Clinical Significance of Hypophosphatasemia in Children.

Low serum alkaline phosphatase (sALP)-hypophosphatasemia-is a characteristic of hypophosphatasia (HPP), but related to several clinical conditions. Here, we evaluated the frequency, persistency and the etiology of hypophosphatasemia in children. In retrospective analyses of sALP measurements from children, evaluated according to in-house constructed age- and sex-specific reference ranges, patients with no normal sALP measurement (Unresolved hypophosphatasemia) were invited for reanalysis. Prospectively, ALP substrates, pyridoxal-5-phosphate (PLP), and phosphoethanolamine (PEA) were measured in patients with persistent hypophosphatasemia. Radiographs and ALPL gene sequencing for HPP were performed to the cases with elevated PEA and/or PLP. From 130,340 sALP measurements of 93,162 patients, hypophosphatasemia was detected in 1404 samples from 867 patients (0.9%). Among them, 745 had at least one normal sALP values in laboratory records, grouped as transient hypophosphatasemia. 75 out of 122 patients with unresolved hypophosphatasemia could be reanalyzed for sALP, of whom PLP and PEA measurements were required in 37 due to persistent hypophosphatasemia. Both PEA and PLP were elevated in 4 patients, and ALPL gene analysis showed heterozygous mutations in 3 patients and homozygous in 1 patient. Elevated PEA with normal PLP were detected in 3 patients, and one had a heterozygous ALPL mutation. Anemia was the most common diagnosis, and upper respiratory tract infections and chronic diseases were more common in transient and unresolved hypophosphatasemia, respectively. In conclusion, reflected persistent hypophosphatasemia frequency was 1/1552 (0.06%) in this large pediatric cohort and, ALPL gene mutations were detected in 13.5% (5/37) of the studied cases. Although biochemical hypophosphatasemia is not uncommon, clinically significant HPP is rare.

Evaluation of vitamin D status and its correlation with gonadal function in children at mini-puberty.

CONTEXT: The effects of Vitamin D on reproductive function in adults have gained interest. Studies have demonstrated some associations. Hypothalamic-pituitary-gonadal axis is activated during the first 6 months of life, called as mini-puberty. This HPG activation is important for future gonadal function. There are no data regarding the association of gonadal hormones and 25(OH)D levels at mini-puberty. Demonstration of any association would form the basis for studies that will search for the effects of 25(OH)D on gonadal hormones at mini-puberty. OBJECTIVE: To characterize the associations between 25(OH)D levels and gonadal hormones at mini-puberty. DESIGN: Cross-sectional cohort analysis. PATIENT(S) OR OTHER PARTICIPANT(S): A total of 180 (94 boys and 86 girls) healthy appropriate-for-gestational-age neonates were included. MAIN OUTCOME MEASURE(S): 25(OH)D, LH, FSH, total testosterone, oestradiol, AMH and inhibin B levels were measured at postnatal 30-45 days. All infants were divided into three groups including vitamin D deficiency (<10 ng/mL), vitamin D insufficiency (10-20 ng/mL) and vitamin D sufficiency (>20 ng/mL). Correlations between vitamin D status and reproductive hormones were analysed. RESULT(S): Total testosterone level was higher (mean: 0.52 ± 0.32 vs 0.26 ± 0.2 ng/mL; P: 0.008) and inhibin B was lower in 25(OH)D deficient than sufficient girls (mean: 21.2 ± 15.71 vs 53.25 ± 47.25 pg/mL; P: 0.021). CONCLUSION(S): A modest effect of 25(OH)D was identified on total testosterone and inhibin B in girls at mini-puberty. The 25(OH)D may have an effect on gonadal function during early life. Randomized controlled trials could clarify the importance of vitamin D on gonadal hormones at mini-puberty.

Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development.

