Epidemiology of type 1 diabetes mellitus in children and adolescents: A 50-year, single-center experience.

BACKGROUND: Global variations in epidemiology of type 1 diabetes mellitus (T1DM) exist. This study is designed to examine demographic and clinical features of T1DM over the past 3 decades as well as evolving trends in epidemiology over last 50 years. METHODS: Clinical characteristics of 925 patients with T1DM over last 30 years (1990-2019) were evaluated and compared to previously published data of 477 patients diagnosed between 1969 and 1990 from one of the major referral centers for diabetes in Turkey. RESULTS: Mean age at diagnosis decreased from 9.5 ± 4.0 to 7.1 ± 3.6 years within the past 50 years (p < .001). Age at diagnosis peaked at 12-14 years between 1969 and 1990, then fell to 10-11.9 years between 1990 and 1999, and to 4-5.9 years between 2000-2009 and 2010-2019 (p = .005). Although the percentage of patients diagnosed <6 years of age is gradually increasing, the percentage between the ages of 6 and 11.9 years is decreasing, and the percentage diagnosed ≥12 years remained stable. A total of 47.5% of patients had ketoacidosis, 38.2% had ketosis, and 14.3% had only hyperglycemia. 23% of patients had severe diabetic ketoacidosis (DKA), whereas 42% had moderate. Over last 3 decades, there has been no change in frequency of ketoacidosis at presentation, but there has been significant decline in severity (p = .865, and p < .001, respectively). Although the frequency of patients with mild DKA increased over time, frequency of patients with moderate DKA decreased; however, no significant difference was observed among patients with severe ketoacidosis. DKA was more frequent and severe in patients <6 years of age (p = .005, and p < .001, respectively). CONCLUSION: Age at diagnosis shifted to younger ages in T1DM in the past 50 years. Half of patients had ketoacidosis at diagnosis and frequency of presentation with DKA did not decrease, but severity decreased slightly. Increase in prevalence of T1DM in the younger age group and the fact that half of patients present with DKA indicate that awareness should be increased in terms of early diagnosis and treatment.

Cardiovascular Risk Factors in Adolescents with Type 1 Diabetes: Prevalence and Gender Differences.

Introduction: Cardiovascular diseases (CVD) are the most important cause of morbidity and mortality in patients with T1D. Children with T1D had similar or higher prevalence of being overweight or obese compared to their healthy peers. In this study we aimed to determine prevalence of CVD risk factors in children and adolescents with T1D and the impact of obesity and sex differences on these factors. Methods: Data of 365 patients (200 girls, 165 boys) who were 10-21 years of age and who had been using intensive insulin therapy with a diagnosis of T1D for at least 3 years were evaluated. Patients were divided into normal weight (NW), overweight (OW) and obese (Ob) groups according to body mass index percentiles. Risk factors for CVD (obesity, dyslipidemia, hypertension) were compared between groups, and impact of gender was also analyzed. Results: Prevalence of OW/Ob was 25.9% which was significantly higher in girls (30.6% vs 20.1%, p<0.001). Rate of hypertension was highest in OW/Ob girls followed by OW/Ob boys, and similar in NW girls and boys (p=0.003). Mean LDL-c and TG levels were highest in OW/Ob girls, followed by OW/Ob boys, NW girls and NW boys, respectively (p<0.001 and p<0.001, respectively). Mean HDL-c levels were similar among groups. Rates of high LDL-c and TG were similar between OW/Ob girls and boys and higher than NW girls, followed by NW boys (p<0.001 and p<0.001, respectively). Rate of low HDL-c was similar in OW/Ob girls and boys, and higher than NW girls, followed by NW boys (p<0.001). Overall, girls were 1.9 times more likely than boys to have two or more risk factors for CVD. Factors associated with risk for CVD in multiple logistic regression analyses were being a girl, followed by higher daily insulin dose, higher HbA1c, longer diabetes duration (r=0.856; p<0.001). Discussion: In spite of the increased prevalence for obesity in both sexes, the trend for CVD risk factors has increased more in obese girls, followed by obese boys and girls who are normal weight. Girls with T1D are more likely to be overweight/obese and to have CVD risk than boys, highlighting the need for early intervention and additional studies to elucidate the causes, particularly in girls with T1D.

Long Term Growth Hormone Therapy in a Patient with IGF1R Deletion Accompanied by Delayed Puberty and Central Hypothyroidism.

