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Dizabilitatea intelectuală (DI) este o afecțiune frecventă, cu consecințe majore pentru individ, familie și societate. Datorită heterogenității sale clinice și genetice, în aproximativ 50% din cazuri etiologia bolii nu poate fi stabilită. Scopul acestui studiu a fost evaluarea capacității de stabilire a diagnosticului etiologic la 369 pacienți cu DI sindromic și rezultat normal sau incert la cariotip folosind o combinație de kituri MLPA. Toţi pacienţii au fost investigaţi prin metoda MLPA, folosind fie kiturile SALSA MLPA P064 sau P096, dacă fenotipul a fost sugestiv pentru un sindrom cu microdeleţie (subgrupul A - 186 pacienți), fie kiturile subtelomerice P036 și P070, dacă fenotipul nu a fost sugestiv pentru un sindrom cu microdeleţie sau rezultatul la cariotipul standard a fost incert (subgrupul B - 183 pacienți). Rezultatele anormale detectate de aceste kituri au fost caracterizate folosind kiturile MLPA corespunzătoare de urmărire (Telomere Follow-up set, P029-A1, P250-B2, ME028-B1). În subgrupul A am identificat 25 de pacienți cu microdeleții (13,4%). Folosind kiturile de screening subtelomeric și de urmărire la subgrupul B am detectat rearanjări criptice în 7,5% din cazuri și am identificat originea materialului suplimentar observat la cariotipul standard la 10 din 11 pacienți. Sumarizând datele obţinute din cele două loturi, folosirea combinată a seturilor MLPA a dus la stabilirea diagnosticului la 10,6% (38/358) dintre pacienții cu cariotip normal. Folosirea seturilor MLPA de urmărire a permis atât confirmarea prezenţei anomaliei, cât şi determinarea dimensiunii ei, ceea ce a facilitat interpretarea semnificaţiei clinice a rearanjărilor. Pentru laboratoarele care nu au acces la tehnologiile bazate pe microarray, folosirea mai multor kituri MLPA reprezintă o strategie eficientă pentru stabilirea diagnosticului etiologic la pacienţii cu DI.

Introducere. Sindromul Down este o boală gravă, lipsită de terapie patogenică. Singurele posibilităţi de reducere a consecinţelor bolii le reprezintă screeningul şi diagnosticul prenatal. Standardul de aur în diagnosticul prenatal este analiza cromosomică a celulelor fetale obţinute prin proceduri invazive. Pentru reducerea complicaţiilor, în ultimii ani au fost dezvoltate diferite metode de detecţie a celulelor sau ADN-ului fetal în sângele matern. Scop. Scopul studiului a fost verificarea aplicabilităţii metodei de cuantificare prin imunoprecipitare a ADN-ului fetal metilat din sângele matern în diagnosticul prenatal al trisomiei 21. Metodă. Am analizat probe de la 12 gravide (7 cu făt cu trisomie 21 şi 5 cu făt euploid confirmate citogenetic), două probe fiind eliminate din considerente tehnice. Pentru fiecare probă am efectuat: extracţia ADN-ului total (matern şi fetal), fragmentarea ADN-ului, imunoprecipitarea ADN-ului metilat, spălarea, izolarea ADN-ului şi qPCR pentru ADN-ul imunoprecipitat. Pentru evidenţierea regiunilor metilate specifice pe cromosomii 21 fetali am utilizat opt perechi de amorse specifice cromosomului 21. În final, am analizat rezultatele qPCR aplicând formula: D=-6,331+0,959XEP4+1,188XEP5+0,424XEP6+0,621XEP7+0,028XEP8+0,387XEP10-0,683XEP11 +0,897XEP12 unde XEPi= valoarea fracţiei pentru fiecare marker. Rezultate. În toate sarcinile normale, valoarea factorului D a fost negativă concordant cu absenţa trisomiei (specificitate 100%). În 5 din 6 sarcini cu trisomie 21 valoarea factorului D a fost pozitivă, ceea ce indică o sensibilitate crescută. Totuşi, pentru estimarea precisă a metodei este necesară analiza mai multor cazuri, ceea ce ar permite obţinerea de date valabile statistic

