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Borealin/CDCA8 deficiency alters thyroid development and results in papillary tumor-like structures.Frontiers in Endocrinology 2023/ mutations are associated with congenital hypothyroidism and thyroid dysgenesis. Borealin is involved in mitosis as part of the Chromosomal Passenger Complex. Although...
BACKGROUND
/ mutations are associated with congenital hypothyroidism and thyroid dysgenesis. Borealin is involved in mitosis as part of the Chromosomal Passenger Complex. Although mutations decrease thyrocyte adhesion and migration, little is known about the specific role of Borealin in the thyroid.
METHODS
We characterized thyroid development and function in Borealin-deficient ( ) mice using histology, transcriptomic analysis, and quantitative PCR.
RESULTS
Thyroid development was impaired with a hyperplastic anlage on embryonic day E9.5 followed by thyroid hypoplasia from E11.5 onward. Adult mice exhibited euthyroid goiter and defect in thyroid hormone synthesis. aged mice had disorganized follicles and papillary-like structures in thyroids due to ERK pathway activation and a strong increase of -like genes described by The Cancer Genome Atlas (TCGA) network of papillary thyroid carcinoma. Moreover, thyroids exhibited structural and transcriptomic similarities with papillary thyroid carcinoma tissue from a human patient harboring a mutation, suggesting a role in thyroid tumor susceptibility.
CONCLUSION
These findings demonstrate Borealin involvement in critical steps of thyroid structural development and function throughout life. They support a role for Borealin in thyroid dysgenesis with congenital hypothyroidism. Close monitoring for thyroid cancer seems warranted in patients carrying mutations.
Topics: Animals; Mice; Cell Cycle Proteins; Congenital Hypothyroidism; Thyroid Cancer, Papillary; Thyroid Dysgenesis; Thyroid Neoplasms
PubMed: 37964961
DOI: 10.3389/fendo.2023.1286747 -
FEBS Open Bio May 2021Thyroid dysgenesis (TD) is a major cause of primary congenital hypothyroidism; however, the molecular mechanism underlying this process is unclear. Current knowledge...
Thyroid dysgenesis (TD) is a major cause of primary congenital hypothyroidism; however, the molecular mechanism underlying this process is unclear. Current knowledge regarding the morphogenesis of the thyroid gland and vascular anomalies affecting thyroid development is limited. To monitor the early stages of thyroid gland development, we generated double transgenic zebrafish embryos Tg(tg:mCherry/flk1:EGFP). We described the volume of the thyroid from 2 days postfertilization (dpf) to 5 dpf using 3D reconstruction images. We treated zebrafish embryos with the fibroblast growth factor (FGF) inhibitor PD166866 to better understand the impact of vascular defects on thyroid development and the effects of drug administration at specific time periods on different stages of thyroid development. The 3D reconstruction data revealed that the thyroid glands underwent significant transformation at critical time points. PD166866 treatment from 48 to 72 hours postfertilization (hpf) and from 72 to 96 hpf did not cause obvious reductions in thyroid volume but did result in observable abnormalities in thyroid morphology. The treatment also affected thyroid volume from 36 to 48 hpf, thus indicating that there are time-point-specific effects of drug administration during thyroid development. Three-dimensional image reconstruction provides a comprehensive picture of thyroid anatomy and can be used to complement anatomical fluorescence information. The effects of an FGF pathway inhibitor on thyroid development were determined to be time-point-dependent.
Topics: Animals; Animals, Genetically Modified; Fibroblast Growth Factors; Humans; Image Processing, Computer-Assisted; Microscopy; Morphogenesis; Thyroid Dysgenesis; Thyroid Gland; Zebrafish
PubMed: 33735512
DOI: 10.1002/2211-5463.13150 -
Diagnostic and Interventional Radiology... 2012Ectopic thyroid tissue may be observed anywhere from the tongue base to the lower neck. It is rarely seen in the mediastinum and abdominal cavity. Computed tomography... (Review)
Review
Ectopic thyroid tissue may be observed anywhere from the tongue base to the lower neck. It is rarely seen in the mediastinum and abdominal cavity. Computed tomography and magnetic resonance imaging are very sensitive for detection and localization of ectopic thyroid tissue. This pictorial essay presents the radiological characteristics of developmental abnormalities and ectopia varieties of the thyroid gland.
