The Results of 16 Years of Iodization: Assessment of Iodine Deficiency Among School-age Children in Antalya, Turkey

Objective: Iodine deficiency (ID) continues to be a problem around the world. This study investigated the prevalence of ID and goiter among school-age children in the city center of Antalya, Turkey. The aim was to investigate the effect of an iodization program, which had been running for sixteen years, on nutritional iodine status in this population. Methods: A total of 1,594 school children, aged 6-14 years, were included in this cross-sectional study. ID was evaluated based on median [interquartile range (IQR)] urine iodine/creatine (UI/Cr) (µg/g) ratio and median (IQR) UI concentrations (UIC) (µg/L). UICs were measured using the Sandell-Kolthoff method. Goiter was determined by palpation and staged according to World Health Organization classification. Results: Median (IQR) UIC was found to be 174.69 (119.17-242.83) µg/L, and UIC was found to be lower than 50 µg/L in 6.5% of the population. The median UI/Cr ratio increased from 62.3 to 163.3 µg/g and goiter rates had decreased from 34% to 0.3% over the 16 years of the program. However, 19% were still classified as ID (mild, moderate or severe) and, furthermore, 11.5% were classified as excessive iodine intake. Conclusion: Comparison of two cross-sectional studies, carried out 16-years apart, showed that Antalya is no longer an ID region. However, surveillance should be continued and the percentage of ID and iodine excess individuals in the population should be monitored to avoid emerging problems.

Remarkable Increase in the Prevalence of Overweight and Obesity Among School Age Children in Antalya, Turkey, Between 2003 and 2015

Objective: Childhood obesity (OB) is an acknowledged global problem with increasing prevalence reported around the world. We conducted this study with the aim of determining the local trend in OB and overweight (OW) prevalence in the last decade and to observe the alteration of OB and OW prevalence by age group. An additional aim was to construct new age- and gender-specific body mass index (BMI) reference percentile charts for Turkish children living in the city center of Antalya. Methods: This cross-sectional study included 1687 school aged children. International Obesity Task Force guidelines were used to determine the OB and OW prevalence. OW was defined as a BMI between 85th and 95th percentile, and OB >95th percentile. The data were compared with a previous study carried out in the same region in 2003. The least mean square method was used to construct the BMI reference percentile charts. Results: The prevalence rates for OB and OW were 9.8% and 23.2%, respectively, with a combined OW/OB rate of 33%. OB prevalence was higher in boys than girls (p<0.05). The prevalence of combined OW/OB was highest at age 9-10 years. The prevalence of OB has increased 2.9 times during twelve years in this location. Conclusion: Comparing the current findings with rates of OW and OB in the previous decade, childhood OB in Antalya has reached alarming levels. Urgent measures integrated into the national education system should be taken to prevent OB. In addition more surveillance studies should be planned to show the future trend of OB prevalence nationally.

Urinary phthalate metabolite concentrations in girls with premature thelarche.

In girls, breast development before eight years of age is called "premature thelarche (PT)". There are few studies in literature that show the interaction between PT and phthalate exposure. The aim of this study was to determine the urinary levels of di-(2-ethylhexyl) phthalate (DEHP) metabolites and other phthalate metabolites in girls with PT. PT group consisted of 29 newly diagnosed subjects. Control group comprised of healthy age-matched girls (n = 25). Urinary phthalate metabolite concentrations were measured by liquid chromatography/tandem mass spectroscopy (LC-MS/MS). The urinary concentrations of mono-(2-ethyl-hexyl)phthalate (MEHP) in the PT group (33.96 ±â€¯6.88 µg/g creatinine) were found to be significantly higher compared to control group (11.54 ±â€¯1.39 µg/g creatinine, p = 0.002). In PT group, %MEHP was also markedly higher vs. control (17.84 ±â€¯3.31 vs. 6.44 ±â€¯1.13, p = 0.001). Our results suggest that DEHP is more efficiently converted to MEHP in girls with PT, the importance of which needs to be further elucidated.

