Meropi Toumba

High prevalence of congenital hypothyroidism in the Greek Cypriot population: results of the neonatal screening program 1990-2000.

OBJECTIVE To evaluate the results of the screening program for congenital hypothyroidism (CH) in the Greek Cypriot population. CHILDREN AND METHODS During 1990-2000, 109,532 neonates were screened by TSH determination. Permanent CH was proven with biochemical findings after discontinuation of treatment for scintigraphy at the age of 3 years. RESULTS Permanent CH was diagnosed in 61 infants, incidence 1/1800, with female/male ratio 2.05/1. The most common clinical findings were omphalocele (61%), large anterior fontanelles (49%) and edema of the eyelids (34%). The more delayed the bone maturation, the lower were initial T4 levels (p = 0.005). Bone maturation tended to be more advanced in thyroid hypoplasia and more delayed in thyroid agenesis (p = 0.049). Scintigraphy of the thyroid with TC99 revealed ectopia in 38%, thyroid agenesis in 36%, thyroid hypoplasia in 24% and dyshormonogenesis in 1.7%. Children with transient CH had significantly lower T4 and higher TSH values initially compared to those with permanent CH after birth; initial TSH level, however, failed to predict the nature of CH. Children with transient CH required less thyroxine dosage to maintain normal thyroid hormone levels and they had a normal thyroid gland on scintigraphy. The TSH level was normalized before the age of 2 months with a starting L-thyroxine dose of 10 microg/kg/daily. CONCLUSIONS The incidence of primary CH in Greek Cypriots is 1/1800 live births. The most common etiology is thyroid dysgenesis. Initial T4 levels correlated with the degree of skeletal maturation and the etiology. Initial TSH level, although lower in children with transient CH, could not predict the nature of CH.

OSTEOPOROSIS SYNDROME IN THALASSAEMIA MAJOR: AN OVERVIEW

Osteoporosis in thalassaemia major (TM) represents a prominent cause of morbidity. The mechanism of pathogenesis of bone disease (BD) in TM is multifactorial and complicated. Peak bone mass is achieved shortly after completion of puberty and normally remains stable until the third decade of life when age-related bone mass begins. Growth hormone (GH) and sex steroids play a crucial role in bone remodeling and in the maintenance of skeletal architecture during adult life. GH and insulin growth factors (IGFs) have anabolic effect in bone formation. Sex steroids act probably by increasing the expression of RANKL by osteoblastic cells and alterations in the RANK/RANKL/OPG system in favor of osteoclasts. Impaired GH secretion and lack of sex steroids in thalassemic patients due to pituitary damage, contribute to failure of achieving optimal peak bone mass. Other endocrine complications such as hypoparathyroidism and vitamin D deficiency have also a detrimental role on bones in TM. It is still questionable whether the international criteria for defining osteopenia and osteoporosis are relevant to patients with TM; also a question arises for the diagnostic methods such as DEXA scan and management of osteoporosis with known treatment protocols, in the thalassaemic patient.

Evaluation of the auxological and metabolic status in prepubertal children born small for gestational age

BACKGROUND Low birth weight (BW) (<2,500 g) is associated with a high risk of impaired postnatal growth and late metabolic consequences. The aim of this study is to describe the postnatal growth pattern and the metabolic status of children born small for gestational age (SGA) and compare them with premature children born with low (1,500-2,500 g) and very low (<1,500 g) BW. CHILDREN AND METHODS 104 prepubertal children (47 males and 57 females) aged 3.0 to 8.9 years were divided into four groups according to their birth weight adjusted for gestational age (GA): SGA-premature (SGApr): BW < -2 SD, GA <37 wk (n = 17); SGA-full-term (SGAt): BW < -2 SD, GA >37 wk (n = 29); low birth weight (LBW): BW = 1,500-2,500 g, GA <37 wk (n = 35); very low birth weight (VLBW): BW <1,500 g, GA <37 wk (n = 23). The control group consisted of 27 full-term appropriate for gestational age, prepubertal children matched for age. All children had anthropometric and laboratory measurements. The HOMA model was used to estimate insulin resistance (IR). RESULTS Weight, height and body mass index (BMI) were significantly lower in the SGA groups -- both term and premature -- (p <0.05) and particularly lower in the VLBW children (p <0.01). At the age of 36 months, 99.6% of SGAt and a smaller percentage of SGApr (88.2%) children achieved catch-up growth. IGF-I and IGFBP-3 levels were lower in the children born SGA, both term and premature, compared to the controls (p <0.05) and especially in those who had catch-up after the age of 6 months (p <0.002). VLBW children aged 6-8.9 years had significantly higher HOMA compared to controls of the same age group (p = 0.005), whereas no evidence of IR was found in the SGA children. None of the children had developed premature adrenarche by the day of examination. CONCLUSIONS Prepubertal children born SGA and VLBW are thinner and shorter than their age-matched controls. A larger percentage of SGA full-term children achieve catch-up growth than SGA premature children by 3 years of age. SGA children and especially those with late catch-up growth have lower IGF-I levels. Children with VLBW show evidence of IR at age 6-8.9 years. None of the girls showed precocious sexual development by the day of examination.

Rising incidence of type 1 diabetes mellitus in children and adolescents in Cyprus in 2000–2004

Introduction:  The incidence of type 1 diabetes mellitus (T1DM) has dramatically increased recently in some countries.

Overview of genetic defects in endocrinopathies in the island of Cyprus; evidence of a founder effect.

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.

Familial Mediterranean fever associated with MEFV mutations in a large cohort of Cypriot patients.

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.

Evidence of digenic inheritance in autoinflammation-associated genes

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.

Expensive therapies in children: benefit versus cost of combined treatment of recombinant human growth hormone and gonadotropin-releasing hormone analogue in girls with poor height potential.

Abstract 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.

A novel MC4R deletion coexisting with FTO and MC1R gene variants, causes severe early onset obesity.

Familial isolated pituitary adenomas (FIPA) constitute 2-3% of pituitary tumours. AIP is the most commonly mutated gene in FIPA. We herein report a novel germline mutation of the AIP gene in a family with FIPA. We present two patients, a father and his 12-year-old daughter, diagnosed clinically and using laboratory measures with acromegaly-gigantism. Both underwent transsphenoidal hypophyseal surgery for macroadenomas. We initially detected a novel heterozygous germline AIP mutation, c.836G>A (p.W279*), in the fathers DNA. We then found the same mutation in his affected daughter. Pituitary adenomas associated with AIP mutations mostly present as FIPA (68%) at an early age (78% occur at <30 years old). They are often growth hormone (GH) - or prolactin - secreting macroadenomas (88%) that have already extended beyond the sella at the time of diagnosis. Acromegalic cases are resistant to somatostatin analogues and multimodal management is frequently essential to control the disease. Our patients had normalized GH/IGF-1 values soon after surgery, although enough time may not have elapsed to reach final cure. While penetrance of the disease can be as low as 10% in FIPA, especially children and young patients with somatotropinoma and prolactinoma should be surveyed for inactivating mutations or deletions in AIP. Determining the causative mutations may be of assistance in early diagnosis, treatment success, and genetic counseling.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 (BMI) 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 beta-barrel. 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.

A family with Camurati-Engelman disease: the role of the missense p.R218C mutation in TGFbeta1 in bones and endocrine glands.

Abstract 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.