Cengiz Kara

Vitamin D Intoxication Due to an Erroneously Manufactured Dietary Supplement in Seven Children

Pediatric cases of vitamin D intoxication (VDI) with dietary supplements have not been previously reported. We report on 7 children with VDI caused by consumption of a fish oil supplement containing an excessively high dose of vitamin D due to a manufacturing error. Seven children aged between 0.7 and 4.2 years were admitted with symptoms of hypercalcemia. Initial median (range) serum concentrations of calcium and 25-hydroxyvitamin D were 16.5 (13.4–18.8) mg/dL and 620 (340–962) ng/mL, respectively. Repeated questioning of the parents revealed use of a fish oil that was produced recently by a local manufacturer. Analysis of the fish oil by gas chromatography/mass spectrometry revealed that the vitamin D3 content was ∼4000 times the labeled concentration. Estimated daily amounts of vitamin D3 intake varied between 266 000 and 800 000 IU. Patients were successfully treated with intravenous hydration, furosemide, and pamidronate infusions. With treatment, serum calcium returned to the normal range within 3 days (range: 2–7 days). Serum 25-hydroxyvitamin D levels normalized within 2 to 3 months. Complications, including nephrocalcinosis, were not observed throughout the 1-year follow-up. In conclusion, errors in manufacturing of dietary supplements may be a cause of VDI in children. Physicians should be aware of this possibility in unexplained VDI cases and repeatedly question the families about dietary supplement use. To prevent the occurrence of such unintentional incidents, manufacturers must always monitor the levels of ingredients of their products and should be rigorously overseen by governmental regulatory agencies, as is done in the pharmaceutical industry.

Etiological classification and clinical assessment of children and adolescents with disorders of sex development.

Objective: In 2006, the Lawson Wilkins Pediatric Endocrine Society (LWPES) and the European Society for Paediatric Endocrinology (ESPE) published a consensus statement on management of intersex disorders. The aim of our study was to determine the etiological distribution of disorders of sex development (DSD) according to the new DSD classification system and to evaluate the clinical features of DSDs in our patient cohort. Methods: We retrospectively reviewed the records of patients followed up during the past three years. The subjects were divided into three etiologic groups according to their karyotypes. The definite diagnosesin each subgroup were established by clinical and laboratory investigations including abdominopelvic imaging as well as basal and stimulated hormone measurements. Molecular genetic testing, except for CYP21A2 gene, could not be performed. Results: Out of a total of 95 patients, 26 had sex chromosome DSD, 45 had 46,XY DSD and 24 had 46,XX DSD. The most common causes of DSDs were Turner’s syndrome (TS), congenital adrenal hyperplasia (CAH) and androgen insensitivity syndrome (AIS). There was a wide variation in age of presentation ranging from 1 day to 17.5 years with a mean of 6.5±6.5 years. The most frequent complaints at presentation were ambiguous genitalia, isolated perineal hypospadias and short stature. Conclusion: The results of our study demonstrate that the new DSD classification system leads to a major change in the distribution of etiological diagnoses of DSDs, which is exemplified by the significant frequencies of TS and vanishing testes syndrome. This alteration expands the clinical spectrum and increases the mean age at diagnosis. However, the most common causes of ambiguous genitalia, such as CAH and AIS, remain unchanged. Further studies using molecular genetic analyses are needed to give a more precise distribution of etiologies of DSDs, especially in 46,XY patients. Conflict of interest:None declared.

Identification of frequency and distribution of the nine most frequent mutations among patients with 21-hydroxylase deficiency in Turkey.

