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.

A New Frameshift Mutation of PTEN Gene Associated with Cowden Syndrome-Case Report and Brief Review of the Literature.

Cowden syndrome (CS) is a rare disease that was first described in 1963 and later included in the large group of genodermatoses. It is the most common syndrome among the PTEN-associated hamartomatous tumor syndromes (PHTS). CS has an autosomal dominant inheritance pattern, with increased penetrance and variable expressivity, making early diagnosis difficult. Mutations in the PTEN gene (phosphatase and TENsin homolog) are involved in its pathogenesis, involving many organs and systems originating in the three embryonic layers (ectodermum, endodermum, and mesodermum). The consequence is the development of hamartomatous lesions in various organs (brain, intestines, thyroid, oropharyngeal cavity, colon, rectum, etc.). Multiple intestinal polyps are common in patients with CS, being identified in over 95% of patients undergoing colonoscopy. The authors describe the case of a patient who presented the first signs of the disease at 3 ½ years (tonsil polyp) but was diagnosed only at the age of 20 following a colonoscopy that revealed hundreds of intestinal polyps, suggesting further molecular testing. A heterozygous frameshift mutation was identified in the PTEN gene, classified as a potentially pathogenic variant (c.762del.p(Val255*)). The authors present this case to highlight the path taken by the patient from the first symptoms to the diagnosis and to emphasize the clinical aspects of this mutational variant that have still not been identified in other patients with this syndrome.

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.

Effects of Burosumab Treatment on Two Siblings with X-Linked Hypophosphatemia. Case Report and Literature Review.

X-linked hypophosphatemia (XLH) or vitamin D-resistant rickets (MIM#307800), is a monogenic disorder with X-linked inheritance. It is caused by mutations present in the Phosphate Regulating Endopeptidase Homolog X-Linked (PHEX) gene responsible for the degradation of the bone-derived hormone fibroblast growth factor 23 (FGF23) into inactive fragments, but the entire mechanism is currently unclear. The inactivation of the gene prevents the degradation of FGF23, causing increased levels of FGF23, which leads to decreased tubular reabsorbtion of phosphorus. Clinical aspects are growth delay, limb deformities, bone pain, osteomalacia, dental anomalies, and enthesopathy. Laboratory evaluation shows hypophosphatemia, elevated alkaline phosphatase (ALP), and normal serum calcium levels, whereas parathormone (PTH) may be normal or increased and FGF23 greatly increased. Conventional treatment consists of administration of oral phosphate and calcitriol. Treatment with Burosumab, a monoclonal antibody that binds to FGF23, reducing its activity, was approved in 2018. Methods. We describe a case of two siblings, a girl and a boy, diagnosed with XLH, monitored by the Genetic Department of the County Emergency Clinical Hospital since 2019. The clinical picture is suggestive for XLH, both siblings exhibiting short stature, lower limb curvature, bone pain, marked walking weakness, and fatigue. Radiological aspects showed marked deformity of the lower limbs: genu varum in the girl, genu varum and valgum in the boy. Laboratory investigations showed hypophosphathemia, hyperphosphaturia, elevated ALP, normal PTH, and highly increased FGF23 in both. DNA analysis performed on the two siblings revealed a nonsense mutation in exone 5 of the PHEX gene: NM_000444.6(PHEX):c.565C > T (p.Gln189Ter). Results. At the age of 13½ on 7 June 2021, the two children started treatment with Burosumab in therapeutic doses and were monitored clinically and biochemically at regular intervals according to the protocol established by the Endocrinology Commission of the Romanian Health Ministry. Conclusions. The first results of the Burosumab treatment in the two siblings are extremely encouraging and suggest a favorable long-term evolution under this treatment.

The Treatment with Interleukin 17 Inhibitors and Immune-Mediated Inflammatory Diseases.

