Insights into Clinical Disorders in Cowden Syndrome: A Comprehensive Review.

PTEN Hamartoma Tumour Syndrome (PHTS) encompasses diverse clinical phenotypes, including Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), Proteus syndrome (PS), and Proteus-like syndrome. This autosomal dominant genetic predisposition with high penetrance arises from heterozygous germline variants in the PTEN tumour suppressor gene, leading to dysregulation of the PI3K/AKT/mTOR signalling pathway, which promotes the overgrowth of multiple and heterogenous tissue types. Clinical presentations of CS range from benign and malignant disorders, affecting nearly every system within the human body. CS is the most diagnosed syndrome among the PHTS group, notwithstanding its weak incidence (1:200,000), for which it is considered rare, and its precise incidence remains unknown among other important factors. The literature is notably inconsistent in reporting the frequencies and occurrences of these disorders, adding an element of bias and uncertainty when looking back at the available research. In this review, we aimed to highlight the significant disparities found in various studies concerning CS and to review the clinical manifestations encountered in CS patients. Furthermore, we intended to emphasize the great significance of early diagnosis as patients will benefit from a longer lifespan while being unceasingly advised and supported by a multidisciplinary team.

Breast Cancer Screening and Prophylactic Mastectomy for High-Risk Women in Romania.

Breast cancer remains a significant contributor to morbidity and mortality within oncology. Risk factors, encompassing genetic and environmental influences, significantly contribute to its prevalence. While germline mutations, notably within the BRCA genes, are commonly associated with heightened breast cancer risk, a spectrum of other variants exists among affected individuals. Diagnosis relies on imaging techniques, biopsies, biomarkers, and genetic testing, facilitating personalised risk assessment through specific scoring systems. Breast cancer screening programs employing mammography and other imaging modalities play a crucial role in early detection and management, leading to improved outcomes for affected individuals. Regular screening enables the identification of suspicious lesions or abnormalities at earlier stages, facilitating timely intervention and potentially reducing mortality rates associated with breast cancer. Genetic mutations guide screening protocols, prophylactic interventions, treatment modalities, and patient prognosis. Prophylactic measures encompass a range of interventions, including chemoprevention, hormonal inhibition, oophorectomy, and mastectomy. Despite their efficacy in mitigating breast cancer incidence, these interventions carry potential side effects and psychological implications, necessitating comprehensive counselling tailored to individual cases.

Microduplication and Microdeletion Syndromes Diagnosed Prenatally Using Single Nucleotide Polymorphism Array.

We present a series of microdeletion and microduplication syndromes (MMSs) observed in our clinical practice over a three-year period from 2020 to 2023. Microdeletion and microduplication syndromes, characterized by chromosomal deletions or duplications of less than five megabases, pose challenges in terms of diagnosis, especially prenatal and clinical management. Clinically, MMSs encompass a broad spectrum of manifestations, ranging from intellectual disability and developmental delays to congenital anomalies, facial dysmorphisms, and neurobehavioral abnormalities. Notable examples include well-characterized syndromes such as DiGeorge syndrome (22q11.2 deletion), Prader-Willi syndrome (15q11-q13 deletion), and Williams syndrome (7q11 deletion). Our study focuses on the genetic foundations and prenatal ultrasound findings of these syndromes, with an emphasis on cases associated with intellectual disability. Using SNP array technology, we delve into the evolving landscape of diagnostic methods, providing a nuanced understanding of copy number variations (CNVs) and their implications. Prenatal diagnosis allows for the early detection of MMSs, enabling parents and healthcare providers to make informed decisions about the pregnancy and plan for appropriate medical care and interventions. Beyond theoretical considerations, our article bridges the gap between research and practical application by offering insights derived from clinical cases. Through the presentation of specific cases, we aim to contribute valuable data to the broader discourse on MMSs, fostering knowledge exchange and enhancing the medical community's awareness of these complex genetic conditions.

Antibiotic Resistance in Helicobacter pylori Isolates from Northwestern and Central Romania Detected by Culture-Based and PCR-Based Methods.