UNLABELLED Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders mainly due to defects in the steroid 21-hydroxylase (CYP21A2) gene. METHODS To determine the mutational spectrum in the Turkish population, the CYP21A2 active gene was analyzed in 100 unrelated patients with the classical form of 21-hydroxylase deficiency using PCR and RFLP. RESULTS Mutations were detected in 78 patients: 64 patients were homozygous for one mutation, seven patients were compound heterozygous with different mutations on each chromosome, two patients were homozygous for two different mutations, five patients were heterozygous, and 22 patients harbored none of the tested mutations. The most frequent mutation was IVS2-13A/C (28.5%), followed by large gene deletion (17%), Q318X (11.5%), I172N (4%), V281L (3.5%), R356W (3.5%), 8-bp (3%), complex alleles (2%), P30L (1%) and E6 cluster (1%). CONCLUSION The distribution of mutation frequencies in our study was slightly different from those previously reported in Turkey and in other parts of the world.

Diabetes care, glycemic control, complications, and concomitant autoimmune diseases in children with type 1 diabetes in Turkey: a multicenter study.

Objective: Epidemiologic and clinical features of type 1 diabetes mellitus (T1DM) may show substantial differences among countries. The primary goal in the management of T1DM is to prevent micro- and macrovascular complications by achieving good glycemic control. The present study aimed to assess metabolic control, presence of concomitant autoimmune diseases, and of acute and long-term complications in patients diagnosed with T1DM during childhood and adolescence. The study also aimed to be a first step in the development of a national registry system for T1DM, in Turkey. Methods: Based on hospital records, this cross-sectional, multicenter study included 1 032 patients with T1DM from 12 different centers in Turkey, in whom the diagnosis was established during childhood. Epidemiological and clinical characteristics of the patients were recorded. Metabolic control, diabetes care, complications, and concomitant autoimmune diseases were evaluated. Results: Mean age, diabetes duration, and hemoglobin A1c level were 12.5±4.1 years, 4.7±3.2 years, and 8.5±1.6%, respectively. Acute complications noted in the past year included ketoacidosis in 5.2% of the patients and severe hypoglycemia in 4.9%. Chronic lymphocytic thyroiditis was noted in 12%, Graves’ disease in 0.1%, and celiac disease in 4.3% of the patients. Chronic complications including neuropathy, retinopathy, and persistent microalbuminuria were present in 2.6%, 1.4%, and 5.4% of the patients, respectively. Diabetic nephropathy was not present in any of the patients. Mean diabetes duration and age of patients with neuropathy, retinopathy and microalbuminuria were significantly different from the patients without these long-term complications (p<0.01). A significant difference was found between pubertal and prepubertal children in terms of persistent microalbuminuria and neuropathy (p=0.02 and p<0.001, respectively). Of the patients, 4.4% (n:38) were obese and 5% had short stature; 17.4% of the patients had dyslipidemia, and 14% of the dyslipidemic patients were obese. Conclusions: Although the majority of the patients in the present study were using insulin analogues, poor glycemic control was common, and chronic complications were encountered. Conflict of interest:None declared.

Rhabdomyolysis without detectable myoglobulinuria due to severe hypophosphatemia in diabetic ketoacidosis.

Clinical signs of hypophosphatemia, even when severe, are rare in diabetic ketoacidosis despite their high frequency in this condition. This article presents a patient with rhabdomyolysis due to severe hypophosphatemia, where the level of serum phosphorus was observed to be as low as 0.42 mg/dL on the 16th hour of ketoacidosis treatment. The patient developed acute tubular necrosis due to rhabdomyolysis, but there was no blood reaction in the urine, and the creatine kinase increased to 1200 U/L. The patient was treated without dialysis and was cured after a polyuria period of 2 months after the oliguric period.

The effect of glucocorticoid replacement therapy on bone mineral density in children with congenital adrenal hyperplasia.