Topics: Adult; Aged; Choristoma; Congenital Abnormalities; Diagnostic Imaging; Female; Humans; Incidence; Incidental Findings; Magnetic Resonance Imaging; Male; Middle Aged; Prognosis; Risk Assessment; Thyroglossal Cyst; Thyroid Dysgenesis; Thyroid Gland; Tomography, X-Ray Computed; Tongue Diseases; Ultrasonography, Doppler
PubMed: 22328282
DOI: 10.4261/1305-3825.DIR.4913-11.2 -
Hormone Research in Paediatrics 2010The pathophysiology of thyroid dysgenesis remains unclear and, until recently, this disorder was generally regarded as sporadic. However, a small but significant... (Review)
Review
The pathophysiology of thyroid dysgenesis remains unclear and, until recently, this disorder was generally regarded as sporadic. However, a small but significant proportion of familial cases have been identified (2%) through the study of subjects with congenital hypothyroidism, and more recent work has revealed an even higher proportion of familial thyroid dysgenesis in both symptomatic and asymptomatic individuals. These studies strongly suggest the existence of a familial component of this disorder involving dominant genetic predisposition factors with a low penetrance.
Topics: Congenital Hypothyroidism; Female; Humans; Male; Pedigree; Phenotype; Thyroid Dysgenesis
PubMed: 20215768
DOI: 10.1159/000284386 -
EMBO Molecular Medicine Dec 2018The genetic causes of congenital hypothyroidism due to thyroid dysgenesis (TD) remain largely unknown. We identified three novel gene mutations that co-segregated with...
The genetic causes of congenital hypothyroidism due to thyroid dysgenesis (TD) remain largely unknown. We identified three novel gene mutations that co-segregated with TD in three distinct families leading to 1.1% of mutations in TD study cohort. (Tubulin, Beta 1 Class VI) encodes for a member of the β-tubulin protein family. gene is expressed in the developing and adult thyroid in humans and mice. All three mutations lead to non-functional α/β-tubulin dimers that cannot be incorporated into microtubules. In mice, knock-out disrupted microtubule integrity by preventing β1-tubulin incorporation and impaired thyroid migration and thyroid hormone secretion. In addition, mutations caused the formation of macroplatelets and hyperaggregation of human platelets after stimulation by low doses of agonists. Our data highlight unexpected roles for β1-tubulin in thyroid development and in platelet physiology. Finally, these findings expand the spectrum of the rare paediatric diseases related to mutations in tubulin-coding genes and provide new insights into the genetic background and mechanisms involved in congenital hypothyroidism and thyroid dysgenesis.
Topics: Animals; Blood Platelets; Humans; Mice; Mice, Knockout; Mutation; Platelet Aggregation; Thyroid Dysgenesis; Tubulin
PubMed: 30446499
DOI: 10.15252/emmm.201809569 -
Endocrinology, Diabetes & Metabolism May 2022Subclinical hypothyroidism (SCH) is the commonest thyroid abnormality in patients with Down syndrome (DS). The purpose of this study was to determine the prevalence and... (Review)
Review
BACKGROUND
Subclinical hypothyroidism (SCH) is the commonest thyroid abnormality in patients with Down syndrome (DS). The purpose of this study was to determine the prevalence and types of thyroid abnormalities, to assess the age at diagnosis, and to examine the screening practice in children with DS in a resource limited setting.
METHODOLOGY
A retrospective study was conducted in children with DS seen at endocrine follow-up clinic. Data were collected from patients' registration book and medical records.
RESULT
A total of 115 patients with DS were included in the study out of which 64 (59.8%) were males. Their median age at diagnosis was 9 months (range 4-15 years). Thyroid function test (TFT) was done at least once for 107 (93%) patients. Abnormal thyroid function was observed in 51 (47.7%) patients. The commonest thyroid abnormality was SCH (30/107, 28%) followed by congenital hypothyroidism (11/107, 10.3%), overt hypothyroidism (9/107, 8.4%) and hyperthyroidism (1/107, 0.9%). Most of the patients (86/107, 80.4%) were tested initially in the first 2 years of life. From those who were tested between the age of 2-6 months (n = 22 patients), seven (31.8%) patients had thyroid abnormalities.
CONCLUSION
Thyroid abnormalities were seen in a remarkable proportion of DS patients. The detection of abnormalities in the patients with age range of 2-6 months demands the need for additional TFT in this age category apart from the standard recommendation. Early diagnosis and management of thyroid abnormalities are important to decrease further impairment of cognition function in children with DS.
Topics: Child; Down Syndrome; Ethiopia; Female; Hospitals; Humans; Hypothyroidism; Infant; Male; Retrospective Studies; Thyroid Diseases; Thyroid Dysgenesis
PubMed: 35426257
DOI: 10.1002/edm2.337 -
Hormone Research 2008Imaging of thyroid dysfunction is safe and clinically relevant in children. In congenital hypothyroidism (CH), thyroid imaging permits a precise characterization of the... (Review)
Review
Imaging of thyroid dysfunction is safe and clinically relevant in children. In congenital hypothyroidism (CH), thyroid imaging permits a precise characterization of the aetiology, which is important for genetic counselling and clinical management. CH may be due to thyroid dysgenesis (ectopia, hypoplasia and athyrosis) or occurs in eutopic glands. In the latter, hypothyroidism may be either transient, especially after iodine overload, or due to permanent autosomal recessive dyshormonogenesis. Thyroid scintigraphy (TS) with either 99mTcO4 or 123I will identify ectopic thyroid tissue, which is the commonest cause of CH. However, recent reports favour the use of 123I, which enhances the accuracy of the aetiological classification. In cases of eutopic thyroid, the measurement of 123I uptake before and after perchlorate administration evaluates the organification process. At all ages, colour Doppler ultrasound scanning (CDU) is helpful in assessing thyroid volume, in identifying nodules and in characterizing tissue vascularization. TS and CDU images of most paediatric thyroid dysfunctions are presented.
