSIONWe identified DGCR8 as the cause of an unreported autosomal dominant mendelian tumor susceptibility syndrome: familial multinodular goiter with schwannomatosis.FUNDINGCanadian Institutes of Health Research, Compute Canada, Alex's Lemonade Stand Foundation, the Mia Neri Foundation for Childhood Cancer, Cassa di Sovvenzioni e Risparmio fra il Personale della Banca d'Italia, and the KinderKrebsInitiative Buchholz/Holm-Seppensen.
Topics: Amino Acid Substitution; Child; Chromosomes, Human, Pair 22; Female; Gene Dosage; Genetic Predisposition to Disease; Genome-Wide Association Study; Goiter, Nodular; HEK293 Cells; Humans; Male; Mutation, Missense; Neoplasm Proteins; Neurilemmoma; Neurofibromatoses; RNA-Binding Proteins; Skin Neoplasms; Exome Sequencing
PubMed: 31805011
DOI: 10.1172/JCI130206 -
Laryngoscope Investigative... Apr 2022The standard treatment for endemic goiter is usually total thyroidectomy. In low- and middle-income countries, the management of thyroid disease, which is commonplace in...
BACKGROUND
The standard treatment for endemic goiter is usually total thyroidectomy. In low- and middle-income countries, the management of thyroid disease, which is commonplace in fully developed countries, is not always possible. The purpose of this study is to establish a treatment algorithm to calculate the extent of thyroidectomy based on the risk factors of each patient.
METHODS
This is a retrospective observational study conducted during the period between 2017 and 2019. A total of 287 patients with thyroid pathology were treated in Maragua Hospital (Kenya). The results of surgical treatment were analyzed after the implementation of an individualized treatment protocol.
RESULTS
One hundred and sixty patients with different types of goiter underwent surgery: solitary nodule (54.4%), multi-nodular goiter (30.6%), diffuse goiter (10.6%), and intrathoracic goiter (3.8%). The techniques used were hemithyroidectomy (78.8%), Dunhill thyroidectomy (9.4%), bilateral subtotal thyroidectomy (6.9%), and total thyroidectomy (3.1%). There was no mortality. The surgical morbidity rate was 16% (only one major complication (3b)). Two cases of dysphonia were resolved in the first week. There were three cases of symptomatic hypocalcaemia, two of which resolved in the first week and the other of which was definitive. The follow-up at 6 months was 67%. The cancer rate found in the resection specimens was 5%.
DISCUSSION
The implementation of individualized surgical protocols for thyroid surgery in sub-Saharan Africa can improve outcomes. The cooperation projects can increase access to complex surgical treatment for patients with limited resources in low- and middle-income countries.
PubMed: 35434333
DOI: 10.1002/lio2.764 -
Diagnostics (Basel, Switzerland) Sep 2021Post-thyroidectomy hypocalcemia is a frequent complication with significant morbidity, and has been shown to increase hospital stay and readmission rates. The evaluation...
Post-thyroidectomy hypocalcemia is a frequent complication with significant morbidity, and has been shown to increase hospital stay and readmission rates. The evaluation of serum parathyroid hormone (PTH) levels after thyroidectomy represents a reliable method to predict post-thyroidectomy hypocalcemia, but it remains infrequently used. This retrospective study investigates serum PTH values 3 h after thyroidectomy as a predictor of hypocalcemia. In this study, we enrolled 141 patients aged between 27 and 71 years eligible for total thyroidectomy who presented with multinodular goiter, suspicious nodule on cytological examination, Graves' disease, or toxic multinodular goiter. Three hours after total thyroidectomy, 53 patients (37.6%) showed a reduction in serum PTH. Of these patients 75.5% developed hypocalcemia by 24 h after surgery and 100% were hypocalcemic after 48 h ( < 0.001). There was no significant difference attributable to the different thyroid diseases, nor to the age of the patients. PTH at 3 h after total thyroidectomy accurately predicts post-operative hypocalcemia. The early detection of patients at risk of developing post-operative hypocalcemia allows for prompt supplementation of calcium and Vitamin D in order to prevent symptoms and allows for a safe and timely discharge.
