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Background: In the past decades, the obesity epidemic in children of all ages has been an important research field for detecting the metabolic causes and consequences of obesity, the major focus being on insulin and adipocytokine levels. Metabolic work-up in obese children is recommended in the age group as young as 2-6 years. There is evidence that birth weight can be a factor causing obesity later in life accompanied by metabolic complications. Methods: Insulin, leptin, and adiponectin levels were analyzed in 269 obese children and 60 controls, as well as 110 newborn children with different birth weight and different length of gestation, using standard methods. Results: In 53.6% of the obese children, complications of obesity such as diabetes mellitus, obesity, hyperlipidemia, heart attack or stroke were found in family members. The peak insulinemia on O G TT was significantly higher in the pubertal compared to the prepubertal group (110.5± 75.9 pU/mL versus 72.2±62.7 pU/mL) (p

Background: Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disorder, characterized by multiple café-aulait macules, axillary and inguinal freckling, tumors of the nervous system, and iris hamartomas. More than 3,100 different pathogenic variants have been reported in the NF1 gene, including missense, nonsense, frameshift, in-frame, splicing, and large deletions. Aims: To determine the NF1 mutational spectrum in patients with NF1 from the Republic of North Macedonia. Study Design: A cohort study. Methods: Molecular analyses included reverse transcription and cDNA sequencing of the NF1 gene and next-generation sequencing using the TruSight Cancer panel, along with the multiple ligation probe amplification method to detect single nucleotide variants and copy number variations. Direct DNA sequencing was also used for the family member analysis. Results: Our 9-year study of patients suspected of having NF1 in the Republic of North Macedonia encompassed molecular characterization of 30 cases of the disease. We identified 28 unique pathogenic NF1 variants (NM_001042492.3), of which ten were novel: c.208delA; c.341_364del; c.1480_1481delTT; c.2325+1G>C; c.2495_2496dupAC; c.2533_2541del; c.4517delC; c.5844C>G; c.6971delA; c.7605_7606delGAinsAT. In addition to the variant spectrum analysis, our research revealed two positive genotypephenotype correlations. One between the clinical manifestation of cognitive impairment and gross deletions in the NF1 gene, and the other between cognitive impairment and truncating variants located in the RAS-GAP functional domain. Conclusion: This is the first study of NF1 patients in the Republic of North Macedonia, and it contributes ten novel variants to the global spectrum of pathogenic NF1 variants. It also corroborates the crucial importance of NF1 genetic testing for a prompt and precise diagnosis, particularly in younger patients. [ABSTRACT FROM AUTHOR]

Background: Killian-Pallister syndrome (KPS) is a rare form of chromosomal mosaicism and is defined by the existence of an extra chromosome 12 in some cell lines in one individual. The degree of mosaicism varies among tissues and dictates the clinical presentation of the syndrome. The clinical features of Killian-Pallister syndrome include mental retardation, typical facial dysmorphism and pigmentation defects. Case presentation: We present a rare case of Killian-Pallister syndrome with severe form of the disease associated with isolated growth hormone deficiency and low-rate mosaicism on buccal smear. The absence of a marker chromosome 12p in lymphocyte cultures and the low degree of mosaicism lead to frequent misdiagnosis of this condition. Conclusions: The selection of tissue sampling is crucial in establishing the diagnosis of Killian-Pallister syndrome. Fluorescent in situ hybridisation on buccal smear remains the golden standard as a screening method if a suspicion of the syndrome exists. [ABSTRACT FROM AUTHOR]

Background: Neurofibromatosis type 1 (NF1) is a common autosomal dominant genetic disorder with an extremely variable phenotype. In childhood NF1 can be associated with optic glioma and central precocious puberty; the latter is more common when the optic chiasm is affected. The mutational spectrum of the NF1 gene is wide and complex; R681X is a rare severe mutation of the NF1 gene known to cause truncation of neurofibromin, with only ten reported cases in the literature so far. Case presentation: We describe a girl with NF1 associated with early central precocious puberty appearing at 2.5 years of age and optic glioma affecting the optic chiasm as seen on magnetic resonance imaging (MRI). Genetic analysis confirmed the presence of R681X. Therapy with a gonadotropin-releasing hormone agonist was instituted with good response to therapy. The lesions on MRI were stable and no significant vision impairment was present during the 6 years of follow-up. Conclusion: Of the ten reported cases of NF1 due to R681X, one has presented with optic glioma and none with precocious puberty. Thus, to our knowledge, this is the first reported case of this mutation presenting with precocious puberty. We believe that this is a contribution to the few reports on the phenotype of this mutation and to the future elucidation of genotype-phenotype correlations of this disease. [ABSTRACT FROM AUTHOR]

