Congenital Heart Malformations Masked by Infantile Gangliosidosis-Case Report and Growing Evidence for Metabolic Disease-Associated Aortopathies.

Gangliosidosis (ORPHA: 79255) is an autosomal recessive lysosomal storage disease (LSD) with a variable phenotype and an incidence of 1:200000 live births. The underlying genotype is comprised GLB1 mutations that lead to ß-galactosidase deficiency and subsequently to the accumulation of monosialotetrahexosylganglioside (GM1) in the brain and other organs. In total, two diseases have been linked to this gene mutation: Morquio type B and Gangliosidosis. The most frequent clinical manifestations include dysmorphic facial features, nervous and skeletal systems abnormalities, hepatosplenomegaly, and cardiomyopathies. The correct diagnosis of GM1 is a challenge due to the overlapping clinical manifestation between this disease and others, especially in infants. Therefore, in the current study we present the case of a 3-month-old male infant, admitted with signs and symptoms of respiratory distress alongside rapid progressive heart failure, with minimal neurologic and skeletal abnormalities, but with cardiovascular structural malformations. The atypical clinical presentation raised great difficulties for our diagnostic team. Unfortunately, the diagnostic of GM1 was made postmortem based on the DBS test and we were able to correlate the genotype with the unusual phenotypic findings.

Increasing Trends in Obesity-Related Cardiovascular Risk Factors in Romanian Children and Adolescents-Retrospective Study.

Childhood obesity has become a global public health issue and its assessment is essential, as an obese child is a future overweight or obese adult. Obesity is no longer a matter of exercising more and eating less, with several factors coming into play and dictating the pattern of fat accumulation and the ease/difficulty of reducing it. In the current paper, we aimed to analyze the cardiovascular impact of obesity in a large number of patients alongside the paraclinical changes that occur due to weight gain, and to perform an analysis on the increase in prevalence throughout our research. The main cardiovascular conditions identified were hypertension (15.36%), septal or concentric hypertrophic cardiomyopathy (11.15%), atherosclerosis risk (13.04%), and hypercholesterolemia (20.94%). We have used echocardiography to measure the thickness of epicardial adipose tissue (useful for assessing the patient's cardiovascular risk), and we observed that it was greater in children with moderate and severe obesity alongside diastolic dysfunction of the left ventricle in the whole group, without any connection with hypertension or coronary impairment. Obese children will be affected by increased cardiovascular mortality and morbidity in adulthood and they may experience early cardiovascular dysfunction. We want to strongly underline the importance and necessity of programs for the early detection and prevention of obesity and its complications, especially since interesting phenomena such as the "obesity paradox" exist and prove that obesity is far less understood than it is at a first glance.

Monitoring and Management of Bardet-Biedl Syndrome: What the Multi-Disciplinary Team Can Do.

Bardet - Biedl syndrome is a rare autosomal recessive multisystem non-motile ciliopathy. It has heterogeneous clinical manifestations. It is caused by mutations in 26 genes encoding BBSome proteins, chaperonines, and IFT complex. The main clinical features are: retinal cone-rod dystrophy, central obesity, postaxial polydactyly, cognitive impairment, hypogonadism and genitourinary anomalies, and kidney disease. The onset of clinical manifestations is variable which makes the diagnosis difficult in some patients. Because of the multiple system involvement, a multidisciplinary approach is necessary. The purpose of this review is to provide monitoring and management directions for a better approach to these patients.

Epidermolysis Bullosa-A Different Genetic Approach in Correlation with Genetic Heterogeneity.

Epidermolysis bullosa is a heterogeneous group of rare genetic disorders characterized by mucocutaneous fragility and blister formation after minor friction or trauma. There are four major epidermolysis bullosa types based on the ultrastructural level of tissue cleavage: simplex, junctional, dystrophic, and Kindler epidermolysis bullosa. They are caused by mutations in genes that encode the proteins that are part of the hemidesmosomes and focal adhesion complex. Some of these disorders can be associated with extracutaneous manifestations, which are sometimes fatal. They are inherited in an autosomal recessive or autosomal dominant manner. This review is focused on the phenomena of heterogeneity (locus, allelic, mutational, and clinical) in epidermolysis bullosa, and on the correlation genotype-phenotype.

