Clinical and Laboratory Characteristics of MODY (Maturity Onset Diabetes of Young) Cases, Genetic Mutation Spectrum and Phenotype-genotype Relationship.

Objective: Maturity-onset diabetes of the young (MODY) occurs due to mutations in genes involved in pancreatic beta cell function and insulin secretion, has heterogeneous clinical and laboratory features, and account for 1-5% of all diabetes cases. The prevalence and distribution of MODY subtypes vary between countries. The aim of this study was to evaluate the clinical and laboratory characteristics, mutation distribution, and phenotype-genotype relationship in a large case series of pediatric Turkish patients genetically diagnosed with MODY. Methods: MODY cases from 14 different pediatric endocrinology departments were included. Diagnosis, treatment, follow-up data, and results of genetic analysis were evaluated. Results: A total of 224 patients were included, of whom 101 (45%) were female, and the mean age at diagnosis was 9.4±4.1 years. Gene variant distribution was: 146 (65%) GCK; 43 (19%) HNF1A; 8 (3.6%) HNF4A, 8 (3.6%) KLF11 and 7 (3.1%) HNF1B. The remaining 12 variants were: PDX (n=1), NEUROD1 (n=3), CEL (n=1), INS (n=3), ABCC8 (n=3) and KJNC11 (n=1). Of the cases, 197 (87.9%) were diagnosed with incidental hyperglycemia, 16 with ketosis (7%) and 7 (3%) with diabetic ketoacidosis (DKA), while 30% presented with classical symptoms of diabetes. Two-hundred (89%) had a family history of diabetes. Anti-GAD antibody was detected in 13 cases, anti-islet antibody in eight and anti-insulin antibody in four. Obesity was present in 16. Distribution of therapy was: 158 (71%) diet only; 23 (11%) intensive insulin treatment; 17 (7.6%) sulfonylureas; 10 (4.5%) metformin; and 6 (2.7%) insulin and oral antidiabetic treatment. Conclusion: This was the largest genetically diagnosed series from Turkey. The most common gene variants were GCK and HNF1A with much lower proportions for other MODY types. Hyperglycemia was the most common presenting symptom while 11% of patients had diabetes-associated autoantibodies and 7% were obese. The majority of patients received dietary management only.

Adherence to Growth Hormone Treatment in Children During COVID-19 Pandemic

Objective: Treatment adherence is crucial for the success of growth hormone (GH) therapy. Reported nonadherence rates in GH treatment have varied widely. Several factors may have an impact on adherence. Apart from these factors, the global impact of the COVID-19 pandemic, including problems with hospital admission and routine follow-up of patients using GH treatment, may have additionally affected the adherence rate. The primary objective of this study was to investigate adherence to treatment in patients receiving GH. In addition, potential problems with GH treatment during the pandemic were investigated. Materials and Methods: This was a multicenter survey study that was sent to pediatric endocrinologists in pandemic period (June 2021-December 2021). Patient data, diagnosis, history of pituitary surgery, current GH doses, duration of GH therapy, the person administering therapy (either parent/patient), duration of missed doses, reasons for missed doses, as well as problems associated with GH therapy, and missed dose data and the causes in the recent year (after the onset of the pandemic) were queried. Treatment adherence was categorized based on missed dose rates over the past month (0 to 5%, full adherence; 5.1 to 10% moderate adherence; >10% nonadherence). Results: The study cohort consisted of 427 cases (56.2% male) from thirteen centers. Median age of diagnosis was 8.13 (0.13-16) years. Treatment indications were isolated GH deficiency (61.4%), multiple pituitary hormone deficiency (14%), Turner syndrome (7.5%), idiopathic GH deficiency (7.5%), small for gestational age (2.8%), and "others" (6.8%). GH therapy was administered by parents in 70% and by patients in 30%. Mean daily dose was 32.3 mcg/kg, the annual growth rate was 1.15 SDS (min -2.74, max 9.3). Overall GH adherence rate was good in 70.3%, moderate in 14.7%, and poor in 15% of the patients. The reasons for nonadherence were mainly due to forgetfulness, being tired, inability to access medication, and/or pen problems. It was noteworthy that there was a negative effect on adherence during the COVID-19 pandemic reported by 22% of patients and the main reasons given were problems obtaining an appointment, taking the medication, and anxiety about going to hospital. There was no difference between genders in the adherence rate. Nonadherence to GH treatment decreased significantly when the patient: administered the treatment; was older; had longer duration of treatment; and during the pandemic. There was a non-significant decrease in annual growth rate as nonadherence rate increased. Conclusion: During the COVID-19 pandemic, the poor adherence rate was 15%, and duration of GH therapy and older age were important factors. There was a negative effect on adherence during the pandemic period.

