SNUPN deficiency causes a recessive muscular dystrophy due to RNA mis-splicing and ECM dysregulation.

SNURPORTIN-1, encoded by SNUPN, plays a central role in the nuclear import of spliceosomal small nuclear ribonucleoproteins. However, its physiological function remains unexplored. In this study, we investigate 18 children from 15 unrelated families who present with atypical muscular dystrophy and neurological defects. Nine hypomorphic SNUPN biallelic variants, predominantly clustered in the last coding exon, are ascertained to segregate with the disease. We demonstrate that mutant SPN1 failed to oligomerize leading to cytoplasmic aggregation in patients' primary fibroblasts and CRISPR/Cas9-mediated mutant cell lines. Additionally, mutant nuclei exhibit defective spliceosomal maturation and breakdown of Cajal bodies. Transcriptome analyses reveal splicing and mRNA expression dysregulation, particularly in sarcolemmal components, causing disruption of cytoskeletal organization in mutant cells and patient muscle tissues. Our findings establish SNUPN deficiency as the genetic etiology of a previously unrecognized subtype of muscular dystrophy and provide robust evidence of the role of SPN1 for muscle homeostasis.

Biallelic variants in SNUPN cause a limb girdle muscular dystrophy with myofibrillar-like features.

Alterations in RNA-splicing are a molecular hallmark of several neurological diseases, including muscular dystrophies where mutations in genes involved in RNA metabolism or characterised by alterations in RNA splicing have been described. Here, we present five patients from two unrelated families with a limb-girdle muscular dystrophy (LGMD) phenotype carrying a biallelic variant in SNUPN gene. Snurportin-1, the protein encoded by SNUPN, plays an important role in the nuclear transport of small nuclear ribonucleoproteins (snRNPs), essential components of the spliceosome. We combine deep phenotyping, including clinical features, histopathology and muscle magnetic resonance image (MRI), with functional studies in patient-derived cells and muscle biopsies to demonstrate that variants in SNUPN are the cause of a new type of LGMD according to current definition. Moreover, an in vivo model in Drosophila melanogaster further supports the relevance of Snurportin-1 in muscle. SNUPN patients show a similar phenotype characterised by proximal weakness starting in childhood, restrictive respiratory dysfunction and prominent contractures, although interindividual variability in terms of severity even in individuals from the same family was found. Muscle biopsy showed myofibrillar-like features consisting of myotilin deposits and Z-disc disorganisation. MRI showed predominant impairment of paravertebral, vasti, sartorius, gracilis, peroneal and medial gastrocnemius muscles. Conservation and structural analyses of Snurportin-1 p.Ile309Ser variant suggest an effect in nuclear-cytosol snRNP trafficking. In patient-derived fibroblasts and muscle, cytoplasmic accumulation of snRNP components is observed, while total expression of Snurportin-1 and snRNPs remains unchanged, which demonstrates a functional impact of SNUPN variant in snRNP metabolism. Furthermore, RNA-splicing analysis in patients' muscle showed widespread splicing deregulation, in particular in genes relevant for muscle development and splicing factors that participate in the early steps of spliceosome assembly. In conclusion, we report that SNUPN variants are a new cause of limb girdle muscular dystrophy with specific clinical, histopathological and imaging features, supporting SNUPN as a new gene to be included in genetic testing of myopathies. These results further support the relevance of splicing-related proteins in muscle disorders.

Genetic Testing for Familial Hypercholesterolemia in a Pediatric Group: A Romanian Showcase.

