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Background : Down syndrome (DS) is the most prevalent chromosomal condition, with the average life expectancy significantly rising from 25 years in 1983 to 60 years in 2020. People with DS generally can participate in most physical activities that individuals without the disability can, despite some physical limitations. However, the varying degrees of cognitive deficits can present challenges when it comes to performing physical activities. Methods : We conducted a prospective, cross-sectional study in the Cardiovascular Rehabilitation Clinic from the Clinical Rehabilitation Hospital from Iași, Romania, between July 2022 and February 2024 that included 28 patients diagnosed with DS. We collected data regarding age and comorbidities and performed several tests (MMSE, timed-up-and-go test, and handgrip strength). Results : The group consisted of 11 (39%) females and 17 (61%) males with a mean age of 28.07 ± 9.51 years. The weight profile of the study group differed according to the degree of physical activity: 62.50% of those with moderate physical activity were moderately overweight, while 75% of those with minimal activity were overweight or obese. The muscle strength and MMSE score was higher in the group of patients who performed moderate physical activity. Regarding comorbidities, there was a statistically significant difference in the percentage of patients with hearing loss among those with minimal physical activity. Conclusions : Our results provide an update on the very limited data available. The study indicates that people with DS are generally less physically active and face unique health challenges (hearing loss, intellectual disabilities, and osteoarticular pathologies).

(1) Background: Down syndrome is characterized by physical abnormalities, intellectual disability (ID), and specific patterns of other health issues. Additionally, individuals with DS are known to experience premature aging and early onset of certain age-related medical conditions. These conditions are linked to higher incident disability and reduced survival rates compared to the general population. (2) Methods: Between July 2022 and February 2024, we conducted a prospective, observational study in the Cardiovascular Rehabilitation Clinic at Iasi Clinical Rehabilitation Hospital. The study included 28 patients diagnosed with Down Syndrome and a control group. Interdisciplinary interventions were tailored to address the needs of a complex patient, incorporating cardiological, endocrinological, genetical, biological and developmental support. Data on physical health, cognitive development, and psychosocial well-being were collected. (3) Results: Our DS group consisted of 11 (39%) females and 17 (61%) males. Their age ranged from 20 to 55 years with a mean of 28.07 ± 9.51. All patients were unmarried, living in urban areas, without a partner but with family support. In the study sample, 96.4% of participants had three or more comorbidities. (4) Conclusions: The high prevalence of multimorbidity, combined with little medication, contributes to a high level of clinical complexity, which appears to be similar to the one of the older non-trisomic population. As individuals with Down syndrome transition into adulthood, they may require a more comprehensive and holistic approach to their healthcare.

From 2007 in US and from 2022 in EU it is mandatory to use TPMS monitoring in new cars. Sensors mounted in tires require a continuous power supply, which currently only is from batteries. Piezoelectric energy harvesting is a promising technology to harvest energy from tire movement and deformation to prolong usage of batteries and even avoid them inside tires. This study presents a simpler method to simultaneous model the tire deformation and piezoelectric harvester performance by using a new simulation approach - dynamic bending zone. For this, angular and initial velocities were used for rolling motion, while angled polarization was introduced in the model for the piezoelectric material to generate correct voltage from tire deformation. We combined this numerical simulation in COMSOL Multiphysics with real-life measurements of electrical output of a piezoelectric energy harvester that was mounted onto a tire. This modelling approach allowed for 10 times decrease in simulation time as well as simpler investigation of systems parameters influencing the output power. By using experimental data, the simulation could be fine-tuned for material properties and for easier extrapolation of tire deformation with output harvested energy from simulations done at low velocity to the high velocity experimental data., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests Cristina Rusu reports financial support was provided by 10.13039/501100000780European Commission. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Bardet-Biedl syndrome (BBS), is an emblematic ciliopathy hallmarked by pleiotropy, phenotype variability, and extensive genetic heterogeneity. BBS is a rare (~1/140,000 to ~1/160,000 in Europe) autosomal recessive pediatric disorder characterized by retinal degeneration, truncal obesity, polydactyly, cognitive impairment, renal dysfunction, and hypogonadism. Twenty-eight genes involved in ciliary structure or function have been implicated in BBS, and explain the molecular basis for ~75%-80% of individuals. To investigate the mutational spectrum of BBS in Romania, we ascertained a cohort of 24 individuals in 23 families. Following informed consent, we performed proband exome sequencing (ES). We detected 17 different putative disease-causing single nucleotide variants or small insertion-deletions and two pathogenic exon disruptive copy number variants in known BBS genes in 17 pedigrees. The most frequently impacted genes were BBS12 (35%), followed by BBS4, BBS7, and BBS10 (9% each) and BBS1, BBS2, and BBS5 (4% each). Homozygous BBS12 p.Arg355* variants were present in seven pedigrees of both Eastern European and Romani origin. Our data show that although the diagnostic rate of BBS in Romania is likely consistent with other worldwide cohorts (74%), we observed a unique distribution of causal BBS genes, including overrepresentation of BBS12 due to a recurrent nonsense variant, that has implications for regional diagnostics., (© 2023 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