Effect of Adrenocorticotropic Hormone Stimulation on Ischemiamodified Albumin Levels in vivo

Objective: Ischemia-modified albumin (IMA) formation is associated with increased reactive oxygen species (ROS) production, while increased cortisol leads to decreased ROS levels. We aimed to evaluate the effect of adrenocorticotropic hormone (ACTH) stimulation on IMA levels and whether the effect was dose-dependent or not. Methods: A total of 99 subjects with normal ACTH test results were included in the study. Of these, 80 had standard-dose ACTH test while 19 had low-dose ACTH test. Blood samples were collected to determine cortisol and IMA levels; at minutes 0, 30, and 60 following the standard-dose ACTH test and at minutes 0 and 30 following the low-dose ACTH test. Results: IMA levels decreased significantly within 30 minutes and the decrease continued up to the sixtieth minute (p=0.002) after standard-dose ACTH stimulation. After ACTH stimulation, a weak negative correlation was found between peak cortisol and IMA levels at the thirtieth minute (r=0.233, p=0.02). There was no significant difference in IMA levels after low-dose ACTH stimulation, despite an increase in cortisol (p=0.161). Conclusion: IMA levels decreased rapidly after standard-dose ACTH stimulation, while a decrease in IMA levels was not observed after low-dose ACTH stimulation. The lack of decrease in IMA levels after low-dose ACTH stimulation suggests a possible dose-dependent relationship between ACTH and IMA. The moderate increase in cortisol with no reduction in IMA levels after low-dose ACTH stimulation and the weak correlation between peak cortisol and 30-minute IMA levels after standard-dose ACTH stimulation suggest that ACTH may have a direct effect on IMA.

3M syndrome: Evaluating the clinical and laboratory features and the response of the growth hormone treatment: Single center experience.

INTRODUCTION & OBJECTIVE: 3 M Syndrome is a rarely encountered autosomal recessive syndrome characterized by low birth weight, severe postnatal growth deficiency, and minor dysmorphic abnormalities. 3 M-related short stature has been attributed to the resistance to growth hormone (GH) to a certain extent rather than to GH deficiency. The resistance to GH, on the other hand, has been associated with impaired protein scaffolding, transport, and p53-mediated apoptosis at the IGF-1 post-receptor pathway. In this context, the objective of this study is to evaluate the clinical, laboratory, and genetic characteristics of the patients with 3 M syndrome, detect the mutations frequently observed in these patients, and assess their response to GH treatment. MATERIAL&METHODS: The sample of this single-center study consisted of patients diagnosed with 3 M syndrome based on genetic tests between 2007 and 2021. Patients' clinic, laboratory, and genetic characteristics pertaining to the time of admission and follow-up were recorded. All patients except one underwent a growth hormone stimulation test (GHST) (Levo-dopa or insulin tolerance test). Insulin-like growth factor (IGF) generation test was performed on those with sufficient GHST results (0.1 mg/kg/day for four days). RESULTS: The median age of the patients, five females and three males, was 2.8 (0.25-8.12) years at admission. All but one patient were small for gestational age (SGA). The patient with normal birth weight was the baby of a diabetic mother. Obscurin-like 1 (OBSL1) variant was detected in all cases. The median height standard deviation score (SDS) at admission was -4.94 ((-5.63)- (-3.27)) SDS, and the median midparenteral height SDS was -1.27 SDS ((-3.1)- (0.34)). All patients were prepubertal at admission. The GHST response was sufficient in five cases. IGF generation test was performed in three cases. Seven patients received GH therapy (35-57 µg/kg/day). Five of these patients discontinued GH therapy since their growth velocity (GV) fell below normal during treatment. In addition, one case discontinued GH therapy because her IGF-1 value was>2 SDS, and another case received gonadotropin-releasing hormone (GnRH) analogs together with GH therapy. The median age and height SDS of the patients were 10.1 (1.79-18) years and -5.09 SDS ((-7.11)- (2.45)), respectively, as of the last follow-up visit. The height SDS values of the two cases that reached the final height were -7.11 SDS and -3.39 SDS. There were no side effects of GH treatment. CONCLUSION: The study findings indicated a good GV during the early stages of the long-term GH treatment administered to patients with 3 M syndrome. However, response to GH therapy decreased in the following years, and the desired improvement in height SDS could not be achieved in patients who reached their final heights. Taken together with the literature data, it has been concluded that initiating GH therapy in the prepubertal period provided better outcomes than after puberty.

