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BACKGROUND: Renal hypokalemia is associated with mutation. This study aimed to investigate the clinical features and pathogenic mutations in patients with renal hypokalemia. METHODS: The patients with hypokalemia were enrolled, and the renal function, thyroid function, renin-aldosterone system, urinary potassium excretion, and exome sequencing were performed. The correlation between the clinical phenotypes and causative genes was assessed. RESULTS: Five patients with hypokalemia were enrolled and diagnosed as tubular hypokalemia. The patients with common clinical manifestations were difficult to differentiate based on atypical laboratory findings. The results of the genetic analysis were as follows: both patient 1 and patient 2 were heterozygous for the c.C625T mutation of the KCNJ1 gene, which is responsible for Bartter syndrome. Patient 3 was heterozygous for the c.G298A mutation of the ATP6V1B1 gene, which is responsible for renal tubular acidosis. Patient 4 had a compound heterozygous mutation of c.G893A of the BSND gene, responsible for Bartter syndrome, and c.1029+5G>A, the ATP6V0A4 gene responsible for distal renal tubular acidosis. Patient 5 had Gitelman syndrome and carried the compound heterozygous mutations c.C1963T and c.G2029A of the SLC12A3 gene. All the above loci were known heterozygous mutations. CONCLUSIONS: The unusual heterozygous mutations were identified in five renal hypokalemia patients. Molecular diagnosis of tubular hypokalemia was conducive to accurate diagnosis and treatment.
Sujet(s)
Syndrome de Bartter , Hétérozygote , Hypokaliémie , Mutation , Humains , Hypokaliémie/génétique , Hypokaliémie/diagnostic , Mâle , Femelle , Syndrome de Bartter/génétique , Syndrome de Bartter/diagnostic , Syndrome de Bartter/complications , Adulte , Syndrome de Gitelman/génétique , Syndrome de Gitelman/diagnostic , Syndrome de Gitelman/complications , Syndrome de Gitelman/physiopathologie , Acidose tubulaire rénale/génétique , Acidose tubulaire rénale/diagnostic , Acidose tubulaire rénale/physiopathologie , Acidose tubulaire rénale/complications , Canaux potassiques rectifiants entrants/génétique , Phénotype , Vacuolar Proton-Translocating ATPases/génétique , Adulte d'âge moyen , Adolescent , Enfant , Potassium/sang , Potassium/urineRÉSUMÉ
The aim of the present study was to explore the association between anemia and the risks and outcomes of diabetic foot (DF) in patients with type 2 diabetes mellitus (T2DM). A total of 145 patients with T2DM were recruited between January and December 2021 and divided into the DF and non-DF groups according to whether they were diagnosed with DF. Individual patient data were extracted and blood samples were evaluated in a biochemical center for routine biochemical and blood-related indicators. The patients' survival rates were followed up until December 2022. An independent-samples t-test and χ2 test were used to compare the differences between the two groups. The association between the various clinical indicators for the DF and non-DF groups was evaluated using single-factor binary logistic regression analysis. Multi-factor binary logistic regression analysis was used to analyze the association between hemoglobin (Hb) and the risk for DF. A Kaplan-Meier survival curve was used to analyze the impact of anemia and DF on the 1-year survival rate. The diabetes duration, number of patients who smoked and consumed alcohol, and serum creatinine and C-reactive protein levels in the DF group were significantly higher than those in the non-DF group (P<0.05). By contrast, the estimated glomerular filtration rate (eGFR) and Hb, albumin (Alb) and total cholesterol levels, were lower in the DF group when compared with those in the non-DF group (P<0.05). All of the study participants were divided into two groups, according to their baseline eGFR [eGFR ≥90 or <90 ml/(min x 1.73 m²)]. It was found that, independently of renal function, lower Hb and Alb levels were associated with a higher incidence of DF. The 1-year survival rate for DF with anemia was significantly lower when compared with that in patients with DF without anemia (P<0.05). In conclusion, the Hb level in patients with T2DM is a protective factor against DF and anemia is an independent risk factor for DF. The present study suggested that anemia is associated with a decrease in the survival rate of patients with DF. This finding provided a theoretical basis for the clinical correction of anemia and improvement of DF prognosis (clinical trial no. 20220003).
