SF-1/NR5A1 mutations are frequently found in 46,XY DSD individuals (9%) and manifest with a broad phenotype. Testes histology is characteristic for fat accumulation and degeneration over time, similar to findings observed in patients with lipoid congenital adrenal hyperplasia (due to StAR mutations). Genotype-structure-function-phenotype correlation remains elusive.

Context:Primary adrenal insufficiency (PAI) is a life-threatening condition that is often due to monogenic causes in children. Although congenital adrenal hyperplasia occurs commonly, several other important molecular causes have been reported, often with overlapping clinical and biochemical features. The relative prevalence of these conditions is not known, but making a specific diagnosis can have important implications for management.Objective:The objective of the study was to investigate the clinical and molecular genetic characteristics of a nationwide cohort of children with PAI of unknown etiology.Design:A structured questionnaire was used to evaluate clinical, biochemical, and imaging data. Genetic analysis was performed using Haloplex capture and next-generation sequencing. Patients with congenital adrenal hyperplasia, adrenoleukodystrophy, autoimmune adrenal insufficiency, or obvious syndromic PAI were excluded.Setting:The study was conducted in 19 tertiary pediatric endocrinology clinics.Patients:Ninety-five children (48 females, aged 0–18 y, eight familial) with PAI of unknown etiology participated in the study.Results:A genetic diagnosis was obtained in 77 patients (81%). The range of etiologies was as follows: MC2R (n = 25), NR0B1 (n = 12), STAR (n = 11), CYP11A1 (n = 9), MRAP (n = 9), NNT (n = 7), ABCD1 (n = 2), NR5A1 (n = 1), and AAAS (n = 1). Recurrent mutations occurred in several genes, such as c.560delT in MC2R, p.R451W in CYP11A1, and c.IVS3ds+1delG in MRAP. Several important clinical and molecular insights emerged.Conclusion:This is the largest nationwide study of the molecular genetics of childhood PAI undertaken. Achieving a molecular diagnosis in more than 80% of children has important translational impact for counseling families, presymptomatic diagnosis, personalized treatment (eg, mineralocorticoid replacement), predicting comorbidities (eg, neurological, puberty/fertility), and targeting clinical genetic testing in the future.

Objective: Serum alkaline phosphatase (ALP) levels show great variation with age and sex in children and adolescents. Additionally, different buffers used even in the same method cause variable results. This detail is not usually taken into account in the evaluation. We aimed to study pediatric age- and sex-specific reference ranges for ALP by colorimetric assay using p-nitrophenyl phosphate as substrate and diethanolamine as buffer and also to compare the ALP levels in patients with different types of rickets. Methods: 1741 healthy children and adolescents (904 girls) were included in the study for normative data. 77 different ALP measurements from 38 nutritional rickets (NR), 7 vitamin D-dependent rickets (VDDR) and 8 hypophosphatemic rickets (HR) patients were included. Results: Reference values for ALP were constructed. ALP levels demonstrated a tetraphasic course with two peaks at infancy and puberty. There was no difference in ALP levels between boys and girls until puberty. However, higher ALP levels were noted at 10-11 years in girls (p=0.02) and at 12-13, 14-15, 16-17 years in boys (p<0.001). ALP levels start to decline after age 12 and 14 in girls and boys, respectively. Serum ALP levels were highest in the VDDR group and lowest in the HR group (median z-score values in HR, VDDR and NR were 3.6, 10.4 and 6.5, respectively; p<0.001). Similarly, plasma parathormone(PTH) levels ranged from highest to lowest in the VDDR, NR and HR groups (median values: 525, 237 and 98 pg/mL, respectively; p<0.001). Conclusions: This normative data will provide a basis for better evaluation of ALP levels determined by the described method. Furthermore, use of z-scores gives a more precise assessment of changes in ALP levels in rickets and other bone disorders. Conflict of interest:None declared.