The Level of Inflammatory Markers and Their Relationship with Fat Tissue Distribution in Children with Obesity and Type 2 Diabetes Mellitus.

OBJECTIVE: This study aimed to determine the changes in proinflammatory and anti-inflam- matory markers in children aged 10-18, who were not diagnosed with type 2 diabetes mel- litus, were obese/overweight, and children with type 2 diabetes mellitus. In addition, we aimed to investigate whether these markers were associated with clinical and laboratory parame- ters, subcutaneous adipose tissue, preperitoneal adipose tissue, visceral adipose tissue, and hepatosteatosis. MATERIALS AND METHODS: Children between the ages of 10 and 18, obese/overweight, with type 2 diabetes mellitus, and with a normal body mass index were included. Fat tissue thick- ness was measured. Tumor necrosis factor-α, interleukin-1ß, interleukin-6, interleukin-18, and interferon-γ as proinflammatory markers and transforming growth factor-ß and interleukin-10 levels as anti-inflammatory markers were studied. RESULTS: Twenty-eight (31.8%) controls, 44 (50%) obese/overweight, and 16 (18.2%) patients with type 2 diabetes mellitus were included in our study. Age, sex, and puberty were similar between the groups. In the type 2 diabetes mellitus group, the subcutaneous fat tissue thick- ness was higher than that in the obese group, and the preperitoneal and visceral fat tissue thicknesses were similar to those in the obese group. Proinflammatory markers and interleu- kin-10 levels were similar in the obese/overweight, type 2 diabetes mellitus, and control groups. Transforming growth factor-ß levels were significantly lower in the type 2 diabetes mellitus group than in the control group (P = .039). Transforming growth factor-ß levels and other labo- ratory variables did not differ significantly in the type 2 diabetes mellitus group. CONCLUSION: While there was no change in all markers in the obese/overweight group com- pared with the control group, proinflammatory markers in the type 2 diabetes mellitus group were similar to those in the obese/overweight and control groups, and transforming growth factor-ß level, an anti-inflammatory marker, was lower in the type 2 diabetes mellitus group than in the control group.

Unfavorable Effects of Low-carbonhydrate Diet in a Pediatric Patient with Type 1 Diabetes Mellitus

A balanced and healthy diet is very important in type 1 diabetes mellitus (T1DM) in childhood. In addition to regulating blood glucose with diet, diet should also support optimal growth. Low-carbohydrate diet aims to provide daily energy from fats and was originally used for childhood epilepsy. We present a patient with T1DM who experienced unfavorable effects when on a low-carbohydrate diet.

Hemolytic Anemia due to Glucose 6 Phosphate Dehydrogenase Deficiency Triggered by Type 1 Diabetes Mellitus

Glucose 6 phosphate dehydrogenase (G6PD) is expressed in all tissues and is necessary to maintain oxidant stress capacity of cells. G6PD deficiency is the most common enzymopathy in humans and is among the important causes of hemolytic anemia. It has been reported that severe hemolytic anemia due to G6PD deficiency may develop in newly diagnosed diabetes, especially during the correction of hyperglycemia. To date, nine cases have been published. Genetic analysis was not performed for G6PD deficiency in these published patients. We present a case of hemolytic anemia due to G6PD deficiency secondary to newly diagnosed type 1 diabetes mellitus. Genetic testing was performed for the index patient and revealed a previously reported missense pathogenic variant (c.653C>T; p.Ser218Phe) in the G6PD gene.

