Manifest Variables Research Articles

Клиническое разнообразие митохондриальной патологии: описание собственных наблюдений

Mitochondrial diseases represent an essential share of genetic diseases. The variability of clinical manifestations of mitochondrial pathologies leads to significant difficulties in its diagnosis. Authors present five clinical case reports of pediatric patients with genetically confirmed mitochondrial diseases (Leber’s hereditary optic neuropathy, MERRF syndrome, mitochondrial complex I deficiency and mitochondrial encephalopathy due to mitochondrial and peroxisome fusion) that were all observed in the University Clinic of the Saint Petersburg State Pediatric Medical University (Saint Petersburg, Russia) in 2021-2023. All the five patients were suggested to receive a personalized energotropic therapy coupled with ketogenic dietary nutrition whilst some did not adhere to the recommended prescriptions for a number of reasons such as insufficient awareness, relatively high cost of treatments etc. therefore beneficial effect of the administered therapy was observed in only two out of three relevant patients.

Genetic diseases with skin fragility in children

Genetic diseases leading to skin fragility are clinically and genetically heterogeneous. Dermatologists and pediatricians should be familiar with the variability of manifestations and manifestation age, in order to differentiate these rare diseases from more common causes of blistering, such as infectious (impetigo contagiosa, herpes infection) or traumatic causes (burns, scalds). This is essential to initiate appropriate diagnostic measures, provide information on treatment and prevention and to refer to specialized centers. The classification of the diseases discussed here is based on the clinical appearance, the histologic cleavage level, and genetic alterations. These diseases are all rare and pathogenetically only partially understood. Treatment methods are mostly symptomatic; causal therapies are the exception. Thanks to advances in mutation detection methods and the assumption of costs for massive parallel sequencing (since 2021) by health insurance companies, rare diseases have moved from the focus of academic research into everyday clinical practice. Due to the rarity, variability of the phenotype and, in many cases, high need for care, it is important in everyday clinical practice to be able to apply apathway for suspected diagnoses and to work together with specialized colleagues and care centers. This study provides an overview of genetic diseases with skin fragility in childhood. Knowledge of the underlying mechanisms leading to skin fragility in childhood can help to recognize rare differential diagnoses from more common infectious and traumatic causes of blistering. This is necessary to enable adequate treatment and referral to specialized care centers and colleagues.

Diagnosis, management and treatment of acquired uterine arteriovenous malformation: A case series and literature review.

The rising prevalence of cesarean sections, abortions, and other surgical interventions involving the uterus has led to an increased incidence of acquired uterine arteriovenous malformations (AVMs). These malformations primarily present as vaginal bleeding, which can significantly impair the quality of life for affected individuals and can pose life-threatening risks in severe instances. Currently, there exists considerable variability in the clinical manifestations, treatment indications, and outcomes associated with uterine AVMs, which substantially complicates clinical diagnosis and management. In this report, we present five cases of uterine AVM that developed following abortion and were treated at our institution. The patients underwent various treatment modalities, with all but one achieving a high rate of fertility preservation. We underscore the importance of tailoring AVM treatment to factors such as patient age, volume of vaginal bleeding, urgency of the situation, size of the lesion, and fertility aspirations.

Proteus Syndrome: Description of Two Clinical Cases

Background. Proteus syndrome is extremely rare congenital multisystem disease with high variability in clinical manifestations. Its prevalence is unknown, there are less than 200 cases in the world literature. The syndrome is a classic example of somatic mosaicism, and all target drugs for its management are based on it. Clinical case description. This article describes two clinical cases with somatic variants of the nucleotide sequence in the AKT1 gene, mosaic form, revealed by the NGS method. Target drug (mTOR-inhibitors group) was assigned in one case. Conclusion. The description of the phenotypic features of patients with Proteus syndrome is crucial as this pathology is very rare. It is necessary to increase the awareness of clinicians about this disease to develop a plan for dynamic follow-up with consideration to life-threatening complications (malignant tumors and thrombembolia risk). Genetic verification of Proteus syndrome is mandatory nowadays as target therapy is actively developed and implemented, thus, revision of clinical guidelines is recommended.