Topics: Adolescent; Child; Child, Preschool; Congenital Hypothyroidism; Echocardiography, Doppler, Color; Female; Humans; Infant; Infant, Newborn; Male; Radionuclide Imaging; Thyroid Gland
PubMed: 18493144
DOI: 10.1159/000129672 -
Journal of Ultrasound Jun 2019The neck structures are located very superficially and are therefore easy to explore by ultrasound examination. Ultrasonography is crucial for the detection of neck...
The neck structures are located very superficially and are therefore easy to explore by ultrasound examination. Ultrasonography is crucial for the detection of neck pathologies in children. High-frequency probes (10-15 MHz) are used for the ultrasound examination on the patient lying in supine decubitus and with their neck stretched out. The outcome of the exam depends mainly on the child's cooperation-hence the need for warm sonographic gel and a comfortable cushion to place under the patient's shoulders. The complete scan of the neck includes the evaluation of the thyroid and salivary glands and the vascular structures as well as the lymph node analysis. In children and adolescents, the thymus is often visualised in the supraclavicular and jugular scans. It appears as a structure, usually hypoechoic, with thin hyperechoic straps, though echogenicity increases with age. In this pictorial essay, the main pathological conditions of the neck in paediatric age will be examined, such as thyroid dysgenesis, thyroiditis, thyroid nodules, lymphadenopathies, cystic lesions, haemangiomas and vascular malformation, cervical thymus, fibromatosis colli and pilomatrixoma.
Topics: Adolescent; Child; Humans; Neck; Pediatrics; Ultrasonography
PubMed: 30187386
DOI: 10.1007/s40477-018-0317-2 -
Hormones (Athens, Greece) 2011
Review
Topics: Animals; Hormone Replacement Therapy; Humans; Thyroid Dysgenesis; Thyroid Gland; Thyroid Hormones
PubMed: 22281882
DOI: 10.14310/horm.2002.1317 -
PloS One 2023The disorder of thyroid gland development or thyroid dysgenesis accounts for 80-85% of congenital hypothyroidism (CH) cases. Mutations in the TSHR gene are mostly...
The disorder of thyroid gland development or thyroid dysgenesis accounts for 80-85% of congenital hypothyroidism (CH) cases. Mutations in the TSHR gene are mostly associated with thyroid dysgenesis, and prevent or disrupt normal development of the gland. There is limited data available on the genetic spectrum of congenital hypothyroid children in Bangladesh. Thus, an understanding of the molecular aetiology of thyroid dysgenesis is a prerequisite. The aim of the study was to investigate the effect of mutations in the TSHR gene on the small molecule thyrogenic drug-binding site of the protein. We identified two nonsynonymous mutations (p.Ser508Leu, p.Glu727Asp) in the exon 10 of the TSHR gene in 21 patients with dysgenesis by sequencing-based analysis. Later, the TSHR368-764 protein was modeled by the I-TASSER server for wild-type and mutant structures. The model proteins were targeted by thyrogenic drugs, MS437 and MS438 to perceive the effect of mutations. The damaging effect in drug-protein complexes of mutants was explored by molecular docking and molecular dynamics simulations. The binding affinity of wild-type protein was much higher than the mutant cases for both of the drug ligands (MS437 and MS438). Molecular dynamics simulates the dynamic behavior of wild-type and mutant complexes. MS437-TSHR368-764MT2 and MS438-TSHR368-764MT1 showed stable conformations in biological environments. Finally, Principle Component Analysis revealed structural and energy profile discrepancies. TSHR368-764MT1 exhibited much more variations than TSHR368-764WT and TSHR368-764MT2, emphasizing a more damaging pattern in TSHR368-764MT1. This genetic study might be helpful to explore the mutational impact on drug binding sites of TSHR protein which is important for future drug design and selection for the treatment of congenital hypothyroid children with dysgenesis.
Topics: Child; Humans; Bangladesh; Congenital Hypothyroidism; Molecular Docking Simulation; Mutation; Receptors, Thyrotropin; Thyroid Dysgenesis
PubMed: 37561783
DOI: 10.1371/journal.pone.0282553