Genotype of congenital adrenal hyperplasia patients with testicular adrenal rest tumor.

Testicular adrenal rest tumor (TART) is one of the important complications that can cause infertility in male patients with congenital adrenal hyperplasia (CAH) and should therefore be diagnosed and treated at an early age. The factors that result in TART in CAH have not been completely understood. The aim of this study is to evaluate the genotype-phenotype correlation in CAH patients with TART. METHOD: Among 230 malepatients with CAH who were followed upwith regular scrotal ultrasonography in 11 different centers in Turkey, 40 patients who developed TARTand whose CAH diagnosis was confirmed by genetic testing were included in this study. Different approaches and methods were used for genotype analysis in this multicenter study. A few centers first screened the patients for the ten most common mutations in CYP21A2 and performed Sanger sequencing for the remaining regions only if these prior results were inconclusive while the majority of the departments adopted Sanger sequencing for the whole coding regions and exon-intron boundaries as the primary molecular diagnostic approach for patients with either CYP21A2 orCYP11B1 deficiency. The age of CAH diagnosis and TART diagnosis, type of CAH, and identified mutations were recorded. RESULTS: TART was detected in 17.4% of the cohort [24 patients with salt-wasting (SW) type, four simple virilizing type, and one with nonclassical type with 21-hydroxylase (CYP21A2) deficiency and 11 patients with 11-beta hydroxylase (CYP11B1) deficiency]. The youngest patients with TART presenting with CYP11B1 and CYP21A2 deficiency were of 2 and 4 years, respectively. Eight different pathogenic variants in CYP21A2were identified. The most common genotypes were c.293-13C>G/c.293-13C>G (31%) followed by c.955C>T/c.955C>T(27.6%) and c.1069C>T/c.1069C>T (17.2%). Seven different pathogenic variants were identified in CYP11B1. The most common mutation in CYP11B1 in our study was c.896T>C (p.Leu299Pro). CONCLUSION: We found that 83% TART patients were affected with SW typeCYP21A2 deficiency,and the frequent mutations detected were c.955C>T (p.Gln319Ter), c.293-13C>G in CYP21A2 and c.896T>C (p.Leu299Pro) inCYP11B1. Patients with CYP11B1 deficiency may develop TART at an earlier age. This study that examined the genotype-phenotype correlation in TART may benefit further investigations in larger series.

Stress Induced Hyperglycemia in Early Childhood as a Clue for the Diagnosis of NEUROD1-MODY

Maturity-onset diabetes of young 'MODY' Type 6 is a rare form of monogenic diabetes caused by mutations in Neuronal differentiation 1 (NEUROD1). Clinical features vary in a large spectrum in terms of age and BMI at diagnosis. Here, we reported the youngest patient with a NEUROD1 variant to the best of our knowledge. A 2.1-year-old girl was referred to pediatric endocrinology clinic for elevated fasting blood glucose (BG) (104 mg/dL) which was detected at another center where she had been evaluated for loss of appetite. Her maternal aunt and uncle had been diagnosed with type 2 diabetes mellitus (DM) at the age of 40 and 45 years; they were obese (BMI: 30.2 and 30.6 kg/m2). At the age of 3.7 years old, she was hospitalized for buccal cellulitis and plasma glucose concentration was 239 mg/dL at admission. Targeted next-generation sequencing (NGS) was performed considering the stress induced hyperglycemia without serious illness, negative islet cell antibodies and insulin autoantibodies, age at the presentation, and family history of DM. NGS analysis revealed a previously reported heterozygous missense variant in NEUROD1. Segregation studies showed that the identified variant was inherited from her 44-year-old mother with a BMI of 27.2 kg/m2 and a normal oral glucose tolerance test (OGTT). Heterozygous NEUROD1 mutations cause low-penetrant diabetes that is heterogeneous in terms of clinical features as some patients fulfill the classic MODY definition and others are mimicking type 2 DM. Clinical manifestations and family history should be carefully evaluated in patients with stress induced hyperglycemia to identify candidate cases for molecular testing, and proper follow-up should be initiated in affected individuals.

Status of Central Precocious Puberty Cases at the Onset of Coronavirus Disease 2019 Pandemic: A Single-Center Experience.

