The Role of Aminopeptidase ERAP1 in Human Pathology-A Review.

Aminopeptidases are a group of enzymatic proteins crucial for protein digestion, catalyzing the cleavage of amino acids at the N-terminus of peptides. Among them are ERAP1 (coding for endoplasmic reticulum aminopeptidase 1), ERAP2 (coding for endoplasmic reticulum aminopeptidase 2), and LNPEP (coding for leucyl and cystinyl aminopeptidase). These genes encoding these enzymes are contiguous and located on the same chromosome (5q21); they share structural homology and functions and are associated with immune-mediated diseases. These aminopeptidases play a key role in immune pathology by cleaving peptides to optimal sizes for binding to the major histocompatibility complex (MHC) and contribute to cellular homeostasis. By their ability to remove the extracellular region of interleukin 2 and 6 receptors (IL2, IL6) and the tumor necrosis factor receptor (TNF), ERAP1 and ERAP2 are involved in regulating the innate immune response and, finally, in blood pressure control and angiogenesis. The combination of specific genetic variations in these genes has been linked to various conditions, including autoimmune and autoinflammatory diseases and cancer, as well as hematological and dermatological disorders. This literature review aims to primarily explore the impact of ERAP1 polymorphisms on its enzymatic activity and function. Through a systematic examination of the available literature, this review seeks to provide valuable insights into the role of ERAP1 in the pathogenesis of various diseases and its potential implications for targeted therapeutic interventions. Through an exploration of the complex interplay between ERAP1 and various disease states, this review contributes to the synthesis of current biomedical research findings and their implications for personalized medicine.

Wolfram Syndrome Type I Case Report and Review-Focus on Early Diagnosis and Genetic Variants.

Background and Objectives: Wolfram syndrome type 1 (OMIM# 222300; ORPHAcode 3463) is an extremely rare autosomal recessive syndrome with a 25% recurrence risk in children. It is characterized by the presence of juvenile-onset diabetes mellitus (DM), progressive optic atrophy (OA), diabetes insipidus (DI), and sensorineural deafness (D), often referred to by the acronym DIDMOAD. It is a severe neurodegenerative disease with a life expectancy of 39 years, with death occurring due to cerebral atrophy. For a positive diagnosis, the presence of diabetes mellitus and optic nerve atrophy is sufficient. The disease occurs because of pathogenic variants in the WFS1 gene. The aim of this article is to present a case report of Wolfram Syndrome Type I, alongside a review of genetic variants, clinical manifestations, diagnosis, therapy, and long-term management. Emphasizing the importance of early diagnosis and a multidisciplinary approach, the study aims to enhance understanding and improve outcomes for patients with this complex syndrome. Materials and Methods: A case of a 28-year-old patient diagnosed with DM at the age of 6 and with progressive optic atrophy at 26 years old is presented. Molecular diagnosis revealed the presence of a heterozygous nonsense variant WFS1 c.1943G>A (p.Trp648*), and a heterozygous missense variant WFS1 c.1675G>C (p.Ala559Pro). Results: The molecular diagnosis of the patient confirmed the presence of a heterozygous nonsense variant and a heterozygous missense variant in the WFS1 gene, correlating with the clinical presentation of Wolfram syndrome type 1. Both allelic variants found in our patient have been previously described in other patients, whilst this combination has not been described before. Conclusions: This case report and review underscores the critical role of early recognition and diagnosis in Wolfram syndrome, facilitated by genetic testing. By identifying pathogenic variants in the WFS1 gene, genetic testing not only confirms diagnosis but also guides clinical management and informs genetic counseling for affected families. Timely intervention based on genetic insights can potentially reduce the progressive multisystem manifestations of the syndrome, thereby improving the quality of life and outcomes for patients.

Developments in Genetics: Better Management of Ovarian Cancer Patients.

The purpose of this article is to highlight the new advancements in molecular and diagnostic genetic testing and to properly classify all ovarian cancers. In this article, we address statistics, histopathological classification, molecular pathways implicated in ovarian cancer, genetic screening panels, details about the genes, and also candidate genes. We hope to bring new information to the medical field so as to better prevent and diagnose ovarian cancer.

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.

The impact of RAS mutation on the treatment strategy of colorectal cancer.

Kirsten rat sarcoma (KRAS) is the most frequently mutated oncogene in colorectal cancer, being present in 30% of patients with localized disease and in almost half of the patients that develop metastatic disease. While the development of chemotherapy doublets and targeted therapy have improved survival in recent years, KRAS mutation still has a controversial role regarding its prognostic and predictive value both in the adjuvant and in the metastatic setting. The impact of KRAS mutation on treatment strategy remains to be better defined. The development of new KRAS inhibitors promising new treatment options is on the horizon.

