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PubMedDate not supplied

[Somatotropic function of the hypophysis in the hypothalamic puberty syndrome].

The STH level was studied in the blood of 105 patients with the hypothalamic pubertal syndrome (HPS). A tendency toward STH hyperproduction was revealed. A comparison of the STH level in the blood and the degree of obesity of the HPS patients showed a clear decrease of the growth hormone in Stage IV obesity. The STH level was almost the same in Stages I, II, III obesity. The STH secretion in the HPS patients correlated with age. The period of disease did not influence hypophysial somatotropic function in the HPS patients. No interrelationship between the content of hydrocortisone and STH in the blood was established. In most of the patients with the HPS, the growth hormone secretion in response to hypoglycemia was undisturbed. Preliminary results obtained with parlodel tests showed an opposite reaction in the HPS patients as compared to healthy ones. Our results confirmed once more that the HPS should not be interpreted as a variant of Icenko-Cushing's syndrome or constitutional obesity in which STH production was lowered.

Adolescent↗

PubMed1985

[Double-outlet right ventricle with intact interventricular septum. Case report, review of the literature and proposed pathogenetic interpretation].

Double Outlet Right Ventricle with intact ventricular septum is an extremely rare malformation. Only nine cases are recorded in the known world literature. A new case is reported, concerning a female infant six months old when first seen, and still alive after atrial septectomy. The anatomical studies in Double Outlet Right Ventricle suggest that only the Ventricular Septal Defect in the outlet septum is an integral part of the malformation and can be defined as "typical". In more than 10% of cases the Ventricular Septal Defect opens into the inlet or trabecular-muscular portions of the septum: these latter locations of the defect should therefore be considered as "associated". Double Outlet Right Ventricle with intact ventricular septum can be interpreted as the variant lacking both typical and associated Ventricular Septal Defect. From the analysis of anatomical descriptions of the ten known specimens of Double Outlet Right Ventricle with intact Ventricular septum, the Authors word out the hypothesis that ventricular septum closure could be referred to a well developed bulbo-ventricular fold (bulbo-ventricular fold synonimous of cono-ventricular flange and bulbo-atrio-ventricular ledge), as a consequence of missed or defective conal absorption. They conceive a range including on one hand the Subarterial Ventricular Septal defect (bulbo-ventricular fold poorly developed due to effective conal absorption), on the other hand the Restrictive Ventricular Septal Defect and Intact Ventricular Septum (bulbo-ventricular fold well developed due to defective conal absorption).

Female↗

PubMed1979

[Impetigo herpetiformis and PUVA-treatment (author's transl)].

Report on a 20 years old pregnant woman, who fulfilled the criteria of the impetigo herpetiformis as well as later those of the pustular psoriasis Zumbusch in her clinical course. The impetigo herpetiformis is interpreted as a variant of the pustular psoriasis occurring during the pregnancy with lowered calcium-level, which increases the endogeneous eruption pressure. After negative attempts of treatment with Prednisolon, antibiotics, and later with Methotrexat an excellent therapeutic effect could be achieved by oral PUVA-treatment.

Administration, Oral↗

PubMed1980

[Delusional psychopathology of the paranoid stage of paranoid schizophrenia].

The psychopathological traits of paranoial delusions were studied in 65 patients with paranoial schizophrenia. Of these patients, 16 had hypochondriacal delusions, 13 delusions of jealousy and 36 delusions of reference and persecution. All cases were studied from the standpoint of structural-dynamic aspects of the development of systematized interpretative delusions. Two variants of the development of such delusions were distinguished: paranoic and mixed. The paranoic variant by its nature appeared to be catathymic (4 cases), in a mixed variant separate elements of sensorial and imaginative delusions were interspersed with a catathymic development of delusions. Such states were mainly expressed in the form of delusions of significance and special significance. An assumption is made that there is a reciprocal transition of catathymic delusions, delusions of significance and special significance in compliance to the development of the morbid process.

Adolescent↗

PubMedDate not supplied

[Polycystosis of the brain].