Clinical and Molecular Genetic Analysis in Three Children with Wolfram Syndrome: A Novel WFS1 Mutation (c.2534T>A).

Wolfram syndrome (WS) is an autosomal recessive disorder caused by mutations in WFS1 gene. The clinical features include diabetes insipidus, diabetes mellitus (DM), optic atrophy, deafness, and other variable clinical manifestations. In this paper, we present the clinical and genetic characteristics of 3 WS patients from 3 unrelated Turkish families. Clinical characteristics of the patients and the age of onset of symptoms were quite different in each pedigree. The first two cases developed all symptoms of the disease in their first decade of life. The heterozygous father of case 2 was symptomatic with bilateral deafness. The first ocular finding of one patient (patient 3) was bilateral cataract which was accompanying DM as a first feature of the syndrome. In this patient's family, there were two members with features suggestive of WS. Previously known homozygous mutations, c.460+1G>A in intron 4 and c.1885C>T in exon 8, were identified in these cases. A novel homozygous c.2534T>A mutation was also detected in the exon 8 of WFS1 gene. Because of the rarity and heterogeneity of WS, detection of specific and nonspecific clinical signs including ocular findings and family history in non-autoimmune, insulinopenic diabetes cases should lead to a tentative diagnosis of WS. Genetic testing is required to confirm the diagnosis.

A Novel Null Mutation in P450 Aromatase Gene (CYP19A1) Associated with Development of Hypoplastic Ovaries in Humans.

OBJECTIVE: The CYP19A1 gene product aromatase is responsible for estrogen synthesis and androgen/estrogen equilibrium in many tissues, particularly in the placenta and gonads. Aromatase deficiency can cause various clinical phenotypes resulting from excessive androgen accumulation and insufficient estrogen synthesis during the pre- and postnatal periods. In this study, our aim was to determine the clinical characteristics and CYP19A1 mutations in three patients from a large Turkish pedigree. METHODS: The cases were the newborns referred to our clinic for clitoromegaly and labial fusion. Virilizing signs such as severe acne formation, voice deepening, and clitoromegaly were noted in the mothers during pregnancy. Preliminary diagnosis was aromatase deficiency. Therefore, direct DNA sequencing of CYP19A1 was performed in samples from parents (n=5) and patients (n=3). RESULTS: In all patients, a novel homozygous insertion mutation in the fifth exon (568insC) was found to cause a frameshift in the open reading frame and to truncate the protein prior to the heme-binding region which is crucial for enzymatic activity. The parents were found to be heterozygous for this mutation. Additionally, all patients had hypoplastic ovaries instead of cystic and enlarged ovaries. CONCLUSION: A novel 568C insertion mutation in CYP19A1 can lead to severe aromatase deficiency. Homozygosity for this mutation is associated with the development of hypoplastic ovaries. This finding provides an important genetic marker for understanding the physiological function of aromatase in fetal ovarian development.

Mitochondrial ATPase subunit 6 and cytochrome B gene variations in obese Turkish children.

OBJECTIVE: Due to the importance of energy metabolism in mitochondria, mitochondrial genome variations are evaluated in energy-related diseases such as obesity. To date, several nuclear genes were found to be related to obesity. Our aim in this study was to investigate the presence of polymorphisms in mitochondrial ATPase subunit 6 (mt-ATP6) and cytochrome b (mt-CytB) genes that may be associated with childhood obesity. METHODS: The mt-ATP6 and mt-CytB genes were amplified and entirely sequenced in a series of 100 obese and in an equal number of healthy Turkish children aged between 6-14 years. RESULTS: A total of 118 synonymous and nonsynonymous variations were detected in the obese and control groups. Only two previously reported synonymous substitutions (mt.8614T>C and mt.8994G>A) in the mt-ATP6 gene were found to be significantly higher in the obese group compared to the control group (p<0.05). In the mt-ATP6 gene, one novel nonsynonymous substitution (mt.8726C>T) and one novel synonymous substitution (mt.9108A>T) were found. In the mt-CytB gene, one nonsynonymous substitution (mt.14880T>C) and two synonymous substitutions (mt.14891C>T and mt.15091C>T) were novel substitutions. CONCLUSION: Two synonymous substitutions (mt.8614T>C and mt.8994G>A) in the mt-ATP6 gene may be associated with childhood obesity. Our study provides the first data about mitochondrial genome variations in a Turkish obese population and also the first in obese children. More cases should be screened in obese groups in order to understand the effects of mitochondrial polymorphisms in the development of obesity.

