Dual-basal-insulin regimen for the management of dawn phenomenon in children with type 1 diabetes: a retrospective cohort study.

Background: Handling of the dawn phenomenon (DP) with multiple daily insulin injection (MDII) regimen is a real challenge. Objective: We aimed to demonstrate the effectiveness of a dual-basal-insulin (a long-acting glargine and an intermediate-acting neutral protamine Hagedorn (NPH)) regimen for the management of DP in children with type 1 diabetes mellitus (T1DM). The primary efficacy outcome was to overcome morning hyperglycemia without causing hypoglycemia during the non-DP period of the night. Design: Retrospective cohort study. Method: Charts of 28 children with T1DM (12 female; 42.8%, mean age 13.7 ± 2.1 years) treated with MDII were retrospectively reviewed. The median duration of diabetes was 4.5 years (range 2-13.5 years). DP was diagnosed using a threshold difference of 20 mg/dL (0.1 mmol/L) between fasting capillary blood glucose at 3 a.m. and prebreakfast. NPH was administered at midnight in addition to daily bedtime (08.00-09.00 p.m.) glargine (dual-basal-insulin regimen). Midnight, 03:00 a.m., prebreakfast and postprandial capillary blood glucose readings, insulin-carbohydrate ratios, and basal-bolus insulin doses were recorded the day before the dual-basal-insulin regimen was started and the day after the titration of the insulin doses was complete. Body mass index standard deviation scores (BMI SDS) at the onset-3rd-12th month of treatment were noted. Results: Before using dual basal insulin, prebreakfast capillary blood glucose levels were greater than those at midnight and at 03:00 a.m. (F = 64.985, p < 0.01). After titration of the dual-basal-insulin doses, there were significant improvements such that there were no statistically significant differences in the capillary blood glucose measurements at the three crucial time points (midnight, 03.00 a.m., and prebreakfast; F = 1.827, p = 0.172). No instances of hypoglycemia were reported, and the total daily insulin per kilogram of body weight did not change. The BMI SDS remained steady over the course of the 1-year follow-up. Conclusion: In this retrospective cohort study, the dual-basal-insulin regimen, using a long-acting glargine and an intermediate-acting NPH, was effective in overcoming early morning hyperglycemia due to insulin resistance in the DP. However, the effectiveness of the dual-basal-insulin regimen needs to be verified by prospective controlled studies using continuous glucose monitoring metrics or frequent blood glucose monitoring.

Early weight gain after diagnosis may have an impact on remission status in children with new-onset type 1 diabetes mellitus.

BACKGROUND: Residual beta-cell function and improvement in insulin sensitivity by reversal of glucose toxicity are two phenomena thought to be related to partial remission (PR). Body fat mass is the major determinant of insulin sensitivity. The aim of this study is to investigate the relationship between the rate of body weight gain after diagnosis of type 1 diabetes mellitus (T1DM) and other clinical factors for the development and duration of PR. METHODS: Children (2-16 years) with new-onset T1DM (n = 99) were grouped into remitters and non-remitters by using insulin dose-adjusted glycosylated hemoglobin (HbA1c) values. Laboratory and clinical data as well as daily insulin requirement per kilogram of body weight at diagnosis and each visit were recorded, and the duration of PR was determined. Changes in body mass index standard deviation score (BMI-SDS) were calculated by the auxological data collected every 6 months. RESULTS: There were 47 remitters (47.5%) and 52 (52.5%) non-remitters. The mean increase in BMI-SDS at the first 6 months of diagnosis was higher in the non-remitters than in the remitters (p = 0.04). Duration of PR was negatively correlated with the change in BMI-SDS between 6 and 12 months after diagnosis. Male sex, younger age, prepubertal status, and lower HbA1c were predictors of remission, among which male sex had the highest chance by multivariate regression. CONCLUSIONS: Early rapid weight gain after diagnosis of T1DM may play a role in the lack of remission and shorter duration of PR. Interventions to prevent early rapid weight gain can maintain the development and prolongation of remission.

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.

Case Report: Severe McCune-Albright syndrome presenting with neonatal Cushing syndrome: navigating through clinical obstacles.