IL-17 inhibitors (IL-17i) are medicines used to treat dermatological and rheumatic diseases They belong to a class of medicines called biological disease-modifying anti-rheumatic drugs (bDMARDs). This class of drugs has had a major impact on the therapy of autoimmune diseases, being much safer and more effective than treatment with small molecules. At the same time, they have highly beneficial effects on skin and joint changes, and their efficacy has been extensively monitored and demonstrated in numerous clinical trials. More and more such drugs are still being discovered today to ensure the best possible treatment of these patients, but more frequently and relatively constantly three agents are used. Two of them (Secukinumab and Ixekizumab) inhibit IL-17A directly, and the third, Brodamulab, inhibits the IL-17A receptor. Although they are extremely effective in the treatment of these diseases, sometimes their administration has been associated with paradoxical effects, i.e., there is an exacerbation of the inflammatory process. Tough, clinical trials of IL-17i have described cases of exacerbation or even onset of inflammatory bowel disease (IBD), such as Crohn's disease and ulcerative colitis, after administration of these drugs in patients previously diagnosed with psoriasis (PS), psoriatic arthritis (PsA), or ankylosing spondylitis (AS). The pathophysiological mechanism of action is not well understood at present. One explanation would be that this hyperreactive inflammatory process would be triggered by Interferon 1 derived from dendritic plasma cells. Even though there are many reports in the recent literature about the role of IL17i in the onset of IBD, conclusions of studies do not converge. Some of them show an increased incidence of IBD in patients treated with IL17i, while some others affirm their safety of them. In the near future we will surely have more data emerging from ongoing meta-analyses regarding safety of use IL17i in patients who are at risk of developing IBD. Clinical and paraclinical evaluation (inflammatory intestinal markers) are carefully advised before recommending treatment with IL-17i and after initiation of treatment, and prospective surveillance by clinical and biomarkers of patients treated with IL-17i is absolutely essential to capture the onset of IBD.

Vitamin D Implications and Effect of Supplementation in Endocrine Disorders: Autoimmune Thyroid Disorders (Hashimoto's Disease and Grave's Disease), Diabetes Mellitus and Obesity.

Background and Objectives: Vitamin D deficiency is involved in numerous pathologies, including endocrine pathology. The purpose of this review consists of presenting the role of vitamin D in the pathophysiology of certain endocrine disorders, autoimmune thyroid disorders (Hashimoto's disease and Grave's disease), diabetes mellitus, and obesity, and whether its supplementation can influence the outcome of these diseases. Materials and Methods: Review articles and original articles from the literature were consulted that corresponded with the thematic. Results: Vitamin D deficiency is frequently encountered in endocrine disorders and supplementation restores the normal values. In Hashimoto's disease, vitamin D deficiency appears to be correlated with a higher titer of anti-TPO antibodies and with thyroid volume, and supplementation was associated with reduction of antibodies in some studies. In other studies, supplementation appeared to reduce TSH levels. In Grave's disease, there was a significant correlation regarding vitamin D levels and thyroid volume respective to the degree of exophthalmos. In diabetes mellitus type 2 patients, supplementation led to some improvement of the HOMA-IR index and HbA1c, whereas obesity data from literature do not report significant beneficial findings. Conclusions: Vitamin D deficiency is highly prevalent in endocrine disorders and its supplementation appears to have numerous beneficial effects.

Clinical Features and Outcome of Infective Endocarditis in a University Hospital in Romania.

Background and Objectives: Characterization of patients with endocarditis regarding demographic, clinical, biological and imagistic data, blood culture results and possible correlation between different etiologic factors and host status characteristics. Material and methods: This is a retrospective observational descriptive study conducted on patients older than 18 years admitted in the past 10 years, in the Cardiology Clinic of the Clinical County Emergency Hospital Oradea Romania, with clinical suspicion of bacterial endocarditis. Demographic data, clinical, paraclinical investigations and outcome were registered and analyzed. Results: 92 patients with definite infective endocarditis (IE) according to modified Duke criteria were included. The mean age of patients was 63.80 ± 13.45 years. A percent of 32.6% had health care associated invasive procedure performed in the 6 months before diagnosis of endocarditis. Charlson's comorbidity index number was 3.53 ± 2.029. Most common clinical symptoms and signs were: shortness of breath, cardiac murmur, fever. Sixty-six patients had native valve endocarditis, 26 patients had prosthetic valve endocarditis and one patient was with congenital heart disease. Blood cultures were positive in 61 patients. Among positive culture patient's staphylococcus group was the most frequently involved: Staphylococcus aureus (19.6%) and coagulase negative Staphylococcus (18.5%). Most frequent complications were heart failure, acute renal failure and embolic events. Conclusions: Staphylococcus aureus IE was associated with the presence of large vegetations, prosthetic valve endocarditis and intracardiac abscess. Coagulase negative Staphylococcus (CoNS) infection was associated with prosthetic valve dysfunction. Streptococcus gallolyticus etiology correlated with ischemic embolic stroke and the presence of large vegetations. Cardiovascular surgery was recommended in 67.4% of patients but was performed only on half of them. In hospital death occurred in 33.7% of patients and independent predictors of mortality were congestive heart failure and septic shock.

