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Contemporary forms of occupational diseases are often characterized by many body systems involved, with response of specific and nonspecific effects. Due to observed transformation in character and course of the main occupational entities, specifying the new clinical classifications, new "List of Occupational Diseases" adapted to ICD-10, by specialists remains topical.
The value of histopathologic parameters in predicting the long-term overall survival probabilities was studied in a series of 123 patients with pathologic stage IA, IB, IIA, IIB, or IIIA Hodgkin's disease, nodular sclerosis type who were treated with curative radiation therapy. The parameters that were studied included the relative proportion of atypical vs reactive cells, amount of eosinophils, presence of necrosis, degree of mitotic activity, intensity of different types of mesenchymal reactions, classification in three subtypes (ie, lymphocyte predominance, mixed cellularity, and lymphocyte depletion) or in two grades (ie, grades 1 and 2), and identification of the syncytial variant. For each parameter, the association with clinical risk factors was also analyzed. The results of this study show that there are no pathologic features that carry a significant predictive value of the overall survival.
Three infants who underwent operation for total anomalous pulmonary venous connection had unobstructed drainage of all the pulmonary veins to both the coronary sinus and left vertical vein. In one patient the anatomy was demonstrated preoperatively and complete correction accomplished without difficulty, but in two patients the second connection was discovered only at postoperative reinvestigation. Arbitrary classification of total anomalous pulmonary venous connection into cardiac, supracardiac, infracardiac, and mixed types does not lend itself to description of such lesions and may obscure their clinical importance. For these less common variants of total anomalous pulmonary venous connection, a more detailed and precise definition of morphology facilitates accurate surgical repair.
Clinical and morphological examinations were carried out in 159 children with nephroblastoma. A working histological classification of tumors with reference to prognosis is proposed. It includes typical (89 cases) and atypical (23 cases) variants of the tumor. Among typical tumors, those with predominance of nondifferentiated blastema are distinguished. The atypical tumors include tubular fetal rhabdomyomatous, cystic, sarcomatous (rhabdoid, clear cell) variants. A group of tumors with marked therapeutic pathomorphosis (27 cases) is distinguished among unclassified tumors. Unfavourable prognosis in tumors with predominance of undifferentiated blastema, sarcomatous variants, and tumors with marked therapeutic pathomorphosis is indicated. Attention is drawn to increased number of glomerulo-like structures and cell anaplasia as a possible unfavourable prognostic sign.
This classification of amyloid and amyloidosis is based on the amyloid fibril proteins, followed by a designation of the fibril protein precursor. Additional information includes the protein type or variant (where applicable) and the clinical diagnosis.
CHARGE syndrome is a rare congenital disorder primarily attributed to heterozygous pathogenic variants of the CHD7 gene. Most pathogenic CHD7 variants are loss-of-function (LoF) variants, whereas the interpretation of missense variants remains challenging in the absence of functional evidence for their pathogenicity. We report a female infant presenting with clinical features characteristic of CHARGE syndrome. Targeted sequencing identified a heterozygous CHD7 variant (NM_017780.4:c.5273A>G), initially annotated as a missense substitution p.Asp1758Gly. This variant has been previously reported and registered with conflicting pathogenicity classifications; however, its transcript-level consequences remain unclear. Long-PCR-based RNA sequencing of total RNA from peripheral blood mononuclear cells revealed two aberrant splicing patterns associated with the variant: a predominant transcript carrying a 28-bp deletion due to cryptic donor splice-site activation, and a minor transcript with partial intron 24 retention. Both transcripts were predicted to result in premature termination codons. These findings demonstrate that c.5273A>G functions as a LoF variant through dual aberrant splicing rather than a simple missense substitution. This case underscores the importance of RNA-level splicing analysis for the accurate interpretation and classification of CHD7 missense variants.