(1) Background: Familial hypercholesterolemia (FH) is a genetic disease that has autosomal dominant inheritance, being characterized by increased levels of low-density lipoproteins (LDLs) due to a decreased clearance of the circulant LDLs. Alimentation is a key factor in patients with FH. Implementing a restrictive diet may have a significant impact on their quality of life, besides the social and environmental factors. (2) Methods: We realized a prospective study that was conducted in the Cardiovascular Rehabilitation Clinic from the Clinical Rehabilitation Hospital and that included 70 patients with FH and 20 controls (adults with no comorbidities). We evaluated their lipid profile, their quality of life through the Short Form-36 Questionnaire, and their eating habits. (3) Results: Lower scores in the quality-of-life questionnaire were obtained in the FH group both in the case of the physical (73.06 vs. 87.62) and the mental component (75.95 vs. 83.10). Women had better physical function (85 vs. 75) and physical role than men (100 vs. 75). The group aged over 65 has the score lowest for all 10 components. Overeating was driven by boredom and was more frequent on weekends in the FH group. None of the patients in the control group felt loneliness or depression associated with overeating. (4) Conclusions: Overeating in patients with FH is associated with a lower quality of life. The complexity of these patients needs a multidisciplinary approach. Thus, the quality-of-life questionnaire should be implemented in their periodic follow-ups in order to increase their general status, paying special attention to geriatric patients.

Introduction: Natural killer (NK) cells are key anti-tumor effectors of the innate immunity. Phenotypic differences allow us to discriminate in between three functional stages of maturation, named immature, mature and hypermature that are distinctive in terms of receptor expression, cytokine secretion, cytotoxic properties and organ trafficking. NKs display an impressive repertoire of highly polymorphic germline encoded receptors that can be either activating, triggering the effector's function, or inhibitory, limiting the immune response. In our study, we have investigated peripheral blood NK cells of acute myeloid leukemia (AML) patients., Methods: The Killer Immunoglobulin-like receptors (KIRs) and the HLA-C genotypes were assessed, as HLA-C molecules are cognate antigens for inhibitory KIRs., Results: The AA mainly inhibitory KIR haplotype was found in a higher proportion in AML, while a striking low frequency of the 2DS3 characterized the mainly activating Bx haplotype. Flow cytometry immunophenotyping evidenced a lower overall count of NK cells in AML versus healthy controls, with lower percentages of the immature and mature subpopulations, but with a markedly increase of the hypermature NKs. The analysis of the KIR2DL1, KIR2DL2, KIR2DL3, KIR3DL1, and NKG2A inhibitory receptors surface expression revealed a remarkable heterogeneity. However, an overall trend for a higher expression in AML patients could be noticed in all maturation subpopulations. Some of the AML patients with complex karyotypes or displaying a FLT3 gene mutation proved to be extreme outliers in terms of NK cells percentages or inhibitory receptors expression., Discussion: We conclude that while the genetic background investigation in AML offers important pieces of information regarding susceptibility to disease or prognosis, it is flow cytometry that is able to offer details of finesse in terms of NK numbers and phenotypes, necessary for an adequate individual evaluation of these patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be considered as potential conflict of interest., (Copyright © 2023 Cianga, Rusu, Pavel-Tanasa, Dascalescu, Danaila, Harnau, Aanei and Cianga.)