OBJECTIVE: The onset of puberty in children is occurring at an increasingly earlier ages. During the coronavirus 2019 pandemic, children experienced epidemic-related changes such as stress, sedentary lifestyle, and weight gain. MATERIALS AND METHODS: Auxological, clinical, endocrinological, and radiological data in the files of 57 patients who were given gonadotropin-releasing hormone analog therapy with the diagnosis of central precocious puberty between April 1 and July 1, 2019 (group 1) and April 1 and July 1, 2020 (group 2) were analyzed retrospectively. RESULTS: A total of 27 patients (26 girls, 1 boy) in group 1 and 30 patients (28 girls, 2 boys) in group 2 were diagnosed with central precocious puberty. Mean ages at diagnosis for groups 1 and 2 were 28.54 ± 0.94 and 7.92 ± 0.96 years, respectively (P = .018). Mean bone age at diagnosis for group 1 was 9.78 ± 1.48 (6.8-12), and for group 2 it was 8.78 ± 1.11 (6.5-12) years (P = .013). The mean age of starting treatment in groups 1 and 2 was 8.94 ± 0.17 (6.8-9.8) and 8.07 ± 0.02 (5.8-10) years, respectively (P = .002). Average birth weights for groups 1 and 2 were 950 ± 1100 (2300-3400) and 3180 ± 717 (870-3820) g, respectively (P = .012). Treatment was started when breast stage was T3 in 57.69% of group 1 and T2 in 75% of group 2, and a statistical difference was found between them (P = .006) and uterine length was higher in group 2 (P = .144). CONCLUSION: During the coronavirus 2019 pandemic, patients who start central precocious puberty therapy were of younger age. In our single-center experience, coronavirus 2019 was not seen to have a significant impact on central precocious puberty.

Evaluation of permanent and transient congenital hypothyroidism in cases referred from National Neonatal Screening Program.

AIM: The incidence of congenital hypothyroidism (CH) has increased world-wide. Lowering cut-off in screening programs has led to an increase in the rate of transient CH. We aimed to evaluate the rates of permanent and transient CH in cases referred from the screening program and to investigate the clinical and laboratory factors which predict transient CH. METHODS: In 109 cases referred from the neonatal screening program to our hospital, from September 2015 to April 2018, 52 primarily diagnosed CH cases were prospectively evaluated. Regularly followed up, 44 CH cases were included in the study at the end of 3 years. RESULTS: 38.2 ± 1.31 weeks (w) and mean birthweight 3021.3 ± 389.6 gram (g) in the transient CH group; both were significantly lower compared to permanent CH cases with 39.06 ± 1.33 w and 3375.3 ± 425.3 g (P = 0.025, P = 0.007) respectively. Transient CH rate was found to be 50% (all hypoplastic) in the dysgenesis group and 73.3% in groups with normal and hyperplasic thyroid gland. While fT4 , thyroid-stimulating hormone, and thyroglobulin levels at diagnosis do not predict transient/permanent CH, levothyroxine (LT-4) dosage was significantly lower in the transient CH group in all years. The optimal cut-off value with highest sensitivity and specificity for LT-4 dosage as a predictive marker to differentiate transient CH from permanent CH was 2.27 µg/kg/day (P = 0.004; sensitivity: 71%, specificity: 83%) at 1st year, 1.85 µg /kg/day (P = 0.013; sensitivity: 66%, specificity: 72%) at 2nd year and 1.69 µg /kg/day at 3rd year (P < 0.0001; sensitivity: 90%, specificity: 83%). CONCLUSION: Transient CH is more frequent than expected. Our results suggest that LT-4 requirement may be a good marker for predicting transient CH, while thyroid hormone levels at the time of diagnosis do not significantly predict permanent and transient CH. Therefore, infants with CH requiring LT-4 doses <2.27 µg/kg/day at 1st year, <1.85 µg /kg/day at 2nd year may be re-evaluated earlier to discriminate transient CH rather than at 3 years of age.

A major health problem facing immigrant children: nutritional rickets.