Try235Phe homozygous mutation of the steroid 5-a reductase type 2 (SRD5A2) gene in a Turkish patient.

Steroid 5-a reductase type 2 isoenzyme (SRD5A2) deficiency is a male-limited autosomal recessive disorder that results in decreased conversion of testosterone to dihydrotestosterone with various de.gree of incomplete virilization in affected 46, XY infants. No clear genotype-phenotype relationship has been reported till date; moreover, the same mutation can result in considerable heterogeneity in clinical manifestations. Of 6 documented cases with Try235Phe homozygous mutation of the SRD5A2 gene, 3 patients had predominantly female external genitalia whereas the other 3 had predominantly male phenotype. We report Try235Phe homozygous mutation of the SRD5A2 gene in a Turkish patient who was initially assigned as a girl because of the predominantly female appearance of the external genitalia.

A combination of nifedipine and octreotide treatment in an hyperinsulinemic hypoglycemic infant.

Hyperinsulinemic hypoglycemia (HH) is the commonest cause of persistent hypoglycemia in the neonatal and infancy periods. Mutations in the ABCC8 and KCNJ11 genes, which encode subunits of the ATP-sensitive potassium channel in the pancreatic beta cell, are identified in approximately 50% of these patients. The first-line drug in the treatment of HH is diazoxide. Octreotide and glucagon can be used in patients who show no response to diazoxide. Nifedipine, a calcium-channel blocker, has been shown to be an effective treatment in a small number of patients with diazoxide-unresponsive HH. We report a HH patient with a homozygous ABCC8 mutation (p.W1339X) who underwent a near-total pancreatectomy at 2 months of age due to a lack of response to diazoxide and octreotide treatment. Severe hypoglycemic attacks continued following surgery, while the patient was being treated with octreotide. These attacks resolved when nifedipine was introduced. Whilst our patient responded well to nifedipine, the dosage could not be increased to 0.75 mg/kg/day due to development of hypotension, a reported side effect of this drug. Currently, our patient, now aged 4 years, is receiving a combination of nifedipine and octreotide treatment. He is under good control and shows no side effects. In conclusion, nifedipine treatment can be started in patients with HH who show a poor response to diazoxide and octreotide treatment.

Urinary bisphenol a levels in girls with idiopathic central precocious puberty.

OBJECTIVE: Bisphenol A (BPA) is an industrial chemical, particularly used to harden plastics. BPA is thought to have negative health effects on both laboratory animals and humans. Consider ing the decline in age of onset of puberty noted in recent years, particularly among girls, the importance of BPA as an estrogenic endocrine disruptor has increased. In this study, we aimed to determine urinary BPA levels in girls with idiopathic central precocious puberty (ICPP). METHODS: Non-obese girls newly diagnosed with ICPP (n=28, age 4-8 years) constituted the study group. The control group consisted of 25 healthy age-matched girls with no history of ICPP or any other endocrine disorder. Urinary BPA levels were measured by using high-performance liquid chromatography. RESULTS: In the ICPP group, urinary BPA levels were significantly higher compared to the control group [median 8.34 (0.84-67.35) µg/g creatinine and 1.62 (0.3-25.79) µg/g creatinine, respectively (OR=8.68, 95% CI:2.03-32.72, p=0.001)]. There was no marked correlation between urinary BPA levels and body mass index in either group. In the ICPP group, no significant correlations were found between urinary BPA levels and serum luteinizing hormone, follicle-stimulating hormone and estradiol levels. CONCLUSIONS: To our knowledge, this is the first study evaluating the urinary BPA levels in Turkish girls with ICPP. Our results indicate that the estrogenic effects of BPA may be an etiologic factor in ICPP.