(1) Background: Familial hypercholesterolemia (FH) is a genetic autosomal dominant disorder characterized by elevated levels of low-density lipoprotein cholesterol (LDL) that develops deposits of lipids in the arterial wall. Since it is underdiagnosed and undertreated, the disease has a high risk of premature cardiovascular disease and death. Patients are not always aware of the changes they should make in their diet. Thus, our study aimed to evaluate through a food frequency questionnaire their eating habits. (2) Methods: We included 70 patients with FH and 20 subjects in a control group that were evaluated through a physical examination and blood tests. They also completed a food frequency questionnaire. (3) Results: Throughout our study, we observed several aspects: regardless of age, patients with FH had higher carbohydrate intakes compared to the control group; from the same group, a positive correlation was observed between salami intake and the levels of glucose and glycated hemoglobin. Moreover, the sour cream preference was associated with higher liver function tests. In the control group, we observed a higher intake of pasta and fast food and fewer fruit portions. (4) Conclusions: As far as we know, this is the first study from Romania that evaluated the eating habits of patients diagnosed with FH. Our study reveals that, although patients with FH avoid junk food, they still have a high intake of carbohydrates when compared to the control group. Further research is needed in order to get a comprehensive nutritional evaluation of these patients.

Natural killer (NK) cells are key innate immunity effectors that play a major role in malignant cell destruction. Based on expression patterns of CD16, CD56, CD57, and CD94, three distinct NK cell maturation stages have been described, which differ in terms of cytokine secretion, tissue migration, and the ability to kill target cells. Our study addressed NK cell maturation in bone marrow under three conditions: a normal developmental environment, during pre-leukemic state (myelodysplastic syndrome, MDS), and during leukemic transformation (acute myeloblastic leukemia, AML). In this study, we used a new tool to perform multicolor flow cytometry data analysis, based on principal component analysis, which allowed the unsupervised, accurate discrimination of immature, mature, and hypermature NK subpopulations. An impaired NK/T cell distribution was observed in the MDS bone marrow microenvironment compared with the normal and AML settings, and a phenotypic shift from the mature to the immature state was observed in NK cells under both the MDS and AML conditions. Furthermore, an impaired NK cell antitumor response, resulting in changes in NK cell receptor expression (CD159a, CD158a, CD158b, and CD158e1), was observed under MDS and AML conditions compared with the normal condition. The results of this study provide evidence for the failure of this arm of the immune response during the pathogenesis of myeloid malignancies. NK cell subpopulations display a heterogeneous and discordant dynamic on the spectrum between normal and pathological conditions. MDS does not appear to be a simple, intermediate stage but rather serves as a decisive step for the mounting of an efficient or ineffective immune response, leading to either the removal of the tumor cells or to malignancy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cianga, Campos Catafal, Cianga, Pavel Tanasa, Cherry, Collet, Tavernier, Guyotat, Rusu and Aanei.)

Objective: Genetic diagnosis and mutation identification are now compulsory for Duchenne (DMD) and Becker muscular dystrophies (BMD), which are due to dystrophin ( DMD ) gene mutations, either for disease prevention or personalized therapies. To evaluate the ethnic-related genetic assortments of DMD mutations, which may impact on DMD genetic diagnosis pipelines, we studied 328 patients with DMD and BMD from non-European countries., Methods: We performed a full DMD mutation detection in 328 patients from 10 Eastern European countries (Poland, Hungary, Lithuania, Romania, Serbia, Croatia, Bosnia, Bulgaria, Ukraine, and Russia) and 2 non-European countries (Cyprus and Algeria). We used both conventional methods (multiplex ligation-dependent probe amplification [MLPA] followed by gene-specific sequencing) and whole-exome sequencing (WES) as a pivotal study ran in 28 patients where DMD mutations were already identified by standard techniques. WES output was also interrogated for DMD gene modifiers., Results: We identified DMD gene mutations in 222 male patients. We identified a remarkable allele heterogeneity among different populations with a mutation landscape often country specific. We also showed that WES is effective for picking up all DMD deletions and small mutations and its adoption could allow a detection rate close to 90% of all occurring mutations. Gene modifiers haplotypes were identified with some ethnic-specific configurations., Conclusions: Our data provide unreported mutation landscapes in different countries, suggesting that ethnicity may orient genetic diagnosis flowchart, which can be adjusted depending on the mutation type frequency, with impact in drug eligibility., (© 2020 American Academy of Neurology.)