Abstract Objectives: 1) To evaluate the effects of glucocorticoid (GC) doses on bone mineral density (BMD) in children with congenital adrenal hyperplasia (CAH), 2) Investigate other factors influencing BMD. Methods: Twenty-six children with CAH and 11 healthy controls included in the study. All of the patients were examined with dual-energy X-ray absorptiometry (DXA) using a Hologic QDR 1000/W densitometer. The metabolic control state, age at diagnosis GC dose (mg/m2/day), pubertal status, 17 hydroxyprogesterone (17 OHP) levels, bone age (BA), and lumber BMD were evaluated in all cases. BMD (g/cm2), BMD z-score corrected to National Standards (cNS-BMD z-score), BMD z-score corrected to BA (cBABMD), bone mineral content (BMC), BMC corrected to puberty (cPBMC), and bone area (BAR) values were determined. Patients were grouped according to mean on-therapy serum 17 OHP levels as tight control (17 OHP<10 nmol/L) (n:13) and poor control (17 OHP>10 nmol/L) (n:13). All groups were compared with each other. Results: The age range was 2.1–15.7 years and the mean age (±SD) 9.3 (±3.5) years. There were no significant differences between the groups in terms of GC doses, lumbar BMD values [BMD (g/cm2), BMD z-score corrected to National Standards (cNS-BMD z-score), BMD z-score corrected to BA (cBABMD), bone mineral content (BMC), BMC corrected to puberty (cPBMC), and bone area (BAR)]. However, the BMI value was higher in children with CAH than normal healthy controls. The BA of the poor control, late diagnosed groups and male patients were higher than tight control, early diagnosed group and female patients, respectively. BMC and BA were lower than the control group in tight control with early diagnosed patients. The cBABMD z-score was lower in males with poor control than males with tight control. There were no similar results in female patients. Conclusions: Although GC treatment seems not to influence BMD in CAH patients in our study, further studies are needed to additionally evaluate daily calcium (Ca) intake, polymorphism of vitamin D receptor, ethnic factors (strict Islamic dress, etc.), socioeconomic status, and 24-h urinary free cortisol level.

Congenital goitrous hypothyroidism, deafness and iodide organification defect in four siblings: Pendred or pseudo-Pendred syndrome?

Pendred syndrome (PDS) is an autosomal recessive disorder characterized by congenital deafness, goiter and iodide organification defect. Presence of inner ear malformations is essential for the clinical diagnosis. Most individuals with PDS are clinically and biochemically euthyroid. Mutations in the PDS gene encoding pendrin protein have been shown to be associated with PDS. It has been recently demonstrated that some families with features of PDS do not have the inner ear malformations and mutations in the PDS gene. This condition has been named as “pseudo−Pendred syndrome” (pseudo−PDS), and has been hypothesized to be of autoimmune origin. Here we report four siblings who have goiter, severe hypothyroidism, a positive perchlorate discharge test and sensorineural deafness, but not the inner ear abnormality which is diagnostic for PDS. We suggest that thyroid peroxidase (TPO) gene should be analyzed in pseudo−PDS patients with congenital goitrous hypothyroidism and deafness. Conflict of interest:None declared.

Myelofibrosis associated with rickets in a child with down syndrome

To the Editor: Rickets is an illness which is seen in childhood due to the lack of vitamin D. Myelofibrosis is rarely associated with rickets. Say and Berkel [1] described the first case of rickets associated with myelofibrosis. All the reported cases are in infanthood [1–13]. We diagnosed and treated myelofibrosis associated with rickets in a 10-year-old male with Down syndrome. The patient presented with fever, thrombocytopenia, and anemia. He had Down syndrome which was genetically proven. His weight (14 kg), height (110 cm), and head circumference (48 cm) were below the third percentile. He had massive hepatosplenomegaly, rachitic rosaries, widened wrists, and ankles. He could sit but not walk. Hemoglobin level was 5.4 g/dl, white blood cell count was 5.6 10/L and platelet count was 26 10/L. Bone marrow aspiration demonstrated decreased erythroid, myeloid and megakaryocytic lineage, and normal myeloid/erythroid ratio. There were no signs of abnormal maturation and myelodysplasia. Leukemic infiltration was not observed. Serum calcium was 5.7 mg/dl (normal range 8.1–10.7), phosphorus 0.73 mg/dl (normal range 2.3–4.7), alkaline phosphatases 587 U/L (normal range 95–280), 25-hydroxy-vitamin D3 level 5 mg/L (normal range 30– 80). A diagnosis of rickets related to lack of D vitamin was made. Secondary hyperparathyroidism was suspected since parathyroid