Clinical expression of familial Williams-Beuren syndrome in a Turkish family.

Williams-Beuren syndrome (WBS) is a rare genetic disorder characterized by distinctive facial features, intellectual disability with a typical neurobehavioral profile, cardiovascular anomalies, and occasional infantile hypercalcemia. Majority of cases occur sporadically, and only a few cases of familial WBS have been reported. Although pre- and post-natal growth retardation is a common clinical feature of the syndrome, growth hormone deficiency is detected only in a few patients. To our knowledge, there has only been one report about familial Williams-Beuren syndrome in the Turkish population. Here, we report on the three molecular cytogenetically confirmed familial Williams-Beuren syndromes detected in a family with familial short stature. The father, daughter, and son analyzed with clinical and laboratory findings, and reasons of the short stature in Williams-Beuren syndrome are discussed through the literature.

A novel DAX-1 mutation presented with precocious puberty and hypogonadotropic hypogonadism in different members of a large pedigree.

Patients with DAX-1 gene mutations on chromosome Xp21 usually present with adrenal hypoplasia congenita and hypogonadotropic hypogonadism. Yet, neither correlation between the type of mutation and the age of onset of the disease nor mechanism of the mutation on puberty is fully understood. Here, we report a novel non-sense p.Gln208X mutation in the amino terminal domain of the DAX-1 gene observed in a large family with three boys presenting with adrenal manifestations at different ages. Furthermore, two boys developed spontaneous puberty that failed to progress at similar ages, whereas the other boy developed precocious puberty at 10 month of age. The unique structure of the DAX-1 gene may explain this phenotypic variability. However, more studies are needed to understand the role of the DAX-1 gene on development of the adrenal gland and hypothalamus-pituitary-gonadal axis.

CTLA-4 (+49A/G) polymorphism and type-1 diabetes in Turkish children.

OBJECTIVE: To evaluate the contribution of cytotoxic T-Iymphocyte antigen-4(CTLA-4)+49A/G polymorphism to the susceptibility to type-1 diabetes (T1D) in Turkish children. METHODS: A case-control study was designed to include 91 Turkish children with T1D and 99 healthy controls. CTLA-4 (+99A/G) gene polymorphism typing was done by PCR amplification followed by restriction fragment length polymorphism method. RESULTS: The genotype and allele frequencies of the CTLA-4 (+99A/G)polymorphism in patients with T1D were not different from those in the controls (p>0.05). The allele frequency of G was 36.2% in patients with T1D,and 31.8% in controls (p>0.05). Additionally, this polymorphism was not associated with the clinical and laboratory characteristics of the patients with T1D (p>0.05). CONCLUSIONS: Our case-control study suggests that the CTLA-4 (+99A/G) gene polymorphism is not associated with T1D in the Turkish population.

Novel and de novo PHEX mutations in patients with hypophosphatemic rickets.

X-linked hypophosphatemic rickets (XLH) is the most common inherited rickets. XLH is caused by inactivating mutations in the PHEX gene and is transmitted as an X-linked dominant disorder. We investigated PHEX mutation in 10 patients from 6 unrelated Turkish families by PCR-sequence analysis. Six different PHEX mutations were detected in the patients. Four of them were novel: c.1217G>A (p.C406Y) in exon 11, c.2078G>T (p.C693F) in exon 21, a splice donor site mutation in intron 13 (IVS13+1G>T), and a splice acceptor site mutation in intron 13 (IVS13-2A>G). De novo PHEX mutations were found exclusively in female patients from 4 families and inherited mutations were detected from remaining two families. The patients' phenotype was consistent with the loss of PHEX function. Literature review of 78 sporadic cases shows that de novo mutations are present in 83% female patients and female/male ratio is 5 to 1. One patient had biallilic PHEX mutations at c.1735G>A (p.G579R) whereas her mother and two siblings carried a monoallelic mutation. The clinical and laboratory findings of the patient with biallilic PHEX mutation were similar to those with monoallelic mutation. The study shows that PHEX mutation is a common cause of either familial or sporadic hypophosphatemic rickets in Turkish population. Gene dosage effect is not observed. The frequent de novo mutations found in the female patients are likely resulting from mutagenesis of X chromosome in paternal germ cells.