Background Colorectal cancer is a successful model of genetic biomarker development in oncology. Currently, several predictive or prognostic genetic alterations have been identified and are used in clinical practice. The RAS gene family, which includes KRAS and NRAS act as predictors for anti-epithelial growth factor receptor treatment (anti-EGFR), and it has been suggested that NRAS mutations also play a role in prognosis: patients harboring NRAS alterations have a significantly shorter survival compared to those with wild type tumours. BRAF V600E mutations are rare and occur mostly in tumors located in the ascending colon in elderly female patients. BRAF is instrumental in establishing prognosis: survival is shorter by 10-16 months in BRAF-mutant patients, and BRAF may be a negative prognostic factor for patients who undergo hepatic or pulmonary metastasectomy. Moreover, this mutation is used as a negative predictive factor for anti-EGFR therapies. Two new biomarkers have recently been added to the metastatic colorectal cancer panel: HER2 and microsatellite instability. While HER2 is still being investigated in different prospective studies in order to validate its prognostic role, microsatellite instability already guides clinical decisions in substituted with advanced colorectal cancer. Conclusions There are current evidences that support using above mentioned genetic biomarkers to better identify the right medicine that is supposed to be used in the right patient. This approach contributes to a more individualized patient-oriented treatment in daily clinical practice.

Baraitser-Winter, Fryns-Aftimos and cerebrofrontofacial syndrome types 1 and 3 have recently been associated with heterozygous gain-of-function mutations in one of the two ubiquitous cytoplasmic actin-encoding genes ACTB and ACTG1 that encode β- and γ-actins. We present detailed phenotypic descriptions and neuroimaging on 36 patients analyzed by our group and six cases from the literature with a molecularly proven actinopathy (9 ACTG1 and 33 ACTB). The major clinical anomalies are striking dysmorphic facial features with hypertelorism, broad nose with large tip and prominent root, congenital non-myopathic ptosis, ridged metopic suture and arched eyebrows. Iris or retinal coloboma is present in many cases, as is sensorineural deafness. Cleft lip and palate, hallux duplex, congenital heart defects and renal tract anomalies are seen in some cases. Microcephaly may develop with time. Nearly all patients with ACTG1 mutations, and around 60% of those with ACTB mutations have some degree of pachygyria with anteroposterior severity gradient, rarely lissencephaly or neuronal heterotopia. Reduction of shoulder girdle muscle bulk and progressive joint stiffness is common. Early muscular involvement, occasionally with congenital arthrogryposis, may be present. Progressive, severe dystonia was seen in one family. Intellectual disability and epilepsy are variable in severity and largely correlate with CNS anomalies. One patient developed acute lymphocytic leukemia, and another a cutaneous lymphoma, indicating that actinopathies may be cancer-predisposing disorders. Considering the multifaceted role of actins in cell physiology, we hypothesize that some clinical manifestations may be partially mutation specific. Baraitser-Winter cerebrofrontofacial syndrome is our suggested designation for this clinical entity.

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.

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: 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.