PubMed: 34574074
DOI: 10.3390/diagnostics11091733 -
Thyroid Research Apr 2022Hyperthyroidism has been treated with radioiodine therapy for eight decades, with known benefits and side-effects. No consensus exists on which activity dosage and...
BACKGROUND
Hyperthyroidism has been treated with radioiodine therapy for eight decades, with known benefits and side-effects. No consensus exists on which activity dosage and pre-therapeutic measurements are required for optimal treatment, balancing risk of incomplete response, therapy-induced hypothyroidism and radiation exposure. A retrospective analysis was performed to assess these questions.
METHODS
Data was collected on radioiodine treatment outcomes for 904 patients treated for Graves' disease or toxic nodular goitres at our institution during 2016-2020. The prescribed absorbed doses were 120 Gy (Graves' disease), 200 Gy (toxic multinodular goitre) and 300 Gy (solitary toxic adenoma). Univariate analysis and multivariate regression modelling were used to find factors linked to treatment outcome.
RESULTS
The cure rate of hyperthyroidism after one administration of radioiodine was 79% for Graves' disease, 94% for toxic multinodular goitre and 98% for solitary toxic adenoma. Thyroid mass, uptake and effective half-life were all significantly associated with cure in Graves' disease, but not in toxic multinodular goitre. The rates of therapy-induced hypothyroidism were 20% and 29% for toxic multinodular goitre and solitary toxic adenoma. Neither the cure rate nor the hypothyroidism rate was found to be superior among patients with individualised effective half-life measurements in toxic nodular goitres. Poor renal function was associated with dubious iodine uptake measurements but was not found to correlate with worse outcome.
CONCLUSIONS
Multiple measurements of individual iodine uptake for kinetics estimation may be unnecessary, and a population-based value can be used instead. Patients with renal impairment had similar outcome as other patients, but with a higher risk of dubious uptake measurements.
PubMed: 35462539
DOI: 10.1186/s13044-022-00126-4 -
Cells Mar 2022Congenital hypothyroidism is a genetic condition in which the thyroid gland fails to produce sufficient thyroid hormone (TH), resulting in metabolic dysfunction and...
Congenital hypothyroidism is a genetic condition in which the thyroid gland fails to produce sufficient thyroid hormone (TH), resulting in metabolic dysfunction and growth retardation. Xb130 mice exhibit perturbations of thyrocyte cytoskeleton and polarity, and develop postnatal transient growth retardation due to congenital hypothyroidism, leading ultimately to multinodular goiter. To determine the underlying mechanisms, we performed transcriptomic analyses on thyroid glands of mice at three age points: week 2 (W2, before visible growth retardation), W4 (at the nadir of growth); and W12 (immediately before full growth recovery). Using gene set enrichment analysis, we compared a defined set of thyroidal genes between Xb130 and Xb130 mice to identify differentially enriched gene clusters. At the earliest postnatal stage (W2), the thyroid glands of Xb130 mice exhibited significantly downregulated gene clusters related to cellular metabolism, which continued to W4. Additionally, mutant thyroids at W4 and W12 showed upregulated gene clusters related to extracellular matrix, angiogenesis, and cell proliferation. At W12, despite nearly normal levels of serum TH and TSH and body size, a significantly large number of gene clusters related to inflammatory response were upregulated. Early postnatal TH deficiency may suppress cellular metabolism within the thyroid gland itself. Upregulation of genes related to extracellular matrix and angiogenesis may promote subsequent thyroid growth. Chronic inflammatory responses may contribute to the pathogenesis of multinodular goiter in later life. Some of the pathoadaptive responses of Xb130 mice may overlap with those from other mutations causing congenital hypothyroidism.