Variability in the age at diagnosis of diabetes in two unrelated patients with a homozygous glucokinase gene mutation.

Homozygous mutations in the glucokinase gene (GCK) result in a complete deficiency of the GCK enzyme, which leads to permanent neonatal diabetes mellitus. Whilst there has been one report of a patient (with a homozygous p.T168A) who was diagnosed with diabetes at the age of 2 months, all other cases were diagnosed with diabetes within the first 2 weeks of life. We now report a second unrelated patient with the same p.T168A GCK mutation who was diagnosed with diabetes at the age of 9 months. We conclude that the specific GCK mutation, as yet unidentified genetic modifiers, and/or environmental factors might have different effects on pancreatic beta-cell functions, causing variability in the age at diagnosis of diabetes.

Wolcott-Rallison syndrome due to a novel mutation (R491X) in EIF2AK3 gene.

Wolcott-Rallison syndrome (WRS) is a rare autosomal recessive disorder characterized by early-onset diabetes, spondyloepiphyseal dysplasia, tendency to skeletal fractures secondary to osteopenia, and growth retardation. Mutations in the eukaryotic translation initiation factor 2α kinase (EIF2AK3) gene are responsible for this disorder. Here, we describe a boy with neonatal diabetes, diagnosed at 2 months of age, who developed severe growth retardation and a skeletal fracture during the follow-up period. The patient's skeletal X-ray revealed findings of skeletal dysplasia. A clinical diagnosis of WRS was confirmed by the identification of a novel homozygous nonsense mutation (R491X) in exon 9 of the EIF2AK3 gene. The aim of this report is to raise the awareness for Wolcott-Rallison syndrome in cases presenting with isolated neonatal diabetes. This patient demonstrates that the other findings of this syndrome might be obscured by a diagnosis of isolated neonatal diabetes.

Clinical and genetic analysis of patients with vitamin D-dependent rickets type 1A.

CONTEXT: Vitamin D-dependent rickets type 1A (VDDR-IA, OMIM 264700) is a rare autosomal recessive disorder and is caused by mutations in the CYP27B1 gene. OBJECTIVES: We aim to investigate CYP27B1 mutation in seven patients from four separate families and characterize the genotype-phenotype correlation. METHODS: The entire coding region of the CYP27B1 gene was sequenced, and genotype-phenotype correlation among patients was assessed. RESULTS: Sequencing analysis identified biallelic CYP27B1 mutations in all patients and monoallelic mutations in their parents. One patient from the first family was compound heterozygous for c.1166G>A (p.Arg389His) and a novel nonsense mutation c.1079 C>A (p.Ser360*). Two patients from the second family were homozygous for a novel splice donor site mutation in intron 1 (c.195 + 2 T>G), causing partial retention of the intron and a shift in the reading frame. Both novel mutations lead to the complete loss of vitamin D1α-hydroxylase activity. Four patients from families 3 and 4 were homozygous for a previously reported duplication mutation in exon 8 (1319-1325dupCCCACCC, Phe443Profs*24). Interestingly, one patient who was presented with severe hypocalcaemia and seizures at 4 months of age as a result of Phe443Profs*24 has improved spontaneously since 11 years of age and does not need regular treatment. Her laboratory tests showed normal serum calcium and 1,25(OH)(2) D after refusing to take medication for 12 months. CONCLUSIONS: There is a good genotype-phenotype correlation in VDDR-IA. However, some patients may recover from the loss of CYP27B1 function, probably due to 1α-hydroxylase activity exerted by a non-CYP27B1 enzyme.

Renal cell carcinoma presented with hypocalcemia in an adolescent.

