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.

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.

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.

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.

Unusual extramedullary relapses in a case of common B-cell acute lymphoblastic leukemia. Case report and review of literature.

BACKGROUND: Acute lymphoblastic leukemia (ALL) represents the most common malignancy in children with an overall cure rate of 85%. Relapses occur in 20% of the cases. Commonly, extramedullary relapses (EMRs) involve central nervous system (CNS) or testes. Unusual EMRs in ALL are relatively rare reported. CASE PRESENTATION: The authors present a 24-year-old woman with ALL, who experienced three unusual EMRs. In 2007, she was diagnosed with B-cell precursor (BCP)-ALL - high-risk (HR) group, and she was treated according to ALL Intercontinental Berlin-Frankfurt-Münster (IC-BFM) 2002∕HR Protocol. She entered complete remission (CR). In 2012, a vaginal wall solid mass infiltrate occurs. Biopsy concluded for EMR of ALL. Chemotherapy was restarted; the patient responded again with CR. Magnetic resonance imaging (MRI) and positron emission tomography∕computed tomography (PET∕CT) examinations during follow-up revealed supraclavicular, mesenteric, and retroperitoneal lymphadenopathies (2014). Pathological examination of the supraclavicular lymph node showed a benign pattern: schwannoma. The patient's evolution worsened, imposing a biopsy from the retroperitoneal tumor which revealed a second EMR of ALL. Again, ALL-REZ BFM 2002 Protocol was started, followed by haploidentical mother-to-child peripheral blood hematopoietic stem cell transplantation (HSCT). After suffering a few managed complications related to the transplant, our patient achieved CR again. In 2017, 10 years after the initial diagnosis, the patient presented for the third time an EMR (gastric wall) and eventually died due to progression of the disease. CONCLUSIONS: The patient presented an extremely aggressive type of ALL with three unusual EMRs: vaginal, retroperitoneal and gastric.

The importance of the histopathological examination in establishing the diagnosis of delayed splenic rupture. Report of a case and literature review.

In forensic activity, splenic ruptures occur frequently in cases involving abdominal trauma due to road traffic collision, strokes, falls and work accidents. Splenic lesions can occur either immediately after the trauma or within variable timeframes after it, the last scenario being the case of a delayed splenic rupture. Delayed splenic rupture is ranked third in abdominal traumatology frequency, after liver and intestine rupture. Delayed splenic rupture is more frequently the result of abdominal contusions or compressions, rather than the result of direct wounds located in the left flank. In the first stage, an intraparenchymatous hematoma is formed. The second stage occurs within a variable timeframe (between two days and one month), either spontaneously or following a second trauma, when the capsule ruptures leading to secondary peritoneal hemorrhage. In order to correctly determine the chronology of splenic lesions, histopathological (HP) investigations have an important role to play. The presence of hemosiderin highlighted by Hematoxylin-Eosin (HE) staining or special stainings, confirms the diagnosis of delayed splenic rupture. This study will present the case of a 55-year-old male from the countryside, a chronic alcohol consumer, animal care provider, who suffered multiple traumatic injuries four days prior to his death. He was found lying on the ground, presenting an open craniocerebral trauma (CCT) with a bleeding wound on the scalp. The autopsy showed CCT with meningeal hemorrhage and subdural hematoma, along with a splenic rupture presumably produced in two stages. The HP investigations did not reveal the presence of hemosiderin in the tested specimen samples. Using this scientific diagnostic criterion, it was thus confirmed that the splenic rupture occurred after the aggression, in another traumatic stage, the same one where the other thanatogenerator lesions occurred, as a result of the victim's collapse from the same level and hitting the planes with irregular surfaces.

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).