Insulin-like growth factor-1 (IGF-1) is the main driver of growth during prenatal life and acts through insulin-like growth factor 1 receptor (IGF1R). Patients with IGF1R defects exhibit variable phenotypic features. A 10.9-year-old boy presented with severe short stature, microcephaly, minor dysmorphic features and mild mental retardation. Genetic analysis for IGF1R revealed heterozygous deletion of the complete IGF1R. At the age of 12.3 years, daily subcutaneous rhGH was started and continued for a total of 5.7 years in two courses with improvement of height velocity as well as final height. Puberty was delayed and eventually he could not develop full puberty suggesting partial hypogonadotropic hypogonadism. Hypothyroidism initially developed during rhGH therapy. However, low T4 levels sustained after cessation of rhGH therapy thus central hypothyroidism is a likely diagnosis. rhGH has partial effect for induction of growth in cases with IGF1R defects. However, long-term treatment with an early onset may have more beneficial effects. In addition, patients with IGF1R defects should be followed for delayed puberty-hypogonadism, and hypothyroidism.

Body composition in sexual precocity.

PURPOSE OF REVIEW: In this review, we have summarized the current data on the effect of sexual precocity and treatment with gonadotropin-releasing hormone analogues (GnRHa) on body composition. RECENT FINDINGS: Higher body weight and weight gain in infancy and childhood may increase the risk of early puberty in girls. The relation between BMI and pubertal onset in boys is controversial. Current studies draw attention to the fact that a similar relationship may exist in boys too. Obesity prevalence is high among girls with central precocious puberty (CPP) and treatment with GnRHa has a different effect on BMI according to baseline body composition. Although BMI values of normal weight girls tend to increase under treatment, they return to normal following treatment. The few studies that have followed up body composition longitudinally in girls show a gradual increase in adiposity, decrease in muscle mass and bone mineral density during GnRHa treatment, whereas bone mass was preserved after treatment. Adequate data are not available in boys to determine the effect of GnRHa therapy on body composition. SUMMARY: Body composition and fat distribution should be monitored longitudinally in patients with CPP treated with GnRHa to ascertain the long-term effects of therapy.

Management of prolactinomas in children and adolescents; which factors define the response to treatment?

PURPOSE: Prevalence, presentation and clinical outcome of prolactinomas vary in children and adults. In this study, we evaluated the clinical features and outcome of children and adolescents with prolactinoma to identify the differences from that of adults, and thus to establish the management strategies for this age group. METHODS: Patients with prolactinoma diagnosed before 18 years of age from a single center in the last 20-years were included. Clinical and laboratory data, radiological findings and treatment outcome were evaluated retrospectively. RESULTS: Twenty-eight patients (23 female; 82.1%) with prolactinoma were included. Median age at diagnosis was 15.2 years (12.6-17.7 years) in girls, 12.9 years (12.0-16.7 years) in boys. First line treatment was cabergoline in 82% of patients and normal prolactin level was achieved with maximum dose of 2 mg/week in 78%. Surgery was required in 28% of patients. Adenomas < 13.5 mm responded conventional doses of CAB. Adenomas > 30 mm were drug resistant or required surgery. Adenomas between 13.5 mm and 30 mm with invasion/extension were more likely to have drug resistance. CAB had to be continued following surgery in all patients. One macroprolactinoma had an increase in size which was accompanied with increasing prolactin level. CONCLUSIONS: All microprolactinomas responded well to DA treatment. However, all adenomas larger than 30 mm was resistant to CAB or required surgery. Probability of drug resistance and requirement of second line therapy were higher in adenomas between 13.5 mm and 30 mm with invasion/extension. Doses over 2 mg/week of CAB in drug-resistant patients may not provide additional benefit. The frequency of follow-up MRI could be determined based on prolactin levels and emergence of new neurological symptoms.

Long-term effect of conventional phosphate and calcitriol treatment on metabolic recovery and catch-up growth in children with PHEX mutation.