Obesity affects more than one billion people worldwide and often leads to cardiometabolic chronic comorbidities. It induces senescence-related alterations in adipose tissue, and senescence is closely linked to obesity. Fully elucidating the pathways through which vitamin D exerts anti-inflammatory effects may improve our understanding of local adipose tissue inflammation and the pathogenesis of metabolic disorders. In this narrative review, we compiled and analyzed the literature from diverse academic sources, focusing on recent developments to provide a comprehensive overview of the effect of vitamin D on inflammation associated with obesity and senescence. The article reveals that the activation of the NF-κB (nuclear factor kappa B subunit 1) and NLRP3 inflammasome (nucleotide-binding domain, leucine-rich-containing, pyrin domain-containing-3) pathways through the toll-like receptors, which increases oxidative stress and cytokine release, is a common mechanism underlying inflammation associated with obesity and senescence, and it discusses the potential beneficial effect of vitamin D in alleviating the development of subclinical inflammation. Investigating the main target cells and pathways of vitamin D action in adipose tissue could help uncover complex mechanisms of obesity and cellular senescence. This review summarizes significant findings related to opportunities for improving metabolic health. [ABSTRACT FROM AUTHOR]

Melanoma is a common and aggressive tumor originating from melanocytes. The increasing incidence of cutaneous melanoma in recent last decades highlights the need for predictive biomarkers studies. Melanoma development is a complex process, involving the interplay of genetic, epigenetic, and environmental factors. Genetic aberrations include BRAF, NRAS, NF1, MAP2K1/MAP2K2, KIT, GNAQ, GNA11, CDKN2A, TERT mutations, and translocations of kinases. Epigenetic alterations involve microRNAs, non-coding RNAs, histones modifications, and abnormal DNA methylations. Genetic aberrations and epigenetic marks are important as biomarkers for the diagnosis, prognosis, and prediction of disease recurrence, and for therapeutic targets. This review summarizes our current knowledge of the genomic and epigenetic changes in melanoma and discusses the latest scientific information. [ABSTRACT FROM AUTHOR]

Coffin-Siris syndrome (CSS) is a rare genetic disorder caused by the haploinsufficiency of one of the various genes that are part of the Brahma/BRG1-associated factor (BAF) complex. The BAF complex is one of the chromatin remodeling complexes, involved in embryonic and neural development, and various gene mutations are associated with cognitive impairment. CSS has a highly variable genotype and phenotype expression, thus lacking standardized criteria for diagnosis. It is generally accepted to associate 5th digit/nail hypoplasia, intellectual disability (ID)/developmental delay and specific coarse facial features. CSS patients usually display miscellaneous cardiac, genitourinary and central nervous system (CNS) anomalies. Many patients also associate intrauterine growth restriction, failure to thrive and short stature, with several cases demonstrating growth hormone deficiency (GHD). We report the case of a 4-year-old girl with severe short stature (-3.2 standard deviations) due to pituitary hypoplasia and GHD that associated hypoplastic distal phalanx of the 5th digit in the hands and feet, severe ID, coarse facial features (bushy eyebrows, bulbous nose, flat nasal bridge, dental anomalies, thick lips, dental anomalies, bilateral epicanthal fold) and CNS anomalies (agenesis of the corpus callosum and bilateral hippocampal atrophy), thus meeting clinical criteria for the diagnosis of CSS. Karyotype was 46,XX. The patient was started on GH replacement therapy, with favorable outcomes. Current practical knowledge regarding CSS diagnosis and management from the endocrinological point of view is also reviewed. [ABSTRACT FROM AUTHOR]

Pregnancy nutrition influences the short-term maternal and fetal prognosis, but also the state of health in the future, an inadequate diet being associated with the risk of chronic diseases in adulthood. The purpose of the study is to characterize the diet of a group of pregnant women in Iasi county in terms of macronutrient intake, but also food patterns. Material and methods. An observational study was performed on a sample of 400 pregnant women which consisted in the application of a validated food frequency questionnaire. The foods consumed were grouped into categories: meat, eggs, fish, milk and dairy products, bread and cereals, vegetables, fruits, soups, seeds and oilseeds, sweets and fast food. Factor analysis (main component analysis method) was used for the analysis of food patterns. Results. The average energy intake in the studied group was 2197 kcal/day (95% CI: 2139.57-2255.74). The intake of macronutrients during pregnancy was 86.01 g protein (95% CI: 83.64-88.39), 76.97 g lipids (95% CI: 74.59-79.35) and 297.12 g carbohydrate (95% Cl: 287.86-306.38). We identified 3 dietary patterns that explained 43.01% of the variation of consumption behaviour: healthy consumption, consisting of a diet rich in soups, fruits, eggs and vegetables; traditional consumption, which has high consumption values for bread, dairy, meat, fat and unhealthy consumption rich in the intake of sweets, fast food and seeds. Conclusions. The identified food patterns draw attention to the existence of a category at risk of developing pathology related to inadequate nutrition in pregnancy. [ABSTRACT FROM AUTHOR]