This paper presents a case with 11-year history of disseminated cerebral polycystosis in a 23-year-old female. Physical examination and CT, MRT, histological and biochemical data suggest that the disease is morphologically progressive; however, the spread on brain lesions showed no correlation with relatively mild clinical manifestations of the disease. Variants of nosological interpretation of histological data are discussed.

Adult↗

PubMed2025

Extracting and calibrating evidence of variant pathogenicity from population biobank data.

Genomic medicine requires a robust evidence base of variant phenotypic impacts, which remains incomplete even in extensively studied genes with monogenic disease associations. Here, we evaluated the broad potential of using population cohort data to identify evidence that can be used in variant assessment. Across 41 genes related to 18 clinically actionable monogenic phenotypes, we calculated variant-level odds ratios of disease enrichment using data from 469,803 UK Biobank participants. We found significant differences in odds ratio values between ClinVar-labeled pathogenic and benign variants in 11 phenotypes, spanning both common and rare disorders. To facilitate clinical translation, we calibrated the strength of evidence provided by variant-level odds ratios to align with American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) interpretation guidelines (PS4 criterion) and found that odds ratios may reach "moderate," "strong," or "very strong" evidence, varying by phenotype and gene. Overall, we found that 2.6% (N = 12,350) of participants harbor a rare variant of uncertain significance (VUS) with at least moderate evidence of pathogenicity-an indication of potentially unrecognized disease risk. Finally, by incorporating computational and functional data alongside population-based odds ratios, we identified variants that met the criteria for clinical reclassification. Notably, using this approach, we identified that 12.4% of rare VUSs in LDLR seen in participants meet diagnostic criteria to be classified as likely pathogenic, demonstrating its potential to scale the reclassification of VUSs.

Humans↗

PubMed2003

[Disease-causing mutations versus neutral polymorphism: use of bioinformatics and DNA diagnosis].

Molecular genetic diagnostics is available for increasing number of genetically determined diseases. A wide spectrum of mutations can be detected by laboratory methods. A mutation can be defined as a change in a specific DNA sequence when compared with the reference sequence published in the gene database. However, in some cases it is difficult to distinguish if the detected sequence variant is a causal mutation or a neutral (polymorphic) variation without any effect on phenotype. The interpretation of rare sequence variants of unknown significance detected in disease-causing genes becomes an increasingly important problem. Further analysis on DNA and on protein levels with the use of bioinformatics are needed to reveal the effect of rare sequence variants. Inherited complex disorders, for example rare hereditary forms of cancer diseases, represent a challenge to molecular geneticists. The identification of exact causal mutation directly responsible for the development of the disease and for the assessment of disease risk resulting from this genetic variation has further implications. Predictive genetic diagnostics allows identify relatives at high risk of genetically determined disease and use of targeted preventive and therapeutic approaches. In severe cases it allows also prenatal or pre-implantation diagnostics.

DNA Mutational Analysis↗

PubMed1985

[Clinico-psychopathologic varieties of the acute Kandinsky-Clerambault syndrome in schizophrenia].

Acute cases of the Kandinsky-Clerambault syndrome first manifested in adulthood were studied in schizophrenic patients. On the basis of the clinical mechanisms of the development of psychosis and the specific features of acute delirious disturbances in the structure of psychosis 3 clinical variants of the acute syndrome of psychic automatism were identified: developing according to the type of reaction in the structure of acute paranoid (the first variant), according to the regularities of endogenic paroxysm in the picture of acute sensory delirium (the second variant) and according to the mechanism of exacerbation of chronic delirium entering the structure of acute interpretative delirium (the third variant).

Acute Disease↗

PubMed2003

[Solitary fibrous pseudopapillary tumor of the lung: pulmonary fibroadenoma and adenofibroma revisited].