A nationwide 'vitamin D prophylaxis augmentation programme' initiated in 2005 in Turkey reduced the prevalence of rickets from 6% in 1998 to 0.1% in 2008 in children under 3 years of age. The programme included free distribution of vitamin D drops to all newborns and infants (0-12 months) visiting primary health stations throughout the country. Free disposal of vitamin D to infants is an effective strategy for preventing vitamin D-deficient rickets.

The growth hormone (GH)-insulin-like growth factor (IGF) axis and insulin are major anabolic effectors in promoting weight gain and linear growth. These two anabolic systems are interlinked at many levels, thus abnormalities in one of these systems effect the other causing disordered metabolic homeostasis. Insufficient portal insulinization in insulin dependent diabetes mellitus (IDDM) results in hepatic GH resistance and increased production of IGF-binding proteins-1 (IGFBP-1) and IGFBP-2. GH resistance is reflected by decreased hepatic IGF-I production. In addition, changes in other GH-dependent proteins are also observed in IDDM. Increased proteolysis of IGFBP-3 results in reduction of intact IGFBP-3. Serum ALS levels are also slightly diminished in untreated diabetic patients. Hepatic resistance to GH is, at least in part, caused by diminished GH receptors as reflected by diminished circulating GHBP levels. In addition, there is also evidence from experimental and human studies suggesting post-receptor defect(s) in GH action. As a result of these changes, circulating total and free IGF-I levels are decreased during insulinopenia. Lack of negative feed-back effect of IGF-I on GH secretion causes GH hypersecretion which increases hyperglycemia by decreasing sensitivity to insulin. GH hypersecretion in poorly controlled diabetic patients may play a role in the pathogenesis of diabetic vascular complications. Most of these abnormalities in the GH-IGF axis in diabetes are reversed by effective insulinization of the patient. Addition of IGF-I treatment to insulin in adolescents with IDDM allows correction of GH hypersecretion, improves insulin sensitivity and glycemic control, and decreases insulin requirements. The effect of IGF-I treatment on diabetic complications has yet to be seen.

In Turkey most patients had vitamin D deficiency, whereas in Egypt they had mostly calcium insufficiency combined with vitamin D deficiency. In this environ, VDR genotypes may predispose to rickets by increased frequency of the F allele. The unique environs and genetic predisposition have to be accounted for in the design of preventive measures, rather than using European or American recommended dietary intake for calcium and vitamin D.

As a transitional society, rapid changes have occurred in the social, economic, nutritional and lifestyle aspects of the Turkish population over the last three decades. As a result, the prevalence of overweight and obesity has shown a dramatic increase in the adult Turkish population, reaching figures as high as 30-40%. Although there is no nationwide figure regarding the prevalence of overweight and obesity in Turkish children and adolescents, several local studies performed between 2000 and 2010 in different regions of the country have demonstrated varying prevalence rates of 10.3%-17.6% and 1.9%-7.8% for overweight and obesity, respectively, in children aged 6-16 years. The differences in the figures obtained in these regions are thought to be due to variations in the subject sampling. The figures appear to vary depending on residential (urban vs. rural) and economic conditions. Belonging to a high-income family, living in a large city, having obese parents, being of high birthweight, consuming sugar-sweetened beverages (soft drinks, juice drinks, etc.), and spending time in front of TV and PC were identified as the most common risk factors. Complications and co-morbidities of obesity have also started to appear in our pediatric population. Metabolic syndrome, diagnosed according to the International Diabetes Federation criteria, was found in 2.3% of Turkish schoolchildren aged 10-19 years. This rate was 28% in obese children. Preventive public measures have started to be implemented by the State and other bodies to control the rising trends in obesity.Conflict of interest:None declared.

Homozygosity for the TACR3 His148Leu mutation leads to failure of sexual maturation in humans, whereas signaling by the mutant receptor in vitro in response to either NKB or senktide is severely impaired. These observations further strengthen the link between NKB, the NKB receptor, and regulation of human reproductive function.