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PubMed2025

Targeted Next-Generation Sequencing in Rare Diseases.

Targeted next-generation sequencing (NGS) in rare disease focuses on genetic analysis of specific regions in genome that are linked to a rare disease. In addition to library preparation, sequencing, and data analysis, targeted NGS includes an additional step of target enrichment of selected genes and regions. It allows for more sensitive and profound sequencing, as it is a fast and cost-effective approach with less data burden and is therefore often a method of choice for identifying rare variants in known genes, especially in diagnostics of rare diseases. Several in silico tools address the pathogenicity predictions of rare variants of unknown significance (VUS) and can therefore facilitate clinical interpretation.

Rare Diseases↗

PubMed2003

Rapid echoplanar diffusion imaging in a case of variant Creutzfeldt-Jakob disease; where speed is of the essence.

Neuroimaging with magnetic resonance imaging (MRI) is important in the diagnosis of Creutzfeldt-Jakob disease (CJD), but is frequently frustrated by patient movement. Diffusion-weighted imaging (DWI) has previously shown markedly restricted diffusion in grey matter structures of patients with CJD, and may add to diagnostic sensitivity. Echoplanar imaging (EPI) sequences, which are usually used for DWI, are also very rapid, and typically allow imaging of the whole brain in less than 1 min. A case of histologically proven variant CJD (vCJD) in which conventional MRI was difficult to interpret confidently owing to motion artefact, but EPI was diagnostic, emphasises the utility of rapid imaging in agitated patients. Comparison of the regional quantitative apparent diffusion coefficient (ADC) with a control group ( n=5) showed restricted diffusion in the caudate (vCJD: 0.63 x 10(-3) mm(2)/s; controls: mean 0.722 x 10(-3) mm(2)/s, SD 0.017) and lentiform (vCJD: 0.65 x 10(-3) mm(2)/s; controls: mean 0.707 x 10(-3) mm(2)/s, SD 0.011) nuclei. T2 effects dominated the signal abnormality on DWI in the pulvinar; ADC was increased (vCJD: 0.87-0.95 x 10(-3) mm(2)/s; controls: mean 0.773 x 10(-3) mm(2)/s, SD 0.038). Our data emphasise variation in diffusion patterns in vCJD, and illustrate the value in using all the components available from the DWI examination for maximum diagnostic information. EPI-DWI provides both rapid T2- and diffusion-dependent information, and is recommended for those patients in whom confusion and agitation is likely to confound standard MRI protocols.

Adult↗

PubMed1994

The clinicopathological correlation of epithelial subtyping in thymoma: a study of 112 consecutive cases.

The clinicopathological features of 112 thymomas collected from the surgical pathological files of Taipei Veterans General Hospital from 1961 to 1991 were investigated to determinate the clinical efficacy of epithelial subtyping. All thymomas were categorized based on the Müller-Hermelink system into three subtypes: cortical thymoma, mixed thymoma, and medullary thymoma. The former was further subclassified into organoid thymoma, conventional cortical thymoma, and well differentiated thymic carcinoma (WDTC) according to the systems of Pescarmona and Kirchner. The association of each subtype with sex, age at diagnosis, clinical stage, presence of myasthenia gravis, and length of survival was studied. As classified by the Müller-Hermelink system, the cortical thymomas as a whole tended to occur in younger patients and were more frequently associated with myasthenia gravis than the medullary thymomas. The cortical thymomas also showed a propensity to be invasive in nature, whereas the medullary thymomas generally behaved as benign tumors. Further subclassification of cortical thymomas into organoid thymoma, conventional thymoma, and WDTC did not provide more information about clinical behavior. By Kaplan-Meier's actuarial survival analyses none of the epithelial subtypes displayed a statistically significant influence on prognosis. It is concluded that staging remains the most important factor affecting the patient's outcome. Because of the existence of many intermediate forms and the deficiency of clinical relevance, the subclassification of cortical thymomas should be interpreted as a morphological continuum rather than as distinct histological variants.

Adolescent↗

PubMed2000

Fetal heart rate monitoring: is it salvageable?

Fetal heart rate monitoring was introduced in the 1960s. After a number of randomized controlled trials in the mid 1980s, doubt arose regarding the efficacy of fetal heart rate monitoring in improving fetal outcome. The potential reasons why fetal heart rate monitoring has not been shown to be efficacious are (1) use of an outcome measure that is not related to variant fetal heart rate monitoring patterns, (2) lack of standardized interpretation of fetal heart rate patterns, (3) disagreement regarding algorithms for intervention of specific fetal heart rate patterns, and (4) the inability to demonstrate the reliability, validity, and ability of fetal heart rate monitoring to allow timely intervention. A recent National Institutes of Health committee proposed detailed, quantitative, standardized definitions of fetal heart rate patterns, which can serve as a basis for determining whether fetal heart rate monitoring is reliable and valid. In this article we examine reasons why fetal heart rate monitoring did not live up to its original expectations and why the randomized controlled trials did not demonstrate efficacy, and we make suggestions for determining whether electronic fetal heart rate monitoring should be abandoned.