Hereditary gingival fibromatosis is a rare disease characterized by various degrees of attached gingival overgrowth. It can be isolated or be part of some syndromes, the isolated form being sporadic or familial with autosomal dominant pattern of transmission. Our patient is a female with moderate gingival enlargement firm on palpation and with normal color. Both mandible and maxilla are involved and have functional impairment (the speech and mastication affected). The onset of the disease was in childhood during the eruption of permanent dentition and the patient was treated by repeated gingivectomy procedures. The personal history rules out the use of medications involved in gingival enlargement. Family history was positive for gingival overgrowth consistent with dominant inheritance. The syndromes with gingival fibromatosis were excluded. The patient was surgically treated and the histological features are consistent with gingival fibromatosis. The complex management includes gingivectomy for functional improvement of speech and mastication. Also, it is important to identify the isolated form or the syndromic one in order to provide appropriate genetic counseling. [ABSTRACT FROM AUTHOR]

Cleidocranial dysplasia (CCD) is a rare autosomal dominant skeletal dysplasia, determined by RUNX2 gene mutation (located on 6p21.1) encoding the transcription factor CBFA1 which has a major role in regulation of bone differentiation. The major clinical features include the presence of wide-large fontanels at birth, short stature and other skeletal abnormalities (brachydactyly, pes planus, genu valgum, scoliosis). Patients often have recurrent respiratory infections and a normal intellect. The disease has a high penetrance and variable expressivity, some patients presenting subtle clinical signs of the disease. We present a patient, L. E., male, diagnosed with cleidocranial dysplasia at the age of 8 years. The history revealed a delayed closure of the anterior fontanel (2 years and 6 months); at the age of 5 years the patient has been diagnosed with pituitary dwarfism and rickets. Clinical examination revealed: short stature, craniofacial dysmorphism (frontal bossing, delayed tooth eruption, agenesis of premolars), sloping shoulders, pectus excavatum, brachydactyly, pes planus and hypoplastic nails feet. Chest X-ray and thorax CT scan revealed the presence of bilateral clavicular hypoplasia and cranial MRI scan revealed the presence of a pituitary hypoplasia, frontal sinus agenesis and hypoplasia of the maxillary sinus. Hand X-ray revealed a delayed bone age. The treatment was symptomatic involving growth hormone replacement therapy and orthodontic, orthopedic and pediatric care. In conclusion, we emphasize the importance of clinical and radiological examination to achieve early diagnosis, to establish an appropriate treatment and prevention of complications of the disease. [ABSTRACT FROM AUTHOR]

Esophageal atresia (EA) is defined as the absence of an esophageal segment and is often associated with tracheoesophageal fistula (TEF). The incidence of EA with/ without TEF is between 1:3,000 and 1: 4,000 newborns. Approximately 50%-70% of cases associate a major congenital anomaly (MCA). Commonly associated malformations are cardiovascular (15-40%), gastrointestinal (25-30%), genitourinary (20-25%) and musculoskeletal (10-15%). Usually, the MCA associated with EA represent the component of a specific plurimalformative syndrome, like VACTERL association and CHARGE syndrome. In 5 to 10% of cases we can detect chromosomal abnormalities (trisomy 21 or 18, microdeletion 22q11.2). We present two patients with EA/TEF and genetic conditions. Case1 - female, 4 days old. Clinical features - intrauterine growth retardation, facial dysmorphism: dolicocephaly, micrognathia, dysplastic ears; prominent calcaneus, EA, heart defect, kidney anomaly. The clinical suspicion of Edwards syndrome was confirmed by karyotype that showed a 47,XX,+18 chromosomal formula. Case 2 - female, 5 days old. Clinical features - EA with TEF, vertebral anomalies, anal atresia, bilateral thumb hypoplasia. This clinical association of MCA was concordant with VACTERL association. Management, prognosis and genetic counseling will be discussed. Our cases illustrate the need for careful genetic evaluation for EA/TEF, especially when these are associated with MCA. [ABSTRACT FROM AUTHOR]