PURPOSE: Disorders or differences of sex development (DSDs) are rare congenital conditions characterized by atypical sex development. Despite advances in genomic technologies, the molecular cause remains unknown in 50% of cases. METHODS: Homozygosity mapping and whole-exome sequencing revealed an ESR2 variant in an individual with syndromic 46,XY DSD. Additional cases with 46,XY DSD underwent whole-exome sequencing and targeted next-generation sequencing of ESR2. Functional characterization of the identified variants included luciferase assays and protein structure analysis. Gonadal ESR2 expression was assessed in human embryonic data sets and immunostaining of estrogen receptor-ß (ER-ß) was performed in an 8-week-old human male embryo. RESULTS: We identified a homozygous ESR2 variant, c.541_543del p.(Asn181del), located in the highly conserved DNA-binding domain of ER-ß, in an individual with syndromic 46,XY DSD. Two additional heterozygous missense variants, c.251G>T p.(Gly84Val) and c.1277T>G p.(Leu426Arg), located in the N-terminus and the ligand-binding domain of ER-ß, were found in unrelated, nonsyndromic 46,XY DSD cases. Significantly increased transcriptional activation and an impact on protein conformation were shown for the p.(Asn181del) and p.(Leu426Arg) variants. Testicular ESR2 expression was previously documented and ER-ß immunostaining was positive in the developing intestine and eyes. CONCLUSION: Our study supports a role for ESR2 as a novel candidate gene for 46,XY DSD.

Hypoglycemia is common in children with cystic fibrosis and seen predominantly in females.

OBJECTIVE: To determine the prevalence of hypoglycemia in children and adolescents with cystic fibrosis (CF) in 2-hour oral glucose tolerance test (OGTT) and continuous glucose monitoring (CGM) under free-living conditions. RESEARCH DESIGN AND METHODS: Height, weight, body mass index (BMI), hemoglobin A1c (HbA1c), and Forced expiratory volume (FEV1%) were measured in children with CF (aged 5-18 years). Following OGTT, CGM was installed for 3 days. The total hypoglycemic and hyperglycemic time (%) during 3 days was measured. Subjects were categorized according to hypoglycemic time <3% (hypo -) and ≥3% (hypo +). Each category was further divided according to hyperglycemic time <3% (hyper -) or ≥3% (hyper +). RESULTS: OGTT and CGM were sequentially performed in 45 CF patients. The frequency of hypoglycemia in OGTT and hypoglycemic time ≧3% of CGM were 13.3% and 27.5%, respectively. After 5 cystic fibrosis-related diabetes (CFRD) subjects were excluded, the number of subjects in each subgroup was 17 (hypo-/hyper-), 12 (hypo-/hyper+), 6 (hypo+/hyper-), and 5 (hypo+/hyper+). Significantly higher insulin at 120 minutes was observed in OGTT in (hypo+/hyper-), as compared with subgroup (hypo-/hyper-) (P = .018). Total insulin levels were also significantly higher in (hypo+/hyper-), than (hypo-/hyper-), but were similar to those in the healthy control group (P = .049 and P = .076, respectively). There was a female predominance in hypoglycemic subjects both in OGTT and subgroup (hypo+/hyper-) in the CGM group (P = .033 and P = .033, respectively). FEV1 was significantly lower in hypo + group as a whole, and (hypo+/hyper+) subgroup than in (hypo-/hyper-), (P = .044 and P = .042, respectively); the difference was independent of body mass index-standard deviation score (BMI-SDS) (P = .15 and P = .12, respectively). CONCLUSION: The frequency of hypoglycemia in children with CF was higher in CGM than that in OGTT. Insulin secretion was delayed and total insulin levels increased in the hypoglycemic patients. Glucose instability/hypoglycemia is associated with poorer lung function in patients with CF, independent of nutritional status.

GCK gene mutations are a common cause of childhood-onset MODY (maturity-onset diabetes of the young) in Turkey.