OBJECTIVES: Hereditary hypophosphatemic rickets (HR) is conventionally treated with phosphate and calcitriol. Exploring genotype and phenotypic spectrum of X-linked hypophosphatemic rickets (XLHR), focusing on short-term, long-term, and pubertal impact of conventional treatment was aimed. METHODS: Sixteen patients from 12 unrelated families with HR were analyzed for phosphate regulating endopeptidase homolog X-linked (PHEX) mutation. Initially Sanger sequencing analysis was performed. If PHEX mutation was not detected, multiplex ligation-dependent probe amplification (MLPA) was performed. If molecular defect was detected, first-degree relatives were analyzed. Thirteen patients (81%) and five first-degree relatives with XLHR were evaluated for genotype-phenotype or gender-phenotype correlation. Clinical characteristics and response to conventional treatment were determined retrospectively. RESULTS: Nine different PHEX mutations were identified; four splice-site, three point mutations, and two single exon deletions. Four were novel mutations. Despite conventional treatment, median adult height was lower than median height on admission (-3.8 and -2.3 SDS, respectively), metabolic and radiographic recovery were not achieved, adherence was low (30%). Although mean adult height was better in compliant patients than noncompliants (-2.6 vs. -3.7 SDS, respectively), they were still short. Correlation between phenotype and genotype or gender could not be shown. Median phosphate decreased significantly throughout puberty (p=0.014). Median pubertal height was lower than prepubertal height (-4.4 vs. -3.6 SDS; respectively), pubertal growth spurt was not observed. Among five patients with a follow-up longer than five years, three had nephrocalcinosis (60%), two had hyperparathyroidism (40%), 4/6 (33%) required correction osteotomy. CONCLUSIONS: Conventional treatment appears to have limited effect on metabolic, clinical and radiographic recovery in XLHR. Metabolic control and growth worsened during puberty. Although, long-term adverse effects are yet to be seen, introduction of burosumab as first-line treatment may be an alternative after infancy.

Central nervous system imaging in girls with central precocious puberty: when is necessary?

OBJECTIVE: The determinants of an increased risk of an organic pathology underlying central precocious puberty (CPP) in girls remain contentious. The present study aimed to determine the clinical and hormonal findings that can be used to differentiate organic and idiopathic CPP in girls as a screening method so that only those considered likely to have organic CPP undergo cranial magnetic resonance imaging (MRI). METHODS: The medical records of 286 girls that received GnRH agonist (GnRHa) therapy for CPP were retrospectively evaluated. Chronological and bone age, height, pubertal stage, and basal/stimulated gonadotropin and estradiol (E2) levels, as well as cranial MRI findings at the time CPP was diagnosed were recorded. Clinical and hormonal parameters that can be used to differentiate between girls with organic and idiopathic CPP were identified using ROC curves. RESULTS: Organic CPP was noted in 6.3% of the participants. Puberty started before age 6 years in 88.9% of the girls with organic CPP. Mean E2 and peak luteinizing hormone (LH) levels were higher in the girls with organic CPP than in those with idiopathic CPP that were matched for pubertal stage, as follows: early stage puberty (Tanner 2 and 3): E2: 62.4 ± 19.8 pg/mL vs. 29.1 ± 9.5 pg/mL; peak LH: 16.8 ± 3.2 IU/L vs. 12.2 ± 3.7 IU/L; advanced stage puberty (Tanner 4): mean E2: 87.6 ± 3.4 pg/mL vs. 64.6 ± 21.2 pg/mL; peak LH: 20.8 ± 0.4 IU/L vs. 16.6 ± 5.8 IU/L (P < 0.001 for all). Thresholds for differentiating organic and idiopathic CPP in girls with early-stage puberty were 38.1 pg/mL for E2 (100% sensitivity and 80.4% specificity) and 13.6 IU/L for peak LH (100% sensitivity and 66.4% specificity). CONCLUSION: Pubertal symptoms and signs generally begin before age 6 years and hormone levels are much higher than expected for pubertal stage in girls with organic CPP. Based on the present findings, cranial MRI is recommended for girls aged < 6 years, as the risk of diagnosing an organic pathology is highest in this age group. Hormone levels higher than expected for pubertal stage might be another indication for cranial MRI, regardless of patient age. Cranial MRI should be performed in girls with early-stage puberty, and an E2 level > 38 pg/mL and/or a peak LH level > 13.6 IU/L.

Urinary bisphenol A levels in prepubertal children with exogenous obesity according to presence of metabolic syndrome.

