Gucev Z.S.,Medical Faculty Skopje |
Tasic V.,Medical Faculty Skopje |
Pop-Jordanova N.,Medical Faculty Skopje |
Sparrow D.B.,Victor Chang Cardiac Research Institute |
And 7 more authors.
American Journal of Medical Genetics, Part A | Year: 2010
The spondylocostal dysostoses (SCDs) are a heterogeneous group of axial skeletal disorders characterized by multiple segmentation defects of the vertebrae (SDV) and abnormality of the thoracic cage with mal-aligned ribs and often a reduction in rib number. The four known monogenic forms of SCD follow autosomal recessive inheritance, have generalized SDV, a broadly-symmetrical thoracic cage, and result from mutations in Notch signaling pathway genes - DLL3, MESP2, LFNG, and HES7. Autosomal dominant (AD) SCD has been reported less often, is very variable, and molecular genetic mechanisms remain elusive. Here,we report a three-generation, non-consanguineous family with four affected individuals demonstrating multiple or generalized SDV. Scoliosis was present and the trunk shortened but the ribs were relatively mildly affected. There were no other significant organ abnormalities, no obvious dysmorphic features, neurodevelopment was normal, and all investigations, including mutation analysis of DLL3, MESP2, LFNG, and HES7, were normal. A non-pathogenic variant was detected in LFNG but it did not segregate with the phenotype. This Macedonian kindred adds to knowledge of AD SCD and to our knowledge is the first to be tested for the four Notch pathway genes known to be associated with SCD. © 2010 Wiley-Liss, Inc.
Macedo D.B.,University of Sao Paulo |
Abreu A.P.,University of Sao Paulo |
Abreu A.P.,Harvard University |
Reis A.C.S.,University of Sao Paulo |
And 22 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2014
Context: Loss-of-function mutations in makorin ring finger 3 (MKRN3), an imprinted gene located on the long arm of chromosome 15, have been recognized recently as a cause of familial central precocious puberty (CPP) in humans. MKRN3 has a potential inhibitory effect on GnRH secretion. Objectives: The objective of the study was to investigate potential MKRN3 sequence variations as well as copy number and methylation abnormalities of the 15q11 locus in patients with apparently sporadic CPP. Setting and Participants: We studied 215 unrelated children (207 girls and eight boys) from three university medical centers with a diagnosis of CPP. All buttwoof these patients (213 cases) reported no family history of premature sexual development. First-degree relatives of patients with identified MKRN3 variants were included for genetic analysis. Main Outcome Measures: All 215 CPP patients were screened for MKRN3 mutations by automatic sequencing. Multiplex ligation-dependent probe amplification was performed in a partially overlapping cohort of 52 patients. Results: We identified five novel heterozygous mutations in MKRN3 in eight unrelated girls with CPP. Four were frame shift mutations predicted to encode truncated proteins and one was a missense mutation, which was suggested to be deleterious by in silico analysis. All patients with MKRN3mutations had classical features of CPP with a median age of onset at 6 years. Copy number andmethylation abnormalities at the15q11locuswerenot detected in the patients tested for these abnormalities. Segregation analysis was possible in five of the eight girls with MKRN3 mutations; in all cases, the mutation was inherited on the paternal allele. Conclusions: We have identified novel inherited MKRN3 defects in children with apparently sporadic CPP, supporting a fundamental role of this peptide in the suppression of the reproductive axis. © 2014 by the Endocrine Society.
Gucev Z.,Medical Faculty Skopje |
Tasic V.,Medical Faculty Skopje |
Saranac L.,Medical Faculty Nis |
Stobbe H.,University of Leipzig |
And 3 more authors.
Hormone Research in Paediatrics | Year: 2012
Background: Four distinct familial types of isolated GH deficiency (IGHD) have been described so far. Objective: We report a novel nonsense GH1 mutation in a father and a son. Patients: Father's height was 137.3 cm (-6.79 SDS); mother's height was 157.3 cm (-1.86 SDS). By the age of 8.25 years, his height was 104.3 cm (-4.82 SDS) and his weight was 18.3 kg (-3.35 SDS). GH stimulation tests had low peak GH value of 6.5 ng/ml (proband) and 6.3 ng/ml (father). Other pituitary hormones and magnetic resonance imaging (MRI) of the pituitary region was normal in both patients. The proband received recombinant human GH (rhGH) treatment (30 μg/kg/day) and he grew 15.4 cm in 15 months. Results: Sequencing of the GH1 gene revealed a novel heterozygous nonsense mutation in both the father and the son (c.199A>T), which introduces a stop codon in exon 3. Conclusion: We present a family with IGHD II, with severe short stature, no phenotypic characteristics of GHD and a novel nonsense mutation in exon 3 of the GH1 gene. As fibroblasts were unavailable, we used computer analysis and we propose a unique mechanism that combines aberrant splicing and derogated GH release from the pituitary with residual secretion of a bioinactive truncated GH peptide. Copyright © 2011 S. Karger AG, Basel.