Familial hypercholesterolemia (FH) is a genetic disease marked by high levels of LDL-cholesterol. This condition has long-term clinical implications, such as cardiovascular events, that are evident during adult life. Here, we report on a single-center cross-sectional showcase study of genetic testing for FH in a Romanian pediatric group. Genetic testing for FH was performed on 20 Romanian pediatric patients, 10 boys and 10 girls, admitted with LDL-cholesterol levels over 130 mg/mL to the National Institute for Mother and Child Health "Alesssandrescu-Rusescu" in 2020. Genetic testing was performed using the Illumina TruSight Cardio panel. We identified pathogenic/likely pathogenic variants that could explain the phenotype in 5/20 cases. The involved genes were LDLR and APOB. Clinical signs that suggest the diagnosis of FH are scarce for the pediatric patient, although it can be diagnosed early during childhood by lipid panel screening. Prevention could prove lifesaving for some of these patients.

Autistic Behavior as Novel Clinical Finding in OFD1 Syndrome.

Orofaciodigital syndrome I (OFD1-MIM #311200) is a rare ciliopathy characterized by facial dysmorphism, oral cavity, digit, and brain malformations, and cognitive deficits. OFD1 syndrome is an X-linked dominant disorder reported mostly in females. The gene responsible for this condition, OFD1 centriole and centriolar satellite protein (OFD1), is involved in primary cilia formation and several cilia-independent biological processes. The functional and structural integrity of the cilia impacts critical brain development processes, explaining the broad range of neurodevelopmental anomalies in ciliopathy patients. As several psychiatric conditions, such as autism spectrum disorders (ASD) and schizophrenia, are neurodevelopmental in nature, their connections with cilia roles are worth exploring. Moreover, several cilia genes have been associated with behavioral disorders, such as autism. We report on a three-year-old girl with a complex phenotype that includes oral malformations, severe speech delay, dysmorphic features, developmental delay, autism, and bilateral periventricular nodular heterotopia, presenting a de novo pathogenic variant in the OFD1 gene. Furthermore, to the best of our knowledge, this is the first report of autistic behavior in a female patient with OFD1 syndrome. We propose that autistic behavior should be considered a potential feature of this syndrome and that active screening for early signs of autism might prove beneficial for OFD1 syndrome patients.

Characterization of sepsis inflammatory endotypes using circulatory proteins in patients with severe infection: a prospective cohort study.

BACKGROUND: Sepsis is a heterogeneous syndrome due to a variable range of dysregulated processes in the host immune response. Efforts are made to stratify patients for personalized immune-based treatments and better prognostic prediction. Using gene expression data, different inflammatory profiles have been identified. However, it remains unknown whether these endotypes mirror inflammatory proteome profiling, which would be more feasible to assess in clinical practice. We aim to identify different inflammatory endotypes based on circulating proteins in a cohort of moderately ill patients with severe infection (Sepsis-2 criteria). METHODS: In this prospective study, 92 inflammatory plasma markers were profiled using a targeted proteome platform and compared between patients with severe infection (Sepsis-2 criteria) and healthy controls. To identify endotypes with different inflammatory profiles, we performed hierarchical clustering of patients based on the differentially expressed proteins, followed by clinical and demographic characterization of the observed endotypes. RESULTS: In a cohort of 167 patients with severe infection and 192 healthy individuals, we found 62 differentially expressed proteins. Inflammatory proteins such as TNFSF14, OSM, CCL23, IL-6, and HGF were upregulated, while TRANCE, DNER and SCF were downregulated in patients. Unsupervised clustering identified two different inflammatory profiles. One endotype showed significantly higher inflammatory protein abundance, and patients with this endotype were older and showed lower lymphocyte counts compared to the low inflammatory endotype. CONCLUSIONS: By identifying endotypes based on inflammatory proteins in moderately ill patients with severe infection, our study suggests that inflammatory proteome profiling can be useful for patient stratification.

Heart function assessment during aging in apolipoprotein E knock-out mice.

