Publications (9)12.93 Total impact
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Article: Overview of genetic defects in endocrinopathies in the island of cyprus; evidence of a founder effect.
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ABSTRACT: Aim: Hereditary endocrinopathies in Cyprus exhibit evidence of a founder effect and display the influence of past migration patterns. The genetic frequency and mutation pattern of a specific disorder of sex development (DSD), which is classified as 46,XX DSD or 46,XY DSD, and the non-classic form of congenital adrenal hyperplasia (NC-CAH) outline a type of genetic drift. Results: Not only the high prevalence of the NC-CAH p.V281L mutation but also the rarity of CAH large lesions present a genetic diversity similar to that observed in the Middle Eastern countries. In addition, both the high frequency of the 5-alpha steroid reductase deficiency (5αSRD) IVS1-2A>G mutation and the carrier frequency of the 17-beta hydroxysteroid dehydrogenase 3 (17β-HSD-3) p.R80Q mutation are good examples of a founder effect. p.R80Q can be considered a founder mutation, even though it has been identified in patients of Dutch, Brazilian, and Portuguese origin. This has led to the speculation that it has a Phoenician origin. Phoenicians as ancient traders migrated around 750 BC from present day Syria, Lebanon, and Israel toward Portugal, Spain, and also to nearby Cyprus. While the 5αSRD IVS1-2A>G mutation has already been extensively reported in Turkish patients, it is very common in the Eastern Mediterranean region. Conclusion: This short article portrays clearly, through specific endocrine genetic disorders, the past migration trends in Cyprus that shaped the present-day gene pool of the Greek-Cypriot population.Genetic Testing and Molecular Biomarkers 08/2012; 16(9):1073-9. · 1.11 Impact Factor -
Article: Duplication of exons 3-10 of the HSD17B3 gene: a novel type of genetic defect underlying 17β-HSD-3 deficiency.
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ABSTRACT: The clinical, biochemical and genetic features of a Cypriot origin male of non-consanguineous parents due to 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD-3) deficiency are presented. The patient, currently a 10 old male, was referred to our clinic because of ambiguous genitalia at birth. Gonads were palpable in the inguinal canal bilaterally and no Müllerian structures identified on pelvic ultrasound. Chromosomal analysis showed an apparently normal male 46,XY karyotype. Diagnosis of 17β-HSD-3 deficiency in the newborn was suspected based on biochemical findings, following human chorionic gonadotrophin (hCG) stimulation test. Sequence analysis and real time PCR along with MLPA identified the patient with a novel 11.96 kb duplication that spans exons 3-10 of the HSD17B3 gene and extends from intron 2 to intron 10 in compound heterozygosity with the known p.R80Q missense mutation leading to 17β-HSD-3. In conclusion, 17β-HSD-3 deficiency was diagnosed in this patient based on endocrinologic evaluation and confirmed with genetic analysis of the HSD17B3 gene. The novel large duplication spanning exons 3-10 of the HSD17B3 gene that we report here in compound heterozygosity with the known p.R80Q leads to 17β-HSD-3 deficiency presenting as 46,XY Disorder of Sex Development. Following diagnosis and appropriate genetic counselling, the patient was raised a boy and successfully underwent surgical correction of crytptorchidism and hypospadias.Gene 03/2012; 499(2):250-5. · 2.34 Impact Factor -
Article: Identification and characterization of a novel X-linked AVPR2 mutation causing partial nephrogenic diabetes insipidus: a case report and review of the literature.
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ABSTRACT: X-linked nephrogenic diabetes insipidus (NDI) is a rare disease characterized by a malfunctioning renal response to the antidiuretic hormone arginine vasopressin (AVP) due to mutations in the AVPR2 gene. A limited number of mutations in the AVPR2 gene resulting in partial phenotype have been described so far. In this mini-review the retrospective analysis of 13 known AVPR2 mutations that have been previously shown in vitro to partially abolish AVPR2 function is described, along with a novel mutation diagnosed in a kindred with partial NDI. In the present study, a 14 year old male and his 73 year old maternal grandfather were diagnosed with partial NDI based on the clinical phenotype, the water deprivation test and the inadequate response to 1-desamino-8-d-arginine vasopressin (DDAVP) administration. Sequencing analysis of the AVPR2 gene revealed the novel missense mutation p.N317S (g.1417A > G) in both patients. This mutation was re-created by site directed mutagenesis in an AVPR2 cDNA expression vector and was functionally characterized, in terms of arginine vasopressin (AVP) and DDAVP response. AVPR2 activity of the p.N317S mutant receptor after the AVP and DDAVP administration, as assessed by cAMP production was reduced and impaired when compared to cells that expressed the wild type AVPR2 gene. In conclusion, the affected members of this family have X-linked NDI with partial resistance to AVP, due to a missense mutation in the AVPR2 gene.Metabolism: clinical and experimental 03/2012; 61(7):922-30. · 2.59 Impact Factor -
Article: Epidemiology of type 1 diabetes mellitus in Cyprus: rising incidence at the dawn of the 21st century.