Asphyxia Neonatorum↗

PubMed1985

Racial variations in normal ureteric course.

Three hundred consecutive normal intravenous urograms were studied. The position of the ureter relative to the vertebral pedicles was assessed at different levels in patients from different racial groups. Medial placement of the ureter (where it overlay or was medial to a pedicle) was considerably commoner in black patients of African origin than in white Northern Europeans. In both races it occurred more frequently in males and in the young, and it was more common on the right side than on the left. The recognition of this normal variant, particularly in the black patient, is important in the interpretation of intravenous urograms.

Adult↗

PubMed1998

p53 codon 72 polymorphism and risk of cervical cancer in UK.

BACKGROUND: A polymorphism at codon 72 of the human tumour-suppressor gene, p53, results in translation to either arginine or proline. A recent report suggested that the risk of human-papillomavirus-associated cervical cancer in white women is higher for those homozygous for the arginine allele than for those who are heterozygous. We examined a similar number of cervical cancers and a larger control group for their p53 codon 72 polymorphism status to see if we could confirm this result. METHODS: Three different groups of UK white women were studied: 96 who had volunteered to take part in a trial of ovarian-cancer screening; 150 attending for routine antenatal care in the Oxford region; and 50 women with cervical cancer. DNA from peripheral blood samples and from archival tissue samples was examined by PCR with allele-specific primers. FINDINGS: The proportions of individuals homozygous for the arginine allele, homozygous for the proline allele, and heterozygous for the two alleles were 59%, 4%, and 36% among women screened for ovarian cancer; 65%, 8%, and 27% among the antenatal-care group; and 54%, 6%, and 40% in women with cervical cancer. Chi2 analysis showed no significant differences in these proportions. INTERPRETATION: In the population studied, individuals homozygous for the arginine variant of codon 72 of the p53 gene were not at increased risk of cervical cancer.

Amino Acid Sequence↗

PubMed1989

Pathophysiology of aplastic anaemia.

No single pathophysiological phenomenon--neither the intrinsic defect of haemopoiesis nor any of the described immune effects--explains aplastic anaemia. Since the intrinsic defect is compatible with near normal haemopoietic function, as seen in autologous bone marrow reconstitution, it cannot be the cause of severe pancytopenia. On the other hand, immune mechanisms cannot be the primary cause of the disease, otherwise haemopoietic function would recover to complete normality after immunosuppressive therapy. From these observations we deduce that the intrinsic defect, a premalignant haemopoietic disorder, can either be clinically quiescent by virtue of repair mechanisms, or induce auto-reactivity of the immune system against the abnormal haemopoietic tissue, drugs, chemicals and viruses acting as non-specific triggers or amplifiers. In this sense, aplastic anaemia could be interpreted as an attempt to 'self-cure' from a variant type of preleukaemia. This means that the original concept of aplastic anaemia being a hypoplastic variant of leukaemia may be true. The fact that aplastic anaemia can present either as acute severe bone marrow failure, as chronic mild pancytopenia or as a myelodysplasia-like syndrome does not imply that the underlying pathophysiological mechanisms are basically different. Variations of the clinical course and the response to immunosuppressive treatment could be explained by variations in the balance between the primary defect and the secondary immune reaction; the co-involvement of accessory cells in the primary disease; the relative time course of the two components and the efficiency of repair mechanisms. From repeated in vitro studies in a large group of aplastic anaemia patients at various stages of disease this concept can be applied to the majority of cases, including chloramphenicol- and virus-induced aplastic anaemia. In a small proportion of patients with pancytopenia occurring after exposure to certain drugs other than chloramphenicol, aplastic anaemia is rapidly and completely reversible after withdrawal of the drug. These patients probably have truly benign aplastic anaemia and thus differ from the majority of patients who are left with a permanently fragile bone marrow once they have acquired aplastic anaemia.

Anemia, Aplastic↗

PubMed1998

The pathophysiological role of estrogen receptor variants in human breast cancer.

The accumulated evidence supports the expression of estrogen receptor variants at both the mRNA and protein levels. The relative level of expression of some estrogen receptor variant mRNAs and possibly progesterone receptor variant mRNAs is altered during breast tumorigenesis and breast cancer progression. The altered expression of estrogen receptor variants may effect estrogen signal transduction as well as the interpretation of assays where the estimation of estrogen receptor levels is used as a guide to treatment strategies and prognosis.