Little evidence has been published regarding the antimicrobial resistance patterns of Helicobacter pylori (H. pylori) strains in Northwestern and Central Romania. The aim of this study was to determine the antibiotic resistance pattern of H. pylori isolates from gastric biopsies collected from patients living in Romania using ETEST® and GenoType HelicoDR. Gastric biopsies were obtained from 148 adult patients, 87 women and 61 men, the majority (131 patients) from Northwestern and Central Romania. Sixty-nine H. pylori strains were detected by both culture and PCR; sixty-three biopsies were negative by both techniques; one biopsy was positive by culture but negative by PCR; and fifteen biopsies were negative by culture but positive by PCR. Primary resistance against clarithromycin, fluoroquinolones, and metronidazole was found in 16.7%, 11.1%, and 13.3% of strains, respectively. No primary resistance has been detected against amoxicillin, tetracycline, and rifampicin. Secondary resistance against clarithromycin, fluoroquinolones, metronidazole, amoxicillin, tetracycline, and rifampicin was found in 75.8%, 30.3%, 65.5%, 1.8%, 1.8%, and 7.3% of the strains, respectively. The most frequent clarithromycin-resistant genotype detected by GenoType HelicoDR was A2147G (62.3%). Concordances between ETEST® and PCR for clarithromycin and fluoroquinolones were 85.5% and 78.3%, respectively. Further investigation of H. pylori resistance should be conducted to ensure proper eradication schemes.

Challenging diagnoses of tetraploidy/diploidy and trisomy 12: utility of first-tier prenatal testing methods.

Introduction: Chromosome mosaicism and low-grade mosaicism present a challenge for diagnosis in the era of SNP array and NGS. Tetraploidy is a rare numerical chromosomal abnormality characterized by the presence of four copies of each chromosome. The prevalence of tetraploidy/diploidy mosaicism cases is extremely rare in the human population. Accurate estimates of the frequency of this chromosomal anomaly are lacking due to its classification as an extremely rare and difficult-to-detect condition. Methods: In this report, we describe two cases involving challenging diagnoses of tetraploidy/diploidy and trisomy 12. We utilized advanced genetic testing techniques, including SNP array, to examine the chromosomal abnormalities in these cases. We compared the results from SNP array to conventional G band karyotyping to assess the utility of first-tier prenatal testing methods. Results:Our analysis revealed two cases of tetraploidy/diploidy and trisomy 12 with atypical presentations. SNP array analysis provided higher resolution and more precise information about the chromosomal anomalies in these cases compared to conventional G band karyotyping. Additionally, the prevalence of tetraploidy/diploidy mosaicism was confirmed to be extremely rare in the population. Discussion: Low-level mosaicism is difficult to diagnose, and in many cases, it has traditionally been identified through techniques such as G band karyotype or FISH. Microarray has become an invaluable diagnostic tool for detecting chromosomal abnormalities, offering high-resolution insights. However, it may not always be able to detect rare occurrences of tetraploidy or tetraploidy/diploidy mosaicism. As a result, it is recommended to perform a G band karyotype analysis after obtaining a negative microarray result before considering other diagnostic methods with a potentially higher yield of diagnosis. For the detection of low-level mosaicism, combined diagnostic methods should be considered. The diagnosis of mosaicism is a multistep process that can be time-consuming, often requiring the application of more than one diagnostic technique. This approach is crucial for accurate diagnosis and comprehensive patient care. Further research is warranted to better understand the underlying mechanisms of these rare chromosomal anomalies and to develop more effective diagnostic strategies for challenging cases.

Hereditary Breast Cancer in Romania-Molecular Particularities and Genetic Counseling Challenges in an Eastern European Country.

In Romania, breast cancer (BC) is the most common malignancy in women. However, there is limited data on the prevalence of predisposing germline mutations in the population in the era of precision medicine, where molecular testing has become an indispensable tool in cancer diagnosis, prognosis, and therapeutics. Therefore, we conducted a retrospective study to determine the prevalence, mutational spectrum, and histopathological prediction factors for hereditary breast cancer (HBC) in Romania. A cohort of 411 women diagnosed with BC selected upon NCCN v.1.2020 guidelines underwent an 84-gene NGS-based panel testing for breast cancer risk assessment during 2018-2022 in the Department of Oncogenetics of the Oncological Institute of Cluj-Napoca, Romania. A total of 135 (33%) patients presented pathogenic mutations in 19 genes. The prevalence of genetic variants was determined, and demographic and clinicopathological characteristics were analyzed. We observed differences among BRCA and non-BRCA carriers regarding family history of cancer, age of onset, and histopathological subtypes. Triple-negative (TN) tumors were more often BRCA1 positive, unlike BRCA2 positive tumors, which were more often the Luminal B subtype. The most frequent non-BRCA mutations were found in CHEK2, ATM, and PALB2, and several recurrent variants were identified for each gene. Unlike other European countries, germline testing for HBC is still limited due to the high costs and is not covered by the National Health System (NSH), thus leading to significant discrepancies related to the screening and prophylaxis of cancer.