BACKGROUND: Apolipoprotein (apo) E isoforms have strong correlations with metabolic and cardiovascular diseases. However, it is not clear if apoE has a role in development of non-ischemic cardiomyopathy. Our study aims to analyze the involvement of apoE in non-ischemic cardiomyopathy. METHODS AND RESULTS: Serial echo-cardiographic measurements were performed in old wildtype and apoE deficient (apoE-/-) mice. Morphological and functional cardiac parameters were in normal range in both groups at the age of 12 month. At the age of 18 months, both groups had shown ventricular dilation and increased heart rates. However, the apoE-/- mice presented signs of diastolic dysfunction by hypertrophic changes in left ventricle, due probably to arterial hypertension. The right ventricle was not affected by age or genotype.  CONCLUSION: Even in the absence of high fat diet, apoE deficiency in mice induces mild changes in the cardiac function of the left ventricle during aging, by developing diastolic dysfunction, which leads to heart failure with preserved ejection fraction. However, further studies are necessary to conclude over the role of apoE in cardiac physiology and its involvement in development of heart failure.

Apolipoprotein E4 Is Associated with Right Ventricular Dysfunction in Dilated Cardiomyopathy-An Animal and In-Human Comparative Study.

ApoE abnormality represents a well-known risk factor for cardiovascular diseases. Beyond its role in lipid metabolism, novel studies demonstrate a complex involvement of apoE in membrane homeostasis and signaling as well as in nuclear transcription. Due to the large spread of apoE isoforms in the human population, there is a need to understand the apoE's role in pathological processes. Our study aims to dissect the involvement of apoE in heart failure. We showed that apoE-deficient rats present multiple organ damages (kidney, liver, lung and spleen) besides the known predisposition for obesity and affected lipid metabolism (two-fold increase in tissular damages in liver and one-fold increase in kidney, lung and spleen). Heart tissue also showed significant morphological changes in apoE-/- rats, mostly after a high-fat diet. Interestingly, the right ventricle of apoE-/- rats fed a high-fat diet showed more damage and affected collagen content (~60% less total collagen content and double increase in collagen1/collagen3 ratio) compared with the left ventricle (no significant differences in total collagen content or collagen1/collagen3 ratio). In patients, we were able to find a correlation between the presence of ε4 allele and cardiomyopathy (χ2 = 10.244; p = 0.001), but also with right ventricle dysfunction with decreased TAPSE (15.3 ± 2.63 mm in ε4-allele-presenting patients vs. 19.8 ± 3.58 mm if the ε4 allele is absent, p < 0.0001*) and increased in systolic pulmonary artery pressure (50.44 ± 16.47 mmHg in ε4-allele-presenting patients vs. 40.68 ± 15.94 mmHg if the ε4 allele is absent, p = 0.0019). Our results confirm that the presence of the ε4 allele is a lipid-metabolism-independent risk factor for heart failure. Moreover, we show for the first time that the presence of the ε4 allele is associated with right ventricle dysfunction, implying different regulatory mechanisms of fibroblasts and the extracellular matrix in both ventricles. This is essential to be considered and thoroughly investigated before the design of therapeutical strategies for patients with heart failure.

The Phenotypic Spectrum of 15q13.3 Region Duplications: Report of 5 Patients.

Chromosome 15q13.3 microduplications are associated with a wide spectrum of clinical presentations ranging from normal to different neuropsychiatric conditions, such as developmental delay (DD), intellectual disability (ID), epilepsy, hypotonia, autism spectrum disorders (ASD), attention-deficit hyperactivity disorder, and schizophrenia. The smallest region of overlap for 15q13.3 duplications encompasses the Cholinergic Receptor Nicotinic Alpha 7 Subunit (CHRNA7) gene, a strong candidate for the behavioral abnormalities. We report on a series of five patients with 15q13.3 duplications detected by chromosomal microarray. The size of the duplications ranged from 378 to 537 kb, and involved the CHRNA7 gene in all patients. The most common clinical features, present in all patients, were speech delay, autistic behavior, and muscle hypotonia; DD/ID was present in three patients. One patient presented epileptic seizures; EEG anomalies were observed in three patients. No consistent dysmorphic features were noted. Neuroimaging studies revealed anomalies in two patients: Dandy-Walker malformation and a right temporal cyst. 15q13.3 duplications are associated with various neuropsychiatric features, including speech delay, hypotonia, ASD, and ID, also present in our patient group. Our study brings detailed clinical and molecular data from five ASD patients with 15q13.3 microduplications involving the CHRNA7 gene, contributing to the existing knowledge about the association of 15q13.3 duplications with neuropsychiatric phenotypes.