Systematic review of thyroid function in NKX2-1-related disorders: Treatment and follow-up.

NKX2-1, a crucial transcription factor in thyroid, lung, and brain development, is associated with rare disorders featuring thyroid dysfunction, neurological abnormalities, and respiratory symptoms. The primary challenge in managing NKX2-1-related disorders (NKX2-1-RD) is early diagnosis of the genetic defect and treating specific endocrine disorders. Levothyroxine (LT4) serves as the standard hypothyroidism treatment, with required dosages influenced by the severity of the individual's disorder, which varies widely among affected individuals. This systematic review aims to assess the effectiveness of LT4 treatment in NKX2-1-RD and explore optimal dosing strategies. The primary focus is on the challenges associated with the prompt diagnosis of genetic defects, rather than the established treatment protocols for individual endocrine failures. Adhering to PRISMA guidelines, the review includes 42 studies involving 110 genetically confirmed NKX2-1-RD patients with hypothyroidism. The study investigates congenital hypothyroidism as the most prevalent endocrine alteration, along with gestational and overt hypothyroidism. The administration of LT4 treatment, dosages, and patient responses are analyzed. Among the findings, congenital hypothyroidism emerges as the predominant endocrine alteration in 41% of patients. Notably, LT4 treatment is administered in only 10% of cases, with a mean dose of 52 μg/day. The variability in initiation and dosage is likely influenced by the age at diagnosis. Positive responses, characterized by TSH adjustments within normal ranges, are observed in 11 monitored patients. Early detection of congenital hypothyroidism is emphasized for timely LT4 initiation. Challenges in standardization are highlighted due to the variability in clinical manifestations and diagnostic procedures across NKX2-1-RD cases. While this review provides valuable insights into thyroid and pituitary disease treatment, limited details on LT4 treatment represent a significant study limitation. Key reporting points for future case studies are proposed to enhance the understanding and management of NKX2-1-RD hypothyroidism.

Drinking motives and alcohol sensitivity mediate multi-dimensional genetic influences on alcohol use behaviors.

Genetic influences account for a substantial proportion of individual differences in alcohol use behaviors (AUBs). However, multiple distinct sets of genes are linked to different AUBs, which may explain their dramatic variability in risk factors and manifestations. In this study, we explore whether intermediate neurobiological traits and alcohol-related cognitions mediate the relationship between polygenic scores (PGS) and multiple AUBs, with the aim to better understand processes captured by different genetic profiles. Using results from prior genome-wide association studies, we derived PGS for 6 AUBs in participants from Spit for Science, a longitudinal study of college students in the U.S. (n=4,549). Self-report measures included personality traits, alcohol expectancies, drinking motivations, and alcohol sensitivity measures as well as drinking frequency, drinking quantity, alcohol use disorder (AUD) symptoms, and maximum drinks in 24 hours. Using linear regression and multiple mediation models, we investigated the direct and indirect effects of PGS on AUBs. In univariable regression results, PGSs indexing broad AUB dimensions such as drinks per week (DPW) and AUD predicted higher levels of sensation-seeking and multiple drinking motives, while BeerPref PGSs (indexing a variable pattern of alcohol problems associated with a preference for beer) predicted higher negative urgency and lower alcohol sensitivity. Mediational models indicated strong direct and indirect effects of DPW PGSs on multiple AUBs via social/enhancement drinking motives and alcohol sensitivity, indirect effects of AUD PGSs on AUD symptoms via coping motives, and indirect effects of BeerPref PGS on all AUBs via the joint effect of mediators including alcohol sensitivity. These findings provide initial evidence that the genetic influences on different AUBs are associated with and partially mediated by intermediate neurobiological and cognitive factors, which may be more amenable to intervention. Greater focus on drinking motives and alcohol sensitivity is warranted in genetic research, as well as attention to the heterogeneous pathways linking genes to alcohol use outcomes.