Background: Café-au-lait skin macules, Cushing syndrome (CS), hyperthyroidism, and liver and cardiac dysfunction are presenting features of neonatal McCune-Albright syndrome (MAS), CS being the rarest endocrine feature. Although spontaneous resolution of hypercortisolism has been reported, outcome is usually unfavorable. While a unified approach to diagnosis, treatment, and follow-up is lacking, herein successful treatment and long-term follow-up of a rare case is presented. Clinical case: An 11-day-old girl born small for gestational age presented with deterioration of well-being and weight loss. Large hyperpigmented macules on the trunk, hypertension, hyponatremia, hyperglycemia, and elevated liver enzymes were noted. ACTH-independent CS due to MAS was diagnosed. Although metyrapone (300 mg/m2/day) was started on the 25th day, complete remission could not be achieved despite increasing the dose up to 1,850 mg/m2/day. At 9 months, right total and left three-quarters adrenalectomy was performed. Cortisol decreased substantially, ACTH remained suppressed, rapid tapering of hydrocortisone to physiological dose was not tolerated, and supraphysiological doses were required for 2 months. GNAS analysis from the adrenal tissue showed a pathogenic heterozygous mutation. During 34 months of follow-up, in addition to CS due to MAS, fibrous dysplasia, hypophosphatemic rickets, and peripheral precocious puberty were detected. She is still regularly screened for other endocrinopathies. Conclusion: Neonatal CS due to MAS is extremely rare. Although there is no specific guideline for diagnosis, treatment, or follow-up, addressing side effects and identifying treatment outcomes will improve quality of life and survival.

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.

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.

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.

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.

Adequacy of basal luteinizing hormone levels in the diagnosis of central precocious puberty.

AIM: To determine the clinical, anthropometric, and laboratory parameters that could be used for differentiating central precocious puberty from premature thelarche in girls who had breast development between the ages of 3 and 8 years. MATERIAL AND METHODS: The study included 344 girls (196 girls with idiopathic central precocious puberty, 148 girls with premature thelarche) who underwent gonadotropin- releasing hormone stimulation tests for breast development. Age at diagnosis, bone age, anthropometric measurements, basal/stimulated hormone levels were recorded. Univariate regression analysis was performed to determine the parameters that could be used for differentiating precocious puberty from premature thelarche. Significant parameters in univariate analyses were grouped according to the thresholds determined using receiver operating characteristic curves and reevaluated through multivariate analysis. RESULTS: The bone age, height-standard deviation score, body mass index-standard deviation score, and growth velocity-standard deviation score at diagnosis were found to be higher; pubertal stages were found to be more advanced; uterus and ovary volumes were found to be larger; and the basal/peak luteinizing hormone, follicle-stimulating hormone, luteinizing hormone/follicle-stimulating hormone levels were found to be higher in the subjects with precocious puberty. There was no difference between estradiol levels between the two groups. The best thresholds to differentiate the two groups were found as 0.65 IU/L (78% sensitivity, 100% specificity), 1.9 IU/L (100% sensitivity, 72% specificity), 0.25 (67% sensitivity, 100% specificity) and 1.1 (69% sensitivity, 71% specificity), respectively, for basal luteinizing hormone, follicle-stimulating hormone, luteinizing hormone/follicle-stimulating hormone ratio, and the growth velocity-standard deviation score. CONCLUSION: In girls presenting with early breast development, a basal luteinizing hormone level of ≥0.65 IU/L and a luteinizing hormone/follicle-stimulating hormone ratio of ≥0.25 are sensitive ways to demonstrate activation of the hypothalamo-pituitary-gonadal axis. Among these, the variable that gives the best sensitivity and specificity is the measurement of basal luteinizing hormone levels (≥0.65 IU/L), which can be used as a screening test in the diagnosis of central precocious puberty.

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.

Long-Term Follow-up of a Case with Proprotein Convertase 1/3 Deficiency: Transient Diabetes Mellitus with Intervening Diabetic Ketoacidosis During Growth Hormone Therapy.

Proprotein convertase 1/3 (PC1/3) deficiency is a very rare disease characterized by severe intractable diarrhea in the first years of life, followed by obesity and several hormonal deficiencies later. Diabetes mellitus requiring insulin treatment and diabetic ketoacidosis have not been reported in this disorder. We herein present a girl with PC1/3 deficiency who has been followed from birth to 17 years of age. She developed deficiencies of all pituitary hormones over time as well as diabetes mellitus while receiving growth hormone (GH) therapy. She was complicated with diabetic ketoacidosis during dietary management of diabetes mellitus, thus insulin treatment was initiated. Insulin requirement to regulate hyperglycemia was short-lived. Repeat oral glucose tolerance test five years later was normal. The findings of this patient show that diabetes mellitus can develop at any time during follow-up of cases with proportein convertase 1/3 deficiency especially under GH therapy.

