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PubMed2025

Clinical and genetic variant re-analysis among pediatric probands undergoing genetic testing for arrhythmia syndromes.

BACKGROUND: Despite increases in genetic testing, longitudinal data regarding changes in diagnostic yield and variant reclassification for inherited arrhythmia syndromes are limited. OBJECTIVE: Determine longitudinal changes in diagnostic yield and variant classification. METHODS: Single-center retrospective study of probands <18 years undergoing genetic testing for suspected inherited cardiac conditions associated with arrhythmias, 2007 to 2018. Variants were classified as diagnostic (pathogenic/likely pathogenic), non-diagnostic (benign/likely benign [B/LB]), or variants of uncertain significance (VUS). Variant reclassification was performed in October 2023 using VarSome and American College of Medical Genetics criteria. We evaluated results by era (early 2007-2013 vs. later 2014-2018, coinciding with Sanger and next-generation sequencing, respectively) and by likelihood of disease based on clinical evaluation. RESULTS: Of 306 probands, initial testing was 23.2% diagnostic, 55.6% non-diagnostic (33.7% no variant, 21.9% B/LB), and 21.2% VUS. When comparing eras, diagnostic yield decreased (34.1%-15.3%), VUS increased (9.3%-29.9%), and non-diagnostic remained similar (55% to 57%). Variants for 22.7% (46/203) of probands with ≥1 variant changed: 9.9% of diagnostic variants (7/71) downgraded to VUS or non-diagnostic, and 60.0% of VUS changed (23.1% upgraded, 36.9% downgraded). B/LB variants did not change. Probands with higher disease likelihood had 6-times the odds of diagnostic results compared to lower disease likelihood, regardless of era (odds ratio 6.3, 95% confidence interval 3.2-12.4, P < .0001). CONCLUSION: Variant reclassification led to changes in 23% of probands, both downgrading and upgrading status, even among probands initially thought to be pathogenic. When comparing later to earlier eras, VUS variants increased while diagnostic yield decreased. Findings support the need for variant re-interpretation and periodic reclassification over time.

Humans↗

PubMed1989

Genetic and phenotypic heterogeneity in disorders of peroxisome biogenesis--a complementation study involving cell lines from 19 patients.

Disorders of peroxisomal biogenesis include the Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum syndrome, and hyperpipecolic acidemia. These names were assigned before the recognition of the peroxisomal defect and the distinction between phenotypes is uncertain. Recent studies have identified at least four complementation groups, and indicate the presence of at least that number of distinct genotypes. The purpose of the present study was to examine the relationship between genotype and phenotype. We studied cultured skin fibroblasts from 19 patients in whom deficiency of peroxisomes had been established. Complementation analysis was performed with the criterion of complementation being the restoration of the capacity to synthesize plasmalogens when fibroblasts from two patients were fused. Six complementation groups were identified, and consisted of one 13 member group, one two member group, and four groups comprising single cases. The phenotype of each group was examined with respect to age of survival, clinical manifestations, and biochemical alterations. The 13 member group included patients with all of the four currently designated phenotypic entities, while the most common phenotype (Zellweger syndrome) was distributed among five of the six groups. We conclude that the currently used clinical categories do not represent distinct genotypes. Apparently different genes code for a similar phenotype and one defective gene may lead to variant phenotypes. Definitive classification and understanding of these disorders await definition of the specific biochemical defect in each of the genotypes.

Adrenoleukodystrophy↗

PubMed1991

Surface osteosarcoma.

Osteosarcoma arising on the periosteal aspect of bone comprises a biologically heterogeneous group of neoplasms. The group as a whole may be referred to by a single descriptive term that emphasizes their common site of origin and underscores their malignant osteogenic potential: surface osteosarcoma. Its biologic heterogeneity may be approached via a number of avenues. Detailed description of individual tumors and grading are frequently employed. However, implementation of a classification system based upon reproducible clinical, roentgenographic, macroscopic, and histologic parameters is advantageous. The suggested classification system serves to clearly define parosteal and periosteal osteosarcoma, as well as recognize unusual variants. Most important, it defines therapeutic strategy. The classification system identifies low-grade, biologically indolent forms (i.e., parosteal osteosarcoma and periosteal osteosarcoma) that are best treated by surgery alone. At the same time, it recognizes high-grade forms with significant potential for life-threatening behavior (i.e., 'dedifferentiated' parosteal osteosarcoma and high-grade surface osteosarcoma) that are best managed by multimodality therapy incorporating chemotherapy and surgery.

Bone Neoplasms↗

PubMed1996

[The grouping of morphological variants of non-Hodgkin's lymphomas (lymphosarcomas) by the degree of malignancy].