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ABSTRACT: The incidence of Type 1 diabetes mellitus (T1DM) in Greek-Cypriot children aged less than 15 years between 1990 and 2009 was examined along with gender differences concerning the age of onset and the seasonal variation at manifestation of the disease. All newly diagnosed cases of T1DM in children less than 15 years old were registered with the capture-recapture method from 1990 until 2009. The overall mean annual incidence during these 20 years is 12.46 per 100,000. A comparison of the incidence between the two decades (1990-1999 vs 2000-2009) indicated a rising trend, from 10.80 per 100,000 person-years during the first decade to 14.44 per 100,000 person-years during the second decade. There was an overall male predominance (M/F: 1.05), which is in agreement with the male predominance in the population less than 15 years of age, except for the group who manifested T1DM at ages 10-15 years where females prevail. The percentage of children who developed T1DM at ages 0-5 years in the total T1DM population increased in the second decade (26.4% vs 19.0%), and significantly more children were diagnosed during the cold months as opposed to the warm months (p<0.001). The incidence of T1DM in Cyprus is rising. The identification of causative environmental factors will theoretically explain this phenomenon and new preventive strategies can therefore potentially be developed.Hormones (Athens, Greece) 01/2012; 11(1):86-93. · 2.44 Impact Factor -
Chapter: Altering Trends in the Epidemiology of Type 1 Diabetes Mellitus in Children and Adolescents
11/2011; , ISBN: 978-953-307-756-7 -
Article: Endocrine profile and phenotype-genotype correlation in unrelated patients with non-classical congenital adrenal hyperplasia.
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ABSTRACT: The aim of this study was to identify the molecular defect in a group of 37 unrelated Greek Cypriot patients affected by NC-CAH and evaluate the relationship between the genotype, phenotype and adrenal androgen levels. Clinical evaluation, biochemical analysis of 17-OHP, Testosterone, Androstenedione, DHEA-S, direct DNA sequencing and MLPA analyses. Eleven known mutations were identified with the p.V281L being the most predominant and observed in 68.9% of the alleles. There was no difference between the two genotypes (mild/mild and mild/severe) with clinical presentation, whereas a proportional relationship between the type of mutation and adrenal androgen levels was found. The frequency of the underlying genetic defect in our patients with NC-CAH is similar to that observed in most Mediterranean populations. Although the genotype cannot solely explain the clinical expression of NC-CAH, discrimination between mild and severe alleles is crucial in antenatal diagnosis and genetic counselling.Clinical biochemistry 05/2011; 44(12):959-63. · 2.02 Impact Factor -
Article: Hormonal dysregulation and bones in thalassaemia--an overview.
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ABSTRACT: Bone disease (BDT) represents a prominent cause of morbidity in patients of both sexes with thalassaemia major (TM). The exact pathogenesis of BDT in TM is multifactorial, still unclear and complicated. Peak bone mass is achieved shortly after completion of puberty and normally remains stable until the third decade of life. After the age of 30 years, age related bone loss begins. Growth hormone (GH) and sex steroids have a crucial role in bone remodelling and therefore are important in helping to establish and maintain peak bone mass for both sexes. The anabolic effects of GH and IGF-1 in bone are important not only for the acquisition of bone mass during adolescence but also for the maintenance of skeletal architecture during adult life. GH deficiency is not a rare finding in adult patients with TM, thus contributing to the development of BDT. Furthermore, patients with TM are often hypogonadal, and therefore the lack of sex steroids in critical periods, such as puberty, contributes to the failure to achieve optimal peak bone mass and to maintain bone mass later in life. Sex steroids probably act by increasing the expression of RANKL by osteoblastic cells, and alterations in the RANK/RANKL/OPG system in favour of osteoclasts are characteristic in TM, where the ratio of sRANKL/OPG is increased. It is still not clear whether DEXA scan is the gold standard for determination of bone density in thalassaemics and if so, whether the WHO criteria for defining osteopenia and osteoporosis are relevant to patients with TM. The question therefore arises whether other methods should be adopted, since DEXA may often overestimate BDT in these patients. BDT in thalassaemia represents a unique clinical entity with a multifactorial aetiology and of complex mechanisms which need to be clarified. It is essential for us to understand the underlying mechanisms of bone destruction and the bony defect at the ultrastructural level in order to be able to design not only preventive strategies but also therapeutic measures.Pediatric endocrinology reviews: PER 11/2008; 6 Suppl 1:107-15. -
Article: Effect of bisphosphonate treatment on bone mineral density in patients with thalassaemia major.