We describe a peculiar pulmonary lesion, that we interpreted as a pseudopapillary variant of solitary fibrous tumor. The patient was a 62-year-old asymptomatic male, non smoking, presenting with a peripheral nodule, 0.8 cm across, located in the lower lobe of the right lung. The patient is alive and well 18 months after surgical excision of the nodule. Microscopically, the lesion was well-circumscribed and characterized by a diffuse pseudopapillary pattern. Pseudopapillae were large, and were covered by a rim of cubic epithelium devoid of atypia. The stromal axis was fibrous and contained scattered bland spindle cells. Immunohistochemically, the latter were strongly positive for vimentin and CD34, focally positive for BCL2 and CD99, negative for cytokeratin, EMA, TTF1, calretinin, smooth muscle actin, desmin and S100 protein; the epithelial cells were immunoreactive for cytokeratin, EMA and TTF1. We interpret this lesion as a peculiar pseudopapillary variant of solitary fibrous tumor, corresponding to what has been reported in the literature as pulmonary adenofibroma and fibroadenoma. The most important differential diagnostic considerations are briefly discussed.

Adenofibroma↗

PubMedDate not supplied

[Ultrasonographic evaluation of the thyroid palpation method in determining its dimensions in children and adolescents].

The authors analyze the diagnostic value of thyroid palpation method (two modifications) comparing its results with those of ultrasonographic volumetry. The study involved 118 children aged 5 and 14 of both sexes living in regions endemic for goiter. The thickness of thyroid isthmus was found virtually the same no matter how greatly the gland was enlarged. The results proved the necessity of age-specific corrections in the criteria of current interpretation of palpation data: the first degree in preschool children was most often indicative of thyroid hypertrophy whereas in the pubertal age it was just a variant of normal size. Interpretation with due account of these amendments improved the reliability of diagnostic value of palpation, its sensitivity being 63 +/- 6, specificity 67 +/- 6, and accuracy 65 +/- 4%. When the results of palpation are adequately interpreted, the examinees' age and sex and the method of examination proper do not influence the data accuracy. The sensitivity of palpation in detection of nodules up to 10 mm in diameter proved to be null (in 6 of the 81 examined adolescents sonographic signs of encapsulated formation were seen in the thyroid). Bearing all this in mind, the authors discuss differentiated approaches to management of children and adolescents with the first degree of palpated enlargement of the thyroid.

Adolescent↗

PubMed2002

Electrospray tandem mass spectrometry of intact beta-chain hemoglobin variants.

In this report, we present data to illustrate how human hemoglobin (Hb) variants can be identified by electrospray tandem mass spectrometry (MS/MS) of the intact Hb chains following the one-step dilution of whole blood. MS/MS spectra were recorded on a series of intact beta-chain human Hb variants. The resultant spectra were interpreted, and using the information gleaned from the fragmentation patterns of known variants, two unknown beta-chain variants were characterized solely by this mass spectrometric method. Fragment ions that serve to identify beta-chain variants were identified. The fragmentation patterns of the intact beta-chain [M + 18H]18+ ions showed classical facile cleavages adjacent to acidic residues and N-terminal to proline residues, with Thr50-Pro51 being the most prominent cleavage site. Abundant product ions were formed by peptide bond cleavage in the regions close to the termini of the beta chain, the central region being less well-represented in the MS/MS spectra. Nearly 50% of the beta-chain primary structure could be determined by MS/MS of the intact chain. However, analysis of the Hb variants where mutations have occurred in the inner region (residues 58-111) of the beta globin proved to be difficult and required mass spectrometric analysis of their tryptic peptides for a complete identification.

Genetic Variation↗

PubMed1992

Pseudosubluxation of C2-C3 in childhood: a frequent clinico-radiological diagnostic error.

Although serious cervical injuries in pediatric patients are very infrequent, the may occur occasionally as a result of a strong blow to the head. Clinical records and radiological pictures, and in some cases computer tomography, help to provide the correct diagnosis. During childhood there are several normal radiological variants that may be interpreted as pathological findings, of which pseudosubluxation C2-C3 is the most frequent. We present two such cases and discuss the clinical and radiological criteria for the differential diagnosis between normal variants and injuries to the cervical spine in pediatric patients.

Adolescent↗

PubMed1995

Extreme hypotrophy of the lower body pole, extensive hypoplasia of the spinal column and multiple anomalies of abdominal organs: a maximal variant of the caudal regression sequence?