OBJECTIVE: Inactivating heterozygous mutations in the GCK gene are a common cause of MODY and result in mild fasting hyperglycaemia, which does not require treatment. We aimed to identify the frequency, clinical and molecular features of GCK mutations in a Turkish paediatric cohort. DESIGN AND PATIENTS: Fifty-four unrelated probands were selected based on the following criteria: age of diagnosis ≤17 years, family history of diabetes in at least two generations, anti-GAD/ICA negative, BMI<95.p and follow-up with diet, oral antidiabetic drug or low-dose insulin treatment (≤0·5U/kg/d). A MODY probability score (www.diabetesgenes.org) was calculated and 21 patients with a score ≥75%, HbA1c levels ≤7·5% (58·5 mmol/mol) and fasting blood glucose (FBG) levels 99-145 mg/dl (5·5-8·0 mmol/l) were selected for Sanger sequencing of the GCK gene. Targeted next-generation sequencing for all known monogenic diabetes genes was undertaken for any patient without a GCK gene mutation. RESULTS: GCK gene mutations (pathogenic or likely pathogenic variants) and a novel intronic variant of uncertain significance (c.208 + 3A>T) were identified in 13/54 probands (24%). Twelve of these patients had a MODY probability score ≥75%. FBG level and 2-h glucose level in OGTT were 123 ± 14 mg/dl (6·8 ± 0·7 mmol/l) (107-157 mg/dl) and 181 ± 30 mg/dl (10·1 ± 1·6 mmol/l) (136-247 mg/dl), respectively. Average of glucose increment in OGTT was 58 ± 27 mg/dl (3·2 ± 1·5 mmol/l) (19-120 mg/dl), and mean HbA1c level was 6·5 ± 0·5% (47·5 ± 5·5 mmol/mol) (5·9-7·6%). Five novel missense mutations were identified (p.F123S, p.L58P, p.G246A, p.F419C, and p.S151C). Two patients treated with low-dose insulin before the molecular analysis were able to stop treatment. CONCLUSIONS: Approximately 1 in 4 MODY cases in this Turkish paediatric cohort have a GCK mutation. Selection of patients for GCK gene analysis using the MODY probability score was an effective way of identifying most (11/12) patients with a GCK mutation.

Higher insulin detemir doses are required for the similar glycemic control: comparison of insulin detemir and glargine in children with type 1 diabetes mellitus.

OBJECTIVE: We aimed to compare hemoglobin A1c (HbA1c), total and basal insulin doses, basal insulin injection frequencies, and body mass index (BMI) in children with type 1 diabetes mellitus (T1DM) who are receiving detemir and glargine as basal insulin in a basal-bolus therapy. METHOD: This retrospective study included 117 (53 females) children and adolescents with T1DM older than 4 yr of age, minimum diabetes duration of 2 yr, and receiving basal-bolus insulin regimen (at least 4 injections/d, insulin aspart or lispro as bolus insulin). Comparisons were made for those receiving insulin detemir (n = 32) or glargine (n = 85) as the basal insulin. RESULTS: Age, pubertal status, BMI standard deviation scores, and diabetes duration were similar in detemir and glargine groups. Glycemic control was similar in both groups (HbA1c levels 8.9 ± 2.1% vs. 8.5 ± 1.7% for detemir and glargine, respectively; p = 0.497). Both mean basal insulin (0.52 vs. 0.41 U/kg/d, p < 0.001) and mean total daily insulin (1.11 vs. 0.93 U/kg/d, p < 0.001) doses were higher in the detemir group. Furthermore, higher ratio of twice-daily basal insulin injection was detected in the detemir group (62.5 vs. 32.9% p = 0.004). Subgroup analysis according to pubertal status, or the number of daily basal injections showed similar results. CONCLUSION: Insulin detemir provides similar glycemic control with glargine, but, approximately 27% higher mean basal and 19% higher mean total insulin doses with two-fold more twice-daily basal insulin injection requirement.

Effects of leukemia inhibitory receptor gene mutations on human hypothalamo-pituitary-adrenal function.

