Iasis Hospital

Paphos, Cyprus

Iasis Hospital

Paphos, Cyprus

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Toumba M.,IASIS Hospital | Toumba M.,Makarios III Hospital | Neocleous V.,Cyprus Institute of Neurology and Genetics | Shammas C.,Cyprus Institute of Neurology and Genetics | And 7 more authors.
Journal of Pediatric Endocrinology and Metabolism | Year: 2013

Objectives: Camurati-Engelmann disease (CED) is a rare form of progressive bone dysplasia due to mutations in the transforming factor gene TGFB1 on chromosome 19q13.1- q13.3. Endocrine complications such as osteoporosis, vitamin D deficiency, delayed puberty and hypogonadotrophic hypogonadism may be present. Methods and results: Genetic analysis of the TGFB1 gene revealed a heterozygous missense mutation p.R218C in exon 4 of chromosome 19q13.1-q13.3 in a 14-year-old girl who presented with typical symptoms of CED, hyperprolactinaemia and menstrual irregularity. The patient responded well to prednisone 5 mg/kg per day as well as calcium and vitamin D supplements. Conclusions: The role of p.R218C in TGFB1 on the mechanism of the disease itself and the complications of it in bones and endocrine glands remain unclear. Early recognition as well as a detailed understanding of the pathogenesis of the disease is important for future treatment options and better quality of life of such patients.


PubMed | University Hospital of Tuebingen, Cork University Hospital, MAGIC Foundation, Childrens Hospital and 22 more.
Type: | Journal: Nature reviews. Endocrinology | Year: 2016

This Consensus Statement summarizes recommendations for clinical diagnosis, investigation and management of patients with Silver-Russell syndrome (SRS), an imprinting disorder that causes prenatal and postnatal growth retardation. Considerable overlap exists between the care of individuals born small for gestational age and those with SRS. However, many specific management issues exist and evidence from controlled trials remains limited. SRS is primarily a clinical diagnosis; however, molecular testing enables confirmation of the clinical diagnosis and defines the subtype. A normal result from a molecular test does not exclude the diagnosis of SRS. The management of children with SRS requires an experienced, multidisciplinary approach. Specific issues include growth failure, severe feeding difficulties, gastrointestinal problems, hypoglycaemia, body asymmetry, scoliosis, motor and speech delay and psychosocial challenges. An early emphasis on adequate nutritional status is important, with awareness that rapid postnatal weight gain might lead to subsequent increased risk of metabolic disorders. The benefits of treating patients with SRS with growth hormone include improved body composition, motor development and appetite, reduced risk of hypoglycaemia and increased height. Clinicians should be aware of possible premature adrenarche, fairly early and rapid central puberty and insulin resistance. Treatment with gonadotropin-releasing hormone analogues can delay progression of central puberty and preserve adult height potential. Long-term follow up is essential to determine the natural history and optimal management in adulthood.


Toumba M.,IASIS Hospital | Toumba M.,Makarios III Hospital | Kokotsis V.,Makarios III Hospital | Savva S.C.,Research and Education Institute of Child Health | And 3 more authors.
Journal of Pediatric Endocrinology and Metabolism | Year: 2014

Objective: The combination therapy of gonadotropin-releasing hormone analogues (GnRHa) and recombinant human growth hormone (rhGH) has been used to increase growth in children with premature sexual maturation and attenuated growth. The aim of this report was to study the benefit over cost of combined treatment in girls with central precocious puberty (CPP) and poor height prognosis and in girls with idiopathic short stature (ISS) and early puberty. Should this expensive treatment be given to such patients? Subjects and methods: Two patient groups were included: five girls with central precocious puberty (CPP) who reached final height (FH) at 16.3±1.2 years and eight girls with ISS who reached FH at 14.7±0.8 years. Patients were treated for 3.5±0.6 years. Results: In both groups, FH improved significantly; in CPP from -1.3 to -0.5 standard deviation score (SDS) (p=0.030) and in ISS from -2.6 to -1.7 SDS (p=0.012). Only girls with CPP reached their target height (-0.5 vs. -0.6 SDS) (p=0.500). Conclusions: Both groups had a total height gain of 5 cm. Each centimetre cost about €2700 per patient. This treatment should be considered only in patients with extremely low height prediction and very early pubertal onset. © 2014 by Walter de Gruyter Berlin Boston 2014.