OBJECTIVES: Recent studies have shown a potential link between chronic exposure to Bisphenol A (BPA) and exogenous obesity, the prevalence of which has been increasing dramatically in all age groups and particularly among children in the last decades. In this study, we aimed at comparing BPA exposure levels between controls and otherwise healthy, drug-naive, pre-pubertal children having exogenous obesity with/without metabolic syndrome. METHODS: A total of 63 pre-pubertal children with exogenous obesity whom 27 of them having metabolic syndrome attending Hacettepe University Ihsan Dogramaci Children's Hospital were included in this study. The control group consisted of 34 age- and sex-matched healthy children with no significant underlying medical conditions. Urinary BPA levels were measured using LC-MS/MS (high-performance liquid chromatography coupled with tandem mass spectrometry) methodology. RESULTS: Urinary BPA levels among obese children were significantly higher than those of the control group (median: 22.9 µg/g-creatinine and 6.9 µg/g-creatinine, respectively; p=0.0001). When adjusted with generalized linear models for age, gender and z scores of body mass index, obese children having metabolic syndrome had significantly higher urinary BPA levels than obese children without metabolic syndrome and both obese groups had considerably elevated levels of urinary BPA than the controls (estimated marginal mean ± standard error: 42.3 ± 7.4 µg/g-creatinine, 22.6 ± 3.5 µg/g-creatinine and 12.1 ± 2.5 µg/g-creatinine, respectively, p=0.0001). CONCLUSIONS: This study shows much higher BPA exposure among obese children with metabolic syndrome during the prepubertal period.

Alpha-Melanocyte-Stimulating Hormone is Elevated in Hypothalamic Obesity Associated with Childhood Craniopharyngioma.

OBJECTIVE: The purpose of this study was to investigate the peripheral concentrations of leptin and neuropeptides taking part in the melanocortin pathway in hypothalamic obesity (HO) associated with craniopharyngioma (CP) and to find a peripheral marker for diagnosis. METHODS: Thirty-one patients (52% girls; median age 16 years) with CP were enrolled in the study group. They were grouped as CP with obesity (CPobesity , n = 17) and CP without obesity (CPnonobesity , n = 14). Two control groups without CP consisted of 27 children with obesity (OC) (55% girls; median age 13.8 years) and 25 children without obesity (normal control [NC]) (72% girls; median age 14.5 years). Obesity was defined as BMI percentile ≥ 95%. Fasting serum concentrations of leptin, brain-derived neurotrophic factor (BDNF), and alpha-melanocyte-stimulating hormone (α-MSH) were measured in the groups. RESULTS: Leptin and BDNF concentrations were correlated with BMI SD score (SDS) in controls (OC + NC) and CP. However, there was no correlation between α-MSH and BMI-SDS in CP or control groups. After adjusting for age, sex, and BMI-SDS, α-MSH was found to be significantly higher in CPobesity than in other groups, whereas leptin and BDNF were comparable among the four groups. CONCLUSIONS: Serum BDNF, just like leptin, increased with BMI, regardless of hypothalamic damage. On the contrary, α-MSH concentration was significantly high in HO, designating a potential biomarker for HO in CP.

Which parameters predict the beneficial effect of GnRHa treatment on height in girls with central precocious puberty?

OBJECTIVE: Data about GnRHa on adult height in girls with central precocious puberty (CPP) have shown variable results, ranging from improvement of growth prognosis to lack of any benefit. This study was designed to delineate the criteria to decide which girls with idiopathic CPP (iCPP) will have a height benefit from GnRHa treatment. DESIGN: Retrospective PATIENTS: 102 girls with iCPP who had reached final height (FH) were included. MEASUREMENTS: Auxological, hormonal and radiological findings at treatment onset, and FHs were extracted from records. RESULTS: Most important factor affecting height gain was chronological age (CA) at treatment onset. All the girls treated ≤6.4 years of age achieved a height gain of ≥1SDS, while none of the girls treated ≥8.3 years of age made the target. 75.6% of patients who started GnRHa between the ages of 6.4 and 8.3 years had a height gain of ≥1SDS. Most important factors affecting height gain in those treated 6.4-8.3 years were advanced bone age (BA), basal estradiol (E2 ) and pubertal stage (r2 : 0.906; P < .001). All individuals with BA advancement of ≥2.6 years or E2 of ≥32.6 pg/ml or pubertal stage of ≥3 had significant height gain, and none of the cases with BA advancement of <2 years or E2 of <21.5 pg/ml or pubertal stage of <2 had a height gain of ≥1SDS. CONCLUSIONS: Treatment with GnRHa is unquestionably beneficial to improve FH in girls with iCPP when initiated ≤6.4 years of age. GnRHa treatment after 8.3 years of age may not improve FH. Girls between the ages of 6.4 and 8.3 years at presentation can have a better height gain if BA (≥2.6 years over CA) and pubertal findings (pubertal stage ≥3 or E2 ≥32.6 pg/ml) are well-advanced.