Correlations between Demographic, Clinical, and Paraclinical Variables and Outcomes in Patients with KRAS-Mutant or KRAS Wild-Type Metastatic Colorectal Cancer-A Retrospective Study from a Tertiary-Level Center in Romania.

Colorectal cancer (CRC) is a significant global public health concern and its characteristics in Eastern Europe are underexplored. In this retrospective study, data of 225 patients with metastatic colorectal cancer (mCRC) from the Colțea Clinical Hospital's Oncology Department in Bucharest were analyzed between 2015 and 2023. They were divided into two groups based on the presence of KRAS mutation. The primary objective of the study was to investigate whether the presence of KRAS mutations influenced the prognosis of mCRC and to identify any demographic, clinical, or paraclinical factors associated with KRAS mutations in stage IV CRC. The overall survival for the entire study population was 29 months. There was a trend towards increased survival in the KRAS wild-type group (31 months) compared to the KRAS-mutant group (26 months), but this difference did not reach statistical significance. We found that lower levels of education, advanced T stage, advanced N stage, and M1 stage at diagnosis negatively impacted prognosis. Real-world data are crucial in shaping public policy strategies to better support patients with metastatic CRC. Understanding the correlations between the demographic, clinical, and paraclinical variables and the outcomes in mCRC patients with KRAS-mutant and KRAS wild-type colorectal cancer is essential for improving patient care and treatment strategies in Romania and beyond.

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.

Case report: Tackling the complexities of an extremely premature newborn with intrauterine growth restriction and congenital metabolic disorders through a multidisciplinary approach.

Background and objectives: The premature birth of a newborn can present a complex challenge for healthcare providers, particularly in cases of extreme prematurity combined with intrauterine growth restriction and multiple metabolic deficiencies. In this report, we aim to shed light on the difficulties and considerations involved in the management of such a case. In addition, our study is aimed to raise awareness of the importance of a multidisciplinary team in managing an extreme premature case with multiple comorbidities. Case presentation and main findings: We present the case of a 28-week premature female newborn with very low birth weight (660 g, percentile <10%) and intrauterine growth restriction. She was born through emergency cesarean delivery due to maternal Hemolysis, Elevated Liver enzymes, and Low Platelet count (HELLP) syndrome and had a high-risk pregnancy (spontaneous twin pregnancy, with one fetus stopping development at 16 weeks and maternal hypertension). In the first hours of life, she presented with persistent hypoglycemia requiring progressive glucose supplementation up to 16 g/kg/day to maintain normal blood glucose levels. The baby then showed favorable progress. However, from days 24 to 25, hypoglycemia recurred and did not respond to glucose boluses or supplementation in both intravenous and oral feeds, leading to the suspicion of a congenital metabolic disorder. Endocrine and metabolic screenings led to suspicion of primary carnitine deficiency and a deficiency in hepatic form of carnitine-palmitoyltransferase type I (CPT1) on the second screening. Conclusion and clinical implications: The study highlights rare metabolic anomalies that can be due to both organ and system immaturity and delayed enteral feeding and excessive use of antibiotics. The clinical implications of this study emphasize the need for careful monitoring and comprehensive care of premature infants to prevent and manage potential metabolic abnormalities by neonatal metabolic screening.

Tuberous Sclerosis, Type II Diabetes Mellitus and the PI3K/AKT/mTOR Signaling Pathways-Case Report and Literature Review.

Tuberous sclerosis complex (TSC) is a rare autosomal dominant neurocutaneous syndrome. It is manifested mainly in cutaneous lesions, epilepsy and the emergence of hamartomas in several tissues and organs. The disease sets in due to mutations in two tumor suppressor genes: TSC1 and TSC2. The authors present the case of a 33-year-old female patient registered with the Bihor County Regional Center of Medical Genetics (RCMG) since 2021 with a TSC diagnosis. She was diagnosed with epilepsy at eight months old. At 18 years old she was diagnosed with tuberous sclerosis and was referred to the neurology department. Since 2013 she has been registered with the department for diabetes and nutritional diseases with a type 2 diabetes mellitus (T2DM) diagnosis. The clinical examination revealed: growth delay, obesity, facial angiofibromas, sebaceous adenomas, depigmented macules, papillomatous tumorlets in the thorax (bilateral) and neck, periungual fibroma in both lower limbs, frequent convulsive seizures; on a biological level, high glycemia and glycated hemoglobin levels. Brain MRI displayed a distinctive TS aspect with five bilateral hamartomatous subependymal nodules associating cortical/subcortical tubers with the frontal, temporal and occipital distribution. Molecular diagnosis showed a pathogenic variant in the TSC1 gene, exon 13, c.1270A>T (p. Arg424*). Current treatment targets diabetes (Metformin, Gliclazide and the GLP-1 analog semaglutide) and epilepsy (Carbamazepine and Clonazepam). This case report presents a rare association between type 2 diabetes mellitus and Tuberous Sclerosis Complex. We suggest that the diabetes medication Metformin may have positive effects on both the progression of the tumor associated with TSC and the seizures specific to TSC and we assume that the association of TSC and T2DM in the presented cases is accidental, as there are no similar cases reported in the literature.