BACKGROUND: Stuve-Wiedemann syndrome (STWS) (MIM #601559) is a rare autosomal recessive disorder caused by mutations in the leukemia inhibitory factor receptor (LIFR) gene. STWS has a diverse range of clinical features involving hematopoietic, skeletal, neuronal and immune systems. STWS manifests a high mortality due to increased risk of sudden death. Heterodimerization of the LIFR mediates leukemia inhibitory factor (LIF) signalling through the intracellular Janus kinase (JAK)/STAT3 signalling cascade. The LIF/LIFR system is highly expressed in and regulates the hypothalamo-pituitary-adrenal (HPA) axis. OBJECTIVES: HPA function was investigated in three STWS patients to characterise consequences of impaired LIF/LIFR signalling on adrenal function. DESIGN: Six genetically proven STWS patients from four unrelated Turkish families were included in the study. Sudden death occurred in three before 2 years of age. Basal adrenal function tests were performed by measurement of early morning serum cortisol and plasma ACTH concentrations on at least two different occasions. Low dose synacthen stimulation test and glucagon stimulation tests were performed to explore adrenal function in three patients who survived. RESULTS: All patients carried the same LIFR (p.Arg692X) mutation. Our oldest patient had attenuated morning serum cortisol and plasma ACTH levels at repeated measurements. Two of three patients had attenuated cortisol response (<18 µg/dl) to glucagon, one of whom also had borderline cortisol response to low dose (1 µg) ACTH stimulation consistent with central adrenal insufficiency. CONCLUSIONS: STWS patients may develop central adrenal insufficiency due to impaired LIF/LIFR signalling. LIF/LIFR system plays a role in human HPA axis regulation.

Infantile loss of teeth: odontohypophosphatasia or childhood hypophosphatasia.

Hypophosphatasia is a hereditary disorder characterized by a deficiency of serum and bone alkaline phosphatase (ALP) activity and defective skeletal mineralization. It is caused by a loss of function mutations in the tissue nonspecific ALP gene (TNSALP) encoding the tissue nonspecific alkaline phosphatase. A 4-year-and-8-month-old girl presented with premature exfoliation of the anterior incisors and canines. Very low ALP level (27 IU/ml) suggested the diagnosis of hypophosphatasia, which was supported by an elevated urine phosphoethanolamine/Cr of 84 µmol/mmol (reference range, <25 µmol/mmol) and serum pyridoxal-5'-phosphate of 393 µg/L (reference range, 3.6-18 µg/L). The phenotype of the patient was subsequently classified as mild childhood hypophosphatasia. TNSALP gene sequencing revealed the homozygous c.382 G > A (p.V128M) mutation. This mutation was previously observed in a series of patients with severe hypophosphatasia, pointing out the possible role of other genetic or environmental factors in the modulation of the hypophosphatasia phenotype.

Clinical and laboratory evaluation of children with congenital hyperinsulinism: a single center experience.

OBJECTIVES: To evaluate and present the data regarding clinical, laboratory, radiological and the results of molecular genetic analysis of patients with hyperinsulinemic hypoglycemia in our clinics. METHODS: A total of 9 patients with CHI followed at Istanbul Medipol University. Data related to gender, age at presentation, birth weight, gestational age, consanguinity, glucose and insulin levels at diagnosis, treatment modalities, response to treatment, the results of genetic analysis and radiological evaluation were gathered from the files. RESULTS: The oldest age at presentation was 6 months. KATP channel mutation was detected in 55% (n: 5). Diazoxide unresponsiveness was seen in 55% (n: 5). Octreotide was effective in 3 of them. 18F-DOPA PET performed in 4 diazoxide unresponsive patients revealed focal lesion in 3 of them. Spontaneous remission rate was 66% (n:6). All the patients with normal genetic result achieved spontaneous remission. Spontaneous remission was even noted in diazoxide unresponsive patients and in patients with focal lesion on 18F-DOPA PET. CONCLUSIONS: Clinical presentation of patients with congenital hypereinsulinism is heterogeneous. Spontaneous remission rate is quite high even in patients with severe clinical presentation. It is important to develop methods that can predict which patients will have spontaneous remission. Reporting the clinical and laboratory data of each patient is important and will help to guide the management of patients with hyperinsulinemic hypoglycemia.

The implications of varicose vein surgery on sleep evaluation scales.