Aim: the purpose of the present study was to determine the relationship between the Clopidogrel genetic response (based on laboratory specific tests) and the worse evolution of the patients with acute coronary syndromes., Material and Methods: The study included 80 patients (11 females and 69 males), aged between 45 - 85 years, admitted in the 1st Department of Cardiology, between January June 2012, diagnosed with acute coronary syndromes (especially unstable angina). All the patients received Clopidogrel as antiplatelet agent, in some cases associated with aspirin. The diagnosis of acute coronary syndrome was based on clinical, ECG, echocardiographic and enzymatic signs. All the patients accepted to be included in the present study and signed a consent formulary. The Clopidogrel resistance was determined by specific genetic laboratory tests., Results and Discussion: Of 80 cases, 4 patients were identified as normal responders (5%), 3 patients were low responders (3.75%), 58 patients were high responders (72.5%) and 15 patients were unpredictable (18.75%). In the high responders' group a lot of hemorrhagic disorders in different territories were identified. Normal responders had a good evolution. In patients with low response and unpredictable status the recurrence of angina and left ventricular failure as complications were frequent., Conclusions: The present study allowed a positive correlation between the haemorrhagic events and the high responder status to Clopidogrel. Low responder patients or those with an unpredictable phenotype had a worse evolution caused by the recurrence of angina or left ventricular failure.

Clopidogrel is an ADP receptor antagonist, an inhibitor of platelet activation and aggregation. The effect is due to its selective and irreversible blockade of the P2Y12 receptor. The concept of clopidogrel resistance emerged since several years ago. This biological finding has a very important impact especially in patients with acute coronary syndromes, explaining by this their worse evolution. Mechanisms of this resistance are very complex including: differences in intestinal absorption, hepatic conversion to the active metabolite through cytochrome 3A4 (CYP3A4) activity, drug interactions, individual variations in the activity of hepatic cytochrome P450 izoenzymes, platelet receptor polymorphisms and also clinical factors. According to this resistance patients are divided in two groups : "low or non-responders" (with a high risk of thrombosis) and "high--responders" (with a high risk of bleeding). Carriers of CYP2C19*2 or *3 alleles have been shown to respond poorly to standard doses of clopidogrel due to reduced metabolic activation of the drug. So, they are likely to develop subsequent thrombotic events. Starting from these, a lot of studies have been performed in order to elucidate the mechanisms of this resistance offering new perspectives regarding a proper administration of antiplatelet therapy in patients with acute coronary syndromes.

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.

Schimke immunoosseous dysplasia (SIOD) is an autosomal recessive multisystem disorder characterized by prominent spondyloepiphyseal dysplasia, T cell deficiency, and focal segmental glomerulosclerosis. Biallelic mutations in swi/snf-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1) are the only identified cause of SIOD, but approximately half of patients referred for molecular studies do not have detectable mutations in SMARCAL1. We hypothesized that skeletal features distinguish between those with or without SMARCAL1 mutations. Therefore, we analyzed the skeletal radiographs of 22 patients with and 11 without detectable SMARCAL1 mutations. We found that patients with SMARCAL1 mutations have a spondyloepiphyseal dysplasia (SED) essentially limited to the spine, pelvis, capital femoral epiphyses, and possibly the sella turcica, whereas the hands and other long bones are basically normal. Additionally, we found that several of the adolescent and young adult patients developed osteoporosis and coxarthrosis. Of the 11 patients without detectable SMARCAL1 mutations, seven had a SED indistinguishable from patients with SMARCAL1 mutations. We conclude therefore that SED is a feature of patients with SMARCAL1 mutations and that skeletal features do not distinguish who of those with SED have SMARCAL1 mutations.

Nephrotic syndrome, an entity described at the beginning of the 20th century, has still an unclear pathophysiology, genetic and immunologic factors being incriminated. Here we report three cases of nephrotic syndrome with genetic involvement. The article presented tremendous progress that have been made over the past few years in enhancing our understanding of the slit-diaphragm and podocyte biology and genetics involvement in nephrotic syndrome.

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.

Genetic causes of mental retardation (MR) are heterogeneous, but subtelomeric rearrangements are an important one. MLPA technique provides the best results in case detection. We have used MLPA to identify subtelomeric rearrangements in children with idiopatic MR. The protocol included: clinical selection; karyotype; antiFMRP test; MLPA. We have selected cases using de Vries diagnostic score. Patient data were recorded in a database. The group was formed of 142 MR children. In 24 (16.9%) the karyotype was abnormal. 16 cases (11.3%) presented speech delay/autism, but antiFMRP test was normal. 60 MLPA tests were done: 46 cases (76.7% were normal, 6 (10%) abnormal, 4 (6.7%) had polymorphism and 4 (6.7%) could not be interpreted. Clinical features of the cases identified are illustrated. In conclusion, the diagnostic score is useful in case selection for further testing and MLPA proves to be efficient in diagnosing subtelomeric rearrangements as a possible cause of idiopatic MR.

