Locus heterogeneity characterizes a variety of skeletal dysplasias often due to interacting or overlapping signaling pathways. Robinow syndrome is a skeletal disorder historically refractory to molecular diagnosis, potentially stemming from substantial genetic heterogeneity. All current known pathogenic variants reside in genes within the noncanonical Wnt signaling pathway including ROR2, WNT5A, and more recently, DVL1 and DVL3. However, $70% of autosomal-dominant Robinow syndrome cases remain molecularly unsolved. To investigate this missing heritability, we recruited 21 families with at least one family member clinically diagnosed with Robinow or Robinow-like phenotypes and performed genetic and genomic studies. In total, four families with variants in FZD2 were identified as well as three individuals from two families with biallelic variants in NXN that co-segregate with the phenotype. Importantly, both FZD2 and NXN are relevant protein partners in the WNT5A interactome, supporting their role in skeletal development. In addition to confirming that clustered -1 frameshifting variants in DVL1 and DVL3 are the main contributors to dominant Robinow syndrome, we also found likely pathogenic variants in candidate genes GPC4 and RAC3, both linked to the Wnt signaling pathway. These data support an initial hypothesis that Robinow syndrome results from perturbation of the Wnt/PCP pathway, suggest specific relevant domains of the proteins involved, and reveal key contributors in this signaling cascade during human embryonic development. Contrary to the view that non-allelic genetic heterogeneity hampers gene discovery, this study demonstrates the utility of rare disease genomic studies to parse gene function in human developmental pathways.

Alström Syndrome is an autosomal recessive disease characterized by multiple organ involvement, including neurosensory vision and hearing loss, childhood obesity, diabetes mellitus, cardiomyopathy, hypogonadism, and pulmonary, hepatic, renal failure, and systemic fibrosis. Alström Syndrome is caused by mutations in ALMS1, and ALMS1 protein is thought to play a role in microtubule organization, intraflagellar transport, endosome recycling and cell cycle regulation. Here, we report extensive phenotypic and genetic analysis of a large cohort of Turkish patients with Alström Syndrome. We evaluated 61 Turkish patients, including 11 previously reported, for both clinical spectrum and mutations in ALMS1. To reveal the molecular diagnosis of the patients, there different approaches were used in combination, a cohort of patients were screened by the gene array to detect the common mutations in ALMS1 gene, then in patients having any of common ALMS1 mutations were subjected to direct DNA sequencing or next generation sequencing for the screening of mutations in all coding regions of the gene. In total, 20 distinct disease-causing nucleotide changes in ALMS1 have been identified, 8 of which are novel, thereby increasing the reported ALMS1 mutations by 6% (8/120). Five disease-causing variants were identified in more than one kindred, but most alleles were unique to each single patient and identified only once (16/20). So far, 16 mutations identified were specific to the Turkish population, and four have also been reported in other ethnicities. Additionally, 49 variants of uncertain pathogenicity were noted, and four of these were very rare and probably or likely deleterious according to in silico mutation prediction analyses. Alström Syndrome has a relatively high incidence in Turkey and the present study shows that the ALMS1 mutations are largely heterogeneous; thus, these data from a particular population may provide a unique source for the identification of additional mutations underlying Alström Syndrome and contribute to genotype-phenotype correlation studies.

The aims of this study were to evaluate serum vitamin D levels in cases of recurrent otitis media and investigate the effect of vitamin D therapy on the risk of re-occurrence of the disease. This prospective study was performed by comparing serum vitamin D levels in children with recurrent otitis media and healthy children. Eighty-four children between 1 and 5 years of age and diagnosed with recurrent otitis media were enrolled as the study group. One hundred-and-eight healthy children with similar demographic characteristics were enrolled as the control group. Patients were divided into groups according to their serum 25(OH) vitamin D levels. In patients with low initial serum vitamin D levels, vitamin D therapy was administered in addition to conventional treatment for otitis media. Mean serum 25(OH) vitamin D level in the study group was 11.4 ± 9.8 ng/mL Serum 25(OH) vitamin D levels were below 20 ng/mL in 69 % (n = 58) of cases in this group. In the control group, mean serum 25(OH) vitamin D level was 29.2 ± 13.9 ng/mL and was below 20 ng/mL in 30 % (n = 32) of cases. Comparison of serum 25(OH) vitamin D levels and PTH in the study and control groups revealed a statistically significant difference (p < 0.05). Treatment was initiated in cases diagnosed with vitamin D deficiency, and patients were followed up in due course. The only episodes detected over the course of 1-year follow-up were one attack in five patients and two attacks in two. We believe that co-administration of supplementary vitamin D together with conventional treatments is appropriate in the management of upper respiratory infections such as otitis media.

There is no significant genotype-phenotype correlation in 5α-RD2. Gonadal malignancy risk seems to be low. If genetic analysis is not available at the time of diagnosis, stimulated T/DHT ratio can be useful, especially if different cut-off values are utilized in accordance with the pubertal status.