Molecular basis and therapeutic targets in prostate cancer: A comprehensive review.

Prostate cancer is one of the most significant causes of morbidity and mortality in male patients. The incidence increases with age, and it is higher among African Americans. The occurrence of prostate cancer is associated with many risk factors, including genetic and hereditary predisposition. The most common genetic syndromes associated with prostate cancer risk are BRCA-associated hereditary breast and ovarian cancer (HBOC) and Lynch syndrome. Local-regional therapy, i.e., surgery is beneficial in early-stage prostate cancer management. Advanced and metastatic prostate cancers require systemic therapies, including hormonal inhibition, chemotherapy, and targeted agents. Most prostate cancers can be treated by targeting the androgen-receptor pathway and decreasing androgen production or binding to androgen receptors (AR). Castration-resistant prostate cancer (CRPC) usually involves the PI3K/AKT/mTOR pathway and requires targeted therapy. Specific molecular therapy can target mutated cell lines in which DNA defect repair is altered, caused by mutations of BRCA2, partner and localizer of BRCA2 (PALB2), and phosphatase and tensin homolog (PTEN) or the transmembrane protease serine 2-ERG (TMPRSS2-ERG) fusion. Most benefits were demonstrated in cyclin dependent-kinase 12 (CDK12) mutated cell lines when treated with anti-programmed cell death protein 1 (PD1) therapy. Therapies targeting p53 and AKT are the subject of ongoing clinical trials. Many genetic defects are listed as diagnostic, prognostic, and clinically actionable markers in prostate cancer. Androgen receptor splice variant 7 (AR-V7) is an important oncogenic driver and an early diagnostic and prognostic marker, as well as a therapeutic target in hormone-resistant CRPC. This review summarizes the pathophysiological mechanisms and available targeted therapies for prostate cancer.

Lateral sinus thrombosis in a young patient with sudden neurosensorial hearing loss and genetic thrombophilia: A case report.

Sensorineural hearing loss (SSHL) with a sudden onset is frequently encountered as a medical emergency in the ear, nose and throat (ENT) practice. The exact pathophysiology of the disease remains unknown, with the most likely etiologies being viral infection, inflammation, drug toxicity, trauma, or autoimmune response. Even though thrombophilia and cerebrovascular complications may lead, among others, to sudden neurosensorial hearing loss, its diagnosis is most often made following the onset of thrombotic complications. A case of a young female patient with unknown congenital hypercoagulation status complicated with lateral sinus thrombosis and unilateral drug-induced reversible hearing loss is presented. Molecular testing confirmed the diagnosis of genetic thrombophilia, due to the homozygous V Leiden, homozygous MTHFR A1298C, and heterozygous MTHFR C677T mutations. Although hereditary thrombophilia is a well-known topic in medical practice, current guidelines require continuous improvement, especially among patients treated in departments where this pathology is more difficult to recognize and manage.

First documented case of Myhre syndrome in Romania: A case report.

Myhre syndrome is a rare genetic autosomal dominant connective tissue disorder, characterized by developmental delay, characteristic facial features, various bone and joint abnormalities, distinctive cardiovascular, ophthalmological and ear, nose and throat (ENT) manifestations, in association with mild to moderate intellectual disability and autism or autism spectrum disorder-like behaviour. The diagnosis of Myhre syndrome is established corroborating the clinical findings with SMAD4 heterozygous mutation identified in the majority of the patients. SMAD4 gene mutations result in abnormal TGF-ß signalling in several cell types, which affects the development of several body systems and leads to the specific phenotype of Myhre syndrome. We herein report the case of an 18-year-old female patient who was diagnosed at the age of 17 years with Myhre syndrome, the first documented case of this syndrome in Romania. Sequence analysis of protein-coding genes using whole-exome analysis identified a 'de novo', heterozygous missense variant of SMAD4, c.1498A>G, p. (Ile500Val), which is pathogenic for Myhre syndrome. Although this condition is rare, a series of particularities were identified in the present case, consisting of severe allergic reactions, recurrent ENT tumour development and delayed dental eruption, which have not been described in Myhre syndrome to date, to the best of the authors' knowledge.

O'Donnel-Luria-Rodan Syndrome: New gene variant identified in Romania (A case report).