Background: Varicose veins commonly occur on the legs and cause discomfort, pain, and aesthetic issues. Varicose vein surgery has an significant impact on sleep disorders such as Restless Leg Syndrome (RLS), daytime sleepiness (DS), and sleep quality (SQ). We intended to determine if preoperative and postoperative sleep quality, excessive daytime sleepiness, and RLS severity impacted in those who had varicose vein surgery. Materials and methods: The research included 160 patients who presented to the Cardiovascular Surgery outpatient clinic with symptoms of leg pain and cramping and were diagnosed with venous insufficiency. The Restless Legs Syndrome Study Group Rating Scale (RLSS), Epworth Sleepiness Scale (ESS), and Pittsburgh Sleep Quality Index (PSQI) tests were performed on patients. The patients' scores on the scales were compared preoperatively and postoperatively. Results: The mean age of the 160 patients was calculated to be 48.7 ± 10.6 years. There were 109 female (68.1%) and 51 male (31.9%). The mean ferritin level of the patients was calculated as 61.4 mL/ng (4.3-421 mL/ng). After varicose vein surgery 63% reported improved sleep quality. Individuals with increased DS had lower postoperative RLSS scores and higher SQ. There was a decrease in postoperative RLSS scores and an increase in postoperative SQ in patients with normal DS (p < 0.001). Postoperative RLSS and DS scores were lower in patients with good SQ (p < 0.001). Conclusion: Patients had a lower RLSS score, a lower DS score, and a higher SQ after varicose vein surgery. Surgical treatment is critical to improving the quality of life and sleep comfort of patients with varicose veins and sleep disorders.

Decline in the Age of Menarche in Istanbul Schoolgirls Over the Last 12 Years

Objective: Menarche is the endpoint of a sequence of maturational events of female puberty. The timing of menarche is a strongly heritable trait. However, secular trends suggest that lifestyle and environmental factors are important. To assess the trend in age at menarche (AAM), and its associated factors in Istanbul over the last 12 years. Methods: A cross-sectional study was carried out between March and April 2022 on schoolgirls aged 9-18 years. A predesigned and self-administered questionnaire was filled out anonymously by the students. The data of AAM was included in the statistical analysis if the time of AAM is remembered in both months and years. A probit model was used to calculate the median AAM. The findings were compared with those from a study performed 12 years ago in the same region of Istanbul. Results: Among 9000 girls to whom the questionnaire was distributed, 1749 (19.5%) responded. The median AAM of 1374 girls whose AAM information was considered valid was 12.04 years (95% confidence interval: 12.01-12.13), 0.7 years lower than was reported 12 years ago (p<0.0001). AAM was correlated positively with maternal AAM, and negatively with body mass index (BMI) standard deviation score and maternal educational status (p<0.0001, p<0.0001 and p=0.002), respectively. There was no correlation between the AAM and birth weight. Girls with BMI percentile ≥85% (n=251) had earlier menarche than the ones with BMI percentile <85% (n=1072) (11.5 vs. 12.1 years, p<0.0001). Among the mother-daughter pairs (n=1162), AAM of girls was 0.91 years (median 0.94 years) earlier than their mothers. Conclusion: The present study demonstrates a significant downward trend in the menarcheal age in Istanbul over the last twelve years. These findings support a strong contribution from genetic factors and BMI on AAM.

Clinical and molecular characterization of Turkish patients with familial hypomagnesaemia: novel mutations in TRPM6 and CLDN16 genes.

BACKGROUND: Recent identification and characterization of novel renal Mg(2+) transporters and ion channels have greatly increased our understanding of the normal physiology of renal magnesium handling. METHODS: The present study deals with the clinical and molecular characterization of eight Turkish children (median age 10.6 years, range 3-16.2 years, five boys and three girls) with primary hypomagnesaemia from six families. RESULTS: All patients initially presented with tetany and convulsions. Laboratory evaluation yielded severely low serum magnesium levels and low serum calcium levels in all patients. While six patients exhibited inadequately low parathyroid hormone levels, the two remaining patients showed hyperparathyroidism, hypercalciuria and nephrocalcinosis. Genetic studies revealed familial hypomagnesaemia with secondary hypocalcaemia (HSH) due to a TRPM6 mutation in six patients and familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) due to a CLDN16 mutation in one patient. CONCLUSIONS: Among recently identified magnesium-wasting disorders, HSH and FHHNC represent two major entities also in the Turkish population. Besides clinical course and laboratory diagnosis of hypomagnesaemia, the detection of renal calcium wasting and parathyroid function are crucial to differentiate between these most prevalent forms of hereditary magnesium deficiency. While TRPM6 mutations underlying HSH almost uniformly lead to a complete loss of function of the TRPM6 protein, the severity of FHHNC phenotype depends on the residual function of the mutated claudin-16 protein.