Purpose: Clinical and genetic study of a case of retinitis pigmentosa following the vision and the quality of life in this disease., Method: This paper presents a female periodically reevaluated in our clinic from the first diagnosis of retinitis pigmentosa which was established ten years ago, with many relatives with the diagnosis of retinitis pigmentosa, has also high hyperopia and optic disc drusen. A particular aspect--she is student at English Faculty and she want to become professor in a school for children with low vision. Clinical evaluation included complete ophthalmic and general examination, family history and also some additional lab and imaging study, In genetic evaluation of this case were used the basic rules of genetics to diagnose the genetic form of retinitis pigmentosa in order to offer a correct genetic counseling., Conclusions: Retinitis pigmentosa needs a broad clinical evaluation and a careful socio-professional rehabilitation of these low-vision patients.

MLPA (Multiplex Ligation-dependent Probe Amplification) is a recently introduced method, based on PCR principle, useful for the detection of different genetic abnormalities (aneuploidies, gene deletions/duplications, subtelomeric rearrangements, methylation status etc). The technique is simple, reliable and cheap. We present this method to discuss its importance for a modern genetic service and to underline its multiple advantages.

Schimke immunoosseous dysplasia (SIOD), which is characterized by prominent spondyloepiphyseal dysplasia, T-cell deficiency, and focal segmental glomerulosclerosis, is a panethnic autosomal recessive multisystem disorder with variable expressivity. Biallelic mutations in switch/sucrose nonfermenting (swi/snf) related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1) are the only identified cause of SIOD. However, among 72 patients from different families, we identified only 38 patients with biallelic mutations in the coding exons and splice junctions of the SMARCAL1 gene. This observation, the variable expressivity, and poor genotype-phenotype correlation led us to test several hypotheses including modifying haplotypes, oligogenic inheritance, or locus heterogeneity in SIOD. Haplotypes associated with the two more common mutations, R820H and E848X, did not correlate with phenotype. Also, contrary to monoallelic SMARCAL1 coding mutations indicating oligogenic inheritance, we found that all these patients did not express RNA and/or protein from the other allele and thus have biallelic SMARCAL1 mutations. We hypothesize therefore that the variable expressivity among patients with biallelic SMARCAL1 mutations arises from environmental, genetic, or epigenetic modifiers. Among patients without detectable SMARCAL1 coding mutations, our analyses of cell lines from four of these patients showed that they expressed normal levels of SMARCAL1 mRNA and protein. This is the first evidence for nonallelic heterogeneity in SIOD. From analysis of the postmortem histopathology from two patients and the clinical data from most patients, we propose the existence of endophenotypes of SIOD.

Fragile X syndrome is the most common inherited cause of mental retardation. It is caused by a progressive expansion of polymeric (CGG)n trinucleotide repeats located on the FMR1 gene at Xq27.3. The spectrum of clinical involvement is broad, clinical diagnosis being difficult especially in young children. Hence, all cases of mental retardation without obvious cause should be tested for fragile X syndrome; the relatives of such a case need to be offered genetic counseling. Cytogenetic and molecular diagnostic tests are available. Recently, an immunocytochemical test has been described to identify fragile X patients, based on detection of FMR1 protein in cells using a monoclonal antibody. This method is used for screening, PCR based tests and Southern blot hybridization being the diagnostic tests for mutation and pre-mutation detection. Prenatal diagnosis is possible.

