RESUMO
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.
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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.
Assuntos
Carcinoma Medular/congênito , Efeito Fundador , Neoplasia Endócrina Múltipla Tipo 2a/epidemiologia , Neoplasia Endócrina Múltipla Tipo 2a/genética , Proteínas Proto-Oncogênicas c-ret/genética , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/genética , Adulto , Arginina/genética , Carcinoma Medular/diagnóstico , Carcinoma Medular/epidemiologia , Carcinoma Medular/genética , Estudos de Coortes , Chipre/epidemiologia , Cisteína/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla Tipo 2a/diagnóstico , Linhagem , Proto-Oncogene Mas , Neoplasias da Glândula Tireoide/diagnósticoRESUMO
Huntington disease (HD) is most prevalent among populations of western European descent and isolated populations where founder effects may operate. The aim of this study was to examine the epidemiology of HD in Cyprus, an island in southern Europe with extensive western European colonization in the past. All registered HD patients in the Cyprus, since 1994, were included. Detailed pedigrees and clinical information were recorded and maps, showing the geographic distribution of HD, were constructed. Requests for genetic testing were also examined. The project identified 58 clinically manifested cases of HD belonging to 19 families. The 16 families of Cypriot origin were concentrated in a confined geographical cluster in southeast Cyprus. In 2015, prevalence of symptomatic HD was 4.64/100 000 population, while incidence was 0.12/100 000 person-years. Prevalence displayed a marked increase during the past 20 years. Disease characteristics of HD patients were similar to those reported in western European populations. Lastly, the uptake of predictive and/or prenatal testing was limited. HD disease characteristics, incidence and prevalence in Cyprus were comparable to western European populations. Together with the geographical clustering observed, these results support the possibility for a relatively recent founder effect of HD in Cyprus, potentially of western European origin.
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Doença de Huntington/epidemiologia , Idade de Início , Alelos , Chipre/epidemiologia , Feminino , Predisposição Genética para Doença , Genótipo , Geografia Médica , Humanos , Doença de Huntington/etiologia , Doença de Huntington/mortalidade , Incidência , Estimativa de Kaplan-Meier , Masculino , Vigilância da População , Prevalência , Prognóstico , Estudos RetrospectivosRESUMO
This paper presents the largest study in Cyprus evaluating the frequency and distribution of BRCA1/2 mutations in a high risk patient cohort. Deleterious mutations in the BRCA1/2 genes were identified in 68 of the 527 patients tested (13%). It is of interest that a quarter of those tested positive, did not have an extensive family history of breast/ovarian cancer but were diagnosed with early onset breast cancer, ovarian cancer under the age of 60 or triple negative breast cancer. The spectrum of mutations identified in our patient cohort is different compared to other Mediterranean countries. Furthermore, several of the mutations detected are novel and have not been identified in other ethnic populations. This highlights the importance of operating a national reference center for cancer genetic diagnosis which offers services tailored to the needs of the Cypriot population.
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Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias Ovarianas/genética , Neoplasias de Mama Triplo Negativas/genética , Adulto , Idoso , Chipre/epidemiologia , Feminino , Predisposição Genética para Doença , Testes Genéticos , Genética Populacional , Humanos , Pessoa de Meia-Idade , Epidemiologia Molecular , Mutação , Neoplasias Ovarianas/epidemiologia , Neoplasias de Mama Triplo Negativas/epidemiologiaRESUMO
Spinal muscular atrophy (SMA) is an autosomal recessive, neurodegenerative disorder characterised commonly by proximal muscle weakness and wasting in the absence of sensory signs. Deletion or disruption of the SMN1 gene causes the disease. The SMN1 gene is located within an inverted duplication on chromosome 5q13 with the genes SMN2, NAIP and GTF2H2. MLPA analysis of 13 Cypriot SMA patients revealed that, 12 patients carried a homozygous SMN1 gene deletion and one patient carried two copies of the SMN1 gene. Two of 13 cases were a consequence of a paternally originating de novo mutation. Five genotypes were identified within the population, with the most frequent being a homozygous SMN1 and NAIP genes deletion. In conclusion, genotype-phenotype correlation revealed that SMN2 is inversely related to disease severity and that NAIP and GTF2H2 act as negative modifiers. This study provided, for the first time, a comprehensive overview of gene copy numbers and inheritance patterns within Cypriot SMA families.
