Halil Saglam

Novel TSHR mutations in consanguineous families with congenital nongoitrous hypothyroidism.

Objective  Nonsyndromic autosomal recessively inherited nongoitrous congenital hypothyroidism (CHNG) can be caused by mutations in TSHR, PAX8, TSHB and NKX2‐5. We aimed to investigate mutational frequencies of these genes and genotype/phenotype correlations in consanguineous families with CHNG.

Thyroid dyshormonogenesis is mainly caused by TPO mutations in consanguineous community

In this study, we aimed to investigate the genetic background of thyroid dyshormonogenesis (TDH).

Testicular Adrenal Rest Tumors in Patients with Congenital Adrenal Hyperplasia

Objective: Early diagnosis and treatment of testicular adrenal rest tumors (TART) is important for gonadal functions and fertility protection in boys with congenital adrenal hyperplasia (CAH). In this descriptive study, we investigated the prevalence of TART in boys with 21-hydroxylase deficient (21OHD) CAH followed in our pediatric endocrine clinic. Methods: The study group consisted of 14 male patients with a mean age of 9.6±5.1 (range: 0.8-18.3) years. Six (42.9%) of the 14 patients were diagnosed as having salt-wasting type (SW) and eight (57.1%) patients - as having the simple virilizing (SV) form of 21OHD. Mean age at diagnosis was 2.9±2.7 (range: 0.03-6.3) years. Two different radiologists performed scrotal ultrasonography. Chronological age, bone age, and anthropometric measurements were evaluated. Serum adrenocorticotropic hormone (ACTH), 17-alpha-hydroxyprogesterone (17OHP) and androstenedione levels were also evaluated in all patients during the follow-up period. Results: Scrotal ultrasonography revealed bilateral TART in two patients (14.3%) and testicular microlithiasis (TM) in four patients (28.6%). One patient had both TART and TM bilaterally. During the follow-up period, the mean serum adrenocorticotropic hormone, 17OHP and androstenedione levels in the total group of patients were 130.0±179.1 pg/mL (21.7-726.5), 5.8±3.3 ng/mL (0.8-11.4) and 4.3±4.1 (0.2-11.0) ng/mL, respectively. Conclusions: Microlithiasis or TART may be frequently encountered during the follow-up of patients with CAH. In order to prevent late complications including infertility, we suggest that ultrasonographic evaluations be performed yearly in all male CAH patients. Conflict of interest:None declared.

TSHR is the main causative locus in autosomal recessively inherited thyroid dysgenesis.

Abstract Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder and results in mental retardation if untreated. Eighty-five percent of CH cases are due to disruptions in thyroid organogenesis and are mostly sporadic, but about 2% of thyroid dysgenesis is familial, indicating the involvement of genetic factors in the aetiology of the disease. In this study, we aimed to investigate the Mendelian (single-gene) causes of non-syndromic and non-goitrous congenital hypothyroidism (CHNG) in consanguineous or multicase families. Here we report the results of the second part (n=105) of our large cohort (n=244), representing the largest such cohort in the literature, and interpret the overall results of the whole cohort. Additionally, 50 sporadic cases with thyroid dysgenesis and 400 unaffected control subjects were included in the study. In familial cases, first, we performed potential linkage analysis of four known genes causing CHNG (TSHR, PAX8, TSHB, and NKX2-5) using microsatellite markers and then examined the presence of mutations in these genes by direct sequencing. In addition, in silico analyses of the predicted structural effects of TSHR mutations were performed and related to the mutation specific disease phenotype. We detected eight new TSHR mutations and a PAX8 mutation but no mutations in TSHB and NKX2-5. None of the biallelic TSHR mutations detected in familial cases were present in the cohort of 50 sporadic cases. Genotype/phenotype relationships were established between TSHR mutations and resulting clinical presentations. Here we conclude that TSHR mutations are the main detectable cause of autosomal recessively inherited thyroid dysgenesis. We also outline a new genetic testing strategy for the investigation of suspected autosomal recessive non-goitrous CH.

Prevalence and correlates of obesity in schoolchildren from the city of Bursa, Turkey.

Background and objectives: The prevalence of childhood obesity has been dramatically increasing worldwide. This study was performed to examine the prevalence and etiological factors of obesity in children aged 6−12 years and to investigate the relative contribution of exogenous factors with respect to sociodemographic data. Methods: A total of 5368 children aged 6−12 years in eight urban elementary schools located in Bursa, the fourth largest city of Turkey, were included in this cross−sectional study. A dietary record for three days and a questionnaire for the assessment of socio−economic and demographic parameters were completed by the parents at home. The height and weight of the children were measured and relative weight and body mass index (BMI) were calculated. Results: The prevalence of overweight, obesity and severe obesity according to BMI were 12.4%, 7.8% and 2.2%, respectively. The female/male ratio among obese children was 1.24. Eighty percent of obese children had one or both parents obese. Age, gender, presence of obesity in parents, higher educational level of the parents, consumption of soft beverages such as soda and juice, physical activity level and higher income of the family were found as the contributing factors to obesity. Conclusion: The prevalence of obesity is increasing in Turkey in parallel to the trend in many countries. There are consistent and predictable sociodemographic parameters that are associated with or may impose a risk factor for obesity. Identification of these risk factors will provide areas to target in the prevention and management of this common problem. Conflict of interest:None declared.

