A novel p.E311K mutation of thyroid receptor beta gene in resistance to thyroid hormone syndrome, inherited in autosomal recessive trait.

Resistance to thyroid hormone (RTH) syndrome is caused by mutations in THRB gene and is inherited mainly as an autosomal dominant trait with dominant negative effect. Most of up-to-now described RTH cases were heterozygous. We studied a 19-year-old woman presenting severe mental impairment, hyperkinetic behavior, learning disability, hearing loss, tachycardia, goiter, strabismus, nystagmus, and normal stature. The laboratory findings revealed elevated TSH, T3, and T4 serum levels. Her parents were healthy with normal serum level of TSH, fT3, and fT4. Sequence based prediction of a substitution was analyzed by SDM, PolPhen, and SNAP software whereas structural visualizations were performed in UCSF Chimera. We found a novel mutation in THRB gene in position 1216 (G to A transition, codon 311) resulting in novel Glu-311-Lys (p.E311K) substitution, homozygous in proband presenting with severe symptoms of RTH and heterozygous in both of her healthy parents, thus suggesting autosomal recessive mode of inheritance. p.E311K substitution was not found in 50 healthy, unrelated individuals. p.E311K was shown to be deleterious by SDM, PolPhen, and SNAP software. Structural visualizations of mutated protein performed by UCSF Chimera software disclosed a loss of hydrogen bonds between E311, R383, and R429 along with abnormal residue-residue contact between K311 and L377. This is a very rare case of a homozygous mutation in a patient with severe symptoms of RTH and lack of symptoms in both heterozygous parents. Although, computational analyses have provided the evidence that p.E311K substitution may affect THRB function, lack of dominant negative effect typical for THRB mutations could not be explained by structure-based modeling. Further in vitro analysis is required to assess the functional consequences of this substitution.

Nodular goiter and thyroid carcinoma in children and adolescents in a moderate endemic area (lower Silesia-Sudeten endemia) in the last twelve years.

Although thyroid carcinoma is more common in the adult population, the risk of a nodule being malignant is greater in children. The aim of our present investigation was to ascertain the percentage of malignancy in nodular goiter observed in patients from the Lower Silesia region in the last 12 years. The examination included 60 children (12 boys and 48 girls) treated in our clinic from 1987 to June 1998. Age varied from 7 to 18 years (mean 14.8 +/- 2.4), most of them in the age group between 13 and 18 years. The following investigations were performed: TSH, T3, T4, thyroid ultrasonography, fine needle aspiration biopsy and Tc99 scintigraphy of the thyroid. Most of the patients were euthyroid; two children demonstrated pressure symptoms. All the patients were treated by operation. Histological examinations revealed the following: nodular goiter in 19 patients, cystic nodular goiter in 5, follicular adenoma in 20, fetal adenoma in 3, nodular goiter and follicular adenoma in 6, papillary carcinoma in 6, and follicular carcinoma in 1 patient. We concluded that an increased incidence of thyroid cancer has been noted in children with nodular goiter in Lower Silesia during the last 12 years. Thyroid cancer was observed mostly in patients with single nodules and was associated with a high risk of malignancy.

Acute bilateral vocal fold paresis as a symptom of benign thyroid disease.

A case of bilateral laryngeal nerve paralysis caused by a small goitre is reported. After thyroidectomy the return of vocal fold movements was observed. A review of the literature is presented. The possibility of acute airway distress caused by a slightly enlarged goitre is emphasized.

[Personal observations for diagnosis and radical surgical treatment of thyroid neoplasms]. / Wlasne doswiadczenia w rozpoznaniu i radykalnym leczeniu operacyjnym raka tarczycy.

Among 59 patients with thyroid cancer, we have analysed the diagnostic procedures as: ultra sonography, scintiscan, fine needle aspiration biopsy, intraoperative frozen section examination and extent of surgery. The cancer was often overlooked in patients with multinodular goitre. We suggest to perform total lobectomy on side with greater changes and subtotal lobectomy on the other side of thyroid gland, in patients with multinodular goitre. The decision whether to reoperate should depend on the final pathology report.

[Acute respiratory failure in the course of thyroid disease]. / Ostra niewydolnosc oddechowa w przebiegu schorzen tarczycy.

During the past 10 years, we have treated 11 patients who were admitted with acute respiratory failure due to goiter. Multinodular goiter was examined in four patients, one patient suffered from Graves disease and six patients had malignant thyroid lesions. Four patients required emergency intubation and in two cases we performed tracheostomy because of significant narrowing of trachea lumen. Diagnosis was made in most cases based on chest x-ray films, laryngoscopic examination, CT scans of the neck and goiters fine needle aspiration biopsy. All patients underwent mostly subtotal thyroidectomy with the standard cervicotomy approach. Five patients required tracheostomy procedures after surgery, three because of local advanced malignancy and two because of postoperative respiratory failure. In two cases pneumonia developed as a postoperative complication. One patient with advanced malignant goiter died. The goiters with progress of trachea compression symptoms should be operated in elective surgery to avoid sudden life-threatening complications like severe dyspnea. When the hoarseness is present the possibility of malignant goiter is particularly high. In our opinion patients with suspected respiratory failure should be referred to the centres with special interest in thyroid surgery.

[Concurrent goiter and vitiligo in a 13-year old boy]. / Wspólwystepowanie wola koloidowego oraz bielactwa nabytego u 13-letniego chlopca.

The coincidence of goitre and vitiligo in 13-year-old boy is reported. Skin changes appeared two years before the thyroid disease was diagnosed. Immunological investigation revealed the presence of anti-thyroid antibodies, which may suggest an autoaggressive etiology of both disorders.

Microsatellite instability in thyroid papillary carcinoma and multinodular hyperplasia.

Microsatellite instability (MSI) is a molecular landmark of mutations in DNA mismatch repair genes. The impaired efficiency of DNA repair mechanisms promotes carcinogenesis as well as contributes to tumour progression. Until now, only few studies on MSI in thyroid tumours have been published. Therefore, the aim of the present study was to investigate MSI as a possible characteristic feature of thyroid tumours. The analysis of 12 thyroid papillary carcinomas and 17 multinodular hyperplasias at 13 microsatellite loci showed MSI and loss of heterozygosity (LOH) in both types of lesion, with more alterations noted in the papillary thyroid carcinomas (in 65%) than in multinodular hyperplasia (in 35%). In carcinomas, LOH occurred more frequently than MSI, while in multinodular hyperplasia the LOH/MSI ratio is almost equal.