Breast Neoplasms↗

PubMed2003

Haemoglobin Etobicoke, an incidental finding in an Irish diabetic.

It is well recognized that haemoglobin variants can be detected during the measurement of HbA1c by high-performance liquid chromatography (HPLC). A number of variants have been reported as compromising the quantification of HbA1c, a marker used in the assessment of glycaemic control in diabetes. We describe a case of haemoglobin Etobicoke, a rare alpha chain variant detected in an Irish diabetic during HbA1c analysis. Its identity was confirmed using a series of investigations. These included haemoglobin electrophoresis at alkaline and acid pH, isoelectric focusing and globin chain electrophoresis. Ultimately mass spectrometry isolated the mutation at position alpha 84 (F5). Haemoglobin Etobicoke, first described in Canada in 1969 has not previously been detected on HbA1c analysis. In the presence of this rare variant, HbA1c, a standard method using HPLC to assess glycaemic control in diabetes is unreliable and alternatives such as fructosamine need to be considered. HbA1c measured by automated HPLC will effectively screen populations where haemoglobin variants were not previously known. Precise identity of these variants when they are detected is crucial to the reliable interpretation of HbA1c analyses.

Blood Protein Electrophoresis↗

PubMed1991

Analysis of the invariant Phe82 residue of yeast iso-1-cytochrome c by site-directed mutagenesis using a phagemid yeast shuttle vector.

A phagemid (pING4) carrying the yeast iso-1-cytochrome c gene was constructed which bears all the elements necessary for replication in yeast and bacteria and may be converted into a single-stranded form of DNA for site-directed mutagenesis and nucleotide sequencing. The recombinant vector was used to create a complete set of 19 amino acid changes at position 82, a phylogenetically conserved phenylalanine residue in mitochondrial cytochrome c. All the different forms of cytochrome c were functional in vivo, based upon their ability to support respiration when the mutant proteins were expressed in a yeast strain (otherwise devoid of cytochrome c) grown on non-fermentable carbon sources, with only the strain containing the Cys82 variant having a substantially decreased growth rate. These results are interpreted in terms of the available structural and functional information previously reported on a subset of cytochrome c proteins with mutations at position 82.

Amino Acid Sequence↗

PubMed2000

A clinicopathologic study of 45 pediatric soft tissue tumors with an admixture of adipose tissue and fibroblastic elements, and a proposal for classification as lipofibromatosis.

The tumor described here as lipofibromatosis is a rare pediatric neoplasm that has been variously interpreted as a type of infantile or juvenile fibromatosis, a variant of fibrous hamartoma of infancy, and a fibrosing lipoblastoma. This report details the clinicopathologic features associated with 45 cases of this soft tissue entity. The study group consisted of 32 males, 12 females, and one person of unstated gender. The patients presented with a soft tissue mass (range, 1-7 cm) involving the hand (n = 18), arm (n = 8), leg (n = 7), foot (n = 6), trunk (n = 5), or head (n = 1). Eight tumors were evident at birth. The individuals ranged in age from 11 days to 12 years (median age, 1 yr) at the time of initial biopsy or resection. Microscopic examination revealed abundant adipose tissue with a spindled fibroblastic element that chiefly involved the septa of fat and skeletal muscle. The process generally did not cause extensive architectural effacement of fat as is common with conventional fibromatoses, and it did not have a primitive nodular fibromyxoid component as is characteristic of fibrous hamartoma of infancy. The fibroblastic element exhibited focal fascicular growth and typically had limited mitotic activity (< or = 1 mitosis/ 10 high-power fields) and cytologic atypia. Oftentimes, small collections of univacuolated cells were present at the interface between some of the fibroblastic fascicles and the mature adipocytes. The tumors entrapped vessels (n = 45), nerves (n = 44), skin adnexa (n = 16), and skeletal muscle (n = 18). Focal immunoreactivity was present in some tumors for CD99, CD34, alpha-smooth muscle actin, BCL-2, and less frequently, S-100 protein, muscle actin (HUC 1-1), and EMA. However, no reactivity was detected for desmin (D33 and D-ER- 1 clones), keratins, or CD57. Follow-up data were available for 25 individuals (median follow-up period, 6 yrs 7 mos) with regrowth of the tumor or persistent disease documented in 17 (72%). The following events were more common in the group with recurrent or persistent disease: congenital onset, male sex, hand and foot location, incomplete excision, and mitotic activity in the fibroblastic element. Although it is likely this tumor comprises part of the spectrum of what has been referred to in the literature as infantile/juvenile fibromatosis, its clinicopathologic features and, in particular, its distinctive tendency to contain fat as an integral component, warrant separate classification as a "lipofibromatosis."