Clinical and laboratory parameters predicting a requirement for the reevaluation of growth hormone status during growth hormone treatment: Retesting early in the course of GH treatment.

OBJECTIVE: We aimed to define the predictive criteria, in the form of specific clinical, hormonal and radiological parameters, for children with growth hormone deficiency (GHD) who may benefit from the reevaluation of GH status early in the course of growth hormone (GH) treatment. DESIGN AND METHODS: Two hundred sixty-five children with growth hormone deficiency were retested by GH stimulation at the end of the first year of GH treatment. The initial clinical and laboratory characteristics of those with a normal (GH≥10ng/ml) response and those with a subnormal (GH<10ng/ml) response were compared to predict a normal GH status during reassessment. RESULTS: Sixty-nine patients (40.6%) out of the 170 patients with isolated growth hormone deficiency (IGHD) had a peak GH of ≥10ng/ml during the retest. None of the patients with multiple pituitary hormone deficiency (MPHD) had a peak GH of ≥10ng/ml. Puberty and sex steroid priming in peripubertal cases increased the probability of a normal GH response. Only one patient with IGHD who had an ectopic posterior pituitary without stalk interruption on MRI analysis showed a normal GH response during the retest. Patients with a peak GH between 5 and 10ng/ml, an age at diagnosis of ≥9years or a height gain below 0.61 SDS during the first year of treatment had an increased probability of having a normal GH response at the retest. CONCLUSION: Early reassessment of GH status during GH treatment is unnecessary in patients who have MPHD with at least 3 hormone deficiencies. Retesting at the end of the first year of therapy is recommended for patients with IGHD who have a height gain of <0.61 SDS in the first year of treatment, especially those with a normal or 'hypoplastic' pituitary on imaging. Priming can increase the likelihood of a normal response in patients in the pubertal age group who do not show overt signs of pubertal development.

Novel and prevalent CYP11B1 gene mutations in Turkish patients with 11-ß hydroxylase deficiency.

11ß-Hydroxylase deficiency is the second most frequent type of congenital adrenal hyperplasia and is more common in those of Turkish descent than in other populations. The purpose of this study is to examine the spectrum of CYP11B1 gene mutations in Turkish patients with 11ß-hydroxylase deficiency. Twenty-eight patients from 24 families, ages ranging from 0.1 to 7 years, were included in the study. Clinical diagnosis was based on virilization and high levels of 11-deoxycortisol. Twenty-six cases exhibited the classical and 2 cases the non-classical form. Mutation screening of 9 CYP11B1 exons was performed by direct DNA sequence analysis, specifically amplifying CYP11B1 gene fragments while avoiding simultaneous amplification of homologous CYP11B2 gene sequences. Seventeen different mutations were detected, 6 of which are novel (p.Gln189Hisfs*70, p.Glu198Gly, p.Thr318Lys, p.Gly446Ser, IVS8+5G>C and exon 3-5 del). All of the identified mutations resulted in the classical form with severe virilization, except for the p.Gly446Ser mutation, which caused a late-onset type of 11ß-hydroxylase deficiency. The c.954G>A;p.Thr318Thr mutation was the most common in our cohort, with an allele frequency of 14.6%.Of the CYP11B1 gene mutations detected, 75% were found in exons 3, 5 and 7 and the half of the mutations were nonsense, splice site, deletion or insertion mutations, causing severe virilization in female patients. The findings are important for genetic counseling and the prenatal diagnosis of Turkish patients with 11ß-hydroxylase deficiency.

Variable Phenotype of Diabetes Mellitus in Siblings with a Homozygous PTF1A Enhancer Mutation.

Neonatal diabetes is a rare form of diabetes, characterized by onset in the first 6 months of life. A number of cases are due to pancreas agenesis. Recently, PTF1A enhancer mutations have been shown to cause neonatal diabetes associated with pancreatic agenesis. Herein, we report the clinical features of two siblings with PTF1A enhancer mutations, one of whom had neonatal diabetes, whereas the elder sister had a milder form of the disease with onset of diabetes at 9 years of age.

Changing Etiological Trends in Male Precocious Puberty: Evaluation of 100 Cases with Central Precocious Puberty over the Last Decade.