NEOCLEOUS V.,The Cyprus Institute of Neurology and Genetics | BYROU S.,The Cyprus Institute of Neurology and Genetics | TOUMBA M.,Iasis Hospital | COSTI C.,The Cyprus Institute of Neurology and Genetics | And 8 more authors.
Journal of Genetics | Year: 2016

Familial Mediterranean fever (FMF) has traditionally been considered as a monogenic autosomal recessive disorder caused by mutations in the MEFV gene with highest incidence among Mediterranean populations. In a considerable number of patients with typical FMF, only one MEFV mutation was identified and the possibility that more than one autoinflammatory gene may be responsible for their disease was investigated. In the present study, an extensive search for possible mutations in three hereditary recurrent fever (HRF) genes was performed in 128 MEFV heterozygous Greek–Cypriots clinically diagnosed based on their phenotype with FMF-like disease from a previous study. Sequence analysis was performed for MVK, TNFRSF1A and NLRP3 genes which is also known to cause HRFs. In total, three patients were identified with heterozygous mutations and a second mutation in an autoinflammatory gene. Two patients carried a MEFV mutation and a NLRP3 mutation, and an additional third carried a MEFV mutation and a TNFRSF1A mutation. Patient 1 carried MEFV p.[Val726Ala] (NM_000243.2:c.2177T >C) and NLRP3 p.[Val198Met] (NM_001243133.1:c.592G >A) variants and patient 2 carried MEFV p.[Glu148Gln] (NM_000243.2:c.442G >C) variant which is of uncertain significance and NLRP3 p.[Arg176Trp] (NM_001243133.1:c.526C >T). Lastly, patient 3 was identified to carry MEFV p.[Met694Val] (NM_000243.2:c.2080A >G) and TNFRSF1A p.[Arg121Gln] (NM_001065.3:c.362G >A) variants. The results from this study indicate that screening of genes known to cause HRFs in patients already identified with a single MEFV mutation, can reveal quite rare but potentially causative mutational combinations at different loci. Such interaction provide further evidence for possible locus–locus interactions and phenotypes resulting from digenic inheritance. © 2016 Indian Academy of Sciences


Neocleous V.,The Cyprus Institute of Neurology and Genetics | Costi C.,The Cyprus Institute of Neurology and Genetics | Kyriakou C.,The Cyprus Institute of Neurology and Genetics | Kyriakides T.C.,Yale University | And 17 more authors.
Annals of Human Genetics | Year: 2015

Familial Mediterranean fever (FMF) is caused by mutations in the MEFV gene and the spectrum of mutations among Greek-Cypriots with FMF-related symptoms was examined. Sequence analysis for exons 2, 3, 5, and 10 of the MEFV gene was performed in a cohort of 593 patients. A total of 70 patients carried mutations in the homozygote or compound heterozygote state, 128 were identified with one MEFV mutation and 395 had no mutations. Of the 268 identified alleles, p.Val726Ala (27.61%) was the most frequent followed by p.Met694Val (19.40%). The missense mutations p.Arg761His (3.73%) and p.Ala744Ser (2.24%) were identified as the rarest. An interesting finding is the high frequency (18.28%) of the complex p.Phe479Leu-p.Glu167Asp that was identified in 49 of the mutated alleles. The MEFV genotypes did not follow a binomial distribution and proved not to satisfy the HWE (P < 0.001). The high percentage (66.61%) of patients with unidentified mutations could be due to mutations in the rest of the coding or noncoding MEFV gene or due to mutations in other genes that are also causing Hereditary Recurrent Fevers. Results from this work indicate the high incidence of FMF in Cyprus and describe the spectrum of the mutations which occur in the country. © 2014 John Wiley & Sons Ltd/University College London.