Basal Serum Thyroxine Level should Guide Initial Thyroxine Replacement Dose in Neonates with Congenital Hypothyroidism

Objective: Initial high-dose sodium levothyroxine (Na-LT4) (10-15 µg/kg/day) replacement for primary congenital hypothyroidism (CH) is recommended in guidelines. However, high-dose Na-LT4 risks iatrogenic hyperthyroidism. The aim of this study was to investigate the normalizing effect of varying initial doses of Na-LT4 on serum thyroid hormone levels. Methods: Fifty-two patients were analyzed retrospectively. The patients were classified into mild (27/51.9%), moderate (11/21.1%) and severe (14/26.9%) CH, based on initial free thyroxine (fT4) levels. Time taken to achieve target hormone levels was compared within groups. Results: Initial mean Na-LT4 doses for mild, moderate and severe disease were 6.9±3.3, 9.4±2.2 and 10.2±2 µg/kg/day. Serum fT4 levels reached the upper half of normal range (>1.32 ng/dL) in a median of 16, 13 and 16 days in patients with mild, moderate and severe CH with the mean time from initial treatment to first control visit of 14.8±6 days (range 1-36). There was no significant difference in terms of time to achieve target fT4 hormone levels according to disease severity (p=0.478). Seven (25.9%), eight (72.7%) and eight (57.1%) patients experienced hyperthyroxinemia (serum fT4 >1.94 ng/dL) in the mild, moderate, and severe CH groups at the first visit, respectively (p=0.016). Conclusion: Not all patients diagnosed with CH require high-dose Na-LT4. Initial dose of Na-LT4 may be selected on the basis of pre-treatment thyroid hormone levels. Some patients with moderate and severe CH, experienced iatrogenic hyperthyroxinemia even though the dose was close to the lower limit of the recommended range in guidelines. We suggest that lower initial doses may be appropriate with closer follow-up within the first week.

Gender-related differences in etiology of organic central precocious puberty.

BACKGROUND: Central precocious puberty (CPP) is idiopathic in 90% of girls and 60% of boys, while some cases are caused by lesions of central nervous system (CNS), a condition often referred to as organic CPP. We aimed to analyze the etiology of organic CPP in a large cohort of girls and boys and determine gender-related differences. METHODS: Medical files of 256 girls and 120 boys diagnosed and treated for CPP in a single center in the last two decades were reviewed. Patients were classified into four groups with respect to previous history and MRI findings: (1) previously established CNS pathology at the time of diagnosis, (2) novel CNS pathology previously asymptomatic, (3) incidentalomas considered to be unrelated to CPP, and (4) completely normal MRI. Group 1 and 2 were considered as organic CPP whereas group 3 and 4 were considered as idiopathic CPP. RESULTS: Prevalence of CNS pathology was significantly higher in boys than girls (21.7% vs 6.2%). Previous CNS pathologies such as developmental anomaly of CNS, parenchymal injury, necrotic lesions and hydrocephalus were present in 3.5% of girls and 8.3% of boys. Prevalence of novel CNS pathology as determined by imaging among neurologically asymptomatic patients was 2.8% in girls and 14.5% in boys. The most common novel CNS pathologies in boys were hamartomas (5%) and suprasellar arachnoid cysts (3.3%); which were significantly lower in girls (0.8 and 0.8% respectively). Onset of organic CPP was before six years in girls, and seven years in boys. CONCLUSIONS: Organic CPP was 3.5 times more common in boys compared to girls. It is possible to detect an underlying CNS pathology in one out of every five boys with CPP. Frequency and distribution of organic etiology also differ between girls and boys, hypothalamic hamartomas and suprasellar arachnoid cysts being more common in boys than girls. The likelihood of novel intracranial pathology associated with CPP is quite low in girls with an onset after six years of age and in boys with an onset after seven years of age.

Treatment response to long term antiresorptive therapy in osteogenesis imperfecta type VI: does genotype matter?

OBJECTIVES: Osteogenesis imperfecta type VI (OI VI) follows a progressive and severe course, yet unlike other forms of severe OI it has a later onset of fractures, and extra-skeletal findings are not part of the clinical picture. Another difference is that there is an increase in unmineralized osteoid tissue in OI VI, which hinders the effect of bisphosphonates-the current standard of treatment for OI. Therefore, the response to standard treatments in OI VI is not satisfactory. Herein, we report long-term follow-up of two cases with novel SERPINF1 mutations, who show great variation in their treatment response to bisphosphonates. CASE PRESENTATION: The first case was given pamidronate at the age of 15 months when he could sit independently, followed a fluctuating course under treatment, fracture rate did not decrease, however he was able to mobilize with walker at the age of 10 years. On the other hand, the second case developed severe deformities and became wheelchair-bound under pamidronate, thus the treatment was switched to denosumab. Unfortunately, there was no improvement under denosumab after 15 months too, and since bone pain increased, denosumab treatment was stopped. He was put on zoledronic acid instead. CONCLUSION: SERPINF1 transcript amount may be an important factor to explain the variation in response to pamidronate therapy. In OI VI patients, the factors affecting the clinical course should be identified and new or combined treatment options should be established.