The prevalence and risk factors of premature thelarche and pubarche in 4- to 8-year-old girls.

AIM: To assess the prevalence of premature thelarche (PT) and pubarche in healthy 4- to 8-year-old girls and to investigate factors associated with early pubertal development. METHOD: Eight hundred and twenty girls were examined by two paediatric endocrinologists to determine Tanner staging. The effects of body mass index, gestational age, intrauterine growth status, age at the first tooth eruption, socio-economical status, maternal age of menarche and consumption of certain food items on early pubertal development were analysed through parametric and nonparametric tests. RESULTS: The prevalence of PT and of premature pubarche was 8.9% and 4.3%, respectively. We found a strong association between the prevalence of PT and the body mass index standard deviation scores (BMI SDS). There were more girls with BMI SDS values above 1 in the PT group (56.1%) than among the remaining subjects (22.9%). Premature thelarche was not significantly associated with intrauterine growth, premature birth, socioeconomic status, age of first tooth eruption or maternal age of menarche. Similarly, the amount of milk, eggs, chicken or fish consumed was not associated with PT. None of the investigated factors were associated with premature pubarche. CONCLUSION: Occurrence of PT is strongly associated with BMI SDS. Studies investigating secular trends in pubertal development must consider a secular change in body mass index.

Steroid Hormone Profiles and Molecular Diagnostic Tools in Pediatric Patients With non-CAH Primary Adrenal Insufficiency.

CONTEXT: There is a significant challenge of attributing specific diagnoses to patients with primary adrenal insufficiency of unknown etiology other than congenital adrenal hyperplasia (non-CAH PAI). Specific diagnoses per se may guide personalized treatment or may illuminate pathophysiology. OBJECTIVE: This work aimed to investigate the efficacy of steroid hormone profiles and high-throughput sequencing methods in establishing the etiology in non-CAH PAI of unknown origin. METHODS: Pediatric patients with non-CAH PAI whose etiology could not be established by clinical and biochemical characteristics were enrolled. Genetic analysis was performed using targeted-gene panel sequencing (TPS) and whole-exome sequencing (WES). Plasma adrenal steroids were quantified by liquid chromatography-mass spectrometry and compared to that of controls. This study comprised 18 pediatric endocrinology clinics with 41 patients (17 girls, median age: 3 mo, range: 0-8 y) with non-CAH PAI of unknown etiology. RESULTS: A genetic diagnosis was obtained in 29 (70.7%) patients by TPS. Further molecular diagnosis could not be achieved by WES. Compared to a healthy control group, patients showed lower steroid concentrations, most statistically significantly in cortisone, cortisol, and corticosterone (P < .0001, area under the receiver operating characteristic curve: .96, .88, and .87, respectively). Plasma cortisol of less than 4 ng/mL, cortisone of less than 11 ng/mL, and corticosterone of less than 0.11 ng/mL had a greater than 95% specificity to ensure the diagnosis of non-CAH PAI of unknown etiology. CONCLUSION: Steroid hormone profiles are highly sensitive for the diagnosis of non-CAH PAI of unknown etiology, but they are unlikely to point to a specific molecular diagnosis. TPS is an optimal approach in the molecular diagnosis of these patients with high efficacy, whereas little additional benefit is expected from WES.

Prevalence of type 1 diabetes mellitus in 6-18-yr-old school children living in Istanbul, Turkey.