A newborn with extreme hypotrophy of the lower body pole and aplasia of the lower spinal column is reported. Additional anomalies of internal organs included absence of one kidney and ureter, a diaphragmatic hernia, and anal atresia. Part of the organs located in the lower body pole were necrotic. There were no excretory apertures, and external genitalia were absent. Chromosomal analysis revealed a 46,XY karyotype. The multiple anomalies seen in this newborn may be interpreted as a maximal variant of the caudal regression sequence.

Abnormalities, Multiple↗

PubMed2002

Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy.

CONTEXT: Warfarin is a commonly used anticoagulant that requires careful clinical management to balance the risks of overanticoagulation and bleeding with those of underanticoagulation and clotting. The principal enzyme involved in warfarin metabolism is CYP2C9, and 2 relatively common variant forms with reduced activity have been identified, CYP2C9*2 and CYP2C9*3. Patients with these genetic variants have been shown to require lower maintenance doses of warfarin, but a direct association between CYP2C9 genotype and anticoagulation status or bleeding risk has not been established. OBJECTIVE: To determine if CYP2C9*2 and CYP2C9*3 variants are associated with overanticoagulation and bleeding events during warfarin therapy. DESIGN AND SETTING: Retrospective cohort study conducted at 2 anticoagulation clinics based in Seattle, Wash. PARTICIPANTS: Two hundred patients receiving long-term warfarin therapy for various indications during April 3, 1990, to May 31, 2001. Only patients with a complete history of warfarin exposure were included. MAIN OUTCOME MEASURES: Anticoagulation status, measured by time to therapeutic international normalized ratio (INR), rate of above-range INRs, and time to stable warfarin dosing; and time to serious or life-threatening bleeding events. RESULTS: Among 185 patients with analyzable data, 58 (31.4%) had at least 1 variant CYP2C9 allele and 127 (68.6%) had the wild-type (*1/*1) genotype. Mean maintenance dose varied significantly among the 6 genotype groups (*1/*1 [n = 127], *1/*2 [n = 28], *1/*3 [n = 18], *2/*2 [n = 4], *2/*3 [n = 3], *3/*3 [n = 5]) (by Kruskall-Wallis test, chi(2)(5) = 37.348; P<.001). Compared with patients with the wild-type genotype, patients with at least 1 variant allele had an increased risk of above-range INRs (hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.03-1.90). The variant group also required more time to achieve stable dosing (HR, 0.65; 95% CI, 0.45-0.94), with a median difference of 95 days (P =.004). In addition, although numbers were small for some genotypes, representing potentially unstable estimates, patients with a variant genotype had a significantly increased risk of a serious or life-threatening bleeding event (HR, 2.39; 95% CI, 1.18-4.86). CONCLUSIONS: The results of our study suggest that the CYP2C9*2 and CYP2C9*3 polymorphisms are associated with an increased risk of overanticoagulation and of bleeding events among patients in a warfarin anticoagulation clinic setting, although small numbers in some cases would suggest the need for caution in interpretation. Screening for CYP2C9 variants may allow clinicians to develop dosing protocols and surveillance techniques to reduce the risk of adverse drug reactions in patients receiving warfarin.

Aged↗

PubMed1994

Normal human tissues, in addition to some tumors, express multiple different CD44 isoforms.

At least 20 different isoforms of the human CD44 lymphocyte-homing receptor/hyaluronan receptor have been described to date that arise from the differential splicing of up to 10 alternative exons (termed v1-v10) encoding the membrane-proximal extracellular domain. Although numerous analyses at the mRNA level have indicated tissue-specific expression of CD44 variants, few analyses have been performed at the protein level because of limited availability of suitable monoclonal antibodies. Recently, however, exon-specific monoclonal antibodies have been generated using bacterial fusion proteins, and these have been reported to detect high levels of vCD44 containing the v6 exon on human tumors. Together with earlier evidence linking this particular exon with tumor metastasis in the rat, these latter experiments have led to the interpretation that v6 splice variants play a causative role in tumor dissemination. In this paper we describe the use of a new and comprehensive panel of CD44 exon-specific monoclonal antibodies generated against a recombinant CD44(v3-10)-immunoglobulin chimera to study vCD44 expression in a large number of normal and neoplastic tissues. We show that the expression of vCD44 varies greatly among different human tumors and that some express either very low levels of vCD44 or no CD44 at all. Furthermore, we demonstrate that expression is not limited to isoforms containing the v6 exon but includes variants carrying v3, v4/5, and v8/9. Additionally, normal epithelial tissues are shown to express considerable levels of these same vCD44 isoforms. Such results argue against a ubiquitous role for vCD44 isoforms in promoting tumor growth and metastasis.