Topics: Animals; Congenital Hypothyroidism; Goiter; Growth Disorders; Mice; Mice, Knockout; Thyroid Hormones; Transcriptome
PubMed: 35326426
DOI: 10.3390/cells11060975 -
Problemy Endokrinologii Oct 2023DICER1 syndrome is a rare genetic disorder with the progressive development of malignant and non-malignant diseases in childhood. The cause of this syndrome is a... (Review)
Review
DICER1 syndrome is a rare genetic disorder with the progressive development of malignant and non-malignant diseases in childhood. The cause of this syndrome is a dusfunction of the endoribonuclease DICER, which plays an important role in the processing of microRNAs with subsequent regulation of the control of the expression of oncogenes and tumor suppressor genes. Clinical manifestations of dyseropathies is very different and may include both endocrine manifestations - multinodular goiter, differentiated thyroid cancers, ovarian stromal tumors, pituitary blastoma, and non-endocrine formations - pleuropulmonary blastoma, cystic nephroma, pineoblastoma. The presence of somatic mutations of the DICER1 gene is a resultant stage in the pathogenesis of dyseropathies, determining the further path of oncogenesis. At present, DICER1 syndrome is diagnosed extremely rarely, which leads to late detection of the components of the disease in the patient, late diagnosis of neoplasms, lack of family counseling. Diagnosis at the early stages of the disease, the development of screening programs for the management of these patients allows minimizing the risks of developing more malignant, aggressive forms of the disease.
Topics: Humans; Ribonuclease III; DEAD-box RNA Helicases; Mutation; Female; Thyroid Neoplasms; Goiter, Nodular; Pulmonary Blastoma
PubMed: 38796764
DOI: 10.14341/probl13383 -
Endocrinology, Diabetes & Metabolism... Jan 2019Pseudohypoparathyroidism (PHP) is a heterogeneous group of rare endocrine disorders characterised by normal renal function and renal resistance to the action of the...
Pseudohypoparathyroidism (PHP) is a heterogeneous group of rare endocrine disorders characterised by normal renal function and renal resistance to the action of the parathyroid hormone. Type 1A (PHP1A), which is the most common variant, also include developmental and skeletal defects named as Albright hereditary osteodystrophy (AHO). We present two cases, a 54- and a 33-year-old male diagnosed with PHP who were referred to us for persistently high levels of serum calcitonin. AHO and multinodular goitre were present in the 54-year-old male, while the second patient was free of skeletal deformities and his thyroid gland was of normal size and without nodular appearance. We performed GNAS molecular analysis (methylation status and copy number analysis by MS-MLPA) in genomic DNA samples for both patients. The analysis revealed a novel missense variant c.131T>G p.(Leu44Pro) affecting GNAS exon 1, in the patient with the clinical diagnosis of PHP1A. This amino acid change appears to be in accordance with the clinical diagnosis of the patient. The genomic DNA analysis of the second patient revealed the presence of the recurrent 3-kb deletion affecting the imprinting control region localised in the STX16 region associated with the loss of methylation (LOM) at the GNAS A/B differentially methylated region and consistent with the diagnosis of an autosomal dominant form of PHP type 1B (PHP1B). In conclusion, hypercalcitoninaemia may be encountered in PHP1A and PHP1B even in the absence of thyroid pathology. Learning points: We describe a novel missense variant c.131T>G p.(Leu44Pro) affecting GNAS exon 1 as the cause of PHP1A. Hypercalcitoninaemia in PHP1A is considered an associated resistance to calcitonin, as suggested by the generalised impairment of Gsα-mediated hormone signalling. GNAS methylation defects, as in type PHP1B, without thyroid pathology can also present with hypercalcitoninaemia.
PubMed: 30703064
DOI: 10.1530/EDM-18-0125 -
Thyroid Research Dec 2022The debate on whether or not there is a difference in the incidence of thyroid cancer between the patients with Solitary thyroid Nodule (STN) and Multinodular Goiter... (Review)
Review
BACKGROUND
The debate on whether or not there is a difference in the incidence of thyroid cancer between the patients with Solitary thyroid Nodule (STN) and Multinodular Goiter (MNG) has been constantly present for the last few decades. With newer studies yielding mixed results, it was imperative to systematically compile all available literature on the topic.
METHODS
PubMed/MEDLINE, Cochrane Central, ScienceDirect, GoogleScholar, International Clinical Trials registry, and reference lists of the included articles were systematically searched for article retrieval. No filter was applied in terms of time, study design, language or country of publication. Rigorous screening as per PRISMA guidelines was undertaken by 2 independent reviewers in order to identify the articles that were most relevant to the topic.