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ABSTRACT Objective: Intrathyroidal injection using an insulin pen filled with a mixture of lidocaine and triamcinolone acetonide is a therapy for subacute thyroiditis (SAT) reported by us previously. We aimed to evaluate the clinical efficacy of ultrasound-guided intrathyroidal injection in the treatment of SAT. Subjects and methods: A total of 93 patients with SAT completed the study. All patients were evaluated via a history and clinical examination followed by thyroid function tests and ultrasonography of the thyroid. After ultrasound-guided intrathyroidal injection, the patients were followed up with respect to the injection frequency, treatment duration, and patient satisfaction. The visual numerical rating scale was used as a pain questionnaire for a given interval. Results: Thyroid pain instantly decreased to scores below 3.0 following the first injection. Sixty-three patients (67.74%) avoided relapse of thyroid pain within 3 injections, which occurred within only 3 days after the first injection. The pain in 27 patients (29.03%) disappeared completely after 4-6 injections. Only 3 patients (3.23%) were found to need more than 6 injections, with 10 cited as the maximum number of injections, the injection took only 17 days altogether. The mean treatment cycle of the intrathyroidal injection was 3.98 days. There were no other associated complications with the novel therapy except infrequent small subcutaneous hematomas, which could be prevented with skilled practice. The average patient satisfaction score was as high as 9.0. Conclusion: Intrathyroidal injection of lidocaine and triamcinolone acetonide using an insulin pen was found to be an advantageous and satisfactory treatment for SAT.
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Objective: : Intrathyroidal injection using an insulin pen filled with a mixture of lidocaine and triamcinolone acetonide is a therapy for subacute thyroiditis (SAT) reported by us previously. We aimed to evaluate the clinical efficacy of ultrasound-guided intrathyroidal injection in the treatment of SAT. Subjects and methods: A total of 93 patients with SAT completed the study. All patients were evaluated via a history and clinical examination followed by thyroid function tests and ultrasonography of the thyroid. After ultrasound-guided intrathyroidal injection, the patients were followed up with respect to the injection frequency, treatment duration, and patient satisfaction. The visual numerical rating scale was used as a pain questionnaire for a given interval. Results: Thyroid pain instantly decreased to scores below 3.0 following the first injection. Sixty-three patients (67.74%) avoided relapse of thyroid pain within 3 injections, which occurred within only 3 days after the first injection. The pain in 27 patients (29.03%) disappeared completely after 4-6 injections. Only 3 patients (3.23%) were found to need more than 6 injections, with 10 cited as the maximum number of injections, the injection took only 17 days altogether. The mean treatment cycle of the intrathyroidal injection was 3.98 days. There were no other associated complications with the novel therapy except infrequent small subcutaneous hematomas, which could be prevented with skilled practice. The average patient satisfaction score was as high as 9.0. Conclusion: Intrathyroidal injection of lidocaine and triamcinolone acetonide using an insulin pen was found to be an advantageous and satisfactory treatment for SAT.
Sujet(s)
Insulines , Thyroïdite subaigüe , Humains , Lidocaïne/usage thérapeutique , Triamcinolone acétonide/usage thérapeutique , Triamcinolone acétonide/effets indésirables , Anesthésiques locaux/usage thérapeutique , Douleur/induit chimiquement , Douleur/traitement médicamenteux , Résultat thérapeutique , Insulines/usage thérapeutiqueRÉSUMÉ
The objective of this study was to clinically and genetically characterize a pedigree with Liddle syndrome (LS). A LS pedigree comprising with one proband and seven family members was enrolled. The subjects' symptoms, laboratory results and genotypes were analyzed. Peripheral venous samples were collected from the subjects, and genomic DNA was extracted. DNA library construction and exome capture were performed on an Illumina HiSeq 4000 platform. The selected variant sites were validated using Sanger sequencing. The mutation effects were investigated using prediction tools. The proband and her paternal male family members had mild hypertension, hypokalemia and muscle weakness, including the absence of low renin and low aldosterone. Genetic analysis revealed that the proband carried a compound heterozygous mutation in SCNN1A, a novel heterozygous mutation, c.1130T > G (p.Ile377Ser) and a previously characterized polymorphism, c.1987A > G (p.Thr633Ala). The novel mutation site was inherited in an autosomal dominant manner and was predicted by in silico tools to exert a damaging effect. Alterations in the SCNN1A domain were also predicted by protein structure modeling. After six months of follow-up, treatment had significantly improved the patient's limb weakness and electrolyte levels. The novel mutation c.1130T > G of the SCNN1A gene was detected in the pedigree with LS. The clinical manifestations of the pedigree were described, which expand the phenotypic spectrum of LS. This result of this study also emphasizes the value of genetic testing for diagnosing LS.