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Atrofias Musculares Espinais da Infância/genética , Chipre , Análise Mutacional de DNA , Família , Feminino , Dosagem de Genes , Estudos de Associação Genética , Humanos , Padrões de Herança , Masculino , Repetições de Microssatélites , Mutação , Linhagem , Proteína 1 de Sobrevivência do Neurônio Motor/genéticaAssuntos
Análise Mutacional de DNA , Síndrome de Cornélia de Lange/genética , Morte Fetal , Testes Genéticos/métodos , Mutação , Proteínas/genética , Autopsia , Proteínas de Ciclo Celular , Síndrome de Cornélia de Lange/diagnóstico , Feminino , Predisposição Genética para Doença , Idade Gestacional , Humanos , Masculino , Fenótipo , Valor Preditivo dos Testes , GravidezRESUMO
Williams-Beuren syndrome is a well-known microdeletion syndrome with a recognizable clinical phenotype. The subtle phenotype of the reciprocal microduplication of the Williams-Beuren critical region has been described recently. We report seven further patients, and a transmitting parent, with 7q11.23 microduplication. All our patients had speech delay, autistic features and facial dysmorphism consistent with the published literature. We conclude that the presence of specific dysmorphic features, including straight, neat eyebrows, thin lips and a short philtrum, in our patients with speech delay and autistic features provides further evidence that the children with 7q11.23 microduplication have a recognizable phenotype.
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Fenótipo , Síndrome de Williams/diagnóstico , Adolescente , Criança , Transtornos Globais do Desenvolvimento Infantil/diagnóstico , Transtornos Globais do Desenvolvimento Infantil/genética , Pré-Escolar , Feminino , Estudos de Associação Genética , Humanos , Transtornos do Desenvolvimento da Linguagem/genética , Masculino , Síndrome de Williams/genética , Síndrome de Williams/patologiaRESUMO
The diagnosis and management of a heterokaryotypic monochorionic pregnancy, in which one of twins had trisomy 13, is presented. Monozygosity and discordant karyotypes were confirmed by amniocentesis of both the sacs. Radiofrequency ablation of the trisomic twin was successfully performed at 18-weeks gestation and the pregnancy ended at term with the birth of a healthy girl who remains well on follow-up at 12 months of age. We reiterate the importance of early amniocentesis of both the sacs in the presence of discordant fetal abnormalities and consideration of selective fetal termination to optimise the outcome of heterokaryotypic monochorionic twin pregnancies.
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Transtornos Cromossômicos/diagnóstico , Doenças em Gêmeos , Diagnóstico Pré-Natal , Trissomia/diagnóstico , Gêmeos Monozigóticos/genética , Adulto , Amniocentese , Ablação por Cateter , Transtornos Cromossômicos/terapia , Cromossomos Humanos Par 13 , Feminino , Aconselhamento Genético , Humanos , Cariotipagem , Gravidez , Síndrome da Trissomia do Cromossomo 13RESUMO
BACKGROUND: Response to radiotherapy varies between individuals both in terms of efficacy and adverse reactions. Finding genetic determinants of radiation response would allow the tailoring of the treatment, either by altering the radiation dose or by surgery. Despite a growing number of studies in radiogenomics, there are no well-replicated genetic association results. METHODS: We carried out a candidate gene association study and replicated the result using three additional large cohorts, a total of 2036 women scored for adverse reactions to radiotherapy for breast cancer. RESULTS: Genetic variation near the tumour necrosis factor alpha gene is shown to affect several clinical endpoints including breast induration, telangiectasia and overall toxicity. In the combined analysis homozygosity for the rare allele increases overall toxicity (P=0.001) and chance of being in the upper quartile of risk with odds ratio of 2.46 (95% confidence interval 1.52-3.98). CONCLUSION: We have identified that alleles of the class III major histocompatibility complex region associate with overall radiotherapy toxicity in breast cancer patients by using internal replication through a staged design. This is the first well-replicated report of a genetic predictor for radiotherapy reactions.
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Neoplasias da Mama/genética , Neoplasias da Mama/radioterapia , Polimorfismo de Nucleotídeo Único , Lesões por Radiação/genética , Radioterapia/efeitos adversos , Fator de Necrose Tumoral alfa/genética , Neoplasias da Mama/irrigação sanguínea , Estudos de Coortes , Feminino , Estudos de Associação Genética , Humanos , RiscoRESUMO
BACKGROUND: Overall, approximately 5% of patients show late normal-tissue damage after radiotherapy with a smaller number having a risk of radiation-induced heart disease. Although the data are conflicting, large studies have shown increased risks of cardiovascular disease (CVD) for irradiated patients compared with non-irradiated ones, or for those treated to the left breast or chest wall compared with those treated to the right. Cutaneous telangiectasiae as late normal-tissue injury have so far only been regarded as a cosmetic burden. METHODS: The relationship between late normal-tissue radiation injury phenotypes in 149 irradiated breast cancer patients and the presence of cardiovascular disease were examined. RESULTS: A statistically significant association between the presence of skin telangiectasiae and the long-term risk of CVD was shown in these patients (P=0.017; Fisher's exact test). INTERPRETATION: This association may represent initial evidence that telangiectasiae can be used as a marker of future radiation-induced cardiac complications. It could also suggest a common biological pathway for the development of both telangiectasiae and CVD on the basis of a genetically predisposed endothelium. To our knowledge this is the first reported study looking at this association.