The commonly used "end diagnosis" phenotype that is adopted in linkage and association studies of complex traits is likely to represent an oversimplified model of the genetic background of a disease. This is also likely to be the case for common types of migraine, for which no convincingly associated genetic variants have been reported. In headache disorders, most genetic studies have used end diagnoses of the International Headache Society (IHS) classification as phenotypes. Here, we introduce an alternative strategy; we use trait components--individual clinical symptoms of migraine--to determine affection status in genomewide linkage analyses of migraine-affected families. We identified linkage between several traits and markers on chromosome 4q24 (highest LOD score under locus heterogeneity [HLOD] 4.52), a locus we previously reported to be linked to the end diagnosis migraine with aura. The pulsation trait identified a novel locus on 17p13 (HLOD 4.65). Additionally, a trait combination phenotype (IHS full criteria) revealed a locus on 18q12 (HLOD 3.29), and the age at onset trait revealed a locus on 4q28 (HLOD 2.99). Furthermore, suggestive or nearly suggestive evidence of linkage to four additional loci was observed with the traits phonophobia (10q22) and aggravation by physical exercise (12q21, 15q14, and Xp21), and, interestingly, these loci have been linked to migraine in previous studies. Our findings suggest that the use of symptom components of migraine instead of the end diagnosis provides a useful tool in stratifying the sample for genetic studies.
BACKGROUND: Classification of heterozygous germline PTEN variants in patients with, or suspected of having, PTEN hamartoma tumour syndrome (PHTS) remains challenging. Accurate classification is essential as these patients require lifelong cancer surveillance. METHODS: We identified all patients with a PTEN variant previously classified as a variant of uncertain significance (VUS), likely pathogenic (LP) or pathogenic (P), collected clinical data and reclassified all variants using the latest PTEN gene-specific American College of Medical Genetics (ACMG) guidelines. Moreover, genotype-phenotype correlations were assessed. RESULTS: 167 patients from 112 families were enrolled. Eighty-seven unique PTEN variants were identified, including 20 novel variants. After applying the PTEN gene-specific ACMG guidelines, 32 variants (36.8%) were reclassified, resulting in 60 PTEN variants classified as LP/P (69.0%), 18 variants classified as VUS (20.7%), while 9 variants were classified as LB/B (10.3%). Genotype-phenotype correlation was performed among 104 patients with LP/P variants: 51 cancer cases were recorded in 41 patients and a distinct PHTS phenotype was observed in 25% of patients, with macrocephaly being present in 99% of patients with a known head circumference. Twenty-three patients had neurodevelopmental delay and/or autism, and we observed an increased prevalence of missense variants in these patients. CONCLUSION: We identified 87 different PTEN variants, and application of PTEN gene-specific ACMG guidelines led to reclassification of 32 variants (36.8%), underscoring the importance of regular variant reassessment using the most recent gene-specific guidelines, ensuring optimal patient management and surveillance.
On the basis of LE cases treated at the Department of Dermatology, Düsseldorf University, during the last few years, we present the various forms of cutaneous lupus erythematosus (CLE). 72% of the patients showed discoid lupus erythematosus (DLE), whereas disseminated discoid LE (DDLE) and lupus panniculitis were found in 3% each. Lupus erythematosus tumidus (LET), as well, must be regarded as exceptional. Subacute cutaneous LE (SCLE) and systemic LE (SLE) showed nearly similar frequency (10 and 12%, resp.). Bullous LE is also very rare and must be considered a variant of SLE. The various forms of cutaneous LE can be differentiated according to clinical presentation and histopathology. Direct immunofluorescence, in contrast, has but limited diagnostic value, except with lesions on the scalp. Exact classification of cutaneous LE is the more essential, as it implies considerable therapeutic and prognostic consequences for the patient.
This is a review article on glycoprotein storage diseases. In each of the separate diseases there is a relatively characteristic combination of clinical lesions, enzyme deficiency and storage of glycoconjugates which form the basis of classification. For most of these disorders, demonstration of the enzymatic deficiency has led to accurate diagnosis of affected individuals recognition of variant and atypical forms, detection of carriers and prenatal diagnosis of affected fetuses. The studies have proved to be informative as to: 1) Identification of previously unrecognized diseases. 2) Identification of the metabolic products of the mutant genes. 3) Classification within a group. 4) Demonstration of genetic principles.