A Rare Cause of Precocious Puberty: Hepatoblastoma

Hepatoblastoma, an embryonal tumor, is one of the most common primary liver tumors in childhood. It secretes human chorionic gonadotropin (hCG), which can cause precocious puberty (PP). Herein, we present a case with PP who had enlarged penile size noticed during a diagnosis of hepatoblastoma. Laboratory examination revealed increased testosterone, alpha-fetoprotein (AFP), and hCG levels. Serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were within prepubertal ranges. The diagnosis of hepatoblastoma was made by liver biopsy. Chemotherapy was administered, and the patient was referred to surgery. Ten months later, testis volumes were below 4 ml bilaterally, and penile length was 5.5 cm. Serum testosterone, AFP, and hCG levels decreased. Resection of the tumor and chemotherapy are essential for the treatment of hepatoblastoma and they can eliminate the symptoms of PP. Conflict of interest:None declared.

Severe Hypospadias Associated with Robertsonian Translocation

In this study, we report a 3-year-old boy with severe scrotal hypospadias with Robertsonian translocation [45,XY,t(13q;14q)]. The patient was born at term with a low birth weight and hypospadias. There was no endocrinological abnormality. His father also has a balanced 13–14 Robertsonian translocation. Two-stage hypospadias repair was carried out. The presence of this chromosomal anomaly and hypospadias are unique to our patient, compared to others with the 45,XY,t(13q;14q) translocation. Although no such association has been reported so far, we thought that severe hypospadias in this case might be associated with this translocation.

A deletion including exon 2 of the TSHR gene is associated with thyroid dysgenesis and severe congenital hypothyroidism.

Abstract Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder and 2% of cases have a familial origin. Our aim in this study was to determine the genetic alterations in two siblings with CH coming from a consanguineous family. As CH is often inherited in an autosomal recessive manner in consanguineous/multi case-families, we first performed genetic linkage studies to all known causative CH loci followed by conventional sequencing of the linked gene. The family showed potential linkage to the TSHR locus and our attempts to amplify and sequence exon 2 of the TSHR gene continuously failed. Subsequent RT-PCR analysis using mRNA and corresponding cDNA showed a large deletion including the exon 2 of the gene. The deletion was homozygous in affected cases whilst heterozygous in carrier parents. Here we conclude that CH in both siblings of this study originates from a large deletion including the exon 2 of the TSHR gene. This study demonstrates that full sequence analysis in a candidate CH gene might not always be enough to detect genetic alterations, and additional analyses such as RT-PCR and MLPA might be necessary to describe putative genetic causes of the disease in some cases. It also underlines the importance of detailed molecular genetic studies in the definitive diagnosis and classification of CH.

Thyroid Functions in Long-Term Survivors of Pediatric Hodgkin’s Lymphoma Treated with Chemotherapy and Radiotherapy

Objective: Post-treatment endocrine disturbances are common in cancer patients who have received radiotherapy or chemotherapy. The objective of this study was to evaluate the thyroid functions of long-term survivors of pediatric Hodgkin’s lymphoma treated with chemotherapy and radiotherapy. Methods: Thyroid functions of 55 Hodgkin’s lymphoma patients (M/F:2.05/1) in complete remission were evaluated retrospectively. Results: The mean age of the patients at diagnosis was 10.35±4.09 (range: 2.83-17) years and the mean follow-up period was 5.54±3.68 (range: 0.92-13.92) years. All patients received chemotherapy; a total of 50 patients (90.9%) underwent radiotherapy, 42 (76.4%) of whom received neck/mantle radiotherapy. Thyroid function tests were abnormal in 14 (24.5%) patients and normal - in the remaining 41 (74.5%). A diagnosis of subclinical and overt hypothyroidism was made in 11 (78.6%) and 3 (21.4%) patients with abnormal thyroid function tests, respectively. Nearly one-fourth (21.4%) of all thyroid function disorders were detected in the first year of follow-up. A statistically significant correlation was found between the dose of mantle radiotherapy and thyroid function disorder (p=0.002). In addition, statistically significant correlations were established between thyroid examination or thyroid ultrasonography findings and thyroid functions (p <0.001 or p=0.006, respectively). Conclusions: Radiation-induced thyroid disorders may develop in pediatric Hodgkin’s lymphoma patients in complete remission starting as early as the first year after treatment and are dose-dependent. Patients, particularly those who have been exposed to radiotherapy of the neck, must be followed up closely for occurrence of thyroid dysfunctions. Conflict of interest:None declared.

An essential splice site mutation (c.317+1G>A) in the TSHR gene leads to severe thyroid dysgenesis.

Abstract Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder and 2% of cases have familial origin. Our aim in this study was to determine the genetic alterations in two siblings with CH coming from a consanguineous family. Because CH is often inherited in autosomal recessive manner in consanguineous/multicase-families, we first performed genetic linkage studies to all known causative CH loci followed by conventional sequencing of the linked gene. The family showed potential linkage to the TSHR locus, and we detected an essential splice site mutation (c.317+1G>A) in both siblings. RT-PCR analysis confirmed the functionality of the mutation. The mutation was homozygous in the cases whereas heterozygous in carrier parents and an unaffected sibling. Here we conclude that thyroid agenesis in both siblings in this study originates from c.317+1G>A splice site mutation in the TSHR gene, and this study underlines the importance of detailed molecular genetic studies in the definitive diagnosis and classification of CH.