OBJECTIVES: Nutritional rickets (NR) is still an important problem and one which increasing influxes of immigrants are further exacerbating. This study evaluated cases of mostly immigrant children followed up with diagnoses of NR in our pediatric endocrinology clinic. METHODS: Details of 20 cases diagnosed with NR between 2017 and 2020 were retrieved from file records. RESULTS: Twenty (11 male) cases were included in the study. Three (15%) were Turkish nationals and the others (85%) were immigrants. Hypocalcemia and hypophosphatemia were detected in 17 and 13, respectively. Alkaline phosphatase (ALP) values were normal in two cases, while ALP and parathyroid hormone (PTH) values were elevated in all other cases, and PTH levels were very high (473.64 ± 197.05 pg/mL). 25-hydroxyvitamin D levels were below 20 ng/mL in all cases. Patients with NR received high-dose long-term vitamin D or stoss therapy. Six patients failed to attend long-term follow-up, while PTH and ALP levels and clinical findings improved at long-term follow-up in the other 14 cases. CONCLUSIONS: The elevated PTH levels suggest only the most severe cases of NR presented to our clinic. Clinically evident NR is therefore only the tip of the iceberg, and the true burden of subclinical rickets and osteomalacia remains unidentified. Public health policies should therefore focus on universal vitamin D supplementation and adequate dietary calcium provision, their integration into child surveillance programs, adequate advice and support to ensure normal nutrition, exposure to sunlight, and informing families of the increased risk not only for resident populations but also for refugee and immigrant children.

Recommendations for Clinical Decision-making in Children with Type 1 Diabetes and Celiac Disease: Type 1 Diabetes and Celiac Disease Joint Working Group Report

It is well-known that in children with type 1 diabetes (T1D), the frequency of Celiac disease (CD) is increased due to mechanisms which are not fully elucidated but include autoimmune injury as well as shared genetic predisposition. Although histopathologic examination is the gold standard for diagnosis, avoiding unnecessary endoscopy is crucial. Therefore, for both clinicians and patients' families, the diagnosis of CD remains challenging. In light of this, a joint working group, the Type 1 Diabetes and Celiac Disease Joint Working Group, was convened, with the aim of reporting institutional data and reviewing current international guidelines, in order to provide a framework for clinicians. Several controversial issues were discussed: For CD screening in children with T1D, regardless of age, it is recommended to measure tissue transglutaminase-immunoglobulin A (tTG-IgA) and/or endomysial-IgA antibody due to their high sensitivity and specificity. However, the decision-making process based on tTG-IgA titer in children with T1D is still debated, since tTG-IgA titers may fluctuate in children with T1D. Moreover, seronegativity may occur spontaneously. The authors' own data showed that most of the cases who have biopsy-proven CD had tTG-IgA levels 7-10 times above the upper limit. The decision for endoscopy based solely on tTG-IgA levels should be avoided, except in cases where tTG-IgA levels are seven times and above the upper limit. A closer collaboration should be built between divisions of pediatric endocrinology and gastroenterology in terms of screening, diagnosis and follow-up of children with T1D and suspicious CD.

Mild phenotype in two siblings with a missense GHR variant.

OBJECTIVES:  Laron syndrome (LS) is a disease caused by growth hormone receptor (GHR) defects. It is characterized by severe postnatal growth retardation and distinctive facial features. CASE PRESENTATION: In this case report, we describe the clinical and biochemical characteristics of two siblings with LS, a sister and a brother, and identify a homozygous c.344A> C (p.Asn115Thr) variant in GHR. The sister was 11 years 9 months old with a height of 127.5 cm (-3.86 SDS), and the brother was 14 years 10 months old with a height of 139 cm (-4.27 SDS). Their phenotype did not have features suggesting classical LS. CONCLUSION: In the current literature, there are three cases with the same missense variant. Our cases differ from them in clinical (higher height SDS, mild dysmorphism including a broad forehead, malar hypoplasia, prominent columella and chin, thick lips) and biochemical characteristics. Here, we present the variable expressivity in the two siblings.