Renal cell carcinoma is very rare in childhood. It is a different entity from its adult counterpart. We report a case of renal cell carcinoma presented with hypocalcemia in a 16-year-old girl that is, to the best of our knowledge, the first such published incident. The patient was treated by radical nephrectomy with regional lymphadenectomy. Hypocalcemia amended after surgery. Neither chemotherapy nor radiotherapy was given. She has remained disease free for 34 months.

Intrathyroidal ectopic thymic tissue may mimic thyroid cancer: a case report.

Ectopic intrathyroidal thymus tissue that may be present as a thyroid nodule is rarely reported. We present a case of a 4-year-old boy with a solitary thyroid nodule. Real-time thyroid ultrasound showed a calcified nodule in the right lobe. Complete blood count, serum calcitonin, and thyroglobulin concentration were normal and antithyroid antibodies were negative. Fine-needle aspiration (FNA) biopsy was revealed as inadequate for cytological examination. During his follow-up, nodular enlargement was found, and the patient was subjected to surgical total excision of the right lobe of the thyroid gland. Pathological examination showed an ectopic intrathyroidal thymus tissue. In childhood, ectopic intrathyroidal thymus tissue can present as an enlarging microcalcified thyroid nodule that may mimic thyroid cancer and may grow during follow-up.

Spontaneous endogenous hypermelatoninemia: a new disease?

Melatonin, a major photoperiod-dependent hormone, regulates circadian rhythms and biological rhythms and acts as a prominent sleep promoter. Symptoms related to hypermelatoninemia have been reported in individuals supplemented with melatonin. However, spontaneous endogenous hypermelatoninemia has not been reported previously. A 6-year-old girl previously diagnosed with Shapiro's syndrome was admitted to our hospital on several occasions during a 1-year period with complaints of altered consciousness, syncope, hypothermia and episodes of sweating. The episodes occurred daily and during sleep and lasted for 1-6 h. During these episodes, she sweated profusely and felt faint and her skin was pale and cool. Other complaints included recurrent abdominal pain, urge incontinence and myopia. She was shown to have hypermelatoninemia (>1,000 pg/ml, normal range 0-150 pg/ml) during these episodes. The duration of her attacks decreased with phototherapy and she was successfully treated with propranolol. To our knowledge, this is the first case of hypermelatoninemia without any detectable organic pathology. We did not determine the exact mechanism of hypermelatoninemia in this patient; however, it might have been related to irregular control of pinealocytes by the suprachiasmatic nucleus or related pathways. Hypermelatoninemia should be considered in patients with spontaneous periodic hypothermia and hyperhidrosis, and also in patients with Shapiro's syndrome.

Analysis of TPO gene in Turkish children with iodide organification defect: identification of a novel mutation.

The objective was to determine molecular genetic analysis of the TPO gene in Turkish children with iodide organification defect (IOD). Patients with a diagnosis of primary hypothyroidism were evaluated. Subjects having a definite diagnosis of autoimmune thyroiditis, thyroid gland dysplasia and, or iodine deficiency were excluded. A total of 10 patients from nine unrelated Turkish families, with an unknown etiology of hypothyroidism, and with a presumptive diagnosis of IOD were included in the study. A perchlorate discharge test (PDT) was performed to all subjects, and sequence analysis of TPO gene was applied in patients with a positive PDT. Five out of 10 patients have a total IOD, while the five remaining patients have a partial IOD according to PDT results. In two sisters, one has a partial and the other one has a total IOD a novel homozygous nonsense p.Q315X mutation was found in exon 8. Additionally, a previously known homozygous missense p.R314W mutation was detected in the same exon in another patient with a total IOD. No TPO gene mutation was detected in any of the seven remaining patients. Two different TPO gene mutations were found to be responsible for IOD in two unrelated Turkish families from the same ethnic background. More subjects should be screened for detecting the prevalence and spectrum profile of TPO mutations in our population that might be helpful for understanding the pathophysiology of congenital hypothyroidism.