A Case of Inherited t(4;10)(q26;q26.2) Chromosomal Translocation Elucidated by Multiple Chromosomal and Molecular Analyses. Case Report and Review of the Literature.

We present a complex chromosomal anomaly identified using cytogenetic and molecular methods. The child was diagnosed during the neonatal period with a multiple congenital anomalies syndrome characterized by: flattened occipital region; slight turricephaly; tall and broad forehead; hypertelorism; deep-set eyes; down slanting and short palpebral fissures; epicanthic folds; prominent nose with wide root and bulbous tip; microstomia; micro-retrognathia, large, short philtrum with prominent reliefs; low set, prominent ears; and congenital heart disease. The GTG banding karyotype showed a 46,XY,der(10)(10pter→10q26.2::4q26→4qter) chromosomal formula and his mother presented an apparently balanced reciprocal translocation: 46,XX,t(4;10)(q26;q26.2). The chromosomal anomalies of the child were confirmed by MLPA, and supplementary investigation discovered a quadruplication of the 4q35.2 region. The mother has a triplication of the same chromosomal fragment (4q35.2). Using array-CGH, we described the anomalies completely. Thus, the boy has a 71,057 kb triplication of the 4q26-q35.2 region, a 562 kb microdeletion in the 10q26.3 region, and a 795 kb quadruplication of the 4q35.2 region, while the mother presents a 795 kb triplication of the 4q35.2 region. Analyzing these data, we consider that the boy's phenotype is influenced only by the 4q partial trisomy. We compare our case with similar cases, and we review the literature data.

Craniofacial morphological changes of familial bilateral hypodontia of maxillary premolars.

The hypodontia of a permanent tooth from a dental group represents a normal evolution in human dentition morphology. Nevertheless, the hypodontia of two teeth within a dental group is a rare developmental anomaly when not associated to a systemic syndrome. The aim of this study was to report two rare cases of four maxillary premolars hypodontia, not including the third molar, of two white women from the same family. There were presented clinical, radiological and genetic findings. These cases are of interest to practitioners for four aspects: the atypical phenotype of hypodontia, the complexity of craniofacial morphological changes, the autosomal dominant familial inheritance with variable expressivity and the difficult classification of diagnosis.

Phenotypic variability in Patau syndrome.

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.

Prenatal diagnosis of gonosomal anomalies: limitations of the FISH method and genetic counseling difficulties in 15 cases.

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.

A case of turner syndrome associated with severe coarctation of the aorta.

Turner Syndrome (TS) is a chromosomal abnormality due to the complete or partial lack of chromosome X, with clinical polymorphic elements: small size, hypogonadism, various visceral abnormalities. About half of the cases may suffer from congenital heart abnormalities. We describe hereunder a case of TS diagnosed with coarctation of the aorta due to high blood pressure detected by accident.

Genotype- phenotype correlation in trisomy X: a retrospective study of a selected group of 36 patients and review of literature.

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.

Inverted duplication deletion of 8P: characterization by standard cytogenetic and SNP array analyses.

Inverted 8p duplication deletions are recurrent chromosomal rearrangements that most often arise through non-allelic homologous recombination (NAHR) during maternal meiosis between segmental duplications made up of the olfactory receptor (OR) gene clusters. The presence of a paracentric inversion polymorphism in 8p23.1, found in approximately 26% of European population, may trigger meiotic misalignment and NAHR between the OR gene repeats. We report clinical, cytogenetic, and molecular findings in a 4 year 8 month-old female with concomitant inverted duplication and terminal deletion of chromosome 8p. The girl, the first child of unrelated parents, was born at term, by normal delivery, after an uneventful pregnancy. Clinical examination revealed dysmorphic features, pectus excavatum, hypertonia, severe developmental delay. Brain ultrasound and MRI showed agenesis of the corpus callosum without other abnormalities. Conventional cytogenetic analysis identified additional material on chromosome 8 at band p21. SNP array analysis further characterized the abnormality as a duplication of about 31.3 Mb, from 8p23.1 to 8p11.1, and additionally revealed a terminal deletion of about 6.8 Mb, from 8p23.3 to 8p23.1. Genomic microarray also identified a region of disomy between deletion and duplication. Chromosome analysis of both parents revealed normal results. Based on clinical examination, conventional cytogenetics and SNP array, we established the diagnosis of inverted duplication deletion of 8p. SNP array analysis precisely defined the breakpoints of rearrangement and, by identifying a region of disomy between the duplication and deletion, indicated that NAHR between segmental duplications was the most likely mechanism for this type of abnormality.