Bardet Biedl syndrome (BBS) is a rare primary ciliopathy with a complex and extremely variable clinical presentation. The core features of the disease are rod-cone dystrophy, postaxial polydactyly, central obesity, urogenital anomalies, learning difficulties and kidney disease, however the impairment of any organ may complicate the clinical picture. Here we report on clinical findings of 25 patients diagnosed with BBS. Our study is the first on a cohort of Romanian BBS patients, aiming to emphasize the complexity of the disease that may have a devastating impact on patients and their families. Thus, an early clinical diagnosis is crucial for anticipation of other system and organ involvement. Periodic follow up, by a multidisciplinary team, may prevent several severe complications, which could accelerate or aggravate the most deleterious aspects of the disease: loss of vision or renal impairment. [ABSTRACT FROM AUTHOR]

Obesity affects more than one billion people worldwide and often leads to cardiometabolic chronic comorbidities. It induces senescence-related alterations in adipose tissue, and senescence is closely linked to obesity. Fully elucidating the pathways through which vitamin D exerts anti-inflammatory effects may improve our understanding of local adipose tissue inflammation and the pathogenesis of metabolic disorders. In this narrative review, we compiled and analyzed the literature from diverse academic sources, focusing on recent developments to provide a comprehensive overview of the effect of vitamin D on inflammation associated with obesity and senescence. The article reveals that the activation of the NF-κB (nuclear factor kappa B subunit 1) and NLRP3 inflammasome (nucleotide-binding domain, leucine-rich-containing, pyrin domain-containing-3) pathways through the toll-like receptors, which increases oxidative stress and cytokine release, is a common mechanism underlying inflammation associated with obesity and senescence, and it discusses the potential beneficial effect of vitamin D in alleviating the development of subclinical inflammation. Investigating the main target cells and pathways of vitamin D action in adipose tissue could help uncover complex mechanisms of obesity and cellular senescence. This review summarizes significant findings related to opportunities for improving metabolic health.

Primary immunodeficiencies are genetic diseases, mainly monogenic, that affect various components of the immune system and stages of the immune response. The category of combined immunodeficiencies with associated or syndromic features comprises over 70 clinical entities, characterized by heterogeneity of clinical presentation, mode of transmission, molecular, biological, mutational and immunological aspects. The mutational spectrum is wide, ranging from structural chromosomal abnormalities to gene mutations. The impact on the function of the proteins encoded by the genes involved is different; loss of function is most common, but situations with gain of function are also described. Most proteins have multiple functions and are components of several protein interaction networks. The pathophysiological mechanisms mainly involve: Missing enzymes, absent or non-functional proteins, abnormal DNA repair pathways, altered signal transduction, developmental arrest in immune differentiation, impairment of cell-to-cell and intracellular communications. Allelic heterogeneity, reduced penetrance and variable expressivity are genetic phenomena that cause diagnostic difficulties, especially since most are rare/very rare diseases, which is equivalent to delaying proper case management. Most primary immunodeficiencies are Mendelian diseases with X-linked or recessive inheritance, and molecular diagnosis allows the identification of family members at risk and the application of appropriate primary and secondary prevention measures in addition to the specific curative ones. In conclusion, recognizing heterogeneity and its sources is extremely important for current medical practice, but also for the theoretical value of improving biological and biomedical applications., (Copyright: © Caba et al.)