Antibodies, Monoclonal↗

PubMed1981

Granuloblastomas of the stomach (so-called eosinophilic granulomas)-- a variant of fibrous histiocytomas?

25 cases of focal connective tissue proliferations in the submucosa of the stomach are presented. These lesions are termed "granuloblastomas" and have many features in common with so-called eosinophilic granulomas of the stomach. We found that granuloblastomas may be subdivided into two groups: (1) 8 cases are considered to be the result of the proliferation of a peculiar granulation tissue with abundant eosionophilic granulocytes, and (2) 17 cases show a more or less marked storiform pattern and the cellularity is constituted by fibroblasts and histiocytes as well as differing amounts of eosinophilic granulocytes. After discussing the concept of "fibrous histiocytomas" it is concluded that at least the second group of granuloblastomas may be interpreted as a pseudotumorous variant of fibrous histiocytomas. It remains to be clarified in future if submucosal neurofibromas can show the histological features of lesions which we designate granuloblastomas.

Adult↗

PubMed2026

A Case Report of a Pedigree with Distal Hereditary Motor Neuropathy Caused by a Homozygous c.1124G>A Variant an the /*9Vaccinia-Related Kinase 1 Gene.

This study aimed to analyze the clinical phenotypes, neurophysiological characteristics, and pathogenicity of gene variants in a pedigree with distal hereditary motor neuropathy (dHMN) caused by VRK1 variants, and to provide evidence to support clinical diagnosis and genetic counseling for this disease. We report a Chinese consanguineous family with dHMN caused by a homozygous c.1124G>A variant in the VRK1 gene. Clinical and electrophysiological data of the proband were collected. Whole-exome sequencing (WES) and validation by Sanger sequencing were performed to identify the variant site, and pathogenicity interpretation was conducted in accordance with American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines. The proband was a 24-year-old male who presented with 2 years of progressive weakness and atrophy of the distal lower limbs, accompanied by slender upper limbs and no sensory disturbance. Electrophysiological examination showed decreased compound muscle action potential (CMAP) amplitude in motor nerves of both upper and lower limbs, indicating peripheral neurogenic damage, while sensory nerve conduction was normal. Genetic testing detected a homozygous c.1124G>A (p.Trp375Ter) variant in the VRK1 gene. His parents and elder sisters were heterozygous carriers, and the pedigree conformed to autosomal recessive inheritance. According to ACMG guidelines, this variant was classified as pathogenic (evidence: PVS1, PM2, PP1). The homozygous VRK1 c.1124G>A variant causes adult-onset dHMN, rather than pontocerebellar hypoplasia type 1A (PCH1A) as annotated in some genetic databases. This pedigree presents distinctive phenotypes, including slender upper limbs and diffusely decreased CMAP amplitudes in both upper and lower limbs, thereby expanding the clinical and genetic spectrum of VRK1-related dHMN in the Chinese population.

Humans↗

PubMed2026

Incidental MSH6 Germline Pathogenic Variant Identified through Tumor-only Comprehensive Genomic Profiling in a Patient with Small Cell Lung Cancer.

A 55-year-old woman was diagnosed with limited-disease small cell lung cancer (LD-SCLC) after incidental detection of a lung nodule. First-line chemotherapy achieved partial response, but recurrence occurred after one year. During second-line therapy, comprehensive genomic profiling (CGP) revealed a germline MSH6 frameshift mutation. Although lung tumor immunohistochemistry showed the retained expression of mismatch repair (MMR) protein, a prior colon cancer specimen showed the loss of MSH6 expression and deficient MMR expression. Germline genetic testing confirmed Lynch syndrome. Cascade testing identified the same mutation in her daughter. This case outlines a tumor-to-germline workflow with testing of at-risk relatives and highlights the importance of prudent interpretation of presumed germline variants.

Humans↗