Prenatal diagnosis of a pure 15q distal trisomy derived from a maternal pericentric inversion: A case report.

Distal trisomy or duplication of 15q is a very rare chromosomal disorder; most of the previously reported cases were derived from unbalanced translocations involving chromosome 15 and another chromosome, whereas other mechanisms (e.g. duplication) have rarely been reported. We herein report a very rare prenatal case of a partial 15q trisomy, a 42.64-Mb duplication of 15q22.2-q26.3, arising from a maternal pericentric inversion of chromosome 15 (p11q22) that was not the result of an unbalanced translocation or duplication, and was not associated with concomitant partial monosomy. Fetal ultrasound revealed isolated thickened nuchal translucency at 12 weeks and multiple abnormalities in the second trimester, including early growth restriction, unilateral ventriculomegaly, narrow cavum septi pellucidi with hypoplasia of the corpus callosum, unilateral postaxial polydactyly, clenched hands and clubfoot with clawing of the toes, and a particular general dysplastic and hypotrophic aspect of the heart. The distinctive aspects of the present case may help to refine the phenotype associated with distal duplication 15q. To the best of our knowledge, this is the first report of a prenatal diagnosis with a 15q22.2-q26.3 duplication that did not result from an unbalanced translocation and did not have a concomitant monosomic component.

Association between genetic variants and depression in a Romanian cohort.

Major depressive disorder (MDD) is beyond doubt a common, disabling, and costly condition. MDD associates hypothalamic-pituitary-adrenal (HPA) axis alterations. We sought to investigate two candidate variants which could have a role in the genetic susceptibility for stress or corticoid-induced MDD: glucocorticoid receptor (GR) - nuclear receptor subfamily 3 group C member 1 (NR3C1) rs41423247 and brain-derived neurotrophic factor rs6265 BDNF:c.442G>A Val66Met. We enrolled 82 Romanian subjects, 1:2 male to female ratio, 53.54±8.98 years old, diagnosed with an episode of major depression at the Clinical Neuropsychiatry Hospital in Craiova, Romania, and 286 healthy controls, 34.28±16.34 years old. All subjects were genotyped using specific ThermoFisher Scientific assays on a ViiA™ 7 real-time polymerase chain reaction (PCR) system. The impact of certain genetic variants may be ethnic-specific. In our Romanian cohort, rs41423247 NR3C1:c.1184+646C>G has a minor allele frequency of 29.2%, and rs6265 BDNF:c.442G>A of 22.2%. Neither reached significance in our study, under any of the association models - dominant, recessive, or allelic. Interpretation of our negative findings requires caution: literature provides arguably more evidence for the association between the analyzed polymorphisms; our study has sample size challenges, from which refined phenotyping limitations derive.

Diagnostic value of digital droplet polymerase chain reaction and digital multiplexed detection of single-nucleotide variants in pancreatic cytology specimens collected by EUS-guided FNA.