The results of long-term follow-up studies indicate the existence of significant differences in the outcome of neurotic and psychopathic states. The most unfavorable outcome was seen in patients with asthenic and unstable psychopathy. A classification of a "good" and "poor" outcome of the disease by means of a computer permitted to distinguish the most significant anamnestic and clinical signs indicating a possible unfavorable prognosis. In the most unfavorable variant of the disease (21% of 124 psychopathic patients) in asthenic, unstable, excitative and hysterical psychopathy there were states with prevalently neurotic and psychopathic symptomatology, nonspecific for any of the above-mentioned forms of psychopathy.
Polysystemic lupus erythematosus is a disease of unclear origin. Spontaneous course is characterized by flares followed by remissions. The classification criteria are often used as diagnostic criteria, but they are insensitive for early diagnosis purpose. Decisional trees and ponderation of the various criteria have been reported to help clinicians for early diagnosis. Clinical variants of lupus erythematosus are numerous such as initial clinical manifestations; epidemiological considerations have shown different subsets with different manifestations depending on ethnicity, age at first symptoms, environmental factors (drug-induced lupus). Genetic background influences the autoantibody profile. Correlations have been reported between serological and clinical presentation.
Von Willebrand disease (VWD) is the most common inherited bleeding disorder, caused by quantitative or qualitative defects in von Willebrand factor (VWF). Diagnosis is challenging and requires integrating bleeding history, VWF antigen and activity measurements, FVIII assays, and specialized phenotyping. Genetic testing is increasingly recognized as a key component. Here, we review current concepts in VWD diagnostics and highlight the Spanish Clinical and Molecular Profile of von Willebrand Disease (PCM-EVW-ES) project as a model for genomics-enabled precision medicine. PCM-EVW-ES is a multicenter initiative involving 48 hospitals, centralized phenotypic testing, and next-generation sequencing of the VWF coding region, enabling definitive classification in 730 individuals with VWD to date. Harmonized recruitment criteria and standardized workflows improve subtype assignment, uncover complex genotypes, refine genotype-phenotype correlations, and facilitate the identification of asymptomatic carriers. The PCM-EVW-ES variant spectrum highlights recurrent disease-causing variants in Spain and underscores the value of coordinated national registries for variant curation. Building on these data, we propose a diagnostic algorithm in which bleeding assessment and first-line VWF/FVIII assays, combined with, early VWF molecular testing increases diagnostic accuracy and guides targeted second-line investigations to confirm and refine VWD subtype classification. We also outline persisting challenges, including the interpretation of variants of uncertain significance and patients without identifiable pathogenic VWF variants, and future directions integrating third-generation sequencing, expanded gene panels, functional studies, and artificial-intelligence-driven multiomic approaches. Together, these advances illustrate how robust multicenter studies can bridge the gap between complex diagnostics and clinical practice in VWD.
The different variants of migraine can be classified in common migraine, classical migraine and complicated migraine. Since objective methods of diagnostic proof are not available, diagnosis and categorisation have to be based on the patient's history and clinical criteria including hard and soft symptoms. Fundamental conditions are the evidence of recurrent headache attacks and the exclusion of other causes of headache.
BACKGROUND: Many histologic classifications of thymic epithelial tumors have been reported to date, but to the authors' knowledge, none of them closely reflect the clinical behavior or prognosis of the tumor. Therefore, it is necessary to establish a biologic marker for thymic epithelial tumors. Variants of CD44 may be important in promoting tumor progression and metastasis. Accordingly, the expression of CD44 isoforms in thymic epithelial neoplasms was investigated using immunohistochemistry to assess their possible value as prognostic indicators. METHODS: Expression of CD44v6 in thymic epithelial tumors was investigated with immunohistochemistry using consecutive surgical specimens resected from 108 patients between 1983 and 2002 at Juntendo University Hospital in Tokyo, Japan. RESULTS: Among the 108 thymic epithelial tumors, 70 were negative for CD44v6, 20 were weakly positive, and 18 were strongly positive. The status of CD44v6 expression (negative vs. weakly plus strongly positive) was found to be correlated with the tumor stage according to the Masaoka staging system (noninvasive vs. invasive tumors) (P = 0.0214). When patients with tumors that were negative and weakly positive for CD44v6 expression were combined, the 5-year, 10-year, and 15-year recurrence-free survival rates were 98.2%, 95.9%, and 86.1%, respectively, whereas the corresponding rates for patients with strongly positive tumors were 73.5%, 73.5%, and 55.1%, respectively. Therefore, these two groups demonstrated a significant difference with regard to recurrence-free survival (P = 0.0172). CONCLUSIONS: CD44v6 expression in thymic epithelial neoplasms demonstrated a significant difference based on the World Health Organization classification, the Masaoka stage (invasive vs. noninvasive tumors), and recurrence, if an appropriate cutoff value was chosen in each case. This suggests that CD44v6 can be used as a marker that reflects the stage of thymic tumors.
