Phenotype variability and different genotype of four patients with thyroid hormone resistance syndrome due to variants in the THRB gene.

BACKGROUND:   Resistance to thyroid hormone (RTH) is a rare dominantly inherited disorder mainly due to variants in the THRB gene leading to decreased end-organ responsiveness to thyroid hormones. CASE REPORT: Clinical and molecular characteristics of four patients with RTH are described. Four patients with various phenotypes were studied; two prepubertal boys and two adults (one male and one female). Sequencing analysis of the THRB was performed. All individuals had persistently elevated free thyroxine and/or free triiodothyronine associated with non-suppressed thyroid-stimulating hormone (TSH), and all had non-autoimmune goiters of various sizes. In both adults, antithyroid drugs were previously administered without successful suppression of the thyroid hormones. The 27-year-old female had resting tachycardia as the only symptom. The 35-year-old male had a degree of cognitive impairment and was initially diagnosed with atrial fibrillation. The eight-year-old boy was diagnosed with attention deficit disorder and had resting tachycardia. The oldest boy (age nine years) underwent thyroid function tests as a part of the investigation for obesity and learning difficulties. Direct sequencing analysis of the THRB gene showed three previously reported variants: p.His435Leu (c.1304A>T) in the 35-year-old male, p.Pro453Thr (c.1357C>A) in the oldest boy, and p.Arg438Cys (c.1312C>T) variant in the other two patients. CONCLUSIONS: Various phenotypes characterize common variants in the THRB gene, asymptomatic, thyroid hormone deprivation symptoms, or thyroid hormone excess symptoms. RTH should be suspected in both adults and children with elevated thyroid hormones and not suppressed TSH. A prompt molecular diagnosis and genetic counseling could prevent unnecessary tests and inappropriate treatments. HIPPOKRATIA 2019, 23(3): 135-139.

Multiple endocrine neoplasia 2 in Cyprus: evidence for a founder effect.

PURPOSE: Multiple endocrine neoplasia type 2 (MEN2) affects patients with RET proto-oncogene mutations. This cohort study refers to patients who were diagnosed with familial medullary thyroid carcinoma (MTC) and underwent RET genetic testing in Cyprus between years 2002 and 2017. METHODS AND PATIENTS: Forty patients underwent RET testing by Sanger sequencing of exons 10-11 and 13-16. Genotyping with STR genetic markers flanking the RET gene along with Y-chromosome genotyping and haplogroup assignment was also performed. RESULTS: RET mutations were identified in 40 patients from 11 apparently unrelated Cypriot families and two non-familial sporadic cases. Nine probands (69.2%) were heterozygous for p.Cys618Arg, one (7.7%) for p.Cys634Phe, one (7.7%) for the somatic delE632-L633 and two (15.4%) for p.Met918Thr mutations. The mean age at MTC diagnosis of patients carrying p.Cys618Arg was 36.8 ± 14.2 years. The age of pheo diagnosis ranged from 26 to 43 years and appeared simultaneously with MTC in 5/36 (13.9%) cases. The high frequency of the p.Cys618Arg mutation suggested a possible ancestral mutational event. Haplotype analysis was performed in families with and without p.Cys618Arg. Six microsatellite markers covering the RET gene and neighboring regions identified one core haplotype associated with all patients carrying p.Cys618Arg mutation. CONCLUSIONS: The mutation p.Cys618Arg is by far the most prevalent mutation in Cyprus followed by other reported mutations of variable clinical significance. The provided molecular evidence speculates p.Cys618Arg mutation as an ancestral mutation that has spread in Cyprus due to a possible founder effect.

Oxidative stress in ß-thalassaemia and sickle cell disease.

Sickle cell disease and ß-thalassaemia are inherited haemoglobinopathies resulting in structural and quantitative changes in the ß-globin chain. These changes lead to instability of the generated haemoglobin or to globin chain imbalance, which in turn impact the oxidative environment both intracellularly and extracellularly. The ensuing oxidative stress and the inability of the body to adequately overcome it are, to a large extent, responsible for the pathophysiology of these diseases. This article provides an overview of the main players and control mechanisms involved in the establishment of oxidative stress in these haemoglobinopathies.