This study investigated the effects of thiamine pyrophosphate (TPP) at dosages of 10 and 20 mg/kg on oxidative stress induced in rat brain tissue with cisplatin and compared this with thiamine. Cisplatin neurotoxicity represents one of the main restrictions on the drug being given in effective doses. Oxidative stress is considered responsible for cisplatin toxicity. Our results showed that cisplatin increased the levels of oxidant parameters such as lipid peroxidation (thio barbituric acid reactive substance (TBARS)) and myeloperoxidase (MPO) in brain tissue and suppressed the effects of antioxidants such as total glutathione (GSH) and superoxide dismutase (SOD). TPP, especially at a dosage of 20 mg/kg, significantly reduced TBARS and MPO levels that increase with cisplatin administration compared with the thiamine group, while TPP significantly increases GSH and SOD levels. In addition, the level of 8-Gua (guanine), a product of DNA damage, was 1.7 ± 0.12 8-hydroxyl guanine (8-OH Gua)/105 Gua in brain tissue in the control group receiving cisplatin, compared with 0.97 ± 0.03 8-OH Gua/105 Gua in the thiamine pyrophosphate (20 mg/kg) group and 1.55 ± 0.11 8-OH Gua/105 Gua in the thiamine (20 mg/kg) group. These results show that thiamine pyrophosphate significantly prevents oxidative damage induced by cisplatin in brain tissue, while the protective effect of thiamine is insignificant.

Objective: Anogenital distances are considered to be a sensitive indicator of external genitalia exposure to factors such as anti-androgens, and/or endocrine distruptors during the prenatal period. Exposure to such factors can lead to changes in the anogenital measurements (AGM) of newborn infants. These measurements can be used to predict masculinization of the external genitalia in healthy newborns. The goal of this study was to determine normal values for AGM in Turkish newborns of both genders. Methods: One hundred fifteen female and 135 male term newborns with no congenital defects were included in this study. A well-trained observer measured the anogenital distance by using a sliding Caliper graduated in millimeters. Anogenital distance was measured from the center of the anus to the posterior convergence of the fourchette in females and from the center of the anus to the junction of the smooth perineal skin with the base of the scrotum in males. Results: Anogenital distance in males and females was 23±0.6 mm and 10.3±0.2 mm, respectively. There were significant differences in anogenital distance values between male and female newborns (p<0.05). Conclusion: The findings of this study provide data that can be used as reference standards with regard to AGM of the posterior genital structures in Turkish male and female newborns. These data will also serve in postnatal evaluations to determine the effects of prenatal exposures to factors affecting development of genitalia. Conflict of interest:None declared.

Obesity is a multifactorial disease developing following impairment of the energy balance. The endocrine system is known to be affected by the condition. Serum thyroid hormones and trace element levels have been shown to be affected in obese children. Changes in serum thyroid hormones may result from alterations occurring in serum trace element levels. The aim of this study was to evaluate whether or not changes in serum thyroid hormone levels in children with exogenous obesity are associated with changes in trace element levels. Eighty-five children diagnosed with exogenous obesity constituted the study group, and 24 age- and sex-matched healthy children made up the control group. Serum thyroid stimulating hormone (TSH), free thyroxine (fT4), free triiodothyronine (fT3), thyroglobulin (TG), selenium (Se), zinc (Zn), copper (Cu), and manganese (Mn) levels in the study group were measured before and at the third and sixth months of treatment, and once only in the control group. Pretreatment fT4 levels in the study group rose significantly by the sixth month (p = 0.006). Zn levels in the patient group were significantly low compared to the control group (p = 0.009). Mn and Se levels in the obese children before and at the third and sixth months of treatment were significantly higher than those of the control group (p = 0.001, p = 0.001). In conclusion, fT4, Zn, Cu, Mn, and Se levels are significantly affected in children diagnosed with exogenous obesity. The change in serum fT4 levels is not associated with changes in trace element concentrations.

The purpose of this study was to investigate the effect of supplementary vitamin D therapy in addition to amitriptyline on the frequency of migraine attacks in pediatric migraine patients. Fifty-three children 8-16 years of age and diagnosed with migraine following the International Headache Society 2005 definition, which includes childhood criteria, were enrolled. Patients were classified into four groups on the basis of their 25-hydroxyvitamin D [25(OH)D] levels. Group 1 had normal 25(OH)D levels and received amitriptyline therapy alone; group 2 had normal 25(OH)D levels and received vitamin D supplementation (400 IU/day) plus amitriptyline; group 3 had mildly deficient 25(OH)D levels and received amitriptyline plus vitamin D (800 IU/day); and group 4 had severely deficient 25(OH)D levels and was given amitriptyline plus vitamin D (5000 IU/day). All groups were monitored for 6 months, and the number of migraine attacks before and during treatment was determined. Calcium, phosphorus alkaline phosphatase, parathormone, and 25(OH)D levels were also determined before and during treatment. Results were compared between the groups. Data obtained from the groups were analyzed using one-way analysis of variance. The number of pretreatment attacks in groups 1 to 4 was 7±0.12, 6.8±0.2, 7.3±0.4, and 7.2±0.3 for 6 months, respectively (all P>0.05). The number of attacks during treatment was 3±0.25, 1.76±0.37 (P<0.05), 2.14±0.29 (P<0.05), and 1.15±0.15 (P<0.05), respectively. No statistically significant differences in calcium, phosphorus, alkaline phosphatase, or parathormone levels were observed (P>0.05). Vitamin D given in addition to anti-migraine treatment reduced the number of migraine attacks.