Central nervous system imaging in girls with central precocious puberty: when is necessary?

ABSTRACT Objectives The determinants of an increased risk of an organic pathology underlying central precocious puberty (CPP) in girls remain contentious. The present study aimed to determine the clinical and hormonal findings that can be used to differentiate organic and idiopathic CPP in girls as a screening method so that only those considered likely to have organic CPP undergo cranial magnetic resonance imaging (MRI). Subjects and methods The medical records of 286 girls that received GnRH agonist (GnRHa) therapy for CPP were retrospectively evaluated. Chronological and bone age, height, pubertal stage, and basal/stimulated gonadotropin and estradiol (E2) levels, as well as cranial MRI findings at the time CPP was diagnosed were recorded. Clinical and hormonal parameters that can be used to differentiate between girls with organic and idiopathic CPP were identified using ROC curves. Results Organic CPP was noted in 6.3% of the participants. Puberty started before age 6 years in 88.9% of the girls with organic CPP. Mean E2 and peak luteinizing hormone (LH) levels were higher in the girls with organic CPP than in those with idiopathic CPP that were matched for pubertal stage, as follows: early stage puberty (Tanner 2 and 3): E2: 62.4 ± 19.8 pg/mL vs. 29.1 ± 9.5 pg/mL; peak LH: 16.8 ± 3.2 IU/L vs. 12.2 ± 3.7 IU/L; advanced stage puberty (Tanner 4): mean E2: 87.6 ± 3.4 pg/mL vs. 64.6 ± 21.2 pg/mL; peak LH: 20.8 ± 0.4 IU/L vs. 16.6 ± 5.8 IU/L (P < 0.001 for all). Thresholds for differentiating organic and idiopathic CPP in girls with early-stage puberty were 38.1 pg/mL for E2 (100% sensitivity and 80.4% specificity) and 13.6 IU/L for peak LH (100% sensitivity and 66.4% specificity). Conclusion Pubertal symptoms and signs generally begin before age 6 years and hormone levels are much higher than expected for pubertal stage in girls with organic CPP. Based on the present findings, cranial MRI is recommended for girls aged < 6 years, as the risk of diagnosing an organic pathology is highest in this age group. Hormone levels higher than expected for pubertal stage might be another indication for cranial MRI, regardless of patient age. Cranial MRI should be performed in girls with early-stage puberty, and an E2 level > 38 pg/mL and/or a peak LH level > 13.6 IU/L.

Novel insights into diabetes mellitus due to DNAJC3-defect: Evolution of neurological and endocrine phenotype in the pediatric age group.

BACKGROUND: A number of inborn errors of metabolism caused by abnormal protein trafficking that lead to endoplasmic reticulum storage diseases (ERSD) have been defined in the last two decades. One such disorder involves biallelic mutations in the gene encoding endoplasmic reticulum resident co-chaperone DNAJC3 (P58IPK ) that leads to diabetes in the second decade of life, in addition to multiple endocrine dysfunction and nervous system involvement. OBJECTIVE: The aim of this study was to define the natural history of this new form of diabetes, especially the course of abnormalities related to glucose metabolism. METHODS: Whole-exome and Sanger sequencing was used to detect DNAJC3 defect in two patients. Detailed analysis of their clinical history as well as biochemical, neurological and radiological studies were carried out to deduce natural history of neurological and endocrine phenotype. RESULTS: DNAJC3 defect led to beta-cell dysfunction causing hyperinsulinemichypoglycemia around 2 years of age in both patients, which evolved into diabetes with insulin deficiency in the second decade of life, probably due to beta cell loss. Endocrine phenotype involved severe early-onset growth failure due to growth hormone deficiency, and hypothyroidism of central origin. Neurological phenotype involved early onset sensorineural deafness discovered around 5 to 6 years, and neurodegeneration of central and peripheral nervous system in the first two decades of life. CONCLUSION: Biallelic loss-of-function in the ER co-chaperone DNAJC3 leads to a new form of diabetes with early onset hyperinsulinemic hypoglycemia evolving into insulin deficiency as well as severe growth failure, hypothyroidism and diffuse neurodegeneration.