O'Donnel-Luria-Rodan (ODLURO) syndrome is a neurodevelopmental disorder with autosomal dominant inheritance. It appears more frequently in males during the first decade of life and is associated with developmental delay, low intelligence quotient, autism spectrum disorder-like behavior, epilepsy, speech delay, aggression, facial and skeletal deformities, gastrointestinal symptoms and hypotonia. Although few cases have been documented, it appears that the phenotype spectrum may vary, especially between the two biological sexes. The present study reported a case of a 5-year-old male patient who was diagnosed with ODLURO at the age of 4 years using whole-exome sequencing. Molecular analysis identified a new mutation in the lysine methyltransferase 2E (inactive) (KMT2E) gene, which was classified as a variant with unknown significance. The father, who presented with non-specific and undiagnosed psychiatric manifestations, presented the same KMT2E variant. The case described in the present study is not only interesting because there are <40 cases described in the literature, but also because a new inherited mutation in the KMT2E gene, present in both father and son, that resulted in different phenotypic manifestations was identified.

Ethnicity-related DMD Genotype Landscapes in European and Non-European Countries.

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.

Novel Mutation in GALT Gene in Galactosemia Patient with Group B Streptococcus Meningitis and Acute Liver Failure.

Classic galactosemia is an autosomal recessive disorder caused by the deficiency of the enzyme galactose-1-phosphate uridyltransferase (GALT) involved in galactose metabolism. Bacterial infections are a known cause of early morbidity and mortality in children with classic galactosemia. The most common agent is Escherichia coli, but in rare situations, other bacteria are incriminated. We report a case of a three-week-old female patient with galactosemia, who presented with Group B Streptococcus (GBS) meningitis/sepsis. She received treatment with antibiotics, supportive therapy, and erythrocyte transfusion, but after a short period of improvement, she presented acute liver failure with suspicion of an inborn error of metabolism. Rapid nuclear magnetic resonance (NMR) spectroscopy from urine showed highly elevated values of galactose and galactitol. Under intensive treatment for acute liver failure and with a lactose-free diet, her clinical features and laboratory parameters improved considerably. Genetic testing confirmed compound heterozygous status for GALT mutations: c.563 A>G [p.Q188R] and c. 910 C>T, the last mutation being a novel mutation in GALT gene. In countries without an extensive newborn screening program, a high index of suspicion is necessary for early diagnosis and treatment of galactosemia.

Association of fragile X syndrome, Robertsonian translocation (13, 22) and autism in a child.

We describe the case of a 6-year-old boy with both fragile X syndrome and Robertsonian Translocation (45, XY, der (13; 22) (q10; q10)). This is the first reported case of a patient with fragile X syndrome with this Robertsonian translocation. Facial features and macroorchidism were consistent with fragile X syndrome. Cognitive impairment is more significant than in his sibling with fragile X syndrome, and the patient also has a prior diagnosis of autism spectrum disorder. We emphasize the challenges in his behavioral management and outline future directions for his management.

Concomitant Myeloproliferative and Lymphoid Neoplasms in Two Patients Positive for JAK2 V617F Mutation. Case Report and Literature Review.

The coexistence of both myeloproliferative and lymphoproliferative neoplasms in the same patient is an uncommon finding. We report two patients who presented such an association. The first patient was initially diagnosed with essential thrombocythemia, developing a clinical and haematological picture consistent with chronic lymphocytic leukaemia several years afterwards. The second patient was diagnosed concomitantly with polycythaemia vera and chronic lymphocytic leukaemia. Both patients were positive for the JAK2 V617F mutation. In the first patient the chronic lymphocytic leukaemia was asymptomatic, stage A, and did not require any additional treatment, while the second patient presented with generalized large lymphadenopathy (stage B) and chronic lymphocytic leukaemia-related symptoms, requiring chronic lymphocytic leukaemia-directed treatment. It is unclear whether there is a pathogenetic link between the myeloproliferative and lymphoproliferative diseases encountered in these patients, both being probably the result of random mutations occurring in distinct initiating cells. However, given the higher risk of lymphoproliferative neoplasms development in myeloproliferative neoplasms patients reported in larger studies, the genomic instability characteristic to myeloproliferative neoplasms may play a role in subsequent lymphoproliferative neoplasms occurrence.

Mitotic stability of small supernumerary marker chromosomes: a study based on 93 immortalized cell lines.