The Desmoplakin Phenotype Spectrum: Is the Inflammation the "Fil Rouge" Linking Myocarditis, Arrhythmogenic Cardiomyopathy, and Uncommon Autoinflammatory Systemic Disease?

Myocarditis is an inflammatory condition of cardiac tissue presenting significant variability in clinical manifestations and outcomes. Its etiology is diverse, encompassing infectious agents (primarily viruses, but also bacteria, protozoa, and helminths) and non-infectious factors (autoimmune responses, toxins, and drugs), though often the specific cause remains unidentified. Recent research has highlighted the potential role of genetic susceptibility in the development of myocarditis (and in some cases the development of inflammatory dilated cardiomyopathy, i.e., the condition in which there is chronic inflammation (>3 months) and left ventricular dysfunction\dilatation), with several studies indicating a correlation between myocarditis and genetic backgrounds. Notably, pathogenic genetic variants linked to dilated or arrhythmic cardiomyopathy are found in 8-16% of myocarditis patients. Genetic predispositions can lead to recurrent myocarditis and a higher incidence of ventricular arrhythmias and heart failure. Moreover, the presence of DSP mutations has been associated with distinct pathological patterns and clinical outcomes in arrhythmogenic cardiomyopathy (hot phases). The interplay between genetic factors and environmental triggers, such as viral infections and physical stress, is crucial in understanding the pathogenesis of myocarditis. Identifying these genetic markers can improve the diagnosis, risk stratification, and management of patients with myocarditis, potentially guiding tailored therapeutic interventions. This review aims to synthesize current knowledge on the genetic underpinnings of myocarditis, with an emphasis on desmoplakin-related arrhythmogenic cardiomyopathy, to enhance clinical understanding and inform future research directions.

Diet and Nutrients in Rare Neurological Disorders: Biological, Biochemical, and Pathophysiological Evidence.

Background/Objectives: Rare diseases are a wide and heterogeneous group of multisystem life-threatening or chronically debilitating clinical conditions with reduced life expectancy and a relevant mortality rate in childhood. Some of these disorders have typical neurological symptoms, presenting from birth to adulthood. Dietary patterns and nutritional compounds play key roles in the onset and progression of neurological disorders, and the impact of alimentary needs must be enlightened especially in rare neurological diseases. This work aims to collect the in vitro, in vivo, and clinical evidence on the effects of diet and of nutrient intake on some rare neurological disorders, including some genetic diseases, and rare brain tumors. Herein, those aspects are critically linked to the genetic, biological, biochemical, and pathophysiological hallmarks typical of each disorder. Methods: By searching the major web-based databases (PubMed, Web of Science Core Collection, DynaMed, and Clinicaltrials.gov), we try to sum up and improve our understanding of the emerging role of nutrition as both first-line therapy and risk factors in rare neurological diseases. Results: In line with the increasing number of consensus opinions suggesting that nutrients should receive the same attention as pharmacological treatments, the results of this work pointed out that a standard dietary recommendation in a specific rare disease is often limited by the heterogeneity of occurrent genetic mutations and by the variability of pathophysiological manifestation. Conclusions: In conclusion, we hope that the knowledge gaps identified here may inspire further research for a better evaluation of molecular mechanisms and long-term effects.

Analysis of laboratory and instrumental data in young patients with COVID-19 and cardiovascular disorders