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Hypertension artérielle , Hypokaliémie , Syndrome de Liddle , Femelle , Humains , Mâle , Hypokaliémie/génétique , Canaux sodium épithéliaux/génétique , Canaux sodium épithéliaux/usage thérapeutique , Hypertension artérielle/génétique , Syndrome de Liddle/diagnostic , Syndrome de Liddle/traitement médicamenteux , Syndrome de Liddle/génétique , Mutation , PedigreeRÉSUMÉ
Mutations in the SLC12A3 gene have been reported to cause Gitelman syndrome (GS). This study aimed to investigate the genetic mutations and clinical features of patients with GS. Four pedigrees (4 GS patients and 14 family members) were enrolled. The symptoms, laboratory results, management, and genotypes were analyzed. Genomic DNA was screened for gene variations using Sanger sequencing. DNA sequences were compared with reference sequences. The effects of the mutations were predicted using prediction tools (Mutation Taster, PolyPhen-2, SIFT, and PROVEAN). Genetic analysis revealed six genetic variants of SLC12A3, including three novel heterozygous mutations (c.2T > C, c.1609C > T, c.3055G > A) and three previously characterized mutations (c.1456G > A, c.2542G > A, c.1077C > G). These mutations were predicted to exert a damaging effect based on predictive in silico tools. GS patients had low blood pressure and low levels of serum K+, serum Mg2+, and 24-h urinary Ca2+ but high levels of 24-h urinary K+. These clinical manifestations and genotypes were consistent with the diagnostic criteria of GS. The study described the phenotypes and genotypes of 4 pedigrees involving GS patients, demonstrating the importance of SLC12A3 gene screening for GS.
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Syndrome de Gitelman , Syndrome de Gitelman/diagnostic , Syndrome de Gitelman/génétique , Humains , Mutation , Pedigree , Phénotype , Membre-3 de la famille-12 des transporteurs de solutés/génétiqueRÉSUMÉ
BACKGROUND: The changes in the electrolyte profiles in patients with diabetic ketoacidosis (DKA) have rarely been reported. This study reports the abnormalities in the electrolyte profile, such as serum potassium, sodium, chloride, calcium, magnesium, and phosphorus. METHODS: Forty individuals in each of the DKA, diabetic ketosis (DK), nonketotic diabetes mellitus, and healthy control groups were included in this study to evaluate their clinical indicators, such as blood glucose, glycated hemoglobin (HbA1c), renal function, electrolytes, and arterial blood gas concentrations. RESULTS: Compared with the other three groups, patients in the DKA group had a longer course of diabetes; significantly higher levels of blood glucose, HbA1c, and serum creatinine (p < 0.05 or p < 0.001); lower estimated glomerular filtration rate (eGFR) (p < 0.001); and higher levels of serum potassium, sodium, phosphorus, magnesium, and effective osmotic pressure (p < 0.05). In the DKA patients, the incidences of hyperkalemia and hypokalemia were 32.5% (p < 0.05 or p < 0.001 vs. the other groups) and 7.5%, respectively. In the DKA patients, type 1 diabetes patients were younger and had higher blood glucose than type 2 patients (p < 0.05), but the electrolyte profiles were not significantly different. There were no significant differences in the serum electrolyte profile between mild to moderate DKA patients and severe DKA patients. Serum potassium was negatively correlated with eGFR (r = -0.378, p = 0.018). Regression analysis showed that eGFR was an important factor affecting serum potassium (ß = -0.378, p = 0.018). CONCLUSIONS: When DKA occurs in diabetes patients, the renal function deteriorates significantly because the electrolytes are generally elevated due to hemoconcentration. Hyperkalemia is the main manifestation, and it is necessary to prevent the decrease in serum potassium during the treatment.