The authors stated that WHO classification allows identification of two groups of morphological variants of non-Hodgkin's lymphomas: low- and high-grade malignancy. These differ by principal clinical characteristics, incidence of complete and partial remissions, survival duration. The analysis of clinical course, long-term and short-term treatment outcomes is provided for 674 patients with the above lymphomas.

Adolescent↗

PubMed2025

Uveal Melanoma and the Lynch Syndrome Tumor Spectrum.

IMPORTANCE: To date, no environmental factors and few therapeutic options are known for uveal melanoma (UM), the most common malignant intraocular primary tumor in adults. Identification of new predisposition factors could lead to better monitoring and possibly improved treatments of patients with UM. OBJECTIVE: To identify new genetic alterations predisposing for UM. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective cohort study conducted at Institut Curie in Paris, France, among 381 consecutive patients diagnosed with UM between July 2021 and February 2023. UM was diagnosed clinically by ophthalmologists, and a senior pathologist confirmed the diagnosis when tumor or biopsy was available. All participants received genetic counseling and consented to extended genetic testing. A panel of 122 genes predisposing to cancer were analyzed by targeted sequencing on germline DNA from these patients. MAIN OUTCOMES AND MEASURES: Frequency of pathogenic variants (PVs) in genes from a targeted panel, with classification of germline PVs done according to the American College of Medical Genetics and Genomics guidelines and the French Unicancer Genetics Group. RESULTS: A total of 79 PVs were identified in 70 participants (41 female and 29 male; mean [SD] age, 60.6 [15.3] years). Among them, 21 were found in clinically relevant genes, with an enrichment in the mismatch repair (MMR) genes, involved in Lynch syndrome, a frequent predisposition to colon and endometrial cancers. This finding suggested MMR germline PVs could also predispose to UM. One tumor was available from a participant carrying a MLH1 germline PV. The tumor exhibited a monosomy 3 with loss of the wild-type allele of MLH1, located on chromosome 3. Loss of expression of MLH1 was observed by immunohistochemistry, and MMR variant signatures SBS6, ID1, and ID2 were identified from the whole-genome sequencing of this tumor, supporting the possibility that MLH1 contributes to the oncogenesis of this UM. CONCLUSIONS AND RELEVANCE: This prospective germline study on patients with UM provided evidence supporting the notion that MMR germline alterations are enriched among patients with UM and may contribute to oncogenesis of UM, and that UM may therefore be a rare tumor manifestation of Lynch syndrome.

Humans↗

PubMed1989

Hepatic vein thrombosis (Budd-Chiari syndrome) in the microgranular variant of acute promyelocytic leukemia.

The microgranular form of acute promyelocytic leukemia (APL) was described in the late 1970s and adopted by the French, American, and British classification system in the early 1980s. Morphologically, this form shows distinct differences from the classic form of APL, but clinically it shares many of the same traits. Among these is the predilection for coagulopathies, including disseminated intravascular coagulation (DIC). This DIC has been associated with one previously reported case of fatal hepatic vein thrombosis (Budd-Chiari syndrome), in association with an untreated case of APL. The authors present a case of the microgranular variant of acute promyelocytic leukemia (FAB-M3V), with autopsy and electron microscopic evidence in support. It is important to recognize this variant form of APL and its association with hepatic vein thrombosis, because any successful attempt at therapy must be instituted early in the course of the disease.

Adult↗

PubMed2002

A variant of congenital muscular dystrophy.

We analyzed three Japanese patients (two boys and a girl) from two families with congenital muscular dystrophy (CMD) and brain involvement. One of the two families had two affected siblings of different sexes. Parental consanguinity was not documented in either family. All patients showed generalized hypotonia and weakness from infancy, delayed psychomotor development, facial muscle involvement, and joint contractures. Serum creatine kinase levels were markedly elevated. The histological change seen on muscle biopsy was characteristic of a dystrophic process, although dystrophin and merosin staining were normal. On MR imaging, cortical dysplasia and cerebral white matter abnormalities were observed. Although these clinical, myopathological and neuroradiological findings were typical of Fukuyama-type CMD (FCMD), full mutational analysis of the fukutin gene revealed neither a 3 kb insertion (Japanese founder mutation) nor point mutations. RT-PCR analysis of RNA isolated from lymphoblasts of a patient revealed normal expression of the FCMD transcript. As classification of CMD should be based on genetic background, our present cases with typical clinical, myopathological and neuroradiological findings of FCMD without mutation of the fukutin gene may represent a new variant (or variants) of CMD that is different from FCMD.

Brain↗

PubMed2006

CD30+ lymphoproliferative disorders: histopathology, differential diagnosis, new variants, and simulators.