Introduction. Despite significant information on cardiovascular damage in older patients with COVID- 19, there is no clear understanding of the variability of cardiac diseases manifestations in young patients. Additionally, summarized data characterizing the severity of myocardial damage in these patients is lacking.Aim. To compare laboratory and functional study data and identify predictors of cardiovascular damage in young patients with COVID-19.Materials and methods. An analysis of 4,453 medical records from 2020 to 2022 was conducted. The focus was on patient age (18- 44 years), primary diagnosis, severity of COVID-19, comorbid conditions, timing of cardiovascular symptom onset, and laboratory and functional study data characterizing cardiovascular system damage. According to the inclusion and exclusion criteria, 132 medical records of patients aged 18 to 44 years with moderate COVID-19 were selected, including 49 with cardiovascular issues and 83 without cardiovascular pathology.Results. Comparative analysis showed that cardiovascular system damage in young patients with moderate COVID-19, compared to those without cardiovascular pathology, was associated with elevated levels of C-reactive protein (CRP) (p=0.001), brain natriuretic peptide (NTproBNP) (p<0.0001), D-dimer (p<0.0001), and troponin I (p<0.0001). CRP levels in patients with pericarditis and acute myocardial infarction (AMI) were higher than in those with acute cerebrovascular accident (ACVA) (p=0.001). No differences in D-dimer levels were found between subgroups (p>0.05). Troponin I and NTproBNP levels in the AMI subgroup were higher than in the pericarditis (p<0.0001 and p=0.047, respectively) and ACVA (p=0.001 and p=0.043, respectively) subgroups. Patients with cardiovascular disorders had a reduced left ventricular ejection fraction (LVEF) (p=0.005) without significant changes in left ventricular end-systolic (p=0.200) and end-diastolic volumes (p=0.119). The lowest LVEF was found in the AMI and ACVA subgroups (p=0.001). Correlation-regression analysis revealed associations between cardiovascular complications and NTproBNP (r=0.673, p<0.001), troponin I (r=0.543, p<0.001), and D-dimer (r=0.363, p<0.001), as well as LVEF (r=-0.341, p<0.001). Significant stochastic relationships were also found between D-dimer and troponin I (r=0.532, p<0.001), NTproBNP (r=0.545, p<0.001); and between LVEF and troponin I (r=-0.420, p<0.001), NTproBNP (r=-0.314, p<0.001). Multivariate regression analysis showed that NTproBNP, with a sensitivity of 86.5% and specificity of 81.9%, is an independent predictor of cardiovascular complications in young patients with moderate COVID-19 (OR=1.175, p=0.001).Conclusion. The results indicate that the severity of COVID-19, regardless of patient age and comorbidities, can be a factor in the development of cardiovascular complications. NTproBNP levels in the blood of COVID-19 patients can be an early marker of cardiovascular risk. However, further research is needed to confirm the pathogenetic role of cardiotropic protein in the development of pericarditis, AMI, and ACVA in these patients.

Gastrointestinal Ultrasound in Infectious Diseases: A Comprehensive Review.

Infectious diseases affecting the gastrointestinal tract often present diagnostic challenges due to the variability in clinical manifestations and overlapping symptoms. Ultrasound imaging has emerged as a valuable tool in the assessment of gastrointestinal pathologies, offering non-invasive and real-time visualization of anatomical structures. This review aims to explore the role of ultrasound in the diagnosis and management of infectious diseases involving the gastrointestinal tract. We discuss the imaging features of various infectious etiologies, such as bacterial, viral, and parasitic infections, highlighting characteristic findings on ultrasound scans. Additionally, we provide insights into the utility of ultrasound for the assessment of treatment response. Through a comprehensive analysis of existing literature and clinical case studies, this review underscores the significance of ultrasound imaging as a frontline modality in the diagnosis and management of infectious diseases affecting the gastrointestinal tract.

Obesity-Related Ciliopathies: Focus on Advances of Biomarkers.

Obesity-related ciliopathies, as a group of ciliopathies including Alström Syndrome and Bardet-Biedl Syndrome, exhibit distinct genetic and phenotypic variability. The understanding of these diseases is highly significant for understanding the functions of primary cilia in the human body, particularly regarding the relationship between obesity and primary cilia. The diagnosis of these diseases primarily relies on clinical presentation and genetic testing. However, there is a significant lack of research on biomarkers to elucidate the variability in clinical manifestations, disease progression, prognosis, and treatment responses. Through an extensive literature review, the paper focuses on obesity-related ciliopathies, reviewing the advancements in the field and highlighting the potential roles of biomarkers in the clinical presentation, diagnosis, and prognosis of these diseases.