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Diabète de type 1 , Acidocétose diabétique , Hyperglycémie , Glycémie , Diabète de type 1/complications , Acidocétose diabétique/diagnostic , Électrolytes , Humains , Potassium , SodiumRÉSUMÉ
OBJECTIVE: To carry out genetic testing for a pedigree affected with carotid body tumor (CBT). METHODS: Members of the pedigree were enrolled and underwent physical examination, ultrasonography and CT scan. Genomic DNA of the proband was extracted from peripheral blood sample and subjected to exome sequencing. Candidate variants were predicted using bioinformatic tools and verified among members from his pedigree. RESULTS: A c.170-1G>T splicing variant of the SDHD gene was detected in 15 individuals from the pedigree. Physical examination and imaging confirmed that 9 of them had CBT and hypertension, while the remaining 6 died of cardiovascular and cerebrovascular diseases. CONCLUSION: The c.170-1G>T variant of the SDHD gene probably underlies the CBT in this pedigree. Genetic testing should be considered for CBT patients with CBT in addition to conventional clinical examination.
Sujet(s)
Tumeur du glomus carotidien , Dépistage génétique , Humains , Mutation , Pedigree , Épissage des ARN , Succinate Dehydrogenase , Exome SequencingRÉSUMÉ
BACKGROUND: To explore the role of lidocaine on subacute thyroiditis (SAT) and the molecular mechanism. METHODS: SAT models were constructed by infecting adenovirus to thyroid follicular epithelial cells. Cells were randomly divided into five groups: model group, low lidocaine, middle lidocaine, high lidocaine, and a control group. Thyroid secretion related factors TG and TPO, T3 and T4 were separately determined by reverse transcription-polymerase chain reaction (RT-PCR) and radioimmunoassay. Flow cytometry was used to determine thyroid follicular epithelial cell apoptosis situation. RT-PCR and Western blot analysis were used to determine the expression of inflammatory cytokines and pyroptosis related factors interleukin (IL)-1α, IL-6, THF-α, ELAVL1, NLR family pyrin domain containing 3 (NLRP3), caspase-1, and IL-1ß. RESULTS: Lidocaine decreased the relative level of TG, TPO, T3, and T4 in adenovirus-infected thyroid follicular epithelial cells. All levels of concentrations, including low, middle, and high, of lidocaine, significantly decreased the apoptosis rate of adenovirus-infected cells. Lidocaine dramatically reduced the protein expression of IL-1α, IL-6, THF-α, ELAVL1, NLRP3, caspase-1, and IL-1ß in adenovirus-infected thyroid follicular epithelial cells. CONCLUSION: Lidocaine can improve SAT through inhibiting expression of inflammatory factors and the pyroptosis pathway.
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OBJECTIVES: Thyroid carcinoma (TC) represents a malignant neoplasm affecting the thyroid. Current treatment strategies include the removal of part of the thyroid; however, this approach is associated with a significant risk of developing hypothyroidism. In order to adequately understand the expression profiles of TNRC6C-AS1 and STK4 and their potential functions in TC, an investigation into their involvement with Hippo signalling pathway and the mechanism by which they influence TC apoptosis and autophagy were conducted. METHODS: A microarray analysis was performed to screen differentially expressed lncRNAs associated with TC. TC cells were employed to evaluate the role of TNRC6C-AS1 by over-expression or silencing means. The interaction of TNRC6C-AS1 with methylation of STK4 promoter was evaluated to elucidate its ability to elicit autophagy, proliferation and apoptosis. RESULTS: TNRC6C-AS1 was up-regulated while STK4 was down-regulated, where methylation level was elevated. STK4 was verified as a target gene of TNRC6C-AS1, which was enriched by methyltransferase. Methyltransferase's binding to STK4 increased expression of its promoter. Over-expressed TNRC6C-AS1 inhibited STK4 by promoting STK4 methylation and reducing the total protein levels of MST1 and LATS1/2. The phosphorylation of YAP1 phosphorylation was decreased, which resulted in the promotion of SW579 cell proliferation and tumorigenicity. CONCLUSION: Based on our observations, we subsequently confirmed the anti-proliferative, pro-apoptotic and pro-autophagy capabilities of TNRC6C-AS1 through STK4 methylation via the Hippo signalling pathway in TC.