Background: In the past decades, the obesity epidemic in children of all ages has been an important research field for detecting the metabolic causes and consequences of obe- sity, the major focus being on insulin and adipocytokine lev- els. Metabolic work-up in obese children is recommended in the age group as young as 2-6 years. There is evidence that birth weight can be a factor causing obesity later in life accompanied by metabolic complications. Methods: Insulin, leptin, and adiponectin levels were ana- lyzed in 269 obese children and 60 controls, as well as 110 newborn children with different birth weight and different length of gestation, using standard methods. Results: In 53.6% of the obese children, complications of obesity such as diabetes mellitus, obesity, hyperlipidemia, heart attack or stroke were found in family members. The peak insulinemia on OGTT was significantly higher in the pubertal compared to the prepubertal group (110.5± 75.9 μU/mL versus 72.2±62.7 μU/mL) (p<0.005). Glucose intolerance was confirmed in 24%. The leptin level was significantly higher and the adiponectin level was lower in pubertal obese children compared to the prepubertal children and controls (p<0.05). In newborns the leptin and adiponectin levels were in correlation with anthropometric parameters: body weight (BW), body length (BL), BW/BL, BMI, and the pondered index (p<0.05). Conclusion: Obese children have high insulinemia in all ages, reaching its peak towards puberty. The leptin and adiponectin levels might be indicators of the metabolic syn- drome. Our findings in newborns might influence the nutritional approach in the future in order to prevent complications of obesity. [ABSTRACT FROM AUTHOR]

Background: The Dandy-Walker malformation (DWM) is one of the commonest congenital cerebellar defects, and can be associated with multiple congenital anomalies and chromosomal syndromes. The occurrence of overlapping 3q deletions including the ZIC1 and ZIC4 genes in few patients, along with data from mouse models, have implicated both genes in the pathogenesis of DWM. Methods and results: Using a SNP-array approach, we recently identified three novel patients carrying heterozygous 3q deletions encompassing ZIC1 and ZIC4. Magnetic resonance imaging showed that only two had a typical DWM, while the third did not present any defect of the DWM spectrum. SNP-array analysis in further eleven children diagnosed with DWM failed to identify deletions of ZIC1-ZIC4. The clinical phenotype of the three 3q deleted patients included multiple congenital anomalies and peculiar facial appearance, related to the localization and extension of each deletion. In particular, phenotypes resulted from the variable combination of three recognizable patterns: DWM (with incomplete penetrance); blepharophimosis, ptosis, and epicanthus inversus syndrome; and Wisconsin syndrome (WS), recently mapped to 3q. Conclusions: Our data indicate that the 3q deletion is a rare defect associated with DWM, and suggest that the hemizygosity of ZIC1-ZIC4 genes is neither necessary nor sufficient per se to cause this condition. Furthermore, based on a detailed comparison of clinical features and molecular data from 3q deleted patients, we propose clinical diagnostic criteria and refine the critical region for WS. [ABSTRACT FROM AUTHOR]

Hypothalamic hamartomas (HH) are rare congenital non-neoplastic lesions of the tuber cinereum, which usually present as precocious puberty of central origin in young girls and respond well to treatment with long acting gonadotropin releasing hormone (GnRH) analogs. No association of this condition with diabetes mellitus of any form has been reported so far. On the other hand, diabetes mellitus in children and adolescents, when it is not autoimmune type 1 diabetes, is difficult to classify. We present a girl with early onset of central precocious puberty at the age of 8 months, due to hypothal-amic hamartoma. Treatment with depot of a GnRH analog for a period of 9 years and 8 months was successful, and her puberty continued 6 months after the discontinuation of triptorelin. At the age of 9 years 6 months, the girl presented with diabetes. She was negative for islet, GAD and IA2 antibodies and her insulinemia and C-peptide remained within normal limits during the 2 years of follow-up. Her metabolic control is excellent with a combination of metformin and a low-dose of mixed insulin. To our knowledge, this is the first description of the simultaneous appearance of these two endocrinological conditions. [ABSTRACT FROM AUTHOR]