[Improvement of genetic diagnostic strategy in velo-cardio-facial syndrome]. / Optimizarea strategiei de diagnostic genetic în sindromul velo-cardio-facial.

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.

[Idiopathic mental retardation--importance of clinical diagnostic scores for case selection]. / Retardul mental idiopatic--importanta scorurilor de diagnostic clinic pentru selectia cazurilor.

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.

[Clinical, epidemiological and cytogenetic studies on 221 patients with Down syndrome]. / Studii clinice, epidemiologice si citogenetice pe un lot de 221 pacienti cu sindrom Down.

UNLABELLED: Down syndrome, determined by 21 trisomy, represents a major cause of infantile morbidity and mortality. AIM: The analysis of dysmorphic features in Down syndrome, incidence of major congenital abnormalities, of some epidemiological parameters and cytogenetic specifics. MATERIAL AND METHOD: Methods used were clinical, epidemiological and cytogenetical. We analysed 221 patients, from Iasi county, with clinical supposition of Down syndrome, identified in the first year of life, between 1985 and 1999. RESULTS: The majority of patients (67%) have more than 5 from 10 characteristics dysmorphic signs of Down syndrome in neonatal period. Visceral congenital abnormalities--82 cases (37.1%) were isolate (cardiac or digestive) or multiple. The presence of one visceral abnormality determined the death of patient in 30 cases (46.15% of death). Medium incidence of Down syndrome in Iasi county was 1.306 per thousand (1/769 new-born), with median value 1.091per thousand and corrected value related to the maternal age 1.056 per thousand. Cytogenetic analysis was performed at 101 patients, in 95 cases (94.05%) clinical suspicion of Down syndrome was correct, patients presenting 21 trisomy (in the majority of cases a homogenous free trisomy). CONCLUSION: The data obtained by us are concordant with the majority of literature studies, that a test the correctness of clinical trial and validate our results.

[Drug therapy at the beginning of the genomic era]. / Terapeutica medicamentoasa la începutul erei genomice (I).

The individualisation of drug therapy according to the genetic profile of each patient would allow to avoid the adverse effects and to reach the maximum therapeutic efficiency, therefore an optimum risk/efficiency ratio. This desideratum has become feasible in the genomic era by identifying and mapping a true mononucleotid polymorphism signature DNA (single nucleotide polymorphism fingerprint--SNP) and by using the new technologies. The present day data regarding the polymorphism of the genetic determinants involved in the response to drugs are synthetically shown, as well as the defining of the new fields--pharmacogenetics and pharmacogenomics. Although superposable and interchangeable up to a point, the term of pharmacogenetics rather refers to the study of the variability of response to drugs according to the genetic profile, the term of pharmacogenomics being reserved to the analysis of the genome (DNA and its products, RNA and proteins), in relation with the response to drugs. The differences among the individuals concerning the pharmacokinetics and the pharmacodynamics can be explained through the polymorphism of the substrata (enzymes, carrier proteins, receptors) that explains the genetic stratification of the population. The development strategies of the drug research and of the pharmaceutical industry will certainly be modulated by the new acquisitions in the field of pharmacogenetics and pharmacogenomics, with the inherent bioethical implications. New specific drugs for the patients possessing peculiar genotypes could be synthesized, the starting off of the prealable stratification of the patients according to their genotype.