Effect of long-term glucocorticoid therapy on bone mineral density of the patients with congenital adrenal hyperplasia.

BACKGROUND AND OBJECTIVES: Congenital adrenal hyperplasia (CAH) is characterized by androgen excess which should be treated with life-long glucocorticoid therapy, thus can affect bone mineralization. We aimed to evaluate the bone mineral density (BMD) and determine the factors affecting bone mineralization in patients with CAH. METHOD: This prospective case-control study was conducted in children, adolescents and young adults with classical 21-hydroxylase CAH, and age-, sex-, and pubertal stage matched healthy controls. Lumbar1-4 BMD was determined by dual-energy X-ray absorptiometry. BMD z-score was calculated using national standards with respect to height age and was referred as `low BMD` if z-score < -1 SD. Univariate analyses were performed between low BMD and normal BMD groups, and multivariate logistic regression analysis was performed to assess the independent predictors of low BMD. Correlations of Body Mass Index (BMI)-z-score, average serum 17-hydroxyprogesterone level, duration of treatment, average and cumulative glucocorticoid doses with BMD z-score were evaluated with Spearman analyses. RESULTS: Each group included 37 cases. BMD z-score of patients with CAH [0.47 (-0.04 - 1.56)] was higher than control group [-0.43 (-0.82 -0.05)]; p= < 0.001. Number of patients with low BMD was similar in both groups; [CAH: 6(16.2%), control: 5(13.5%); p= 0.744]. BMI- z-score was higher in patients with CAH when compared to control group; p= < 0.001. BMI z-score was lower in low BMD group as comparison to normal BMD group; p= 0.041. Each 1.0 decrease in BMI z-score, risk of having low BMD was found to increase by 1.79 (%95 CI: 1.03- 3.12, p= 0.040). BMI-z-score, average serum 17-hydroxyprogesterone level, duration of treatment, average and cumulative glucocorticoid doses were not found to be correlated with BMD z-score. CONCLUSION: Long-term glucocorticoid therapy did not have negative effect on BMD of patients with CAH. Higher BMI z-score in patients with CAH may have a positive effect on preserving bone health. Precautions should be taken for increased risk of obesity.

Clinical and Molecular Analysis in 2 Families With Novel Compound Heterozygous SBP2 (SECISBP2) Mutations.

CONTEXT: Selenocysteine insertion sequence binding protein 2 (SECISBP2, SBP2) is an essential factor for selenoprotein synthesis. Individuals with SBP2 defects have characteristic thyroid function test (TFT) abnormalities resulting from deficiencies in the selenoenzymes deiodinases. Eight families with recessive SBP2 gene mutations have been reported to date. We report 2 families with inherited defect in thyroid hormone metabolism caused by 4 novel compound heterozygous mutations in the SBP2 gene. CASE DESCRIPTIONS: Probands 1 and 2 presented with growth and developmental delay. Both had characteristic TFT with high T4, low T3, high reverse T3, and normal or slightly elevated TSH. The coding region of the SBP2 gene was sequenced and analysis of in vitro translated wild-type and mutant SBP2 proteins was performed. Sequencing of the SBP2 gene identified novel compound heterozygous mutations resulting in mutant SBP2 proteins E679D and R197* in proband 1, and K682Tfs*2 and Q782* in proband 2. In vitro translation of the missense E679D demonstrated all four isoforms, whereas R197* had only 2 shorter isoforms translated from downstream ATGs, and Q782*, K682Tfs*2 expressed isoforms with truncated C-terminus. Reduction in serum glutathione peroxidase enzymatic activity was also demonstrated in both probands. CONCLUSIONS: We report 2 additional families with mutations in the SBP2 gene, a rare inherited condition manifesting global selenoprotein deficiencies. Report of additional families with SBP2 deficiency and their evaluation over time is needed to determine the full spectrum of clinical manifestations in SBP2 deficiency and increase our understanding of the role played by SBP2 and selenoproteins in health and disease.

Treatment with Depot Leuprolide Acetate in Girls with Idiopathic Precocious Puberty: What Parameter should be Used in Deciding on the Initial Dose?