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Protein-Serine-Threonine Kinases/génétique , ARN long non codant/antagonistes et inhibiteurs , ARN long non codant/génétique , Protéines de liaison à l'ARN/antagonistes et inhibiteurs , Protéines de liaison à l'ARN/génétique , Tumeurs de la thyroïde/génétique , Tumeurs de la thyroïde/métabolisme , Animaux , Apoptose/génétique , Autophagie/génétique , Séquence nucléotidique , Lignée cellulaire tumorale , Prolifération cellulaire/génétique , Déméthylation de l'ADN , Régulation négative , Hétérogreffes , Voie de signalisation Hippo , Humains , Protéines et peptides de signalisation intracellulaire , Souris , Souris de lignée BALB C , Souris nude , Modèles biologiques , ARN antisens/génétique , Transduction du signal , Tumeurs de la thyroïde/anatomopathologie , Régulation positiveRÉSUMÉ
OBJECTIVE To screen for mutations in a Chinese pedigree affected with hypokalemic periodic paralysis. METHODS The proband and nine family members were enrolled for the analysis of CACNA1S and SCN4A gene mutations. Genomic DNA was extracted from peripheral blood samples. The coding regions of the two genes were amplified with PCR and subjected to Sanger sequencing. Potential impact of suspected mutations was predicted with Bioinformatics software. The mutations were also verified among 100 healthy controls. RESULTS The proband and 5 family members (including 5 males and 1 female) had presented with episodes of flaccid paralysis accompanied by low serum potassium. Genetic testing has identified a c.664C>T (p.Arg222Trp) mutation in the proband, which has been reported previously. The same mutation was identified in other 5 affected members from the family. No mutation of the CACNA1S gene was detected. CONCLUSION The c.664C>T mutation of the SCN4A gene probably underlies the hypokalemic periodic paralysis in this family. All patients from the family have shown a complete penetrance of the disease.
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Dépistage génétique/méthodes , Paralysie périodique hypokaliémique/génétique , Mutation , Canal sodique voltage-dépendant NAV1.4/génétique , Adulte , Sujet âgé , Asiatiques/génétique , Séquence nucléotidique , Chine , Analyse de mutations d'ADN , Femelle , Humains , Paralysie périodique hypokaliémique/diagnostic , Paralysie périodique hypokaliémique/ethnologie , Mâle , Adulte d'âge moyen , PedigreeRÉSUMÉ
Transplanted mesenchymal stem cells (MSCs) have been shown to contribute to myocardial repair after myocardial infarction (MI), primarily through production and secretion some growth factors and cytokines related to cell survival and regeneration. Further improvement of the therapeutic potential of MSCs appears to be an attractive strategy for MI treatment. CXC chemokine receptor (CXCR) 7 is the receptor for stromal cell-derived factor-1 (SDF-1), an important chemokine that is essential for tissue repair and angiogenesis. SDF-1/CXCR7 axis plays a critical role in the mobilization, recruitment and function of MSCs during tissue regeneration. Here, we depleted miR-142 that targets CXCR7 in MSCs cells through expression of antisense of miR-142, resulting in enhanced expression of CXCR7 in these miR-142-depleted MSCs (md-MSCs). In vitro, presence of md-MSCs reduced hypoxia-induced cardiac muscle cell apoptosis in a more pronounced manner than MSCs. In vivo, compared to transplantation of MSCs, transplantation of md-MSCs further enhanced cardiac re-vascularization and further improved cardiac functions after MI in mice. Together, our data suggest that depletion of miR-142 in MSCs may improve their therapeutic effects on MI.
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OBJECTIVE: To investigate the clinical features and mutations of RET proto-oncogene in a pedigree affected with multiple endocrine neoplasia type 2A (MEN2A). METHODS: Clinical data of the family members was collected. Genomic DNA from peripheral blood leukocytes were extracted and subjected to PCR amplification. Exons 8, 10, 11, 13, 14, 15, 16 of the RET gene was sequenced. RESULTS: A missense mutation p.C634W was detected in 8 members from the family. Among them, 3 were diagnosed with pheochromocytoma, 1 with medullary thyroid carcinoma, 1 with medullary thyroid carcinoma and pheochromocytoma, 1 with medullary thyroid carcinoma and hyperparathyroidism. One member was found with thyroid enlargement but refused further examination, and another one was identified as carrier of the RET gene mutation. CONCLUSION: A p.C634W mutation has been detected in a family affected with MEN2A, in which most carriers have developed clinical symptoms. RET mutation detection should be routinely performed for families affected with MEN2A.