CD30+ lymphoproliferative disorders of the skin (CD30+ LPD) represent a well-defined spectrum of primary cutaneous T-cell lymphomas which have been recognized as distinct entities in recent lymphoma classifications. Lymphomatoid papulosis and anaplastic large-cell lymphoma share the expression of CD30 antigen as a common phenotypic hallmark but differ in regard to their clinical and histologic features as well as their biologic behavior. This article summarizes the histologic features of CD30+ LPD and presents recently identified new clinicopathologic variants of CD30+ LPD. There is an increasing number of reactive inflammatory disorders and neoplastic diseases which are composed of or contain a significant number of CD30+ cells and mimic LyP or anaplastic large cell lymphoma clinically or histologically. Differential diagnostic considerations focus on other lymphoproliferative processes with CD30+ tumor cells as well as non-lymphoid neoplasms and inflammatory simulators. The term CD30+ pseudolymphoma is proposed to designate inflammatory processes with CD30+ T cells. The final diagnosis of CD30+ LPD is based on a synthesis of clinical, histologic, phenotypic, and molecular genetic findings.

Biomarkers, Tumor↗

PubMed2006

A working group classification of focal prostate atrophy lesions.

Focal atrophy is extremely common in prostate specimens. Although there are distinct histologic variants, the terminology is currently nonstandardized and no formal classification has been tested for interobserver reliability. This lack of standardization hampers the ability to study the biologic and clinical significance of these lesions. After informal and formal meetings by a number of the authors, focal atrophy lesions were categorized into 4 distinct subtypes as follows: (i) simple atrophy, (ii) simple atrophy with cyst formation, (iii) postatrophic hyperplasia, and (iv) partial atrophy. In phase 1 of the study, pathologists with varying levels of experience in prostate pathology were invited to view via the Internet a set of "training" images with associated descriptions of lesions considered typical of each subtype. In phase 2 of the study, each participant provided diagnoses on a series of 140 distinct "test" images that were viewed over the Internet. These test images consisted of the 4 subtypes of atrophy and images of normal epithelium, high grade prostatic intraepithelial neoplasia, and carcinoma. The diagnoses for each image from each pathologist were compared with a set of "standard" diagnoses and the kappa statistic was computed. Thirty-four pathologists completed both phases of the study. The interobserver reliability (median kappa) for classification of lesions as normal, cancer, prostatic intraepithelial neoplasia, or focal atrophy was 0.97. The median kappa for the classification of atrophy lesions into the 4 subtypes was 0.80. The median percent agreement with the standard diagnosis for the atrophy subtypes were: simple 60.6%, simple with cyst formation 100%; postatrophic hyperplasia 87.5%; partial atrophy 93.9%. The lower percentage for simple atrophy reflected a propensity to diagnose some of these as simple atrophy with cyst formation. Seven pathologists completed the phase 2 analysis a second time, and their intraobserver reproducibility was excellent. Three of 4 pathologists with low agreement with the standard diagnosis for simple atrophy improved their scores after repeating the analysis after re-examination of the "training set" of images. In conclusion, these criteria for variants of focal prostate atrophy may facilitate studies to examine the relation between various patterns of prostate atrophy and prostate cancer.

Atrophy↗

PubMedDate not supplied

[Diagnosis and classification of variants of color vision in the light of new methodological approaches].

The authors suggest that the parameters of color force of the receptors and the possible abnormal disposition of their maximal sensitivity by the spectrum be taken into consideration in the diagnosis of color perception. Assessment of color force was acknowledged to be more significant than of color abnormalities, both from a viewpoint of occupational selection, and from a clinical viewpoint. This is reflected in the suggested classification of color vision and in recommendations for use in practical ophthalmology of new threshold tables created by Yustova-Alexeyeva et al. These tables are based on the results of colorimetric investigations, and the results of their trials are reliable.

Calorimetry↗

PubMed2005

A preliminary study of angiographic classification and its correlation to treatment of central arteriovenous malformation in the jaw.