RESULTS
Twenty-two studies spanning from 1992 to 2018 were included in this analysis and encompassed 50,321 patients, 44.2% of which belonged to the STN subgroup and 55.37% to the MNG subgroup. MNG was found to be associated with a significantly lower risk of thyroid cancer (OR = 0.76; 95% CI 0.61-0.96) when compared with STN. Papillary carcinoma was the most frequently occurring carcinoma across both groups, followed by follicular and medullary carcinomas. A subgroup analysis was performed to assess the efficacy of the two most commonly employed diagnostic tools i.e. surgery and fine needle aspiration cytology (FNAC), however it yielded nonsignificant results, indicating a comparable usefulness of the two. Another subgroup analysis run on the basis of the presumed iodine status of the participants also yielded nonsignificant results.
CONCLUSION
There is a higher incidence of thyroid cancer among patients of STN, however, given the low quality of existing evidence on the topic, it is crucial to conduct larger studies that can establish association with a greater precision.
PubMed: 36464691
DOI: 10.1186/s13044-022-00140-6 -
Turkish Journal of Medical Sciences Nov 2017Background/aim: To evaluate the malignancy risk of thyroid nodules in different clinical thyroid diseases. Materials and methods: Patients who underwent thyroidectomy...
Background/aim: To evaluate the malignancy risk of thyroid nodules in different clinical thyroid diseases. Materials and methods: Patients who underwent thyroidectomy between 2007 and 2014 were grouped as euthyroid, hypothyroid, and hyperthyroid. Further classification was made depending on the presence of solitary/multiple thyroid nodules. Results: Among 2870 patients, 1719 (59.9%) were euthyroid, 962 (33.5%) were hyperthyroid, and 189 (6.6%) were hypothyroid. Overall malignancy was detected in 980 (34.1%) patients. Malignancy rates were 42.1%, 42.9%, and 18.3% in the euthyroid, hypothyroid, and hyperthyroid groups, respectively (P < 0.001). A total 41.4% of patients with euthyroid nodular goiter (ENG) and 46.3% of patients with euthyroid multinodular goiter (EMNG) had thyroid malignancy (P = 0.169). Mean tumor size and capsular and vascular invasion were significantly lower in EMNG than in ENG. Among hypothyroid patients, 45.7% with solitary and 42.2% with multiple nodules were malignant (P = 0.705). When toxic nodular goiter and toxic multinodular goiter were analyzed together, malignancy rate was 24.7% (104/421), and when Graves with nodule/nodules was considered, it was 19.7% (59/299). Conclusion: In hypothyroid or euthyroid patients who underwent thyroidectomy, malignancy rate was higher than 40%, and was lower in hyperthyroid patients. Patients with multiple nodules carry a similar risk of malignancy as patients with solitary nodules, independent of the functional status.
PubMed: 29151324
DOI: 10.3906/sag-1611-67 -
Journal of Family & Community Medicine 2024Multinodular goiter (MNG) is a chronic benign nodular enlargement of the thyroid gland. It presents as an anterior painless neck mass, potentially progressing to exert...
Multinodular goiter (MNG) is a chronic benign nodular enlargement of the thyroid gland. It presents as an anterior painless neck mass, potentially progressing to exert pressure on the trachea and esophagus and giving rise to compressive symptoms. MNG is a common thyroid gland disorder; however, retropharyngeal goiter is considered rare with few reported cases. We report the cases of two patients who presented to our institution with MNG with retropharyngeal extension: a 62-year-old female patient who presented with a progressive anterior neck mass with dilated neck veins; and a 49-year-old male who presented with a painless anterior neck mass. Both patients successfully underwent total thyroidectomy with an uneventful postoperative recovery. The clinical presentation of MNG with retropharyngeal extension varies with patients; hence, a high index of suspicion is of the utmost significance. While the retropharyngeal extension does not cause compressive symptoms, it should raise the suspicion of a large retrosternal component.
PubMed: 38800791
DOI: 10.4103/jfcm.jfcm_263_23