Keppler-Noreuil K.M.,Human Genome Research Institutes |
Sapp J.C.,Human Genome Research Institutes |
Lindhurst M.J.,Human Genome Research Institutes |
Parker V.E.R.,University of Cambridge |
And 27 more authors.
American Journal of Medical Genetics, Part A | Year: 2014
Somatic mutations in the phosphatidylinositol/AKT/mTOR pathway cause segmental overgrowth disorders. Diagnostic descriptors associated with PIK3CA mutations include fibroadipose overgrowth (FAO), Hemihyperplasia multiple Lipomatosis (HHML), Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi, Scoliosis/skeletal and spinal (CLOVES) syndrome, macrodactyly, and the megalencephaly syndrome, Megalencephaly-Capillary malformation (MCAP) syndrome. We set out to refine the understanding of the clinical spectrum and natural history of these phenotypes, and now describe 35 patients with segmental overgrowth and somatic PIK3CA mutations. The phenotypic data show that these previously described disease entities have considerable overlap, and represent a spectrum. While this spectrum overlaps with Proteus syndrome (sporadic, mosaic, and progressive) it can be distinguished by the absence of cerebriform connective tissue nevi and a distinct natural history. Vascular malformations were found in 15/35 (43%) and epidermal nevi in 4/35 (11%) patients, lower than in Proteus syndrome. Unlike Proteus syndrome, 31/35 (89%) patients with PIK3CA mutations had congenital overgrowth, and in 35/35 patients this was asymmetric and disproportionate. Overgrowth was mild with little postnatal progression in most, while in others it was severe and progressive requiring multiple surgeries. Novel findings include: adipose dysregulation present in all patients, unilateral overgrowth that is predominantly left-sided, overgrowth that affects the lower extremities more than the upper extremities and progresses in a distal to proximal pattern, and in the most severely affected patients is associated with marked paucity of adipose tissue in unaffected areas. While the current data are consistent with some genotype-phenotype correlation, this cannot yet be confirmed. © 2014 Wiley Periodicals, Inc.
Krstevska-Konstantinova M.,Medical Faculty Skopje |
Jovanovska J.,Medical Faculty Skopje |
Tasic V.B.,Medical Faculty Skopje |
Montenegro L.-R.,University of Sao Paulo |
And 3 more authors.
Journal of Pediatric Endocrinology and Metabolism | Year: 2014
Aim: The genetic background of idiopathic central precocious puberty (ICPP) is not well understood. The genetic activation of pubertal onset is thought to arise from the effect of multiple genes. Familial ICPP has been reported suggesting the existence of monogenic causes of ICPP. Kisspeptin and its receptor are found to be involved in gonadotropin-releasing hormone (GnRH) secretion and puberty onset. Mutations in their genes, KISS1 and KISSR, have been suggested to be causative for ICPP. Methods: ICPP was defined by pubertal onset before 8 years of age in girls, and a pubertal luteinizing hormone (LH) response to GnRH testing. Twenty-eight girls with ICPP were included in the study [age at diagnosis was 5.72±2.59, with a mean bone age advancement of 1.4 years (-0.1 to 2.8). Height at onset of therapy in SD score was 0.90±1.48 for age]. Luteinizing hormone-releasing hormone test was performed in all subjects, and all of them had a pubertal response (LH 20.35±32.37 mIU/mL; FSH 23.32±15.72 mIU/mL). The coding regions of KISS1 and KISS1R were sequenced. Results: No rare variants were detected in KISS1 or KISS1R in the 28 subjects with ICPP. Conclusions: We confirmed that mutations in KISS1 and KISS1R are not a common cause for ICPP.
PubMed | Medical Faculty Skopje
Type: Editorial | Journal: Prilozi (Makedonska akademija na naukite i umetnostite. Oddelenie za medicinski nauki) | Year: 2013
58 years after the creation of impact factor (IF) the professional public shows interest in IFs and their significance for academia and individuals. Really, is a medical journal with IF needed for Macedonia? Some other small and developing countries have pursued and accomplished this goal: Serbia, Slovenia, and Croatia. On the other hand the survey of publications in Macedonian medical journals has been found to lack quality. We believe that to strive to obtain an IF would be beneficial for all Macedonian interest groups involved. This would introduce an ambition among the members of Macedonian academia to publish (so far rare), than to publish in Pubmed listed journals (ambition present in very few Macedonian academics) and then to publish in journals with the highest IF possible (so far a very exclusive group of Macedonian medical professionals). In time this will help in creating and enforcing legal obligation for the academia for a promotion based on merit of IF scientific publications. We believe that this is possible only by Parliament legislation. This will be of benefit for Macedonian patients, the medical community and will unable this country to contribute to the universe of science. Lastly it would certainly be helpful in getting a Macedonian university in the prestigious first 500 Shangai list. Key words: impact factor, Macedonia, medical journals.