Perinatal outcomes of high-dose vitamin D administration in the last trimester

In recent years, interest in the evaluation of vitamin D levels and the possible outcomes of their deficiency during pregnancy has increased. However, there is no consensus on when to start vitamin D supplementation, its duration, dosage, and the optimum level during pregnancy. The toxicity of vitamin D is as important as its deficiency. From the history of a 5-day-old male baby who was investigated for hypercalcemia, it was learned that the mother took 300,000 IU vitamin D-five ampoules/oral at 30 weeks of gestation every other day. The infant was born prematurely, postpartum bradycardia required positive pressure ventilation, and his hypercalcemia lasted approximately 4 months despite treatment. Maternal excessive and inappropriate use of vitamin D can cause preterm labor and severe hypercalcemia, which is a life-threatening complication in the neonatal period. This case is presented to draw attention to the negative effects of maternal high-dose vitamin D during pregnancy.

A case of prohormone convertase deficiency diagnosed with type 2 diabetes.

Prohormone convertase 1/3, encoded by the proprotein convertase subtilisin/kexin type 1 gene, is essential for processing prohormones; therefore, its deficiency is characterized by a deficiency of variable levels in all hormone systems. Although a case of postprandial hypoglycemia has been previously reported in the literature, prohormone convertase insufficiency with type 2 diabetes mellitus has not yet been reported. Our case, a 14-year-old girl, was referred due to excess weight gain. She was diagnosed as having type 2 diabetes mellitus based on laboratory test results. Prohormone convertase deficiency was considered due to the history of resistant diarrhea during the infancy period and her rapid weight gain. Proinsulin level was measured as >700 pmol/L(3.60-22) during diagnosis. In genetic analysis, a c.685G> T(p.V229F) homozygous mutation in the PCSK1 gene was detected and this has not been reported in relation to this disorder. In conclusion, patients with recurrent resistant diarrhea during infancy followed by rapid weight gain need to be evaluated with the diagnosis of prohormone convertase deficiency.

Is Bioavailable Vitamin D Better Than Total Vitamin D to Evaluate Vitamin D Status in Obese Children?

Introduction: Free hormones are biologically more active in target tissues. Thus, measurement of vitamin D taking into account bioavailability and free vitamin D may be preferable, especially when evidence is contradictory, as in obese children. In order to assess bioavailablity and free vitamin D, using a previously reported formula, vitamin D-binding protein (VDBP) level was measured and VDBP polymorphisms were also evaluated because of variations in binding affinity. Methods: Eighty-four obese and 78 healthy children were included. Anthropometry, calcium, phosphorus, alkaline-phosphatase, parathyroid hormone (PTH), 25 hydroxyvitamin D [25(OH)D], bioavailable-free vitamin D, and VDBP concentration and polymorphism were evaluated in the whole group. Results: Obese girls had significantly higher PTH than normal weight girls (p=0.001). Regardless of gender, obese children had significantly higher concentrations of VDBP (p=0.008) and PTH (p=0.002). When samples taken in winter were analyzed, PTH and VDBP were found to be higher and bioavailable and free vitamin D lower in the obese group. There was no difference in terms of total vitamin D between groups during the winter season. Conclusion: While total, free, and bioavailable vitamin D in the obese group was similar to the control group in autumn, free and bioavailable vitamin D in the winter was lower in the obese than the control group. In addition, PTH was higher in the obese group in both autumn and winter. Therefore, more research is needed to evaluate the variability of free and bioavailable vitamin D according to body habitus, season and the effect any differences may have.

Evaluation of the pathophysiological role of Fetuin A levels in adolescents with polycystic ovary syndrome.

OBJECTIVES: Polycystic ovary syndrome (PCOS) is an endocrinopathy, in which hyperandrogenism and hyperinsulinism have both occurred. Fetuin-A, a natural inhibitor of tyrosine kinase, leads to insulin resistance. The aim was to evaluate the relationship between fetuin-A and hyperandrogenism and hyperinsulinism and the role of fetuin-A in the pathophysiology of PCOS. METHODS: Thirty-eight cases with PCOS and 40 healthy adolescents were included in the study. PCOS and controls were divided into obese/non-obese subgroups. LH, FSH, total and free testosterone (TT, FT), SHBG, androstenedione, DHEAS were measured in patients with PCOS. Fasting glucose, insulin, lipid profile, AST, ALT, HsCRP, and fetuin levels of PCOS patients and healthy controls were also measured. RESULTS: Fetuin-A levels were higher in PCOS patients than in controls. In the obese-PCOS group, when compared to non-obese PCOS patients; the levels of SHBG and HDL were low while cholesterol, LDL, triglyceride, HOMA-IR, FT, FAI, and HSCRP levels were high, but Fetuin-A levels were similar. In the obese-PCOS group, fetuin-A levels were higher than in obese-controls. HOMA-IR and fetuin-A levels were higher in non-obese PCOS patients than in non-obese controls. In the PCOS group, fetuin-A was positively correlated with TT, FT, FAI and androstenedione and negatively correlated with SHBG. Regression analysis demonstrated that FT, SHBG, and androstenedione significantly predicted fetuin-A levels (R2=54%). In non-obese PCOS patients and controls, fetuin-A was positively correlated with insulin and HOMA-IR. CONCLUSIONS: These results suggest a relationship between androgen levels and fetuin-A in PCOS cases, independent of insulin resistance, and may shed light on further studies.