Objective: Doses of gonadotropin releasing hormone (GnRH) analogues used to treat idiopathic central precocious puberty (iCPP) vary among clinicians. Study aims were to evaluate the efficacy of a monthly 3.75 mg dose of leuprolide acetate (LA) to suppress the hypothalamo-pituitary-gonadal (HPG) axis in girls with iCPP and to determine factors that may have an impact on the supressing dose. Methods: Study subjects were 220 girls receiving LA for iCPP. LA was started at a dose of 3.75 mg/28 days. Suppression was assessed using the GnRH test at the third month. To assess clinical suppression signs and symptoms of puberty were also evaluated. The dose of LA was increased to 7.5 mg/28 days in those who had a peak luteinising hormone (LH) ≥2 IU/L and in whom adequate clinical suppression of puberty was absent. Receiver operating characteristic curves were used to determine thresholds for clinical and hormonal factors affecting the suppressing dose of LA. Logistic regression analyses were used to investigate thresholds which might differentiate between those requiring high dose for suppression and those in whom lower dose LA was adequate. Results: Peak stimulated LH <2 IU/L was achieved in 88.6% with a dose of LA of 3.75 mg (0.11±0.03 mg/kg). Significant variables for differentiating the two doses were body weight (Wt) of 36.2 kg and/or body mass index (BMI)-standard deviation scores (SDS) of 1.64 (p<0.001). Multiple logistic regressions showed that Wt and BMI-SDS values above thresholds indicated requirement of LA at a dose of 7.5 mg/28 days (p<0.001). Conclusion: Monthly injections of 3.75 mg LA is an effective treatment in the majority of girls with iCPP. However, a higher initial dose may be preferred in patients with a Wt ≥36 kg or BMI-SDS ≥1.6 for effective suppression of the HPG axis.

What is the evidence for beneficial effects of growth hormone treatment beyond height in short children born small for gestational age? A review of published literature.

Background An increasing body of evidence supports the view that both an adverse intrauterine milieu and rapid postnatal weight gain in children born small for gestational age (SGA) contribute towards the risk for the development of chronic diseases in adult life. Content The aim of this review was to identify and summarize the published evidence on metabolic and cardiovascular risk, as well as risk of impaired cardiac function, intellectual capacity, quality of life, pubertal development and bone strength among children born SGA. The review will then address whether growth hormone (GH) therapy, commonly prescribed to reduce the height deficit in children born SGA who do not catch up in height, increases or decreases these risks over time. Summary Overall, there are limited data in support of a modest beneficial effect of GH therapy on the adverse metabolic and cardiovascular risk observed in short children born SGA. Evidence to support a positive effect of GH on bone strength and psychosocial outcomes is less convincing. Outlook Further evaluation into the clinical relevance of any potential long-term benefits of GH therapy on metabolic and cardiovascular endpoints is warranted.

Long-term effects of GnRH agonist treatment on body mass index in girls with idiopathic central precocious puberty.

Introduction Studies evaluating effects of gonadotropin-releasing hormone agonist (GnRHa) on weight and body-mass-index (BMI) in girls with idiopathic central precocious puberty (iCPP) include short-term effects. The aim of this study is to investigate changes in BMI during and 2 years after completion of GnRHa to determine the factors that may impact BMI in girls with iCPP. Methods Medical files of 138 girls who completed GnRHa were evaluated. All patients had weight and height measurements at the beginning and end of treatment, and 111 patients had anthropometric measurements 2 years after the completion of treatment. Results In the beginning, 82 (59.4%) had normal weight (NW), 42 (30.4%) were overweight (OW), and 14 (10.2%) were obese (OB). Analysis of BMI-standard deviation score (SDS) in the whole group showed an overall increase during GnRHa treatment (0.92 ± 0.74 vs. 1.20 ± 0.51, p < 0.001). Changes in BMI-SDS (ΔBMI-SDS) during GnRHa differed between NW and OW/OB (0.45 ± 0.31 vs. 0.03 ± 0.20, p < 0.001). BMI-SDSs of both groups returned to baseline scores (or initial levels) 2 years after the completion of treatment. Two factors affecting ΔBMI-SDS in multiple linear regression analyses were baseline BMI and Δheight-SDS, both correlated negatively with ΔBMI-SDS. Conclusions The present study is one of the studies evaluating BMI change over a long period of time in girls with CPP. Although BMI-SDS increased during GnRHa in NW girls, it was reversible in follow-up after treatment. However, BMI-SDS did not change during and in follow-up in OW/OB girls. Conserving BMI-SDS in OW/OB girls may be related to the fact that weight management programs were recommended for these patients. Dietary recommendations should be provided for children with NW who undergo GnRHa, as is the case for OW patients.