Implications of Celiac Disease in Prospective Corneal Refractive Surgery Patients: A Narrative Review.

Celiac disease (CeD) is a prevalent autoimmune disorder incited by gluten consumption, resulting in intestinal damage. Affecting approximately one in 133 people globally, CeD often remains undiagnosed due to its varied clinical presentations. The prevalence and diagnosis of CeD are influenced by several factors, including demographics and genetics, and it often coexists with other autoimmune diseases. Thus, the objective of this paper was to review the literature on ophthalmic manifestations of CeD and to create preliminary considerations for these patients wishing to undergo elective corneal refractive surgery (CRS). A literature review was conducted through July 2024, and relevant search terms were used to identify contributing papers. The review enabled the development of detailed considerations for the ocular manifestations of CeD and recommended management strategies for healthcare teams before and following CRS. The 24 papers included in this study illustrate that nutritional deficiencies and autoimmune concerns linked to CeD have distinctive ocular presentations. Based on these findings, patients with CeD may exhibit unconventional ocular manifestations beyond their typical gastrointestinal symptoms, such as decreased endothelial cell density (ECD), vitamin A deficiency leading to dryness, altered corneal nerve density, cataracts, uveitis, changes in choroidal thickness, papilledema, and neurological issues such as nystagmus. Patients with CeD may also experience synergistic impacts from concomitant autoimmune conditions such as Type 1 Diabetes Mellitus (T1DM) in addition to the coexistence of thyroid ophthalmopathy. Recognizing that CeD is an autoimmune disorder that can be exacerbated by other conditions, it is essential to conduct a thorough evaluation for elective CRS. Due to the variability in ocular manifestations among CeD patients, individualized evaluations are crucial for determining surgical candidacy and optimizing outcomes, especially for patients who may not be well controlled. Evaluations are likely to encompass a subjective assessment through a questionnaire exploring the patient's past medical history related to CeD. These questions can range from inquiring about general past medical history related to CeD regarding dietary gluten intake and weight loss to joint pain and cognitive impairments such as brain fog. Clinicians should also perform a comprehensive objective assessment utilizing slit-lamp biomicroscopy, Schirmer test, tear break-up time (TBUT), optical coherence tomography (OCT), Scheimpflug imaging, or fundoscopy. Although there is currently no specific information regarding CRS recommendations for patients with CeD, we believe the considerations outlined in this paper should serve as preliminary guidelines for clinicians. While our findings have formed considerations for future healthcare teams, further research is needed to fully understand the impact of CeD on CRS outcomes and refine these recommendations.

Axial Disease in Psoriatic Arthritis: A Challenging Domain in Clinical Practice.

Psoriatic arthritis (PsA) is a chronic inflammatory condition affecting about one-third of individuals with psoriasis. Defining axial involvement in PsA (axPsA) remains debated. While rheumatologists guide clinical practice, consensus on axPsA is still lacking. This paper explores historical and upcoming definitions from the Axial Involvement in Psoriatic Arthritis (AXIS) study, which aims to establish a validated axPsA definition. Epidemiological data reveal diverse axPsA prevalence rates, emphasizing its complex relationship with peripheral arthritis and enthesitis. Unique genetic, clinical, and radiological features differentiate axPsA from ankylosing spondylitis (AS), necessitating refined classification criteria. The recommendations from the Assessment of Spondylarthritis international Society (ASAS) provide valuable guidance due to the limited direct evidence. Emerging therapies, including interleukin-23 (IL-23) inhibitors or Janus kinase (JAK) inhibitors, are under investigation for axPsA. Currently, secukinumab, an interleukin-17 (IL-17) inhibitor, is an evidence-based option for axPsA management. However, given the variability in individual patient responses and disease manifestations, personalized, evidence-based treatment approaches remain essential for optimizing patient outcomes. In the final section, two real-life cases illustrate the challenges in managing axPsA, emphasizing the importance of tailored therapies. Achieving precision in defining axPsA remains a formidable task, making detailed criteria essential for effective strategies and improving patient outcomes.