Evaluation of Growth Hormone Results in Different Diagnosis and Trend Over 10 Year of Follow-up: A Single Center Experience

Objective: The aim was to evaluate the results of diagnosis, follow-up and treatment of the patients who recieved growth hormone (GH) treatment for the last 10 years and to determine the differences in the process and results over the years. Methods: Anthropometric, clinical, laboratory data, treatment adherence and side effects were evaluated retrospectively in 767 patients who recieved GH treatment between 2009-2018. Patients were grouped as isolated GH deficiency (IGHD), multiple pituitary hormone deficiency (MPHD), small for gestational age (SGA), and Turner syndrome (TS) depending on diagnosis. Results: GH treatment was started in 689 cases (89.8%) with IGHD, 24 (3.1%) with MPHD, 26 (3.4%) with SGA and 28 (3.7%) with TS. Median age of GH treatment onset was the earliest in SGA (8.4 years) and the latest in the IGHD group (12.0 years). At the time of treatment cessation, height standard deviation score (SDS) in IGHD and MPHD was significantly higher than treatment initiation time, whereas there was no significant difference in TS and SGA. One hundred eighty-nine cases reached the final height. Final heights for girls/boys were: IGHD 154/164.9 cm; MPHD 156.2/163.5 cm; TS 146.7 cm; and SGA 145.7/-cm, respectively. Target height SDS-final height SDS median values were IGHD: 0.1, MPHD: 0.6, SGA: 0.5, TS: 2.4 respectively. The patients' treatment compliance was high (92%) and the incidence of side effects was low (2.7%). Conclusion: In our cohort, GH treatment start age was late and no difference in this was observed in the last 10 years. The improvement in the height SDS was most marked in the IGHD and MPHD groups, the least in the TS and SGA groups.

Long-term Clinical Follow-up of Patients with Familial Hypomagnesemia with Secondary Hypocalcemia

Objective: Familial hypomagnesemia with secondary hypocalcemia (HSH) is an autosomal recessive disease caused by a mutation in the transient receptor potential melastatin 6 (TRPM6) gene and is characterized by selective magnesium malabsorption. Affected cases are usually diagnosed during infancy and usually present with seizures due to hypocalcemia and hypomagnesemia. Irreversible neurological deficits and arrhythmias can be observed without appropriate treatment. The aim was to evaluate the long-term follow-up of patients with genetically confirmed HSH. Methods: A total of six patients with HSH, two of whom were siblings, were included. Age at diagnosis, clinical, laboratory and follow-up data on admission were recorded. All 39 exons of the TRPM6 gene and flanking exon-intron junctions from genomic DNA were amplified and sequenced in all cases. Results: The median (range) follow-up duration was 12.1 (7.6-21.7) years. All cases were diagnosed in infancy. Four different mutations, three of which had not been previously reported, were detected in the TRPM6 gene. Treatment compliance was good and there were no severe complications in the long-term follow-up of cases. However, mental retardation, specific learning difficulty and attention deficit/hyperactive disorder were observed as comorbidities. Conclusion: Of the four different TRPM6 mutations in this small cohort, three had not been previously reported. The long-term prognosis of HSH appears to be good, given early diagnosis and good treatment compliance. This long-term follow-up and prognostic data and the three novel mutations will contribute to the published evidence concerning this rare condition, HSH, and it is hoped will prevent negative outcomes.