Unlabelled: Trisomy X (47,XXX) is a gonosomal aneuploidy characterized by the presence of an extra X chromosome in a female person. Usually the diagnosis is established made postnatally by chromosome analysis in patients with suggestive clinical signs. Clinical signs vary by age. In prepubertal patients have a growth retardation associated with uncharacteristic facial dysmorphism, mild mental retardation with behavioral disorders, plus clinical signs of ovarian dysgenesis, postpubertal., Aim: We analyzed retrospectively the genotype - phenotype correlations for a selected group of 36 patients diagnosed with trisomy X (homogeneous or mosaic) by cytogenetic methods (X chromatin and karyotype)., Material and Methods: Analysis of the clinical data of 36 patients diagnosed with trisomy X and correlation with the results of X chromatin and karyotype., Results: Clinical signs detected in patients with homogeneous trisomy X 47,XXX (22.22%), mosaic 46,XX/47,XXX (16.66%) or 47,XXX/48,XXXX (5.55%) were prepubertal, growth retardation associated with dysmorphic facial (upslanted palpebral fissure, epichantus, thin lips) and postpubertal, signs of ovarian dysgenesis (secondary amenorrhea, early menopause). The phenotype of patients with different gonosomal mosaic corresponding to Turner syndrome, incorporating a cell line with trisomy X (55.55%) was variable, correlated with the type of chromosomal abnormalities detected., Conclusions: The results of our study are similar to those obtained in other studies and emphasizes that phenotypic variability of patients with trisomy X feature makes it difficult to genotype - phenotype correlations.

Unlabelled: Prenatal diagnosis (PD) by FISH or cell culture is today an important tool for the prevention of chromosomal anomalies. A difficult issue is prenatal detection of gonosomal anomalies. Most gonosomal anomalies neither affect life expectancy nor cause psychomotor retardation, but sexualization disorders and the lack of reproductive potential are a constant finding., Aim: This study aimed at identifying the medical problems the specialists and the parental couple are faced with at the time of the diagnosis of fetal gonosomal anomalies., Material and Methods: This retrospective study (2004-2012) was conducted in the Prenatal Genetic Diagnosis Department of "CuzaVoda" Maternity by FISH technique in 1685 pregnancies. The AneuVysion probes were used for identifying and enumerating chromosomes 13, 18, 21, X, and Y via fluorescence in situ hybridization (FISH) in interphase nuclei obtained from amniotic fluid., Results: Fifteen fetuses were selected in which we were faced with difficulties interpreting the number of gonosomes: monosomy X (5 cases), pseudomosaicism XX/XY (3), trisomy XXY (3 cases), trisomy XYY (1 case), 45,X/46.XX mosaicism (1 case) and triploidy XXX (2 cases). Later, by repeating the analysis, 2 cases with pseudomosaicism XX/XY were excluded. A case highlighting the limitations of the FISH test was that of a fetus in which the FISH test revealed trisomy XXY, while postnatal karyotyping showed a six cell line mosaicism (marker and ring X chromosomes)., Conclusions: All parental couples received nondirective genetic counseling, respecting the individuals' dignity and rights of self-determination. Parents received information on the natural course of the disease, treatment options, and psychological support and were involved in their child's recovery.

Unlabelled: Patau syndrome has an incidence of 1/10.000-20.000, the clinical diagnosis being suggested by the triad cleft lip and palate, microphthalmia/anophthalmia and postaxial polydactyly. Most frequent cytogenetic abnormality is free and homogeneous trisomy 13 (80.0%), rarely being detected trisomy mosaics or Robertsonian translocations. The objective of the study was to identify phenotypic features of trisomy 13., Material and Methods: The retrospective study was conducted on a trial group of 14 cases diagnosed cytogenetically with trisomy 13 between January 2000 and December 2012 at lasi Medical Genetics Centre., Results: Of the 14 cases, 3 were evaluated pathologically (two aborted foetuses and one stillborn), 8 cases were detected in the neonatal period, and 3 in infancy. Clinical diagnosis was supported by the identification of a model of abnormal development, mainly characterized by: maxillary cleft (lip and palate--5 cases; lip--1 case), ocular abnormalities (microphthalmia/anophthalmia--7 cases; cyclopia--1 case), postaxial polydactyly (7 cases), scalp defects (6 cases), congenital heart anomalies (10 cases, 6 patients with atrial septal defect), complete holoprosencephaly (4 cases), ear abnormalities (11 cases), broad nasal root (10 cases). An important issue in confirming the phenotypic variability of Patau syndrome is that the classic clinical triad was identified only in one case., Conclusions: Patau syndrome is a disease with variable expression and is characterized by a pattern of abnormal prenatal development characterized by facial dysmorphia, polydactyly and severe birth defects (heart, brain) that generate an increased in utero and perinatal mortality.