The Etiology and Clinical Features of Non-CAH Gonadotropin-Independent Precocious Puberty: A Multicenter Study

AIM The causes of gonadotropin-independent precocious puberty are diverse, and often have overlapping clinical and biochemical features. With the exception of congenital adrenal hyperplasia (CAH), disorders that cause gonadotropin-independent precocious puberty (GIPP) are uncommon. The literature is devoid of any large-scale studies on the etiologic distribution of GIPP. The aim of this study was to determine the frequency of each etiology in a cohort of patients with GIPP (excluding those with CAH), and to evaluate the clinical and laboratory features of these patients. MATERIALS AND METHODS This multicenter, nationwide web-based study collected data on patients who presented with non-CAH GIPP in Turkey. RESULTS Data were collected for 129 patients (102 girls and 27 boys) from 29 centers. Based on the data collected, the estimated prevalence of non-CAH GIPP in the studied population was 14 in 1 000 000 children. Functional ovarian cyst was the most common etiology, accounting for 37% of all cases, followed by McCune-Albright syndrome (MAS) (26%). Among the patients with MAS, 11.7% had fibrous dysplasia, 32.3% had café-au-lait spots, and 52.9% had both. Human chorionic gonadotrophin-secreting tumors included choriocarcinoma of the liver, hepatoblastoma, and germ cell tumors of the sellar-suprasellar region and mediastinum. Patients with adrenocortical tumors presented at an earlier age than those with other etiologies. Ovarian tumors included mature cystic teratoma, dysgerminoma, juvenile granulosa tumor, and steroid cell tumor. Despite overlapping features, it was possible to identify some unique clinical and laboratory features associated with each etiology. CONCLUSION This largest cohort of patients with non-CAH GIPP to date yielded an estimation of the frequency of non-CAH GIPP in the general pediatric population and showed that girls were affected at a rate 4-fold greater than that of boys owing to functional ovarian cysts and MAS, which were the two most common etiologies. The data collected also provided some unique characteristics associated with each etiology.

Turner syndrome and associated problems in turkish children: A multicenter study

Objective: Turner syndrome (TS) is a chromosomal disorder caused by complete or partial X chromosome monosomy that manifests various clinical features depending on the karyotype and on the genetic background of affected girls. This study aimed to systematically investigate the key clinical features of TS in relationship to karyotype in a large pediatric Turkish patient population. Methods: Our retrospective study included 842 karyotype-proven TS patients aged 0-18 years who were evaluated in 35 different centers in Turkey in the years 2013-2014. Results: The most common karyotype was 45,X (50.7%), followed by 45,X/46,XX (10.8%), 46,X,i(Xq) (10.1%) and 45,X/46,X,i(Xq) (9.5%). Mean age at diagnosis was 10.2±4.4 years. The most common presenting complaints were short stature and delayed puberty. Among patients diagnosed before age one year, the ratio of karyotype 45,X was significantly higher than that of other karyotype groups. Cardiac defects (bicuspid aortic valve, coarctation of the aorta and aortic stenosis) were the most common congenital anomalies, occurring in 25% of the TS cases. This was followed by urinary system anomalies (horseshoe kidney, double collector duct system and renal rotation) detected in 16.3%. Hashimoto’s thyroiditis was found in 11.1% of patients, gastrointestinal abnormalities in 8.9%, ear nose and throat problems in 22.6%, dermatologic problems in 21.8% and osteoporosis in 15.3%. Learning difficulties and/or psychosocial problems were encountered in 39.1%. Insulin resistance and impaired fasting glucose were detected in 3.4% and 2.2%, respectively. Dyslipidemia prevalence was 11.4%. Conclusion: This comprehensive study systematically evaluated the largest group of karyotype-proven TS girls to date. The karyotype distribution, congenital anomaly and comorbidity profile closely parallel that from other countries and support the need for close medical surveillance of these complex patients throughout their lifespan.