BACKGROUND AND AIMS: EUS-guided FNA is recommended as a first-line procedure for the histopathologic diagnosis of pancreatic cancer. Molecular analysis of EUS-FNA samples might be used as an auxiliary tool to strengthen the diagnosis. The current study aimed to evaluate the diagnostic performances of K-ras testing using droplet digital polymerase chain reaction (ddPCR) and a novel single-nucleotide variant (SNV) assay performed on pancreatic EUS-FNA samples. METHODS: EUS-FNA specimens from 31 patients with pancreatic masses (22 pancreatic ductal adenocarcinomas, 7 chronic pancreatitis, and 2 pancreatic neuroendocrine tumors) were included in the study. K-ras testing was initially performed by ddPCR. In addition, mutational status was evaluated using an SNV assay by NanoString technology, using digital enumeration of unique barcoded probes to detect 97 SNVs from 24 genes of clinical significance. RESULTS: The overall specificity and sensitivity of cytologic examination were 100% and 63%, respectively. K-ras mutation testing was performed using ddPCR, and the sensitivity increased to 87% with specificity 90%. The SNV assay detected at least 1 variant in 90% of pancreatic ductal adenocarcinoma samples; the test was able to detect 2 K-ras codon 61 mutations in 2 cases of pancreatic ductal adenocarcinoma, which were missed by ddPCR. The overall diagnostic accuracy of the cytologic examination alone was 74%, and it increased to 91% when the results of both molecular tests were considered for the cases with negative and inconclusive results. CONCLUSIONS: The current study illustrated that integration of K-ras analysis with cytologic evaluation, especially in inconclusive cases, can enhance the diagnostic accuracy of EUS-FNA for pancreatic lesions.

Phenotype Heterogeneity in 3q29 Microduplication Syndrome.

3q29 microduplication syndrome is characterized by widely variable clinical presentation, but generally mild features. Developmental delay, particularly speech, and intellectual disability, eye abnormalities and heart defects are more frequently seen in affected individuals, although it is difficult to delineate a recognisable pattern. We describe a clinical case with a 1.65Mb duplication at 3q29 (chr3:195,979,518-197,638,922, GRCh37) identified by aCGH. The uncharacteristically late onset of the 34 years-old woman is marked by mild intellectual disability, progressive cortical atrophy and recurrent mucosal infections with Candida albicans. The gene content of the duplicated region-29 genes, including PAK2, DLG1, BDH1, FBXO45 and TFRC-seems closely linked to neuronal development and synaptic function, explaining brain and eye development related findings. We speculate on the possible involvement of genes like RNF168 in the aetiology of immunodeficiency. In-depth studies are needed to understand the pathophysiological mechanisms leading to the traits seen in this very rare syndrome.

Author Correction: The Henna pigment Lawsone activates the Aryl Hydrocarbon Receptor and impacts skin homeostasis.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The Henna pigment Lawsone activates the Aryl Hydrocarbon Receptor and impacts skin homeostasis.

As a first host barrier, the skin is constantly exposed to environmental insults that perturb its integrity. Tight regulation of skin homeostasis is largely controlled by the aryl hydrocarbon receptor (AhR). Here, we demonstrate that Henna and its major pigment, the naphthoquinone Lawsone activate AhR, both in vitro and in vivo. In human keratinocytes and epidermis equivalents, Lawsone exposure enhances the production of late epidermal proteins, impacts keratinocyte differentiation and proliferation, and regulates skin inflammation. To determine the potential use of Lawsone for therapeutic application, we harnessed human, murine and zebrafish models. In skin regeneration models, Lawsone interferes with physiological tissue regeneration and inhibits wound healing. Conversely, in a human acute dermatitis model, topical application of a Lawsone-containing cream ameliorates skin irritation. Altogether, our study reveals how a widely used natural plant pigment is sensed by the host receptor AhR, and how the physiopathological context determines beneficial and detrimental outcomes.

Human Monocytic Suppressive Cells Promote Replication of Mycobacterium tuberculosis and Alter Stability of in vitro Generated Granulomas.