MED25-related developmental disorder (Basel-Vanagaite-Smirin-Yosef syndrome) is a rare autosomal recessive disorder, defined by severe neurodevelopmental delay, corpus callosum abnormalities, ocular involvement, epilepsy, and marked facial appearance. MED25 pathogenic variants interfere with the functioning of the Mediator complex, which is responsible for RNA polymerase II transcription. We report a 9-year-old girl who presents with significant global developmental delay, agenesis of the corpus callosum, congenital cataracts, epilepsy, hypotonia, musculoskeletal abnormalities, and typical craniofacial features. Trio-based whole-exome sequencing revealed compound heterozygous variants in MED25: a maternally transmitted truncating variant (c.1366 C > T; p.Gln456*) and a paternally inherited missense variant (c.430 C > T; p.Leu144Phe). The new classification of the missense variant as potentially pathogenic is supported by a systematic ACMG re-evaluation supported by segregation analysis, phenotypic specificity, computational prediction, and structural localization in the MED25 Activator Interaction Domain (ACID). Comparative phenotypic analyses show strong agreement with reported cases but add more data to fine-tune clinical spectrum. This article broadens the allelic and phenotypic spectrum of MED25-related developmental disorder and highlights the need for comprehensive evaluation across molecular, structural, and phenotypic pathways to elucidate variant signature in rare genetic disease models correctly.
PURPOSE: The Australian Genomics Cardiovascular Disorders Flagship investigated genome sequencing as a first-line genetic test in 600 individuals with cardiomyopathy, primary arrhythmia syndromes, or congenital heart disease. Analysis of disease-specific virtual gene panels achieved a genetic diagnosis in 38% of participants. We sought to increase genetic diagnosis yields by analyzing lesser-evidenced disease genes, the mitochondrial genome, and by functional analysis of predicted splice-altering variants. METHODS: Genome sequences of 520 participants with cardiomyopathy or primary arrhythmia syndromes were reanalyzed in 572 cardiac genes and the mitochondrial genome. Participants with congenital heart disease were excluded. Variants predicted in silico to disrupt splicing were assessed with blood RNA and minigenes. RESULTS: A new genetic diagnosis was achieved in 4% (19/520) of participants, including deep intronic and mitochondrial genome variants. Ten participants had diagnostic variants in lesser evidenced disease genes; 9 had splicing variant pathogenicity functionally validated. Eleven participants had a newly identified variant of uncertain significance with high suspicion of pathogenicity, warranting clinical review. Our data supported the gene-disease association of 1 new cardiomyopathy gene, TBX20. CONCLUSION: Identifying new gene-disease relationships, maintaining contemporary gene panels, and integrating functional studies to refine splicing variant classifications increase genetic diagnoses for cardiomyopathies and primary arrhythmia syndromes.
In the new WHO classification, the category of Burkitt lymphoma includes classic Burkitt lymphoma and a variant-Burkitt-like-lymphoma. In addition, three subcategories--endemic, non-endemic, and immunodeficiency-associated--were proposed to reflect the major clinical and genetic subtypes of this disease. Endemic Burkitt lymphoma is well known to carry EB virus(EBV). However, not more than 20% of the sporadic Burkitt lymphoma carry EBV. One of the three alternative forms of the Ig/myc translocation are regularly present in all Burkitt lymphomas, whether EBV positive or negative. Thus, translocation, rather than EBV, must be considered as the main rate-limiting event in the development of Burkitt lymphoma. EBV may increase the probability of this event by expanding the target cell population at risk.