BACKGROUND/AIMS: There are few studies in the literature that have evaluated the etiological factors in boys with central precocious puberty (CPP), and these studies are limited in terms of the sample size. In the present study, we aimed to evaluate the etiological factors in male CPP cases. METHODS: One hundred male CPP subjects, aged between 9 months and 10.5 years, were included. The medical records were screened, and age at diagnosis, bone age, body weight, height, pubertal stage, imaging findings of the pituitary gland, testosterone, and basal and stimulated gonadotropin levels were recorded. RESULTS: There was no underlying cause in 74% of the cases, and an organic cause was determined in only 26%. Most of the organic cases had been diagnosed before the age of 7 years, whereas most of the idiopathic cases had been diagnosed after the age of 7 years. CONCLUSION: An organic cause was determined in 26% of the male patients with CPP. This rate is one of the lowest rates in the literature and indicates that the number of idiopathic male CPP cases is increasing over time. When a boy is diagnosed with CPP above the age of 7 years, the odds of detecting an underlying pathology are very low, and these cases are mostly idiopathic.

A rare but important adverse effect of tacrolimus in a heart transplant recipient: diabetic ketoacidosis.

Heart transplantation indications in pediatric population include congenital heart diseases, cardiomyopathies and retransplants. Cardiomyopathy is the primary indication for 11 to 17 years of age. The surveillance after transplantation is a very important issue because of both the rejection risk and the adverse effects due to medications after transplantation. Immunosuppressive agents that are commonly used after heart transplantations have several toxicities. Here we present an adolescent patient diagnosed with dilated cardiomyopathy, performed heart transplantation, treated with tacrolimus and suffered from diabetic ketoacidosis due to tacrolimus. After the diagnosis was made the appropriate fluid and insulin therapy was started immediately and ketoacidosis resolved in the first 24 hours of the therapy. The diagnosis revised as new onset diabetes mellitus after transplantation and the tacrolimus dosage titrated to therapeutic level. After glycemic control the patient discharged with rapid acting insulin, three times daily, before meals; and long acting insulin once daily at night. In ten month follow up time the insulin dosages were progressively reduced.

Need for comprehensive hormonal workup in the management of adrenocortical tumors in children.

OBJECTIVE: Clinical findings do not reflect the excess hormonal status in adrenocortical tumors (ACTs) in children. Identification of abnormal hormone secretion may help provide the tumor marker and delineate those patients with a risk of adrenal suppression following tumor removal. To analyze the impact of complete hormonal assessment regardless of the clinical presentation in hormone-secreting ACTs in childhood. METHODS: Association of hormonal workup at diagnosis with the clinical findings and frequency of adrenal suppression postoperatively were analyzed in 18 children with ACT. RESULTS: Seventeen of the 18 patients had functional ACT. Clinical findings suggested isolated virilization and isolated Cushing's syndrome in 38.8% and 17.6% of patients, respectively. Hormonal workup revealed a frequency of 83.3% for hyperandrogenism. The majority of the tumors (50%) had mixed type hormonal secretion. Hypercortisolism existed in 28.5% of children with isolated virilization and hyperandrogenism was found in 2/3 of children with isolated Cushing's syndrome. Various androgens other than dehydroepiandrosterone sulfate were also determined to be high in hyperandrogenism. Increased testosterone was a highly prevalent tumor marker. Nine patients (3 with no signs of hypercortisolism) had adrenal suppression following tumor removal which lasted 1-24 months. CONCLUSION: Complete hormonal workup showed the predominance of mixed hormone-secreting type of tumor in the patients who lacked the appropriate clinical findings and also showed that patients lacking signs of Cushing's syndrome could have postoperative adrenal suppression. Clinical findings may not reflect the abnormal hormone secretion in all cases and tumor markers as well as risk of postoperative adrenal suppression can best be determined by complete hormonal evaluation at the time of diagnosis.

HNF1B mutation in a Turkish child with renal and exocrine pancreas insufficiency, diabetes and liver disease.

A small-for-gestational age female infant presented with bilateral hypoplastic kidneys at 3 months of age. She developed chronic renal insufficiency. Insulin-requiring, non-autoimmune diabetes was documented at 6 years of age. She had mild steatosis and iron deposition in the liver, and mal-development of pancreas. Genetic studies revealed a heterozygous mutation (S148L) of the HNF1B gene, compatible with an HNF1B-MODY phenotype (MODY5). This is the first case of HNF1B-MODY reported from Turkey and represents a particularly severe phenotype of the disease.