The Importance of Implementing a Transition Strategy for Patients with Muscular Dystrophy: From Child to Adult-Insights from a Tertiary Centre for Rare Neurological Diseases.

Progress in the field of muscular dystrophy (MD) using a multidisciplinary approach based on international standards of care has led to a significant increase in the life expectancy of patients. The challenge of transitioning from pediatric to adult healthcare has been acknowledged for over a decade, yet it continues to be a last-minute concern. Currently, there is no established consensus on how to evaluate the effectiveness of the transition process. Our study aimed to identify how well patients are prepared for the transition and to determine their needs. We conducted a descriptive, cross-sectional study on 15 patients aged 14 to 21 years. The patients completed a sociodemographic and a Transition Readiness Assessment Questionnaire (TRAQ). We also analyzed the comorbidities of these patients. Our study revealed that only 46.7% of the patients had engaged in a conversation with a medical professional, namely, a child neurologist, about transitioning. A total of 60% of the participants expressed having confidence in their self-care ability. However, the median TRAQ score of 3.6 shows that these patients overestimate themselves. We emphasize the necessity for a slow, personalized transition led by a multidisciplinary team to ensure the continuity of state-of-the-art care from pediatric to adult healthcare services and the achievement of the highest possible quality of life for these patients.

Recognition of early warning signs and symptoms - the first steps on the road to Autism Spectrum Disorder diagnosis.

OBJECTIVE: To identify developmental symptoms reported at firsts doctor visits by parents of children later diagnosed with Autism Spectrum Disorder (ASD). DESIGN: Cohort study. SETTING: The study was conducted in the Department of Psychiatry Research of "Prof. Dr. Alexandru Obregia" Clinical Psychiatry Hospital from Bucharest between September 2019 and May 2021. PATIENTS: 105 cases: 82 boys and 23 girls, 100 children with autism, and 5 patients with Asperger's syndrome. INTERVENTION: ASD was diagnosed according to the DSM-5 criteria, ADOS-1 (Autism Diagnostic Observation Schedule, 1st Edition) and/or ADI-R (Autism Diagnostic Interview-Revised) tests scores; features reported by the parents for which they presented to the doctor for a diagnosis were taken into consideration. MAIN OUTCOME MEASURES: The age at first presentation to the doctor; the most common early signs reported by the parents of children with ASD. RESULTS: The age at first presentation to the doctor in our group was between 9 months and 14 years. The most common early signs reported by parents were: delayed language development, deficits in understanding verbal instructions/indications, and hyperactivity and aggressivity. In the case of patients with Asperger's syndrome, the reported features were hyperactivity and aggressivity, learning difficulties, and social interaction problems. Regression and delay in language development occurred more often in boys than in girls. CONCLUSIONS: Parents, as well as family doctors or paediatricians, should pay great attention to the children's behaviour, alongside their cognitive and language development. Early detection is essential for early intervention and our results can be used to develop training programs for parents and paediatricians for early recognition of ASD.

Changes in skeletal dysplasia nosology.

Skeletal dysplasia (SD), also called osteochondrodysplasia (OCD), is a large group of skeletal disorders (over 400 distinct entities) caused by abnormalities in bone development and growth. SDs varies according to different natural histories, prognoses, hereditary patterns to etiopathogenetic mechanisms. At birth, the incidence is low, reported at the level of each entity, but taken collectively; the incidence is estimated at 1:5000 births. Nosology is a branch of medical science. It deals with the systematic classification of diseases and disorders. Thus, combining information about the catalogue of clinically distinct disorders, pending molecular explanations, and genotype-phenotype correlations, the classification of SDs will be more accurate. This is extremely useful for diagnosing patients with genetic skeletal diseases, especially given the expected flow of information with new sequencing technologies. Over the years, various terms and classifications of SD have been used and have attempted to order and classify this group of genetic diseases according to clinical, radiological, and molecular criteria. In 2019, the Nosology Committee of the International Skeletal Dysplasia Society (ISDS) updated the classification of SD. This new classification divides SD into 42 large groups that include 461 entities. Advances in next-generation sequencing techniques have revolutionized the entire field of genetics, with 437 different genes are currently identified in 426 (92.4%) of SDs. Nosology is a real help for the clinician in establishing a diagnosis as accurately as possible, for the recognition of new diseases while serving as a guide for the interpretation of new genetic variants.