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Prédisposition génétique à une maladie/génétique , Néoplasie endocrinienne multiple de type 2a/génétique , Mutation faux-sens , Protéines proto-oncogènes c-ret/génétique , Adulte , Sujet âgé , Séquence nucléotidique , Carcinome médullaire/génétique , Carcinome neuroendocrine/génétique , Enfant , Enfant d'âge préscolaire , Exons/génétique , Santé de la famille , Femelle , Humains , Mâle , Adulte d'âge moyen , Pedigree , Phéochromocytome/génétique , Proto-oncogène Mas , Analyse de séquence d'ADN/méthodes , Tumeurs de la thyroïde/génétiqueRÉSUMÉ
SUMMARY Resistance to thyroid hormone (RTH) coexisting with ectopic thyroid is rare. Here we report a case of RTH with ectopic thyroid. A ten-year-old girl had been misdiagnosed as congenital hypothyroidism and treated with levothyroxine since she was born. Ten-year follow-up showed that the elevated thyrotropin was never suppressed by levothyroxine and no signs indicating hyperthyroidism or hypothyroidism despite elevated FT3 and FT4 levels. Therefore the girl developed no defects in physical and cognitive development. Pituitary adenoma was excluded by magnetic resonance imaging. Ultrasonography did not find the thyroid gland in the normal place, while the thyroid scan found a large lingual thyroid gland. The octreotide inhibition test showed a reduction in thyrotropin by 41.98%. No mutation was detected in the thyroid hormone receptor (THR) β, THRα, thyrotropin receptor (TSHR), and GNAS1 genes. To our knowledge, it is an interesting RTH case coexisting with lingual thyroid.
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Humains , Femelle , Enfant , Récepteurs des hormones thyroïdiennes/génétique , Syndrome de résistance aux hormones thyroïdiennes/complications , Dysgénésie thyroïdienne/complications , Thyroxine/usage thérapeutique , Facteurs temps , Maladies de la langue/imagerie diagnostique , ADN/isolement et purification , Thyréostimuline/analyse , Analyse de mutations d'ADN , Études de suivi , Syndrome de résistance aux hormones thyroïdiennes/génétique , Hypothyroïdie congénitale/diagnostic , Erreurs de diagnostic , Dysgénésie thyroïdienne/génétique , Dysgénésie thyroïdienne/imagerie diagnostiqueRÉSUMÉ
Resistance to thyroid hormone (RTH) coexisting with ectopic thyroid is rare. Here we report a case of RTH with ectopic thyroid. A ten-year-old girl had been misdiagnosed as congenital hypothyroidism and treated with levothyroxine since she was born. Ten-year follow-up showed that the elevated thyrotropin was never suppressed by levothyroxine and no signs indicating hyperthyroidism or hypothyroidism despite elevated FT3 and FT4 levels. Therefore the girl developed no defects in physical and cognitive development. Pituitary adenoma was excluded by magnetic resonance imaging. Ultrasonography did not find the thyroid gland in the normal place, while the thyroid scan found a large lingual thyroid gland. The octreotide inhibition test showed a reduction in thyrotropin by 41.98%. No mutation was detected in the thyroid hormone receptor (THR) ß, THRα, thyrotropin receptor (TSHR), and GNAS1 genes. To our knowledge, it is an interesting RTH case coexisting with lingual thyroid.