Toumba M.,Iasis Hospital
Georgian medical news | Year: 2012

Until recently, growth hormone (GH) and insulin-like growth factor 1 (IGF-1) were considered to control only linear growth. Apart from growth effect, GH has additional important physiological functions in the human body influencing several metabolic processes, body composition, muscle strength, and bone mineral density. In adolescence, where the majority of these physiological functions reach a zenith, GH plays a crucial role. The ability of GH to trigger cardiac muscle growth by direct and indirect effects plays a pivotal role in the physiology of the heart. Patients with childhood or adulthood onset of GH deficiency are exposed to increased risk for cardiovascular morbidity. GH treatment may have beneficial effect on the cardiovascular system in GH deficient adolescents. On the other hand discontinuation of GH treatment in these patients may result in the accumulation of relevant cardiovascular risk factors such as increase in body and abdominal fat and LDL and total cholesterol concentrations. No potential adverse cardiac effects of GH therapy have been so far demonstrated in short stature patients with normal GH secretion. Nevertheless, no evidence of heart hypertrophy or cardiomypathy has been documented in adolescents with GH excess has been reported in adults. Nonetheless, normalization of GH and IGF-1 levels in such patients is essential in order to arrest cardiovascular disease later in life.


Skordis N.,Cyprus Institute of Neurology and Genetics | Skordis N.,Paedi Center for Specialized Pediatrics | Skordis N.,University of Nicosia | Shammas C.,Cyprus Institute of Neurology and Genetics | And 6 more authors.
Journal of Endocrinological Investigation | Year: 2015

Objectives: To seek evidence on the prevalence of CYP21A2 genetic defects and consequences in girls with premature adrenarche (PA). Methods: The study included 59 girls diagnosed with PA. Direct DNA sequencing and MLPA analysis were performed to identify mutations in CYP21A2 gene. Results: Twelve girls were diagnosed with non-classic congenital adrenal hyperplasia (NC-CAH) based on stimulated 17-hydroxyprogesterone (17-OHP) levels and the presence of two mutations in CYP21A2, 19 were heterozygotes. The most frequent mutations detected were the mild p.Val281Leu and p.Pro453Ser. Higher levels of mean stimulated 17-OHP were found in the carriers of the p.Val281Leu mutation. The detection rate for two CYP21A2 mutations was higher in girls with PA than in adult females with hyperandrogenemia in our studied population. A notable increased allelic frequency for the known p.Asn493Ser polymorphism was observed in the pool of the 28 girls with PA in whom no mutation was identified. Conclusions: In girls with PA, the frequency of the underlying CYP21A2 genetic defects is similar to that observed in other populations. The carrier status is likely a contributing factor in the genotype-phenotype correlation in NC-CAH. However, polymorphisms and other genes may be implicated in the clinical manifestation of the disease. © 2014 Italian Society of Endocrinology (SIE).


Neocleous V.,The Cyprus Institute of Neurology & Genetics | Shammas C.,The Cyprus Institute of Neurology & Genetics | Phelan M.M.,University of Liverpool | Fanis P.,The Cyprus Institute of Neurology & Genetics | And 8 more authors.
Hormones | Year: 2016