Adipose Tissue↗

PubMed1994

Molecular determinants of the V3 loop of human immunodeficiency virus type 1 glycoprotein gp120 responsible for controlling cell tropism.

We and others have identified the major determinant of cell tropism in human immunodeficiency virus type 1 (HIV-1) as the V3 loop of glycoprotein gp120. We have conducted a detailed study of two molecularly cloned isolates of HIV-1, HIVJR-CSF and HIVNL4-3, that differ in their tropism for immortalized CD4+ cell lines, by constructing a series of site-directed mutations within the V3 loop of HIVJR-CSF based on the sequence of HIVNL4-3. The phenotypes of these mutants fall into two classes, those which are viable and those which are not. A spontaneous mutant with significantly altered growth properties was also recovered and found to have an additional single amino acid change in the V3 loop sequence. The carboxy-terminal beta-strand part of the V3 loop is the major determinant of cell tropism. However, the results presented here indicate that the functional role of the V3 loop sequences can only be interpreted properly in the context of the original gp120 backbone from which they were derived. These findings show that over-simplistic interpretation of sequence data derived from unknown mixtures of HIV variants in infected persons may be highly misleading.

Amino Acid Sequence↗

PubMed1993

Pachyonychia congenita with late onset of nail dystrophy--a new clinical entity?

Pachyonychia congenita syndrome (PCS) is a genetic disease with an autosomal dominant mode of transmission in which the main sign, pachyonychia, usually arises at birth or in childhood together with other disorders of keratinization. A 28-year-old woman developed subungual hyperkeratosis of all toe-nails and thumb-nails associated with pain on pressure and walking. She had a scrotal tongue with leucokeratotic areas, blister formation, plantar hyperkeratosis, palmoplantar hyperhidrosis and dental cavities since childhood. The present case, interpreted as PCS of late onset, could be a clinical variant of the Jadassohn-Lewandowsky syndrome with the late onset of pachyonychia or else an additional form of PCS due to the expression of a new and different allele.

Adult↗

PubMed2006

Fine needle aspiration cytology of the thyroid: a comparison of 5469 cytological and final histological diagnoses.

OBJECTIVE: We evaluated the efficacy of fine needle aspiration cytology (FNAC) of the thyroid in a series of 5469 lesions with histological control and studied the causes of, and the possibility of reducing the limitations of the method. METHODS: FNAC was always performed by a pathologist under the guidance of a clinician, using a 22-gauge needle. Generally two aspirations were carried out, and usually four slides were obtained for each nodule; they were then stained with May-Grünwald-Giemsa and with Papanicolaou. The cytological diagnoses were classified in four groups: inadequate, benign, suspicious and malignant. RESULTS: We obtained a complete sensitivity of 93.4%, a positive predictive value of malignancy of 98.6%, and a specificity of 74.9%. At histological control, the cytological diagnosis of Hurthle cell neoplasm corresponded to a significantly higher incidence of malignant neoplasms than the diagnosis of non-Hurthle cell follicular neoplasm (32.1% versus 15.5%). There were 66 false-negative findings, the main cause of diagnostic error (24 cases) being failure to recognize the follicular variant of papillary carcinoma. The number of inadequate FNACs was low (4.2%). CONCLUSION: Our study confirmed the great efficacy of thyroid FNAC. A cytological diagnosis of Hurthle cell neoplasm should be considered an indicator of high risk. Awareness that failure to recognize the follicular variant of papillary carcinoma was the main problem in the interpretation of thyroid FNAC should lead to a decrease of false-negative diagnoses. The inadequate rate was very low, as it was the pathologist personally who performed the needle aspiration.

Adolescent↗

PubMed2005

Assessment of the "nearly normal" cervical spine radiograph: C2-C3 pseudosubluxation in an adult with whiplash injury.

C2-C3 pseudosubluxation is a well recognized normal anatomical variant in children and this physiological spondylolisthesis often makes the interpretation of paediatric cervical spine radiographs difficult. In direct contrast, this finding is rare in adults and has not been reported as a diagnostic difficulty following neck injury. We report a case of C2-C3 pseudosubluxation occurring in a 27 year old woman presenting with neck pain 1 week after a road traffic accident. Although there are effective radiological guidelines for cervical spine radiograph evaluation in children, there is no evidence that these can be applied to the adult cervical spine. Flexion and extension cervical spine views have limitations. In such cases, magnetic resonance imaging is required to definitively exclude pathological injury.