Clinical and radiological variants of the nail–patella syndrome: Why is it important to make a correct diagnosis?

BACKGROUND: Nail–patella syndrome is an autosomal dominant disease caused by LMX1B mutations, characterized by a combination of dermatological and musculoskeletal abnormalities. The classic tetrad of the nail–patella syndrome includes hypoplasia of the nail plates, absence or hypoplasia of the patella, elbow joint contractures, often accompanied by posterior subluxation of the radial head, presence of “iliac horns” on radiographs of the pelvic bones, and renal changes. However, its diagnosis and treatment are not described in sufficient detail in domestic and foreign literature. AIM: This study aimed to analyze the variability of clinical and radiological manifestations in children with nail–patella syndrome. MATERIALS AND METHODS: Nine patients with nail–patella syndrome were examined and treated (aged 4 months to 14 years). All children presented to the H. Turner National Medical Research Center for Children’s Orthopedics and Trauma Surgery with a diagnosis of congenital multiple arthrogryposis. The examination results excluded this diagnosis. The diagnosis of nail–patella syndrome has been verified. RESULTS: Various variants of the nail–patella syndrome have been identified, with lesions to only the elbow joints (n = 3), damage to the upper and lower extremities (n = 5), and damage to only the lower extremities (n = 1). All patients had hypoplasia of fingernail plates. However, the pathognomonic sign – “iliac horns” on radiographs of the pelvic bones – was noted only in 33% of cases. Regarding functional disorders of the kidneys, proteinuria was observed in one patient, which appeared at the age of 15 years. In two cases, the parents suffered from this disease. A genetic examination was performed in three patients: a pathogenic variant in LMX1B was detected in a heterozygous state. All patients underwent conservative treatment for knee and elbow joint contractures and foot deformities. When casting, the presence of dislocation of the radial head or patella was considered. Surgical treatment was performed on five patients. The results of surgery on the lower extremities (knee contractures, foot deformities, and hip dislocation) were good in 87% of the cases. Recurrence of flexion contractures in the elbow joints was observed both after conservative and after surgical treatment in all cases; however, their severity varied. CONCLUSIONS: Clinical observations were considered to attract the attention of doctors of different specialties to a rare pathology. Moreover, a molecular genetic study is recommended for the timely diagnosis of the nail–patella syndrome, determining the treatment techniques and disease prognosis.

Pathogenesis and modern methods for treatment of hip infectious arthritis: a review

Background. One of the little-studied but long-known problems is determining the optimal treatment regimen for patients with infectious arthritis of the hip joint. Existing studies offer various methods of conservative and surgical treatment, which, however, do not have a fundamental evidence base. The polyetiology and variability of the clinical manifestations of infectious arthritis of the hip joint and the severity of the consequences in case of incorrectly chosen tactics require a differentiated approach to treatment and development of certain diagnostic and treatment algorithms. The aim of the review – to identify pathogenesis factors that are significant for the choice of treatment tactics and to analyze modern methods of treating infectious arthritis of the hip joint based on the data from available medical literature. Methods. For analysis, we selected 90 foreign and domestic sources published between 1997 and 2023. Inclusion criteria were: clinical studies, analytical reviews and meta-analyses of the literature. The search was performed in eLIBRARY, PubMed and Google Scholar databases. Results. The analysis showed that, despite the comparable effectiveness and advantages of individual treatment methods, their use is limited to certain indications, and the choice of the optimal one for a particular patient should take into account many etiopathogenetic factors, clinical, laboratory and instrumental data, the role of which is still insufficiently studied. Currently, throughout the world the “gold standard” for radical surgical treatment remains the technique of two-stage hip arthroplasty using an antibacterial spacer. However, encouraging results of alternative treatment methods require continued search for ways to optimize diagnostic and therapeutic tactics.