BACKGROUND: Type 1 diabetes mellitus (T1DM) is among the most common chronic diseases in childhood and the incidence of T1DM is increasing worldwide. There is no actual data regarding the frequency of T1DM in Turkish children. OBJECTIVES: We aimed to assess current prevalence of T1DM in 6-18-yr-old school children living in Istanbul. METHODS: Total number of students and children on insulin treatment were reported by the schools, as the first part of the study. At the second step, the study team visited 203 schools for confirmation of the reported data. RESULTS: One thousand and ninety children in a population of 1 630 751 school children were reported to have T1DM, which made the total prevalence of T1DM 0.67/1000 (95% confidence interval 0.6/1000-0.7/1000). A population of 217 030 children (α=0.05 and ß=0.20) from 203 schools were screened. The difference between the reported and detected prevalence was 0.032/1000 (215 detected vs. 222 reported, p>0.05). Comparison of the current data with the prevalence reported in a smaller population in Ankara, Turkey, 16 yr ago, demonstrated that the prevalence of T1DM is higher in the current study (0.46/1000 vs. 0.16/1000, 0.57/1000 vs. 0.34/1000, and 0.92/1000 vs. 0.69/1000 at primary, secondary, and high schools, respectively). CONCLUSION: This first pediatric T1DM prevalence data in a large pediatric population in Istanbul, Turkey, estimated the prevalence of T1DM as 0.67/1000. This prevalence is 2.5-fold higher than that reported in Ankara, Turkey, in 1993, suggesting that T1DM prevalence is increasing in Turkey as in the other parts of the world.

The role of makorin ring finger protein-3, kisspeptin, and neurokinin B in the physiology of minipuberty.

BACKGROUND: There is no data regarding the interrelationships of circulating Makorin Ring Finger Protein-3 (MKRN3), Kisspeptin (KISS1), and Neurokinin B (NKB) concentrations during minipuberty in humans. OBJECTIVE: To determine temporal changes in circulating concentrations of MKRN3, KISS1, NKB, and gonadotropins and investigate interrelationships between them in healthy full-term (FT) and preterm (PT) infants during minipuberty period. METHODS: A prospective study of 6-month follow-up performed. Eighty-seven healthy newborns, 48 FT (19 boys/29 girls), and 39 PT (21 boys/18 girls) (gestational age 31-37 weeks), were included. Blood samples were taken at 7 days (D7), 2 months (M2), and 6 months (M6) of age. Serum MKRN3, KISS1, NKB, LH, FSH, total testosterone (TT), and estradiol (E2) concentrations were measured. RESULTS: Seventy infants completed the study. MKRN3, KISS1, and NKB concentrations were similar in FT girls and boys. PT boys and girls also had similar concentrations of MKRN3, KISS1, and NKB. FT babies had significantly higher NKB concentrations than PT babies at D7, M2, and M6. MKRN3 and KISS1 concentrations do not differ between FT and PT babies. A strong positive correlation was found between MKRN3 and KISS1 at each time point and in all groups. FSH, LH, TT/E2 concentrations decrease while those of MKRN3 and KISS1 have a trend to increase toward the end of minipuberty. No correlation was detected between gonadotropins and MKRN3, KISS1, NKB concentrations. CONCLUSION: Strong positive correlation demonstrated between KISS1 and MKRN3 suggests that interrelationship between molecules controlling minipuberty is not similar to those at puberty.

Cranial MRI Abnormalities and Long-term Follow-up of the Lesions in 770 Girls With Central Precocious Puberty.

CONTEXT: Central precocious puberty (CPP) may arise from central nervous system (CNS) lesions in a few affected girls. Recently, the incidence of girls with CPP has increased mostly in 6-8 year olds, in whom the necessity of magnetic resonance imaging (MRI) is debated. OBJECTIVE: To investigate the frequency, long-term outcome and potential predictors of CNS lesions in a large cohort of girls with CPP. METHODS: A multicenter cohort of 770 Turkish girls with CPP who had systematic cranial MRI between 2005 and 2017. Age at puberty onset was <6 years in 116 and 6-8 years in 654. CNS lesions were followed until final decision(6.2 ± 3.1 years). Potential predictors of CNS lesions were evaluated by univariate analyses. RESULTS: A total of 104/770 (13.5%) girls had abnormal brain MRI. Of these, 2.8% were previously known CNS lesions, 3.8% had newly detected and causally related CNS lesions, 3.1 % were possibly, related and 3.8% were incidental. Only 2 (0.25%) neoplastic lesions (1 low grade glioma and 1 meningioma) were identified; neither required intervention over follow-up of 6 and 3.5 years respectively. Age at breast development <6 years (odds ratio [OR] 2.38; 95% CI 1.08-5.21) and the peak luteinizing hormone/follicle-stimulating hormone (LH/FSH) ratio >0.6 (OR 3.13; 95% CI 1.02-9.68) were significantly associated with CNS lesions. However, both patients with neoplastic lesions were >6 years old. CONCLUSION: Although age and LH/FSH ratio are significant predictors of CNS lesions, their predictive power is weak. Thus, systematic MRI seems to be the most efficient current approach to avoid missing an occult CNS lesion in girls with CPP, despite the low likelihood of finding a lesion requiring intervention.