Adult↗

PubMed2000

Small cell malignant melanoma: a variant of naevoid melanoma. Clinicopathological features and histological differential diagnosis.

AIMS: To describe the clinical and histopathological features of a rare variant of naevoid melanoma, small cell melanoma, and discuss the histological differential diagnoses. METHODS: The clinical and histological features of cases of malignant melanoma with the histological features of small (non-Merkel like) melanoma were reviewed and documented. In addition, five cases had available material for immunohistochemistry and this was performed using antibodies to the S100 protein and melan-A, and the HMB-45 antibody. RESULTS: There were 15 cases of small cell melanoma from 14 (10 female, four male) patients, aged between 30 and 77 (mean, 48.6) years. The trunk was the most common location. In more than half the cases, the provisional diagnosis was melanoma/borderline lesion. All shared similar histological appearances of an intraepidermal component of in situ melanoma and a dermal component of nests of cells with hyperchromatic nuclei and scanty cytoplasm, usually in tightly packed nests. All components (junctional and intradermal) of the lesions investigated by immunohistochemistry were positive both for S100 protein and melan-A. All junctional components were positive with HMB-45, but with variable staining of the dermal components with this antibody. CONCLUSIONS: Small cell malignant melanoma is postulated to be a distinct histopathological entity and a rare variant of naevoid melanoma. Such lesions can be difficult to interpret and easily missed at scanning magnification because the cells of the dermal component mimic benign naevus cells.

Adult↗

PubMed2006

Subtypes of written expression in elementary school children: a linguistic-based model.

The purpose of this study was to provide a reliable and valid classification scheme for written expression that captured the linguistic variability present in a typical elementary school sample. This empirically derived classification model was based on the following linguistic-based writing skills: (a) understandability of discourse, (b) grammar, (c) semantics, (d) spelling, and (e) reading comprehension. The sample included 257 fourth-grade (n = 142) and fifth-grade (n = 115) students (46.3% boys, 79.4% White, age range = 8;3-11;7 years; M = 10.10). All of the students were receiving their writing instruction in the regular education setting, with approximately one third receiving some type of educational assistance. The sample fell in the middle socioeconomic stratum. Cluster analytic techniques derived different possible solutions. Results of a series of internal validity studies provided strong evidence that the six-cluster solution was both stable and interpretable, with subtypes reflecting normal as well as writing disability variants. Further, the writing disability subtypes ranged from global impairment to more specific linguistic impediments. Based on their characteristics, the clusters were named (a) Average Writers (n = 102), (b) Low Semantics (n = 31), (c) Low Grammar (n = 18), (d) Expert Writers (n = 33), (e) Low Spelling-Reading (n = 13), and (f) Poor Text Quality (n = 60). Subtypes differed on the percentages of children in selected subtypes manifesting specific writing deficits as well as on selected aspects of measures of metacognition, self-efficacy, and self-regulation of the writing process. Results provide researchers with a foundation to further investigate the underlying neurolinguistic and neurocognitive processes that may strengthen or undermine students' ability to produce a quality written product and to design and implement intervention techniques to address the various subtype patterns inherent in a regular elementary school classroom.

Analysis of Variance↗

PubMed2004

Where to set the threshold between well differentiated and poorly differentiated follicular carcinomas of the thyroid.

A critical review of the literature reveals that different types of thyroid carcinomas have been interpreted as poorly differentiated, including the tall and columnar cell variants as well as carcinomas with insular, trabecular, and solid growth patterns. In some publications the growth patterns have been emphasized, while in others histologic patterns and cytologic features are considered important for identification. However, insular, trabecular, nodular, and solid growth patterns lack specificity because they can be observed in hyperplastic lesions and benign thyroid tumors. The cytologic features of the vast majority of poorly differentiated thyroid carcinomas are similar to or overlap with those of papillary or follicular carcinomas. Cytologic atypia, mitotic activity, and necrosis--believed by some investigators to be useful clues in the diagnosis of poorly differentiated carcinomas--do not reflect cell differentiation, especially in endocrine organs. It is therefore not surprising that the immunohistochemical profile and the molecular abnormalities described in this heterogeneous group of carcinomas lack specificity and are not useful diagnostic tools. Because poorly differentiated thyroid carcinomas have not been well defined, currently it is not possible to set the threshold between well-differentiated and poorly differentiated thyroid carcinomas with follicular phenotype. The authors believe that the vast majority of poorly differentiated thyroid carcinomas are in fact examples of papillary or follicular carcinomas with unusual growth patterns.

Adenocarcinoma, Follicular↗