Sujet(s)
Récepteurs des hormones thyroïdiennes/génétique , Dysgénésie thyroïdienne/complications , Syndrome de résistance aux hormones thyroïdiennes/complications , Enfant , Hypothyroïdie congénitale/diagnostic , ADN/isolement et purification , Analyse de mutations d'ADN , Erreurs de diagnostic , Femelle , Études de suivi , Humains , Dysgénésie thyroïdienne/imagerie diagnostique , Dysgénésie thyroïdienne/génétique , Syndrome de résistance aux hormones thyroïdiennes/génétique , Thyréostimuline/analyse , Thyroxine/usage thérapeutique , Facteurs temps , Maladies de la langue/imagerie diagnostiqueRÉSUMÉ
BACKGROUND: The mutations in the dual oxidase maturation factor 2 (DUOXA2) and dual oxidase 2 (DUOX2) genes have been identified in patients with congenital hypothyroidism (CH). This study reports a set of dizygotic twins with CH due to the mutations in the DUOX2/DUOXA2 system. METHODS: The dizygotic twins, a boy and a girl, both aged 7 years, were born to euthyroid nonconsanguineous parents; they were diagnosed with CH at neonatal screening and were enrolled in this study. The DUOXA2, DUOX2, paired box 8 (PAX8), thyroid peroxidase (TPO), and thyrotropin receptor (TSHR) genes were considered for mutation screening. Genomic DNA was extracted from peripheral blood leukocytes, and Sanger sequencing was used to screen for the mutations in the exon fragments. Family members of the patients were also enrolled and evaluated. RESULTS: The fraternal twins each harbored a single heterozygous mutation, including c.738C>G (p.Y246X) in the boy inherited from the paternal DUOXA2 allele and c.2654G>A (p.R885Q) in the girl from the maternal DUOX2 allele. The two mutations have been previously reported. The boy showed enlarged thyroid lobes and a little calcification in the left lobe, while the girl's thyroid gland was severely underdeveloped and the girl had obvious complications due to irregular treatment. The germline mutations from this family were consistent with an autosomal recessive inheritance pattern. No mutations in the PAX8, TPO, and TSHR genes were detected in this study. CONCLUSIONS: The inactivating mutations in the DUOXA2 (p.Y246X) and DUOX2 (p.R885Q) genes were identified in a set of dizygotic twins with CH. The girl was more severe in several aspects than her brother. The similar genetic defect resulted in very different outcomes.
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Hypothyroïdie congénitale/génétique , Protéines membranaires/génétique , Mutation , NADPH oxidase/génétique , Jumeaux dizygotes , Enfant , Dual oxydases , Femelle , Hétérozygote , Humains , MâleRÉSUMÉ
BACKGROUND: The objective of the study was to determine the genetic basis of goitrous congenital hypothyroidism (GCH) in Chinese siblings. METHODS: The proband and her younger brother with GCH were enrolled for molecular analysis of the dual oxidase 2 (DUOX2), dual oxidase maturation factor 2 (DUOXA2), and thyroid peroxidase (TPO) genes. Mutation screening was performed by Sanger sequencing the fragments amplified from genomic DNA. The detected mutations were verified among the close relatives of the patients and 105 controls. All participants underwent clinical examination and laboratory tests. RESULTS: Analysis of the TPO gene revealed two heterozygous mutations, the frameshift mutation c.2422delT in the exon14 of the TPO gene, that has been reported previously, and a novel missense mutation c.1682C>T (p.T561M) in the exon10 of the TPO gene. Nine family members of the patients were enrolled for mutation screening. The patients' parents and grandfathers harbored a single heterozygous mutation. The germline mutations from this family were consistent with an autosomal recessive inheritance pattern. No mutations in the DUOXA2 and DUOX2 genes were observed. CONCLUSIONS: The inactivating mutations (c.2422delT and p.T561M) in the TPO gene were identified in the Chinese siblings with GCH. The compound heterozygous mutations can cause GCH.
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Autoantigènes/génétique , Hypothyroïdie congénitale/génétique , Hypothyroïdie congénitale/anatomopathologie , Iodide peroxidase/génétique , Protéines de liaison au fer/génétique , Mutation/génétique , Adulte , Dual oxydases , Femelle , Hétérozygote , Humains , Nourrisson , Mâle , Protéines membranaires/génétique , Adulte d'âge moyen , NADPH oxidase/génétique , Pedigree , Pronostic , Jeune adulteRÉSUMÉ
Inactivating mutations of the thyrotropin receptor (TSHR) gene are responsible for non-goitrogenic congenital hypothyroidism (CHNG). This study aimed to investigate mutations in the TSHR gene in 20 children with CHNG. Genomic DNA was extracted from peripheral blood leukocytes and was used for mutation screening by direct sequencing. Analyses of the TSHR gene revealed two novel variants in a 2-year-old boy with thyroid hypoplasia: a missense mutation c.1582C>T (p.R528C) and a splice-site deletion c.392+4del4. Bioinformatics analysis demonstrated that both variants are capable of causing disease. Family members of the patient with two mutations and normal controls were also recruited and investigated. Germline mutations from the proband's family were consistent with an autosomal recessive inheritance pattern. These findings indicate that two novel inactivating mutations (p.R528C and c.392+4del4) in the TSHR gene can cause CHNG.