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ABSTRACT: Bisphosphonates are potent inhibitors of osteoclastic bone resorption and have been recently used in thalassaemia major (TM) osteoporosis with encouraging results. The aim of the study is to investigate the effect of two Bisphosphonate drugs, Alendronate and Pamidronate on bone mass in patients of both genders with TM, treated in our Center. 53 (22 males, 31 females) Thalassaemic patients of Greek Cypriot origin were randomly divided into two groups. 29 patients in group A with a mean age of 33, 32 years were treated with alendronate and 24 patients in group B with a mean age of 34, 36 years received pamidronate for a period of 2 years. The effectiveness of both drugs was estimated based on the change of Bone mineral density (BMD) values of lumbar spine and femoral neck. Bone mineral density (BMD) of lumbar spine and femoral neck was measured by dual-energy X-ray absiorptiometry. All patients were on the standard treatment protocol of Thalassaemia. Statistical analysis was performed with the SPSS program. After completion of treatment with pamidronate the mean lumbar spine BMD has improved from -2.813 to -2.174 (p<0.001) and the mean hip BMD from -2.138 to -2.078 (p=0.018). The change of spine BMD in patients who received alendronate was from -2.720 to -2.602 (p=0.059) and the changes in BMD at the femoral neck from -2.035 to -2.007 (p=0.829). This study demonstrates the efficacy of two bisphosphonate drugs in improving BMD values in patients with TM and osteoporosis. Since the origin of bone disease in TM is multifactorial and some of the underlying pathogenic mechanisms are still unclear, further research in this field is needed, which will allow the design of optimal therapeutic measures.Pediatric endocrinology reviews: PER 11/2008; 6 Suppl 1:144-8. -
Article: Late diagnosis of 5alpha steroid-reductase deficiency due to IVS12A>G mutation of the SRD5a2 gene in an adolescent girl presented with primary amenorrhea.
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ABSTRACT: The clinical spectrum of 5α-reductase deficiency, caused by mutations in the SRD5A2 gene, ranges from complete female appearance of the external genitalia at birth to nearly complete male phenotype. A 14-year-old girl presented with primary amenorrhea (PA) and lack of breast development. She was 173 cm in height, had an increased amount of pubic hair and clitoromegaly (3 cm), with a 4 cm blind vaginal pouch. Gonads were palpable in the inguinal canal bilaterally and no uterus was identified on ultrasound. Chromosomal analysis showed a 46,XY karyotype. The Testosterone/DHT ratio was high (16.5) and further increased to 29.4 after stimulation with hCG, thus favouring the diagnosis of 5α-reductase deficiency. Since the issue of gender change was not considered, gonadectomy was performed followed by successful feminisation with hormonal replacement therapy. GENETIC STUDIES: Molecular analysis of the SRD5A2 gene by DNA sequencing of all 5 exons revealed the presence of the splice mutation A>G at position -2 of the acceptor site of intron 1/exon 2 (IVS1-2A>G) in homozygosity. Both non-consanguineous parents were found to be heterozygotes for this mutation. Although rare, SRD5A2 gene defect should be suspected in any girl presenting with PA and virilisation at puberty. The IVS1-2A>G mutation of the SRD5A2 gene predominates in Greek-Cypriot patients with 5α-reductase deficiency and very likely reflects a founder effect.Hormones (Athens, Greece) 10(3):230-5. · 2.44 Impact Factor
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2012
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Cyprus Institute of Neurology and Genetics
Nicosia, Nicosia District, Cyprus
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