OBJECTIVE: To elaborate on the classification of central arteriovenous malformations (AVMs) in the jaw based on angioarchitecture and to evaluate the correlation of this classification with treatment options. STUDY DESIGN: X-ray films and digital subtraction angiograms (DSA) of 25 cases with AVMs in the jaw were retrospectively reviewed to evaluate the appearance of bone resorption, feeding arteries, nidus of the malformations, and draining veins. Based on the findings a classification of angioarchitecture was recommended. Furthermore, the treatment results of these cases were reviewed to assess the correlation of this classification system with treatment options. RESULTS: The angiographic pictures of 25 cases with central AVMs could be divided into 5 types: Type I (n = 5) had diffused microarteriovenous fistulas (AVFs); type II (n = 8) had 1 large venous pouch with all the feeding arteries draining into it; type III (n = 7) had a large venous pouch as well as diffused microAVFs (I+II); type IV (n = 2) had multiple venous pouches; and type V (n = 3) had multiple venous pouches and diffused microAVFs (I + IV). The angioarchitecture corresponded well to the x-ray appearance in all cases except 1 (96%). With respect to the treatment outcomes, type II, III, and IV AVMs gained clinical cure in 100% of the cases, whereas type I and type V AVMs obtained clinical cure only in 60% and 33.3% of the cases, respectively. CONCLUSIONS: Central AVMs in the jaw contained variant patterns of angioarchitecture and could be divided into 5 types. This angiographic classification was helpful for decision making about appropriate therapy.

Adolescent↗

PubMed1999

[Worldwide consensus: the way from the KIEL classification to the REAL classification to the WHO classification].

The history of lymphoma classification has been long and controversial. However, within the last thirty years much has been learned about the biology of lymphoma. The concept of classifying malignant lymphoma according to the (proposed) normal counterpart was developed in the KIEL classification. In 1994, the so-called revised European/American lymphoma classification was published as a consensus of pathologists from both sides of the Atlantic. Its clinical significance was proven in the International Lymphoma Classification Project. The upcoming WHO-Classification is based on the principle to define disease entities that can be recognized by the pathologists and are of clinical relevance. Within these entities, histopathological variants and clinical subtypes are described, which may or may not bear prognostic relevance. Prognostic factors can be defined within an entity, on a clinical, morphological, immunohistochemical or genetic basis.

Diagnosis, Differential↗

PubMed2006

[Gilbert's syndrome: a clinicogenetic trial].

AIM: To improve diagnosis of Gilbert's syndrome (GS) basing on functional and genetic methods of examination. MATERIAL AND METHODS: GS was diagnosed in 88 patients aged 15-72 years using clinical and genetic tests. RESULTS: Genotyping has detected changes in promotor part of the gene coding uridindiphosphateglucuroniltransferase. In homozygous carriers GS was characterized by a higher baseline level of bilirubin, distinct response to functional tests, frequent combination with essential tremor. In heterozygous patients GS often ran latently. CONCLUSION: Four variants of GS course were established: dispepsic, asthenovegetative, jaundice, latent. Low-caloric diet followed by fenobarbital raised sensitivity and specificity of the test. A clinical classification of GS is proposed. The detected disorders of antipirin pharmacokinetics allow prognosis of the risk of unwanted reactions to the drugs metabolized by monooxigenases of the liver.

Adolescent↗

PubMed1977

[Clinical picture of recurring aphthae in the mouth mucosa].

Various classifications of recurrent aphthous ulcers, their differential diagnosis, especially the herpetic ulcers of the oral mucous membranes, are discussed. The clinical and histological pictures show three variants, the minor form, the major form or periadenitis mucosa necrotica recurrens (Sutton), and the herpetiforme aphthous ulcers. Recent investigations discussing the etiology of these ulcers assume that an auto-antigen might be responsible for the immuno-pathological mechanism. This auto-antigen is supposed to be formed by the contamination of the oral mucosa with microorganisms, particularly streptococci.

Adult↗

PubMed2023

H4C5 missense variant leads to a neurodevelopmental phenotype overlapping with Angelman syndrome.

Recurrent de novo missense variants in H4 histone genes have recently been associated with a novel neurodevelopmental syndrome that is characterized by intellectual disability and developmental delay as well as more variable findings that include short stature, microcephaly, and facial dysmorphisms. A 4-year-old male with autism, developmental delay, microcephaly, and a happy demeanor underwent evaluation through the Undiagnosed Disease Network. He was clinically suspected to have Angelman syndrome; however, molecular testing was negative. Genome sequencing identified the H4 histone gene variant H4C5 NM_003545.4: c.295T>C, p.Tyr99His, which parental testing confirmed to be de novo. The variant met criteria for a likely pathogenic classification and is one of the seven known disease-causing missense variants in H4C5. A comparison of our proband's findings to the initial description of the H4-associated neurodevelopmental syndrome demonstrates that his phenotype closely matches the spectrum of those reported among the 29 affected individuals. As such, this report corroborates the delineation of neurodevelopmental syndrome caused by de novo missense H4 gene variants. Moreover, it suggests that cases of clinically suspected Angelman syndrome without molecular confirmation should undergo exome or genome sequencing, as novel neurodevelopmental syndromes with phenotypes overlapping with Angelman continue to be discovered.