Unlabelled: Velo-Cardio-Facial Syndrome (VCFS) is characterized by congenital heart defects (CHD), palatal abnormalities, facial dysmorphism, neonatal hypocalcemia, immune deficit, speech and learning disabilities. SVCF is caused by microdeletion 22q11.2. Microdeletion is detected by fluorescence in situ hybridization (FISH). The highly variable phenotype makes diagnosis and selection for FISH more difficult., Aim: To retrospectively analyze and compare the phenotype of children with a clinical diagnosis of VCFS with/without 22q11 deletion; to verify the validity of literature guidelines and to describe combinations of clinical features that should lead to molecular analysis., Material and Methods: The present study was performed in 21 patients with a clinical diagnosis of VCFS. Methaphase chromosome spreads were prepared from phytohaemagglutinin stimulated lymphocyte culture by standard methods before FISH. The patients were divided into two groups according to FISH test: positive and negative., Results: The features commonly noticed in FISH positive patients were: palatal abnormalities/hypernasal speech, learning disabilities, facial dysmorphism, tapered fingers (6/6), CHD (5/6) and recurrent infections (2/6). In FISH negative patients the following were found: learning disabilities, CHD (12/15); facial dysmorphism (10/15), family history of CHD (7/15), short stature (6/15), hypocalcemia, tapered fingers (5/15), recurrent infections (3/15) and palatal cleft (2/15). In both groups, Tobias and McDonald-McGinn guidelines were positive., Conclusions: VCFS has a highly variable phenotype. Our study suggests that 22q11.2 deletion analysis by FISH should be performed in patients who have at least 2 (newborn)/3 (child, adult) specific criteria: CHD, hypocalcemia, palatal abnormalities, facial dysmorphism, learning disabilities, digital anomalies, and immune deficit.

Unlabelled: Reproductive Disorders (RD), manifested by the biological inability to conceive (primary sterility) or inability to carry a pregnancy to full-term (infertility), affect 10-15% of reproductive-aged couples. The genetic etiology of RD is represented, in the majority of cases, by the chromosomal abnormalities., Aim: To retrospectively analyze the karyotype results in a selected group of couples with RD., Material and Method: The present study was performed in 266 couples with RD: 80 (30.07%) with primary sterility (ST), 149 (56.01%) with Recurrent Spontaneous Abortions (RSA) and 37 (13.90%) with Stillborn Children (SC). A GTG-banded karyotype was performed on both partners of each couple., Results: We identified a chromosomal abnormality in 43 individuals (16.16%): 20 cases (7.51%) with ST, 13 cases (4.88%) with RSA and 10 cases (3.75%) with SC. The affected partner was female in 23 cases (8.64%) and male in 20 cases (7.51%). A X chromosome (numerical or structural) abnormality was detected in 18 cases (6.76%), most frequent X chromosome monosomy mosaicism in female and trisomy XXY in male; a balanced structural chromosomal abnormality (BSC) was detected in 23 couples (8.64%); in other two males with ST, the karyotype result was 46,XX., Conclusions: The results of our study are similar to other reported studies and underline the major etiologic role of chromosomal abnormalities in RD and the importance of chromosomal analysis for the etiologic diagnosis and genetic counseling of these patients.

We present a retrospective study aimed to identify the correlation between de Vries clinical score and the detection of chromosomal abnormalities in mentally retarded (MR) children. We have used the score to identify patients who should be tested by karyotyping and subsequently MLPA (multiplex ligation dependent probe amplification) for subtelomeric rearrangements. Our group is formed of 36 children with variable MR associated with other anomalies. 18 children had chromosomal defects, whereas 18 had normal karyotypes. In the first group, total scores varied between 3 and 7. Chromosomal anomalies identified were: numerical (4) and structural (14). Chromosomes involved were: 1, 4, 5, 7, 8, 9, 17, X. Deletions were the most common and correlate with a greater score (> or = 4). Common clinical features were: short stature, microcephaly, nasal, ear and hand anomalies. In the second group the most frequent clinical feature was hand anomaly (61.2%) and cases with a high score have to be further tested (e.g. using MLPA) in order to identify minor defects. In our opinion a high score indicates the karyotype and then a MLPA testing. In conclusion, we present a retrospective study that proves the use of de Vries diagnostic score in the identification of chromosomal abnormalities in MR children.