OBJECTIVE: Heterozygous mutations on the melanocortin-4-receptor gene (MC4R) are the most frequent cause of monogenic obesity. We describe a novel MC4R deletion in a girl with severe early onset obesity, tall stature, pale skin and red hair. CASE REPORT: Clinical and hormonal parameters were evaluated in a girl born full-term by non-consanguineous parents. Her body mass index (BM I) at presentation (3 years) was 30 kg/m2 (z-score: +4.5SDS). By the age of 5.2 years, she exhibited extreme linear growth acceleration and developed hyperinsulinemia. METHODS: Direct sequencing of the MC4R, MC1R and for the known FTO single nucleotide polymorphism (SNP) rs9939609 was performed for the patient and her family. RESULTS: A novel heterozygous MC4R p.Met215del (c.643_645delATG) deletion was identified in the patient, her father and her brother, both of whom exhibited a milder phenotype. 3D structural dynamic simulation studies investigated the conformational changes induced by the p.Met215del. The patient and her mother were also found to be carriers of the obesity risk associated FTO rs9939609 SNP. Finally, the identification of the known p.Arg160Trp MC1R variant in the patient accounts for the red hair and pale skin phenotypic features. CONCLUSION: The p.Met215del causes global conformational and functional changes as it is localized at the alpha-helical transmembrane regions and the membrane spanning regions of the betabarrel. This novel mutation produces a severe overgrowth phenotype that is apparent as from infancy and is progressive in childhood. The additional negative effect of environmental and unhealthy lifestyle habits as well as a possible co-interaction of FTO rs9939609 SNP may worsen the phenotype. © 2016, Hellenic Endocrine Society. All rights reserved.


PubMed | Bristol Institute for Transfusion science, Makarios Hospital, Apollonion Private Hospital, The Cyprus Institute of Neurology and Genetics and 10 more.
Type: | Journal: BMC research notes | Year: 2016

After the discovery that cell-free fetal DNA (cffDNA) is circulating in the maternal plasma of pregnant women, non-invasive prenatal diagnosis for fetal RhD in maternal plasma in RhD negative women at risk for haemolytic disease of the newborn (HDN) was clinically established and used by many laboratories. The objectives of this study are: (a) to assess the feasibility and report our experiences of the routine implementation of fetal RHD genotyping by analysis of cffDNA extracted from maternal plasma of RhD negative women at risk of HDN, and (b) to estimate the RhD phenotype frequencies, the RHD genotype frequencies and the RhD zygosity in the Cypriot population.cffDNA was extracted from maternal plasma of 73 RhD negative pregnant women. Real-Time Multiplex-PCR was used to amplify regions of RHD gene in exons 4, 5 and 10. RhD phenotypes were determined on 445 random samples using conventional agglutination slide test.The fetus was predicted to be positive in 53 cases and negative in 18 cases. Two of cases were identified as D-variants, weak D type-1 and 11. The frequency of RhD negative homozygosity in the Cypriot population was estimated to be 7.2%, while the frequencies of RHD hemizygosity and RhD positive homozygosity was calculated to be 39.2 and 53.6%, respectively.Fetal RHD genotyping can be accurately determined using cffDNA from maternal plasma. The implementation of the test has eliminated all use of unnecessary anti-D and reduced the total use of anti-D by 25.3% while achieving appropriate management of the RhD negative pregnancies.


PubMed | Iasis Hospital
Type: | Journal: Georgian medical news | Year: 2012

Until recently, growth hormone (GH) and insulin-like growth factor 1 (IGF-1) were considered to control only linear growth. Apart from growth effect, GH has additional important physiological functions in the human body influencing several metabolic processes, body composition, muscle strength, and bone mineral density. In adolescence, where the majority of these physiological functions reach a zenith, GH plays a crucial role. The ability of GH to trigger cardiac muscle growth by direct and indirect effects plays a pivotal role in the physiology of the heart. Patients with childhood or adulthood onset of GH deficiency are exposed to increased risk for cardiovascular morbidity. GH treatment may have beneficial effect on the cardiovascular system in GH deficient adolescents. On the other hand discontinuation of GH treatment in these patients may result in the accumulation of relevant cardiovascular risk factors such as increase in body and abdominal fat and LDL and total cholesterol concentrations. No potential adverse cardiac effects of GH therapy have been so far demonstrated in short stature patients with normal GH secretion. Nevertheless, no evidence of heart hypertrophy or cardiomypathy has been documented in adolescents with GH excess has been reported in adults. Nonetheless, normalization of GH and IGF-1 levels in such patients is essential in order to arrest cardiovascular disease later in life.

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