The authors present the case of a foetus with Jeune syndrome (asphyxiating thoracic dystrophy) in a woman with a previous deceased child with the same disease, and also with a normal sibling. The diagnosis was mentioned at 26 week of pregnancy, based on ultrasonographic findings: short proximal bones (under 3 percentiles), and a diminished thoracic circumference, (although greater than 10 percentiles for the gestational age). There was an interdisciplinary agreement for the therapeutic termination of the pregnancy, and the post-expulsion assessment confirmed the diagnosis. This case demonstrates a higher incidence of Jeune dystrophy than the one expected for an autosomal recessive disease, with 2 out of 3 children affected, instead of 25%. It also shows that the earliest change is the one regarding the shortened long bones, often difficult to notice before 20 weeks, fact which favors a detailed genetic sonogram done after this limit.

Craniofrontonasal syndrome (CFNS) is an X-linked disorder characterized by a more severe manifestation in heterozygous females than in hemizygous males. Heterozygous females have craniofrontonasal dysplasia (CFND) and occasionally extracranial manifestations including midline defects and skeletal abnormalities, whereas hemizygous males show no or only mild features such as hypertelorism and rarely show cleft lip or palate. Mutations in the EFNB1 gene in Xq12 are responsible for familial and sporadic CFNS. The EFNB1 gene encodes ephrin-B1, a transmembrane ligand that also exhibits receptor-like effects. We performed mutation analysis in nine unrelated families and 29 sporadic patients with CFNS. DNA sequencing revealed mutations in 33 (86.8%) cases including 26 distinct novel mutations. A recurrent nonsense mutation, c.196C>T/R66X, was detected in one family and four sporadic patients. The majority of mutations (26/33) were located in exons 2 and 3 of the EFNB1 gene encoding the extracellular ephrin domain. The mutation spectrum includes frameshift, nonsense, missense, and splice site mutations, with a predominance of frameshift and nonsense mutations resulting in premature truncation codons. For the first time we describe mutations in exons 4 and 5 of EFNB1. Of particular interest are the frameshift mutations located in the last 25 codons of EFNB1 encoding the carboxyterminal end of ephrin-B1. They result in an extension by 44 residues. These mutations disrupt the intracellular binding sites for Grb4 and PDZ-effector proteins involved in reverse signaling. We conclude that the major causes of familial as well as sporadic CFNS are loss of function mutations in the EFNB1 gene that comprise premature termination or abrogate receptor-ligand interaction, oligomerization, and ephrin-B1 reverse signaling., ((c) 2005 Wiley-Liss, Inc.)

Rett syndrome is a form of X-linked mental retardation limited to females, expressed by postnatal microcephaly, moderate/severe mental retardation and prominent autistic features. We present a case to illustrate this rare entity, but also to discuss the suggestive behaviour and to underline the importance of diagnostic criteria. Our case associates porencephaly and positive CMV test that raised diagnostic difficulties in the beginning.

Turner's Syndrome is a rare chromosomal disorder of females (1 : 2500) characterized by short stature and the lack of sexual development at puberty. Other physical features may include a webbed neck, heart defects, kidney abnormalities, and/or various other malformations. Diagnosis should be considered in individuals with primary or secondary amenorrhea and adult women with unexplained infertility, particularly when such individuals also are short in stature. In childhood, growth hormone therapy is standard to prevent short stature as an adult. Estrogen replacement therapy usually is required, but starting too early can compromise adult height. The most frequent, the possibility of a good diagnosis appears at puberty. The early diagnosis needs the karyotyping as screening method. The correct treatment, which is made on time, has a good mental and social life influence.

Löwe syndrome is a form of X-linked mental retardation with short stature, cataracts, renal tubular dysfunction and hypotonia. We present 2 cases to illustrate this rare entity, but also to discuss the suggestive aspect of the face and to underline the importance of molecular tests for genetic counselling. Both cases associate ocular, cerebral and renal defects. Molecular tests changed the recurrence risk in the first family.

The case of a 75 years old woman with hereditary hemorrhagic telangiectasia (HHT) is presented. This condition is an autosomal dominant mucocutaneous and visceral fibrovascular dysplasia in which telangiectasia, arteriovenous malformations and aneurysms may be widely distributed throughout the cardiovascular system. It is usually recognized as a "triad" of telangiectasia, recurrent epistaxis and a family history of the disorder.