Abstract: The lowest incidence of childhood type 1 diabetes in Europe has been reported from the Republic of Macedonia. To assess the possible genetic contribution we analyzed the distribution of HLA-DR-DQ haplotypes among 163 diabetic children and 239 healthy controls. Similar disease associations were found as in other Caucasian populations. HLA-(DR3)-DQA1*05-DQB1*02 was the most common disease associated haplotype, but several DRB1*04-DQB1*0302 haplotypes were also found increased among patients. DRB1*0402 was the most common DR4 allele among them. The high frequency of protective (DR11/12)-DQA1*05-DQB1*0301 and (DR14)-DQB1*0503 haplotypes as well as of neutral (DR1/10)-DQB1*0501 and (DR16)-DQB1*0502 haplotypes were characteristic for the background population. Although a relatively low frequency of predisposing and a high frequency of protective haplotypes was detected, the haplotype frequency distribution did not markedly differ from that reported from other Eastern Mediterranean populations and these differences cannot be the sole explanation for the low disease incidence in Macedonia. [Copyright &y& Elsevier]

Individuals with autism spectrum disorder (ASD) exhibit an increased burden of de novo mutations (DNMs) in a broadening range of genes. While these studies have implicated hundreds of genes in ASD pathogenesis, which DNMs cause functional consequences in vivo remains unclear. We functionally test the effects of ASD missense DNMs using Drosophila through "humanization" rescue and overexpression-based strategies. We examine 79 ASD variants in 74 genes identified in the Simons Simplex Collection and find 38% of them to cause functional alterations. Moreover, we identify GLRA2 as the cause of a spectrum of neurodevelopmental phenotypes beyond ASD in 13 previously undiagnosed subjects. Functional characterization of variants in ASD candidate genes points to conserved neurobiological mechanisms and facilitates gene discovery for rare neurodevelopmental diseases., Competing Interests: Declaration of interests The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing completed at Baylor Genetics Laboratories., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Diagnostic re-evaluation is important for all patients with congenital hypothyroidism (CH) for determining the etiology and identifying transient CH cases. Our study is a first thyroxine therapy withdrawal study conducted in Macedonian CH patients for a diagnostic re-evaluation. We aimed to evaluate the etiology of CH, the prevalence of transient CH and identify predictive factors for distinguishing between permanent (PCH) and transient CH (TCH)., Materials and Methods: Patients with CH aged >3 years underwent a trial of treatment withdrawal for 4 weeks period. Thyroid function testing (TFT), ultrasound and Technetium-99m pertechnetate thyroid scan were performed thereafter. TCH was defined when TFT remained within normal limits for at least 6-month follow-up. PCH was diagnosed when TFT was abnormal and classified according the imaging findings., Results: 42 (55%) patients had PCH and 34 (45.0%) patients had TCH. Thyroid agenesia was the most prevalent form in the PCH group. Patients with TCH had lower initial thyroid-stimulating hormone (TSH) values ( P  < 0.0001); higher serum thyroxine levels ( P  = 0.0023) and lower mean doses of levothyroxine during treatment period ( P  < 0.0001) than patients with PCH. Initial TSH level <30.5 IU/mL and levothyroxine dose at 3 years of age <2.6 mg/kg/day were a significant predictive factors for TCH; sensitivity 92% and 100%, specificity 75.6% and 76%, respectively., Conclusion: TCH presents a significant portion of patients with CH. Initial TSH value and levothyroxine dose during treatment period has a predictive role in differentiating TCH from PCH. Earlier re-evaluation, between 2 and 3 years age might be considered in some patients requiring low doses of levothyroxine., (© 2018 The authors.)

The incidence of congenital hypothyroidism (CH) is increasing in different areas around the world. Potential causes include changes in population ethnic composition, environmental factors, changing screening program methodology and lowering of TSH cutoff levels. The incidence of CH in different regions of Macedonia has not been evaluated before. A total of 251,008 newborns from all eight regions in the country have been screened between 2002 and 2015, by measurement of the thyroid-stimulating hormone (TSH) from blood spots, sampled 48-72 h after birth, using the DELFIA assay. Overall CH incidence confirmed at birth was 1/1976. The highest CH incidence was observed in the Vardar region (1/970), while the Eastern region had the lowest incidence (1/4202; p =0.021). In the other regions, the following CH incidence was detected: Northeastern 1/1459, Pelagonia 1/1627, Polog 1/1444, Skopje 1/2430, Southwestern 1/3226, and Southeastern 1/1843. Interestingly, in the Vardar region, 4.44% of the screened newborns had a TSH concentration > 5 mIU/L, as an indicator of regional iodine deficiency, compared to the Eastern region where 1.66% of newborns had a TSH > 5 mIU/L. The higher CH incidence in some of the regions may be due to increasing exposure to environmental toxic agents and/or deficient iodine intake. Further research into the potential environmental determinants of increased CH risk is warranted., Competing Interests: The authors declare no conflict of interest.