PubMed | Medical Faculty Skopje
Type: Case Reports | Journal: Prilozi (Makedonska akademija na naukite i umetnostite. Oddelenie za medicinski nauki) | Year: 2013
Hypomethylation of the imprinting control region 1 (ICR 1) at the IGF2/H19 locus on 11p15 is linked to Silver-Russel syndrome (SRS).We tested the hypothesis that the severity of the phenotype in SRS patients is dependent on the clinical severity score (CSS) (1). Three SRS patients were clinically scored and their scores ranged between 12, 13 and 13. Two of the three SRS patients (66%) had hypomethylation of one allele.All three patients had high CSS. Nevertheless, only two of them had hypomethylation of one H19 allele. Interestingly, two of them had ventricular septal defects, but only one had H19 hypomethylation. All children had low birth length and weight, a classic facial phenotype, haemihypertrophy (>2.5 cm thinner left arm/leg in comparison to the right one), shorter leg, and striking thinness (BMI of >16.0). One child was operated for cryptorchidismus, and the same child had elbow contracture. Two children had scoliosis. All three children were short (-3 to 5.5 SD), and treatment with GH resulted in growth on the third percentile. Since one child had no hypomethylation and two had a lower degree of hypomethylation, the higher CSS (12, 13 and 13) was not followed by a higher degree of hypomethylation of the IGF2/H19 locus.
PubMed | Medical Faculty Skopje
Type: Journal Article | Journal: Prilozi (Makedonska akademija na naukite i umetnostite. Oddelenie za medicinski nauki) | Year: 2013
Obesity and overweight are a pandemic phenomenon in the modern world. Childhood and adolescent obesity often ends up in obesity in adults. The costs of obesity and its consequences are staggering for any society, crippling for countries in development. The etiology is complex, but most often idiopathic. Hormonal, syndromic and medication-induced obesity are well investigated. Genetic causes are increasingly described. Novel technologies such as whole exome sequencing identify ever more candidate genes influencing or causing obesity. All insights into the complex problem of obesity in a team approach to treatment: diet, psychology, medications and surgery. We briefly review epidemiology, etiology, consequences and treatment approaches in childhood and adolescent obesity, with special emphasis on emerging knowledge of its genetics.
PubMed | Medical Faculty Skopje
Type: Case Reports | Journal: Hormone research in paediatrics | Year: 2012
Four distinct familial types of isolated GH deficiency (IGHD) have been described so far.We report a novel nonsense GH1 mutation in a father and a son.Fathers height was 137.3 cm (-6.79 SDS); mothers height was 157.3 cm (-1.86 SDS). By the age of 8.25 years, his height was 104.3 cm (-4.82 SDS) and his weight was 18.3 kg (-3.35 SDS). GH stimulation tests had low peak GH value of 6.5 ng/ml (proband) and 6.3 ng/ml (father). Other pituitary hormones and magnetic resonance imaging (MRI) of the pituitary region was normal in both patients. The proband received recombinant human GH (rhGH) treatment (30 g/kg/day) and he grew 15.4 cm in 15 months.Sequencing of the GH1 gene revealed a novel heterozygous nonsense mutation in both the father and the son (c.199A>T), which introduces a stop codon in exon 3.We present a family with IGHD II, with severe short stature, no phenotypic characteristics of GHD and a novel nonsense mutation in exon 3 of the GH1 gene. As fibroblasts were unavailable, we used computer analysis and we propose a unique mechanism that combines aberrant splicing and derogated GH release from the pituitary with residual secretion of a bioinactive truncated GH peptide.
PubMed | Medical Faculty Skopje and Macedonian Academy of science and Arts
Type: Case Reports | Journal: Prilozi (Makedonska akademija na naukite i umetnostite. Oddelenie za medicinski nauki) | Year: 2015
Wildervanck syndrome (WS) combines features of Klippel-Feil syndrome (KFS), sixth nerve palsy, and deafness. This is a case of a 23 year old woman, diagnosed with KFS (a triad of short neck, low posterior hairline and restricted neck movements) at the age of 20 days. The manifestations of the WS in this patient are severe: she has torticollis, and an extremely severe scoliosis. In addition, she is short (-3 SD; parental target height + 0.8SD) and has mixed sensorineural and conductive deafness. She also has ptosis, strabismus and a high myopia. Radiologically, there are multiple coalitions of cervical vertebrae. Intelligence is unaffected (IQ 95), but deafness, strabismus and high myopia forced her early out of school. Karyotype is 46, XX. In brief, this is a patient with severe WS and additional anomalies. Short and/or reduced parental target height is a part of WS.