Tuberculosis (TB) has tremendous public health relevance. It most frequently affects the lung and is characterized by the development of unique tissue lesions, termed granulomas. These lesions encompass various immune populations, with macrophages being most extensively investigated. Myeloid derived suppressor cells (MDSCs) have been recently identified in TB patients, both in the circulation and at the site of infection, however their interactions with Mycobacterium tuberculosis (Mtb) and their impact on granulomas remain undefined. We generated human monocytic MDSCs and observed that their suppressive capacities are retained upon Mtb infection. We employed an in vitro granuloma model, which mimics human TB lesions to some extent, with the aim of analyzing the roles of MDSCs within granulomas. MDSCs altered the structure of and affected bacterial containment within granuloma-like structures. These effects were partly controlled through highly abundant secreted IL-10. Compared to macrophages, MDSCs activated primarily the NF-κB and MAPK pathways and the latter largely contributed to the release of IL-10 and replication of bacteria within in vitro generated granulomas. Moreover, MDSCs upregulated PD-L1 and suppressed proliferation of lymphocytes, albeit with negligible effects on Mtb replication. Further comprehensive characterization of MDSCs in TB will contribute to a better understanding of disease pathogenesis and facilitate the design of novel immune-based interventions for this deadly infection.

Apolipoprotein E in Cardiovascular Diseases: Novel Aspects of an Old-fashioned Enigma.

The presence of different APOE isoforms represents a well-known risk factor for cardiovascular diseases. Besides the pleiotropic effects of APOE polymorphism on heart and neurological diseases, this review summarizes the less-known functions of APOE and the possible implications for cardiovascular disorders. Beyond the role as lipid transporting protein, its involvement in lipid membrane homeostasis and signaling, as well as its nuclear transcriptional effects suggests a more complex role of APOE, receiving great interest from researchers and physicians from all medical fields. Due to the presence of different APOE isoforms in human population, understanding APOE's role in pathological processes represents not only a challenge, but a demand for further development of therapeutic strategies for cardiovascular diseases.

Assessing tumor angiogenesis in colorectal cancer by quantitative contrast-enhanced endoscopic ultrasound and molecular and immunohistochemical analysis.

BACKGROUND AND OBJECTIVES: Data on contrast-enhanced endoscopic ultrasound (CE-EUS) for colorectal cancer (CRC) evaluation are scarce. Therefore, we aimed to assess the vascular perfusion pattern in CRC by quantitative CE-EUS and compare it to immunohistochemical and genetic markers of angiogenesis. PATIENTS AND METHODS: We performed a retrospective analysis of CE-EUS examinations of 42 CRC patients, before any therapy. CE-EUS movies were processed using a dedicated software. Ten parameters were automatically generated from the time-intensity curve (TIC) analysis: peak enhancement (PE), rise time (RT), mean transit time, time to peak (TTP), wash-in area under the curve (WiAUC), wash-in rate (WiR), wash-in perfusion index (WiPI), wash-out AUC (WoAUC), and wash-in and wash-out AUC (WiWoAUC). The expression levels of the vascular endothelial growth factor receptor 1 (VEGFR1) and VEGFR2 genes were assessed from biopsy samples harvested during colonoscopy. Microvascular density and vascular area were calculated after CD31 and CD105 immunostaining. RESULTS: Forty-two CE-EUS video sequences were analyzed. We found positive correlations between the parameters PE, WiAUC, WiR, WiPI, WoAUC, WiWoAUC, and N staging (Spearman r = 0.437, r = 0.336, r = 0.462, r = 0.437, r = 0.358, and r = 0.378, respectively, P < 0.05), and also between RT and TTP and CD31 vascular area (r = 0.415, and r = 0.421, respectively, P < 0.05). VEGFR1 and VEGFR2 expression did not correlate with any of the TIC parameters. CONCLUSIONS: CE-EUS with TIC analysis enables minimally invasive assessment of CRC angiogenesis and may provide information regarding the lymph nodes invasion. However, further studies are needed for defining its role in the evaluation of CRC patients.

Determination of VEGFR-2 (KDR) 604A>G Polymorphism in Pancreatic Disorders.

