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  • Author: Mirjana Kocova x
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Clinical Features and Diagnostic Approach in Patients with Undervirilised External Male Genitalia

Clinical Features and Diagnostic Approach in Patients with Undervirilised External Male Genitalia

Background. Sex development in humans is a complex and multiple step process. SRY gene on Y chromosome has met the criteria for a testis determining factor, however subsequent stages of differentiation require the expression of several other genes. Male pseudohermaphroditism refers to genetically XY male with differentiated testes and varying degree of undermasculinization of the external genitalia.

Aim. Our study aimed at exploring the clinical characteristics, cytogenetic and SRY gene analyses in a group of 14 pediatric patients with male pseudohermaphroditism.

Material and Methods. Clinical presentations were: micropenis and/or penoscrotal/perineal hypospadia in 86%, altered appearance of the scrotum in 79% and Mullerian duct remnants in 50% of the patients.

Results. Cytogenetic analyses revealed a normal male karyotype in all patients. SRY gene was found positive in all 14 patients.

Conclusion. We concluded that SRY gene analysis in patients with male pseudohermaphroditism confirms the clinical diagnosis and directs further investigations. SRY gene analysis is a quick and relatively simple diagnostic method that can be included at the early stage diagnostic of sex differentiation disorders.

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Hashimoto Thyroiditis in Childhood – Review of the Epidemiology, Genetic Susceptibility and Clinical Aspects of the Disease


Chronic autoimmune thyroiditis or Hashimoto’s thyroiditis (HT) is the most common cause of thyroid diseases in children and adolescents. It is also the most common cause of acquired hypothyroidism with or without goiter. The incidence of autoimmune thyroiditis has increased dramatically over the past few decades, affecting up to 5% of the general population in iodine sufficient areas. HT is caused by the complex interplay of genetic, environmental, and endogenous factors. Significant progress has been made in identifying and characterizing the genes involved in pathogenesis of the disease.

The aim of this review is to analyze current opinions and options regarding the etiology, genetic contribution to the pathogenesis, evaluation, diagnosis, treatment, and prognosis of the HT in children.

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Direct Molecular Diagnosis of CYP21A2 Point Mutations in Macedonian and Serbian Patients with 21-Hydroxylase Deficiency/Direktna Molekularna Dijagnoza CYP21A2 Tačkaste Mutacije Kod Makedonskih I Srpskih Pacijenata Sa Nedostatkom 21-Hidroksilaze


Background: Steroid 21-hydroxylase deficiency is present in 90-95% of all cases with congenital adrenal hyperplasia (CAH), an autosomal recessive disorder. It can present as the severe classical salt wasting (SW) or simple virilising (SV) form, or the milder, nonclassical form. Nine pseudo- gene-derived point mutations account for about 80% of all defects in the CYP21A2 gene coding the 21-hydroxylase enzyme.

Methods: We have studied nine CYP21A2 point mutations in 61 Macedonian and 24 Serbian patients with different clinical presentations of CAH, using the PCR/ACRS method.

Results: Six different mutations were detected in 71.3% of alleles of the Macedonian patients. The most prevalent mutation was IVS2. Mutations were detected in 85.4% of the SW, 83.4% SV and 47.7% LO alleles. In the Macedonian patients the most common genotype was IVS2/IVS2. Five different mutations were detected in 64.6% of alleles of the Serbian patients. The most preva- lent was P30L. Mutations were present in 83.3% SW, 80% SV and 50% of the LO alleles. In the Serbian patients, the P30L/P30L genotype was the most frequent.

Conclusions: Specific CYP21A2 mutations are involved in different clinical forms of CAH. High frequency of P30L was found in both populations. Also, high prevalence of the mild P30L mutation was found in both the Macedonian and Serbian classical SV patients. Our findings support the role of the P30L mutation in pronounced virilisation. An unusual finding is the low frequency of V281L in the Macedonian non-classical patients and its absence in the ones from Serbia.

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Newborn Screening for Thyroid-stimulating Hormone as an Indicator for Assessment of Iodine Status in the Republic of Macedonia


Background: Iodine deficiency is associated with goiter and impaired brain function leading to cretinism. An increased frequency of thyroid-stimulating hormone (TSH) measurements above 5 mIU/L on newborn screening points toward an impaired iodine status of the population.

Methods: A 13-year retrospective analysis was performed in 228,266 newborns participating in the national thyroid newborn screening program. The TSH concentration was measured in dry blood spots collected by heel stick on filter paper, 48 hours after birth, using fluoroimmunometric DELFIA method.

Results: Out of 236,378 live-born infants, 228,266 (96.6%) have been screened for TSH, of which 198,213 (86.8%) were retrospectively evaluated for TSH levels above 5 mIU/L. Neonates with congenital hypothyroidism, prematurity, and low birth weight were excluded from the evaluation, as well as the inadequately sampled neonates (13.2%). A national prevalence of 3.08% newborns (n=6,105) with TSH > 5 mIU/L was found. Higher percentages were noted in two regions of the country, indicating possible mild iodine deficiency in these regions and shifting the overall average to above 3%.

Conclusions: Our results indicate overall iodine sufficiency in the Macedonian population. Additional assessment of the iodine intake in the regions with suspected mild iodine deficiency is needed to prevent suboptimal cognitive and psychomotor outcomes.

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Metabolic Setup and Risks in Obese Children/Metabolički Profil I Rizici Kod Gojazne Dece


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.

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Comparing Preterm and Term Newborns Serum Adiponectin and Leptin Concentrations and their Correlations with Anthropometric Parameters


Introduction: Serum adipocytokines concentration, their mutual relationship and correlations with anthropometric data could be indicators of fetal and neonatal growth maturity level in term and preterm infants.

Objectives: Study was designed to assess the correlation of the anthropometric parameters with leptin and adiponectin levels in healthy preterm and term newborns.

Design and Methods: A cohort of 110 neonates of both sexes, born pre term (PT) (n=36) or at term (AT) (n=74), additionally classified as AT-AGA (n=36), AT-SGA (n=18), AT-LGA (n=20) and PT-AGA (n=24), PT-SGA (n=12), according to the Lubchenco curves Mother Body Mass Index-MBMI, Birth Weight-BW, Birth Length-BL, Body Weight/Body Length ratio-BW/BL, Body Mass Index-BMI, Ponderal Index-PI, was recorded after birth.

Results: Sex has no influence on mean serum leptin and adiponectin level. However, differences between AT and PT groups were highly (p<0.01) significant (2.20 ± 1.02; 30.77 ± 22.64 and 1.24 ± 0.35; 9.44 ± 4.82 ng/mL, respectively). Significant difference was found in adiponectin levels between ATAGA and AT-LGA compared to AT-SGA subgroup (32.8 ± 25.41 and 43.40 ± 16.98 vs 12.67 ± 2.45 ng/ mL, respectively, (p<0.01; p<0.01). There was a significant difference between leptin levels (1.93 ± 0.70; 1.71 ± 0.53 vs 3.12 ± 1.27 ng/mL) in AT-AGA and AT-SGA compared to AT-LGA newborns, respectively, (p<0.01; p<0.01). No significant differences were found in leptin and adiponectin levels neather between PT subgroups (1.30 ± 0.38 ng/mL) nor between PT group and AT-SGA (1.71 ± 0.53 ng/mL) subgroup. Leptin and adiponectin levels were positively correlated with all anthropometric parameters: BW, BL, BW/BL, BMI, and PI (p<0.05).

Conclusion: These results indicate that the stage of body growth maturity is positively correlated to adipocytokines involved in fetal growth regulation.

Open access