Male↗

PubMed2006

Diffuse large B-cell lymphoma: a heterogeneous group of non-Hodgkin lymphomas comprising several distinct clinicopathological entities.

Diffuse large B-cell lymphoma (DLBCL) as defined by the World Health Organization (WHO) classification is clinically, morphologically and genetically a heterogeneous group of malignant proliferations of large lymphoid B cells. Over the last 6 years, several studies have been published improving our understanding of these lymphomas. These studies analyzed DLBCL by their gene expression profile, provided further information on some of the variants of DLBCL listed in the WHO classification and stressed the impact of the site of origin of these tumors. This review summarizes these recent data and explores their impact on the recognition of new clinicopathological lymphoma entities.

B-Lymphocytes↗

PubMed1996

Reliable computer-assisted classification of the EEG: EEG variants in index cases and their first degree relatives.

A method which optimizes on global properties of sample recordings is proposed for the definition of and the discrimination between electroencephalogram (EEG) classes. The sample was drawn from students at the University of Heidelberg from 1974 to 1978 and consists of 15 healthy index cases clinically ascertained as belonging to the low voltage EEG group. In addition, the three clinically defined groups: diffuse beta (18 index cases), borderline alpha (12 index cases) and monomorphous alpha (18 index cases) have been included in the study, as well as the first degree relatives of the index cases, thus providing a clinical classification into four groups. The proposed method provides an automatic and reliable classification algorithm using discriminant and cluster analysis. The relation between such an automatized classification and clinical classification schemes is investigated. In particular, the inheritance of the low voltage EEG, the question on sex differences and the question of a simple Mendelian mechanism had been examined. The method of random splittings had been applied for discriminant and cluster analysis. Our findings can be summarized as follows: (1) except for the monomorphous alpha EEG group, the clinical classification shows rather marginal separation (discriminating performance 60% to 75%), while a new and more reliable grouping scheme improves the discriminating performance up to 87% to 91%. The latter scheme leads to the concept of personal channel pattern (PCP) and was compared to the clinical classification scheme by means of contingency tables; (2) only a weak correlation between the clinically and PCP-based groups could be found (Cramér Index: 0.27). Accordingly, we continued to investigate the extent to which the proposed EEG classification scheme can nevertheless explain the genetic mechanisms apparently involved in the low voltage EEG. We thus considered the role of sex differences manifest in our proposed new grouping scheme; (3) males occurred more frequently in the new group 3 and females more frequently in the new group 1. In this regard, a much better correlation of the new groups between mothers and children than between fathers and children was observed; and (4) with help of our new PCP scheme, we have been able to reproduce a simple two gene Mendelian scheme to explain inheritance of the clinical low voltage EEG group. In this PCP-based scheme, the low voltage property does not occur when dominance of a certain gene (called gene A) is absent.

Adult↗

PubMed2005

Postinfectious inflammatory disorders: subgroups based on prospective follow-up.

BACKGROUND: Acute disseminated encephalomyelitis (ADEM) refers to a monophasic acute multifocal inflammatory CNS disease. However, both relapsing and site-restricted variants, possibly associated with peripheral nervous system (PNS) involvement, are also observed, and a systematic classification is lacking. OBJECTIVE: To describe a cohort of postinfectious ADEM patients, to propose a classification based on clinical and instrumental features, and to identify subgroups of patients with different prognostic factors. METHODS: Inpatients of a Neurologic and Infectious Disease Clinic affected by postinfectious CNS syndrome consecutively admitted over 5 years were studied. RESULTS: Of 75 patients enrolled, 60 fulfilled criteria for ADEM after follow-up lasting from 24 months to 7 years. Based on lesion distribution, patients were classified as encephalitis (20%), myelitis (23.3%), encephalomyelitis (13.3%), encephalomyeloradiculoneuritis (26.7%), and myeloradiculoneuritis (16.7%). Thirty patients (50%) had a favorable outcome. Fifteen patients (25%) showed a relapsing course. Poor outcome was related with older age at onset, female gender, elevated CSF proteins, and spinal cord and PNS involvement. All but two patients received high-dose steroids as first-line treatment, with a positive response in 39 (67%). Ten of 19 nonresponders (53%) benefited from high-dose IV immunoglobulin; 9 of 10 had PNS involvement. The data were not controlled. CONCLUSIONS: A high prevalence of "atypical variants" was found in this series, with site-restricted damage or additional peripheral nervous system (PNS) involvement. Prognosis and response to steroids were generally good, except for some patient subgroups. In patients with PNS involvement and steroid failure, a favorable effect of IV immunoglobulin was observed.

Adult↗