Elevated 1-h post-load plasma glucose levels in normal glucose tolerance children with obesity is associated with early carotid atherosclerosis.

CONTEXT: Evidence suggests that the 1-h post-load plasma glucose (1-h PG) ≥155mg/dL during an oral glucose tolerance test (OGTT) predicts development of type 2 diabetes (T2DM) and associated complications, among adults with normal glucose tolerance (NGT), but relevant data on children is scarce. OBJECTIVES: To investigate whether NGT children with obesity whose 1-h PG is ≥155mg/dL have an increased carotid intima-media thickness (IMT) and exhibit non-alcoholic fatty liver disease (NAFLD) diagnosed by ultrasonography, as compared with NGT subjects with 1-h PG <155mg/dL and impaired glucose tolerance (IGT). METHODS: Cardio-metabolic profile, OGTT, measurements of carotid IMT and liver ultrasonography were analyzed in 171 non-diabetic children with obesity. Subjects were divided into 3 groups: NGT subjects with a 1-h PG <155mg/dL, NGT subjects with a 1-h PG ≥155mg/dL, and IGT subjects. RESULTS: As compared with NGT individuals with a 1-h PG <155mg/dL, NGT individuals with a 1-h PG ≥155mg/dL exhibited higher carotid IMT (0.75±0.15mm vs. 0.68±0.15mm; p<0.05). No significant differences were observed in carotid IMT between IGT and NGT subjects with a 1-h PG ≥155mg/dL (0.75±0.18mm vs 0.75±0.15mm; p>0.05). Of the three glycemic parameters, 1-h and 2-h PG, but not fasting glucose, were significantly correlated with carotid IMT. There were no significant differences for increased risk of having NAFLD between the three groups. CONCLUSIONS: These data suggest that a value of 1-h PG ≥155mg/dL in children and adolescents with obesity is as important as IGT with respect to cardiovascular risks.

Hereditary vitamin D-resistant rickets: a report of four cases with two novel variants in the VDR gene and successful use of intermittent intravenous calcium via a peripheral route.

Background Hereditary vitamin D-resistant rickets (HVDRR) is caused by vitamin D receptor (VDR) defects. Patients with HVDRR do not respond to standard doses of calcitriol and oral calcium (Ca) treatment and need to be treated with intravenous Ca (IV-Ca) via a central route. However, central catheter-related complications can cause significant morbidity. Case presentation Four unrelated patients with HVDRR presenting with rickets and alopecia totalis were administered intermittent IV-Ca treatment (2-5 times/week) through a peripheral route. No complications such as infection, extravasation or arrhythmias were detected upon peripheral infusion. Peripheral 1-22 months' duration of IV-Ca normalized parathyroid hormone (PTH) and alkaline phosphatase (ALP) in all patients, after which, oral Ca of 200-400 mg/kg/day and calcitriol of 0.5 µg/kg/day were sufficient to maintain normal PTH levels. Molecular studies on the VDR gene showed a previously reported homozygous c.454C > T (p.Q152*) pathogenic variant in two patients. Two novel homozygous variants in the other two patients were detected: (1) c.756-2A > G, which affects the splice acceptor site, and (2) c.66dupG (p.I23Dfs*20) variant leading to a frameshift that results in a premature stop codon. Conclusions Peripheral IV-Ca treatment is an effective and practical alternative treatment mode that provides dramatic clinical benefit in patients with HVDRR.