Pancreatic disorders have a high prevalence worldwide. Despite the fact that screening methods became more effective and the knowledge we have nowadays about pancreatic diseases has enhanced, their incidence remains high. Our purpose was to determine whether single nucleotide polymorphism (SNP) of VEGFR-2/KDR (vascular endothelial growth factor receptor 2/kinase insert domain receptor) influences susceptibility to develop pancreatic pathology. Genomic DNA was extracted from blood samples collected from patients diagnosed with acute pancreatitis (n = 110), chronic pancreatitis (n = 25), pancreatic cancer (n = 82) and healthy controls (n = 232). VEGFR-2 (KDR) 604A>G (rs2071559) polymorphism frequency was determined with TaqMan allelic discrimination assays. Statistical assessment was performed by associating genetic polymorphism with clinical and pathological data. In both pancreatic disorders and healthy control groups the polymorphism we studied was in Hardy-Weinberg equilibrium. Association between increased risk for pancreatic disorders and studied polymorphism was statistically significant. KDR 604AG and AG + GG genotypes were more prevalent in acute pancreatitis and pancreatic cancer patients than in controls. These genotypes influence disease development in a low rate. No association was found between chronic pancreatitis and KDR 604AG and AG + GG genotypes. In Romanian cohort, we found an association between the KDR 604A→G polymorphism and acute pancreatitis and pancreatic cancer. Carriers of the -604G variant allele were more frequent among acute pancreatitis and pancreatic cancer than among controls, suggesting that KDR 604G allele may confer an increased risk for these diseases. In the future, more extensive studies on larger groups are necessary, in order to clarify the role of VEGFR2 polymorphisms in pancreatic pathology.

The association between chronic pancreatitis and the iNOS-2087A>G polymorphism.

INTRODUCTION: Chronic pancreatitis is morphologically characterized by ductal dysplasia, breeding grounds for the proliferation of the ductal cells, the degenerative changes in pancreatic acinar cells and fibrosis, and it is defined on the basis of the clinical, morphological and functional criteria. AIM: The aim of our study is to examine the existence of a possible correlation between the iNOS-2087A>G polymorphism and chronic pancreatitis by means of the genetic analysis. MATERIAL AND METHOD: We have conducted the study at the Gastroenterology Clinic and the Research Center of Gastroenterology and Hepatology of the University of Medicine and Pharmacy, Craiova, between March 2015 - September 2016. The study had a prospective character. Both for the 58 patients diagnosed with chronic pancreatitis and for the 132 patients in the witness group, the biological material was represented by blood, (around 2.5 - 5 milliliters of venous blood) let on EDTA and kept at 4°C up to the separation of the DNA molecule. All the patients were genotyped for the iNOS - 2087A>G polymorphism, by means of the Real Time PCR technique with TaqMan probes. RESULTS: Analysing the prevalence of the iNOS genotypes within the study group and witness group, we have noticed that, statistically speaking, there are no significant differences between the two groups. CONCLUSION: As a conclusion, in the study lot we can sustain that the risk of developing chronic pancreatitis is not increased by the presence of the iNOS-2087A>G polymorphism.

Morphological and genetic abnormalities in a Jacobsen syndrome.

Jacobsen syndrome (JS) is a contiguous gene syndrome caused by partial deletion of the long arm of chromosome 11. The syndrome is rare and there are very few observations regarding the pubertal period of the affected individuals. We report the case of a 22-year-old female, with JS, monitored since the age of three months. She presented intrauterine growth retardation, failure to thrive and feeding difficulties from the first year of the life, and she learned to walk at the age of four years. Phenotypically, the case is characterized by distinctive facial and limb abnormalities. She shows spasticity and profound delay in gross and fine motor skills. Additionally, she has severe learning difficulties, non-verbally communicates, and displays hetero-aggressive and auto-aggressive behavior. The evolution of puberty was characterized by hypogenitalism and primary amenorrhea. Thrombocytopenia and IgM deficiency became apparent also at puberty. Array comparative genomic hybridization (aCGH) analysis confirmed a deletion of 16.3 Mb on 11q23.3-q23.4. We report this case as the first documented case of JS in Romania, as well as for clinical particularities (long period of survival and late appearance of hematological and immunological disorders).