Proopiomelanocortin (POMC) deficiency is a rare monogenic disorder with early-onset obesity. Investigation of this entity have increased our insight into the important role of the leptin-melanocortin pathway in energy balance. Here, we present a patient with POMC deficiency due to a homozygous c.206delC mutation in the POMC gene. We discuss the pathogenesis of this condition with emphasis on the crosstalk between hypothalamic and peripheral signals in the development of obesity and the POMC-melanocortin 4 receptors system as a target for therapeutic intervention.

There have been recent advances in the understanding of the etiology of idiopathic central precocious puberty (iCPP) including new genetic associations. The aim of this clinical study was to determine the frequency of MKRN3 mutation in cases of familial iCPP. Potential sequence variations in the maternally imprinted MKRN3 gene were evaluated in 19 participants from 10 families using next-generation sequencing analysis. MKRN3 variation was found in only one of the 19 (5.3%) subjects. The male patient, who had a medical history of precocious puberty, had a heterozygous mutation, NM_005664.3:c.630_650delins GCTGGGC (p.P211Lfs*16). The father of this patient also had a history of precocious puberty and had the same mutation. p.P211Lfs*16 is a novel variant and it was identified as probably pathogenic by in silico analysis, consistent with the clinical findings. Given that MKRN3 mutation was detected in only one patient, with a paternal history of precocious puberty, this reinforces the importance of accurate family history taking. The detected incidence of MKRN3 variants in our case series was much lower than reported elsewhere which suggests a need for further studies in Turkish iCPP patients.

Background: Vitamin D and its active form are potent immuno­modulators and are known to play an important role in the glucose/insulin metabolism. Studies on type 2 diabetes mellitus (T2DM) have shown that vitamin D increases insulin efficacy; however, there are no studies that define a similar relationship in type 1 diabetes mellitus (T1DM). The aim of this study was to investigate the relation between serum vitamin D levels and the insulin requirement used in children with T1DM. Subjects and methods: A total of 100 patients with T1DM aged 4.7–19.9 years were included in the study. Serum calcium, phosphorus, alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin D (25OHD), and 1,25-dihydroxyvitamin D were measured. A serum 25OHD level of <10 ng/mL was accepted as vitamin D deficiency, whereas <20 ng/mL was accepted as vitamin D insufficiency. Results: We found vitamin D deficiency in 28% and vitamin D insufficiency in 43% of our patients, whereas 29% had normal serum 25OHD levels. The insulin requirement of patients with a serum 25OHD level below 10 ng/mL were significantly higher than those of patients with a serum 25OHD level above 10 ng/mL (p=0.012). This result did not change in those with diabetes duration of over 1 year. There was weak correlation between the daily insulin requirements and serum vitamin D levels (r=–0.212, p=0.032). Conclusion: We found a significantly higher insulin requirement in T1DM children with decreased serum 25OHD levels and decreased insulin sensitivity. We recommend checking the level of serum 25OHD in children with diabetes and starting treatment if it is deficient/inadequate.

Context Homozygous leptin (LEP) and leptin receptor (LEPR) variants lead to childhood-onset obesity. Objective To present new cases with LEP and LEPR deficiency, report the long-term follow-up of previously described patients, and to define, based on all reported cases in literature, genotype-phenotype relationships. Methods Our cohort included 18 patients (LEP = 11, LEPR = 7), eight of whom had been previously reported. A systematic literature review was conducted in July 2022. 42/47 studies on LEP/LEPR were selected. Results Of 10 new cases, two novel pathogenic variants were identified in LEP (c.16delC) and LEPR (c.40+5G>C). Eleven patients with LEP deficiency received metreleptin, four of whom had been treated for over 20 years. One patient developed loss of efficacy associated with neutralizing antibody development. Of 152 patients, including 134 cases from the literature review in addition to our cases, frameshift variants were the most common (48%) in LEP and missense variants (35%) in LEPR. Patients with LEP deficiency were diagnosed at a younger age (3 (9) vs. 7 (13) years, p = 0.02), and had a higher median BMI SD score (3.1 (2) vs. 2.8 (1) kg/m2, p = 0.02), which was more closely associated with frameshift variants (p = 0.02). Patients with LEP deficiency were more likely to have hyperinsulinemia (p = 0.02). Conclusion Frameshift variants were more common in patients with LEP deficiency whereas missense variants were more common in LEPR deficiency. Patients with LEP deficiency were identified at younger ages, had higher BMI SD scores, and had higher rates of hyperinsulinemia than patients with LEPR deficiency. Eleven patients benefited from long-term metreleptin, with one losing efficacy due to neutralizing antibodies.

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. MODY cases from 14 different pediatric endocrinology departments were included. Diagnosis, treatment, follow-up data, and results of genetic analysis were evaluated. 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. 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.

Purpose: We aimed to determine the frequency of transient congenital hypothyroidism (TCH) in 17 participating centers in Türkiye, evaluate the etiological distribution in permanent congenital hypothyroidism (PCH) cases, and investigate the role of laboratory and clinical findings in predicting TCH. Methods: This retrospective observational multicenter study included patients from 17 pediatric endocrinology centers identified by “National Newborn Screening Program” (NNSP) who were born in 2015 and followed for 6 years. Demographic, clinical, and laboratory information of the cases were compiled through the database http://cedd.saglik-network.org (CEDD-NET). Results: Of the 239 cases initially treated for CH, 128 (53.6%) were determined as transient in whom a trial of levothyroxine (LT4) withdrawal was performed at a median age of 36 (34–38) months. Among the patients with PCH (n = 111), thyroid dysgenesis was diagnosed in 39.6% (n = 44). The predictive factors for TCH were: LT4 dose at the withdrawal of treatment, and initial newborn blood screening (NBS)-TSH level. Based on the receiver operating characteristic (ROC) curve analysis to predict optimal cut-offs for TCH predictors, LT4 dose < 2.0 µg/kg/day at treatment discontinuation was predictive for TCH and was associated with 94.5% specificity and 55.7% sensitivity, with an area under the curve (AUC) of 0.802. The initial NBS-TSH level value < 45 µIU/mL was predictive for TCH with 93.1% specificity and 45.5% sensitivity, with an AUC of 0.641. In patients with eutopic thyroid gland only LT4 dose < 1.1 µg/kg/day at withdrawal time was predictive for TCH with 84.7% sensitivity and 40.4% specificity, with an AUC of 0.750. Conclusion: According to our national follow-up data, the frequency of TCH was 53.6%. We determined the LT4 dose < 2.0 µg/kg/day at discontinuation of treatment and the initial NBS-TSH level < 45 µIU/mL as the best cut-off limits to predict TCH.