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.

Genetics of congenital solid tumors.

When we discuss the genetics of tumors, we cannot fail to remember that in the second decade of the twentieth century, more precisely in 1914, Theodore Boveri defined for the first time the chromosomal bases of cancer. In the last 30 years, progresses in genetics have only confirmed Boveri's remarkable predictions made more than 80 years ago. Before the cloning of the retinoblastoma 1 (RB1) gene, the existence of a genetic component in most, if not all, solid childhood tumors were well known. The existence of familial tumor aggregations has been found much more frequently than researchers expected to find at random. Sometimes, the demonstration of this family predisposition was very difficult, because the survival of children diagnosed as having a certain tumor, up to an age at which reproduction and procreation is possible, was very rare. In recent years, advances in the diagnosis and treatment of these diseases have made it possible for these children to survive until the age when they were able to start their own families, including the ability to procreate. Four distinct groups of so-called cancer genes have been identified: oncogenes, which promote tumor cell proliferation; tumor suppressor genes, which inhibit this growth/proliferation; anti-mutational genes, with a role in deoxyribonucleic acid (DNA) stability; and micro-ribonucleic acid (miRNA) genes, with a role in the posttranscriptional process.

Choroidal melanoma, unfavorable prognostic factors. Case report and review of literature.

Uveal melanoma is the most common intraocular tumor characterized by increased metastatic potential. The tumor develops from uveal melanocytes that, from an embryological point of view, derive from the cells of the anterior neural crest. The risk factors associated with melanoma development are close related to patient phenotype: light-colored hair and iris, fair skin. Recent studies have shown the link between choroidal melanoma and choroidal pigmentation of white-haired and light-colored eyes individuals. Increased pigmentation of the choroid is associated to marked increase in melanocyte density, which from a histological point of view can be a starting point for choroidal carcinogenesis. This case report is about a 36-year-old patient who presented in an outpatient ophthalmological examination for intermittent vision blurring. The ophthalmological examination revealed a view of 0.8 and nasally from the optic nerve head, a prominent tumor-shaped formation was detected during the fundus examination. The presence of a choroidal melanoma was suspected and eye ultrasound, angio-fluorography, optical coherence tomography (OCT) were performed and confirmed the diagnosis. Due to the small size, a team of three ophthalmologists decided to make brachytherapy. The procedure consisting of brachytherapy was temporarily applied to the scleral wall and was done at Debrecen University Hospital, Hungary, the follow-up monitoring being done at the Clinic in Oradea, Romania. Although the initial prognosis was optimistic, after four years of brachytherapy the tumor recurred, the dimensions found were over 14 mm, which is why enucleation was decided. Prior to enucleation, no computed tomography (CT) metastases were detected. Five months after enucleation, hepatic metastases occurred and after another two months, death occurred.

Congenital anomalies of digits - a clinical-epidemiological study of 301 patients.

INTRODUCTION: Congenital anomalies of digits (CAD) can occur as isolated malformations, in combination with other malformation of the limbs, or as part of a genetic syndrome. The purpose of this work is to provide an overview of CAD, on morphological, genetic and epidemiological basis. PATIENTS AND METHODS: We conducted a retrospective analysis of a cohort of 301 patients with CAD. Following the Swanson classification, the list of anomalies under study included: adactyly and oligodactyly, syndactyly and symphalangism, polydactyly, macrodactyly, amniotic bands syndrome, and generalized skeletal anomalies. RESULTS: In Bihor County, Romania, the Department of Medical Genetics recorded 4916 patients with congenital anomalies (2.03% out of 241 601 live newborns) between 1984 and 2018. Of these, 301 (6.1%) patients had CAD. The prevalence of CAD was 1:800 living newborns. The most common CAD were polydactyly, followed by syndactyly, brachydactyly, adactyly and oligodactyly. Upper extremities were four times more frequently affected than lower extremities, while both upper and lower extremities were affected in a quarter of all cases. CAD were isolated in 64% of patients, while 14% were associated with other anomalies of the extremities and 22% were associated with recognized genetic syndromes. CONCLUSIONS: Our study, by its size and the long period of clinical observation, provides opportunities to generalize and compare our data with similar studies, offering the possibility for improved knowledge of the epidemiology of CAD and potential improvements in genetic counseling.