Psychosomatic dyssomnia in patients with different forms of diffuse alopecia: variability and intensity of clinical manifestations

Psychosomatic dyssomnia in patients with different forms of diffuse alopecia: variability and intensity of clinical manifestations

Drug-induced liver injury in HIV-infected patients with active tuberculosis

High prevalence, variability of clinical manifestations, limited knowledge about mechanisms of toxicity, and difficulty in diagnosis make drug-induced liver injury one of the unsolved problems in clinical medicine. Drug-induced liver injury during antiretroviral and antituberculosis therapy is a serious complication, which can reach a severe degree, leading to acute liver failure. Studies to identify the frequency, type, and severity of drug-induced liver injury in HIV-infected patients with active tuberculosis are essential. The article summarizes the current data of scientific publications on the frequency, type, and severity of drug-induced liver injury in patients treated with antiretroviral and antituberculosis drugs. A search and subsequent analysis of scientific publications in MedLine, the Cochrane Library, PubMed, and Scopus was performed. Available data indicate a high incidence of drug-induced liver injury and variation in types and severity among TB/HIV patients. This necessitates the need to examine patients taking ART and anti-TB drugs for the occurrence of liver damage, especially those with high-risk conditions such as viral hepatitis and alcohol use. It should remain a key component of TB/ HIV treatment.

Reduced levels of MRE11 cause disease phenotypes distinct from ataxia telangiectasia-like disorder.

The MRE11/RAD50/NBS1 (MRN) complex plays critical roles in cellular responses to DNA double-strand breaks. MRN is involved in end binding and processing, and it also induces cell cycle checkpoints by activating the ataxia-telangiectasia mutated (ATM) protein kinase. Hypomorphic pathogenic variants in the MRE11, RAD50, or NBS1 genes cause autosomal recessive genome instability syndromes featuring variable degrees of dwarfism, neurological defects, anemia, and cancer predisposition. Disease-associated MRN alleles include missense and nonsense variants, and many cause reduced protein levels of the entire MRN complex. However, the dramatic variability in the disease manifestation of MRN pathogenic variants is not understood. We sought to determine if low protein levels are a significant contributor to disease sequelae and therefore generated a transgenic murine model expressing MRE11 at low levels. These mice display dramatic phenotypes including small body size, severe anemia, and impaired DNA repair. We demonstrate that, distinct from ataxia telangiectasia-like disorder caused by MRE11 pathogenic missense or nonsense variants, mice and cultured cells expressing low MRE11 levels do not display the anticipated defects in ATM activation. Our findings indicate that ATM signaling can be supported by very low levels of the MRN complex and imply that defective ATM activation results from perturbation of MRN function caused by specific hypomorphic disease mutations. These distinct phenotypic outcomes underline the importance of understanding the impact of specific pathogenic MRE11 variants, which may help direct appropriate early surveillance for patients with these complicated disorders in a clinical setting.

Endoprosthesis in distal esophageal perforations: A therapeutic possibility

Esophageal perforation presents a diagnostic and therapeutic challenge due to its variability in clinical manifestations and the lack of published literature.

TEK gene-related primary congenital glaucoma: Phenotypic features and mutational spectrum in a Mexican cohort of 10 unrelated families.

Primary congenital glaucoma (PCG) is one of the leading causes of visual damage and blindness, severely affecting the quality of life of affected children. It is characterized by cupping of the optic disc and loss of ganglion cells due to elevated intraocular pressure. While most PCG patients exhibit epiphora, photophobia, and buphthalmos with corneal opacity, variability in phenotypic manifestations is not uncommon. Prompt diagnosis and treatment of PCG affected individuals becomes relevant to preserve visual function throughout their lives. Most PCG cases are sporadic or autosomal recessive; however, an incompletely dominant autosomal dominant form arising from mutations in the TEK gene has recently been demonstrated. Here, we describe the clinical and mutational features of a cohort of Mexican patients with TEK-related PCG. Our results support the involvement of the TEK gene as an important cause of the disease in our ethnic group and expand the mutational spectrum causing PCG by reporting 10 novel disease-causing variants.