Small supernumerary marker chromosomes (sSMC) are known for being present in mosaic form as 47,+mar/46 in >50% of the cases with this kind of extra chromosomes. However, no detailed studies have been done for the mitotic stability of sSMC so far, mainly due to the lack of a corresponding in vitro model system. Recently, we established an sSMC-cell bank (Else Kröner-Fresenius-sSMC-cellbank) with >150 cell lines. Therefore, 93 selected sSMC cases were studied here for the presence of the corresponding marker chromosomes before and after Epstein-Barr virus-induced immortalization. The obtained results showed that dicentric inverted duplicated-shaped sSMC are by far more stable in vitro than monocentric centric minute- or ring-shaped sSMC. Simultaneously, a review of the literature revealed that a comparable shape-dependent mitotic stability can be found in vivo in sSMC carriers. Additionally, a possible impact of the age of the sSMC carrier on mitotic stability was found: sSMC cell lines established from patients between 10-20 years of age were predominantly mitotically unstable. The latter finding was independent of the sSMC shape. The present study shows that in vitro models can lead to new and exciting insights into the biology of this genetically and clinically heterogeneous patient group.

The relationship between factor V Leiden, prothrombin G20210A, and MTHFR mutations and the first major thrombotic episode in polycythemia vera and essential thrombocythemia.

Arterial and venous thrombosis are the most frequent complications in patients with polycythemia vera and essential thrombocythemia. We sought to demonstrate a possible contribution of the factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase (MTHFR) 677 C > T and 1298 A > C mutations to the thrombotic risk in patients with polycythemia vera and essential thrombocythemia along with other biological features of these patients. We included 86 patients with polycythemia vera, of which 34 (39.5 %) had major thrombosis and 95 patients with essential thrombocythemia, of which 22 (23.1 %) had major thrombosis. In the whole cohort of patients, only the factor V Leiden mutation was significantly associated with both arterial and venous thrombosis in univariate and multivariate analysis (odds ratio (OR) = 4.3; 95 % confidence interval (CI) = 1.5-12.5; p = 0.008 and OR = 4.3; 95 % CI = 1.2-15.9; p = 0.02, respectively). Other factors significantly associated with thrombosis in both univariate and multivariate analysis were male sex (OR = 2.8, 95 % CI = 1.4-5.4, p = 0.002 and OR = 3.5, 95 % CI = 1.6-7.6, p = 0.002, respectively) and the JAK2 V617F mutation (OR = 5.5, 95 % CI = 2.1-15, p = 0.0001 and OR = 6.9, 95 % CI = 2.2-21.2, p = 0.001, respectively). In conclusion, among the four mutations analyzed (factor V Leiden, prothrombin G20210A, and MTHFR 677 C > T and 1298 A > C), only factor V Leiden is a major contributor to thrombosis in polycythemia vera and essential thrombocythemia.

HFE gene C282Y, H63D and S65C mutations frequency in the Transylvania region, Romania.

BACKGROUND AND AIMS: HFE-associated haemochromatosis is one of the most frequent autosomal recessive disorders in the Caucasian population. Although most of the cases are homozygous individuals for the C282Y mutation, another two mutations, H63D and S65C, have been reported to be associated with milder forms of the disease. This study was a first attempt to evaluate the distribution of these HFE gene mutations in the Transylvania region. METHODS: Two-hundred and twenty-five healthy, unrelated volunteers originating from the Transylvania region, Romania, were screened for the HFE gene C282Y, H63D and S65C mutations, using molecular genetics assays (Polymerase Chain Reaction-Restriction Fragments Length Polymorphism). RESULTS: For the C282Y mutation, 7 heterozygotes (3.1%) were found, but no homozygous individual. In the case of the H63D mutation, 40 heterozygotes (17.8%) and 4 homozygotes (1.75%) for the mutant allele were evidenced. We found a compound heterozygous genotype (C282Y/H63D) in one individual (0.45%). Thus, the allele frequencies of the C282Y and H63D were 1.75% and 10.9%, respectively. Three individuals (1.3%) were found to harbour the S65C mutation in a heterozygous state, but none in a homozygous state: the allele frequency of the mutant allele was 0.75%. CONCLUSIONS: The distribution of the HFE gene C282Y, H63D and S65C mutations found in our group matches the tendencies observed in other European countries: a decreasing gradient from Northern to Southern Europe for the C282Y mutation; high frequency for the H63D mutation, and low frequency for the S65C mutation in most of the countries.