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Hypothyroïdie congénitale/génétique , Récepteur TSH/génétique , Enfant , Enfant d'âge préscolaire , Femelle , Humains , Mâle , MutationRÉSUMÉ
BACKGROUND: The thyroperoxidase (TPO) genetic variants in thyroid carcinoma is scarcely reported. OBJECTIVE: We report on a pedigree of thyroid papillary carcinoma and hypoechoic thyroid nodules with the TPO gene mutations. METHODS: The compound heterozygotic mutations of the TPO gene (c.2268-2269 insT and c.2090 G>A) in two patients with congenital goiters hypothyroidism were demonstrated. Fifteen family members of the proband and 105 control individuals were enrolled. The participants underwent clinical examination and molecular screening for TPO mutation. The hypoechoic thyroid nodules underwent fine needle aspiration biopsy. RESULTS: The mutation c.2268-2269 insT was detected in the four family members with normal thyroid hormone levels. The other two members harbored the c.2090 G>A mutation. The heterozygotes had degeneratively hypoechoic thyroid nodules. The control individuals showed no mutation. The maternal grandfather developed a multifocal papillary thyroid carcinoma with lymph gland and nerve invasion in the left lobe of the thyroid gland. The maternal grandfather harbored the TPO c.2268-2269 insT mutation but without BRAFV600E mutation. Malignant cells were not observed in other members by fine needle aspiration biopsy. CONCLUSION: TPO genetic variants may be associated with thyroid carcinoma and hypoechoic thyroid nodules in a few cases. Long-term follow-up in the pedigree with congenital goiter is reasonable.
Sujet(s)
Autoantigènes/génétique , Carcinome papillaire/génétique , Iodide peroxidase/génétique , Protéines de liaison au fer/génétique , Mutation/génétique , Tumeurs de la thyroïde/génétique , Nodule thyroïdien/métabolisme , Adulte , Sujet âgé , Carcinome papillaire/anatomopathologie , Hypothyroïdie congénitale/génétique , Hypothyroïdie congénitale/anatomopathologie , Femelle , Humains , Mâle , Pronostic , Tumeurs de la thyroïde/anatomopathologie , Nodule thyroïdien/anatomopathologie , Jeune adulteRÉSUMÉ
BACKGROUND: Mutations in the dual oxidase maturation factor 2 (DUOXA2) and thyroid peroxidase (TPO) genes have been reported to cause goitrous congenital hypothyroidism (GCH). The aim of this study was to determine the genetic basis of GCH in affected children. METHODS: Thirty children with GCH were enrolled for molecular analysis of the DUOXA2 and TPO genes. All subjects underwent clinical examination and laboratory testing. Genomic DNA was extracted from peripheral blood leukocytes, and Sanger sequencing was used to screen for DUOXA2 and TPO gene mutations in the exon fragments amplified from the extracted DNA. Family members of those patients with mutations were also enrolled and evaluated. RESULTS: Analysis of the TPO gene revealed six genetic variants, including two novel heterozygous mutations, c.1970T> C (p.I657T) and c.2665G> T (p.G889X), and four mutations that have been reported previously (c.670_672del, c.2268dup, c.2266T> C and c.2647C> T). Three patients harbored the same mutation c.2268dup. The germline mutations from four unrelated families were consistent with an autosomal recessive inheritance pattern. Conversely, no mutations in the DUOXA2 gene were detected. CONCLUSION: Two novel inactivating mutations (c.1970T> C and c.2665G> T) in the TPO gene were identified. The c.2268dup mutation occurred frequently. No mutations in the DUOXA2 gene were detected in this study.