Clinical and genetic diversity of congenital hyperammonemia.

Congenital hyperammonemia (HA) due to inborn errors of metabolism is a rare condition with a high rate of mortality. The main effects occur at the central nervous system (CNS) level, being neurotoxic by alteration of the neurotransmitter function. HA can be triggered by an inappropriate diet, infection or stress, but can also occur without a precise cause. In cases of metabolic crises, patients require immediately intensive care. In the last seven years (2011-2017), we cared in the Department of Genetics, "Dr. Gavril Curteanu" Municipal Clinical Hospital, Oradea, Romania, six patients with different causes of congenital HA: one case with argininosuccinate lyase deficiency, two cases (brothers) with argininosuccinate synthase deficiency, one case with non-ketotic hyperglycinemia, one case hyperglycinemia and one case with HA with unknown etiology. The medical surveillance and care of these children over a long period of time raise serious problems for the family and society. These patients are dependent on medical services: qualified medical staff (pediatrician, geneticist, radiologist, biochemist, nutritionist, and psychologist), expensive and repeated medical investigations, prolonged and costly medication. Most of these costs could be avoided by early diagnosis and treatment, rigorous monitoring of HA, ensuring proper diet and medication. Our experience regarding the clinical and genetic particularities of patients with congenital HA could be an opportunity for the better knowledge of special needs of these patients, especially regarding the psychological and social aspects.

Double autosomal trisomy with mosaicism 47,XY(+8)∕47,XY(+21). Morphological and genetic changes of a rare case.

The co-occurrence in the same individual of two numerical chromosomal abnormalities (double aneuploidy) is a very rare condition, especially for autosomes. Clinical presentations are variable depending on the predominating aneuploidy. The authors present a rare case of a male infant with multiple congenital anomalies: craniofacial dysmorphism, short neck, agenesis of the corpus callosum, ventricular septal defect, bilateral broad hallux, large first interdigital space of the toes, plantar furrows, prominent calcaneus and right kidney agenesis. The karyotype identified 82% of mitosis with trisomy 8 (47,XY,+8) and 18% with trisomy 21 (47,XY,+21). The evolution was fatal because of eating difficulties, severe growth retardation and recurrent respiratory infections. He died at the age of five months. We report this case as a very rare double autosomal mosaicism, with a complete clinical and morphological description, as the first documented case in Romania.

Empty sella associated with growth hormone deficiency and polydactyly.

Empty sella means the absence of the pituitary gland on cranial computed tomography or magnetic resonance imaging. Empty sella syndrome is the pathological variant of the imaging-described empty sella. We present the case of a male Caucasian child, aged four years and two months, for short stature and diagnosed by imaging procedures as empty sella. The cause of short stature was isolated growth hormone (GH) deficiency. Associated he presented left hand postaxial polydactyly. In connection with this particular case, we propose a review of current knowledge in empty sella syndrome. The particularity of reported case consists of association empty sella with GH deficiency and polydactyly. The association of empty sella with polydactyly is not reported yet in the medical literature and is probably coincidental.

Anatomic variants in Dandy-Walker complex.

Dandy-Walker complex (DWC) is a malformative association of the central nervous system. DWC includes four different types: Dandy-Walker malformation (vermis agenesis or hypoplasia, cystic dilatation of the fourth ventricle and a large posterior fossa); Dandy-Walker variant (vermis hypoplasia, cystic dilatation of the fourth ventricle, normal posterior fossa); mega cysterna magna (large posterior fossa, normal vermis and fourth ventricle) and posterior fossa arachnoid cyst. We present and discuss four cases with different morphological and clinical forms of the Dandy-Walker complex. In all four cases, diagnosis was reached by incorporation of clinical (macrocephaly, seizures) and imaging [X-ray, computed tomography (CT), magnetic resonance imaging (MRI)] data. Two patients were diagnosed with Dandy-Walker complex, one patient was diagnosed with Dandy-Walker variant in a rare association with neurofibromatosis and one patient was diagnosed with a posterior fossa arachnoid cyst associated with left-sided Claude Bernard-Horner syndrome, congenital heart disease (coarctation of the aorta, mitral stenosis) and gastroesophageal reflux. In all forms of DWC, the clinical, radiological and functional manifestations are variable and require adequate diagnostic and therapeutic measures.

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).