Cardiofaciocutaneous syndrome - a longitudinal study of a case over 33 years: case report and review of the literature.

Cardiofaciocutaneous (CFC) syndrome [Online Mendelian Inheritance in Man (OMIM) #115150] is characterized by craniofacial dysmorphism, heart malformation, ectodermal abnormalities, neuromotor delay and intellectual disability. It is not a frequent disease, about 300 cases have been reported in the medical literature. We describe the case of a 34-year-old patient presenting with CFC syndrome phenotype, monitored since the age of 1 1∕2 years. Clinical findings included craniofacial dysmorphism, development delay, heart malformation and severe intellectual disability. The evolution was with progressive intellectual disability, hypogonadism, hypertrophic cardiomyopathy, wrinkled palms and soles. Molecular analysis showed a heterozygous variant in the B-Raf proto-oncogene, serine∕threonine kinase (BRAF) gene (7q34): NM_001354609.2:c.1502A>G, with pathogenic significance. We report this case, observed along a period of 33 years, for illustration of clinical evolutive particularities, and for difficulties in establishing the positive diagnosis.

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.

Health systems sustainability in the framework of rare diseases actions. Actions on educational programmes and training for professionals and patients.

Rare disease community is one of the largest patient populations in the world estimated to be 350 million of people. Collectively common, rare diseases pose a significant medical and economic burden for health systems worldwide. In this respect, rare diseases are considered a priority of public health. The study is a review aimed to determine whether there is evidence that education plays a key role in building sustainable health system and will allow better health and well-being for people with rare diseases to be achieved. This review shows evidence that providing quality education through different ways and actions the lives of people suffering from a rare disease and their families can be improved.

Anesthetic Management of a Down Syndrome Patient with Subocclusive Syndrome.

The present study aims to describe the anesthetic management of a patient with Down syndrome in connection to the degree of difficulty in orotracheal intubation and the associated risks of general anesthesia. The established diagnosis was subocclusive syndrome, requiring an emergent surgical intervention. Preoperatively, the patient was stabilized, and secondly, a series of clinical and paraclinical investigations were carried out in order to assess the best management of the anesthetic procedure. Risk factors were identified, including ischemic heart disease, grade II obesity, hyperglycemia, patient's old age and marked mental retardation. The results of examinations that were carried out showed that the degree of difficulty of orotracheal intubation was low. Finally, the preoperative assessment indicated that the most appropriate approach for this patient was to perform a general anesthesia with endotracheal intubation. However, special care was given to the anesthetic and postoperative condition of the patient in order to lower the possible complications of the surgical intervention.

Endotracheal Intubation in a Down Syndrome Adult Undergoing Cataract Surgery - a Multidisciplinary Approach.

The present case report aims to describe and discuss the approach for the management of difficult endotracheal intubation in an adult with Down syndrome undergoing cataract surgery. A 26-year-old female with Down syndrome and a validated diagnosis of cataract requiring surgery was examined in order to assess the degree of difficulty of endotracheal intubation. Patients with Down syndrome have characteristic craniofacial abnormalities which require a thorough pre-operative assessment to anticipate and prepare for a difficult endotracheal intubation. Before the surgery, a series of clinical and paraclinical examinations were conducted. Although cataract surgery generally requires loco-regional anesthesia, in our case it was performed under general anesthesia. Indicators of potentially difficult intubation were macroglossia, prognathism, short neck, limited degree of head extension and obesity. The pre-operative examinations, which revealed a high degree of endotracheal intubation, allowed the anesthetist to achieve a better peri- and intra-operative management of the patient.

Cherubism: a case report.

Cherubism is a familial benign fibro-osseous disease of the jaws. On radiography, the lesions exhibit bilateral multinuclear radiolucent areas. Histopathology reveals multinucleated giant cells in the background of proliferating fibrous connective tissue. Mutations in the SH3BP2 gene are identified as the cause of cherubism. A 12-year-old girl with prominence of the lower face was investigated. Her chief complaint was her facial appearance with asymmetrical swelling of the cheeks. Clinical and radiographic examinations, and biopsy, biochemical analysis and genetic investigations were performed.