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PubMed2000

[Primary ciliary dyskinesia. A new phenotypic variant].

Primary ciliary dyskinesia (PCD) is a genetic disorder characterized by the inability of ciliated structures to beat effectively. Clinical course includes recurrent sinus and ear infections, chronic or recurrent bronchitis and infertility in men. Although several phenotypes have been described, lung function deterioration secondary to bronchiectasis becomes severe only rarely. That upper airway tract infections go unnoticed has not been reported. We report a case of PCD characterized by immotile sperm, severe obstructive respiratory disorder that required a sequential double lung transplant with the absence of recurrent sinus and ear infections.

Adult↗
PubMed2001

[Multiorgan resection in combination with intraoperative, hyperthermic chemotherapy in recurrent fibrolamellar hepatocellular carcinoma. An individual therapeutic concept for a 21-year-old patient].

The fibrolamellar karzinoma of the liver (FLC) as an uncommon variant of the hepatocellular karzinoma (HCC) is an indolent growing tumor. In its prior manifestation the FLC occurs at the adolescence and young adult stage. Early stage diagnosis and aggressive surgical treatment achieve better long-term results than usual resection of the HCC. Usually the FLC is, caused by its inconspicuous clinical appearance, diagnosed at a stage too advanced for effective surgical treatment. Especially the young patient's age and the remaining therapeutic options for palliative or curative treatment postulate a difficult decision for the surgeon. When a subtotal hepatectomy cannot be performed, total hepatectomy with liver transplantation is a valuable option. Palliative treatment protocols include systemic chemotherapy, ethanol instillation and chemoembolisation. We report the case of a 21-year-old male patient who presented with a recurrent intrahepatic FLC, peritoneal karzinomatosis confined to the right lower abdomen including gastric, splenic, diaphragmatic and colon transversum metastasis 14 months after primary surgery. We selected this patient as a reasonable candidate for an extended resection in trying to offer the optimal therapeutic modality. Thus we performed a right hemihepatectomy, near complete resection of the right diaphragm, total gastrectomy with lymphadenectomy including en bloc resection of spleen, colon transversum, omentum majus and peritonectomy of the paravesical region. Furthermore hyperthermic intraperitoneal chemotherapy was carried out the next day. The patient's postoperative course remained uncomplicated with fast recovery. Presently, 6 months after surgery, the patient has no evidence of recurrence.

Adult↗
PubMed1986

Telangiectatic osteosarcoma of the mandible.

A telangiectatic variant of osteosarcoma of the mandible was seen in a 15-year-old Chinese girl. It was first diagnosed as an aneurysmal bone cyst both radiologically and pathologically. There were local recurrences despite repeated surgery, and subsequent response to chemotherapy and radiotherapy was poor. The patient died 16 months later with direct cerebral invasion, but no distant metastases. Diagnostic and clinicopathologic correlative aspects of this tumor variant are discussed, but more study of this tumor variant in the jaw is needed because this is probably the first case fully reported.

Adolescent↗
PubMed2006

Mutation screening in patients with syndromic craniosynostoses indicates that a limited number of recurrent FGFR2 mutations accounts for severe forms of Pfeiffer syndrome.

Crouzon Syndrome (CS), Pfeiffer syndrome (PS) and the phenotypically related Jackson-Weiss (JW) variant are three craniosynostotic conditions caused by heterozygous mutations in Fibroblast Growth Factor Receptor (FGFR) genes. Screening a large cohort of 84 patients with clinical features of CS, PS or JW by direct sequencing of genomic DNA, enabled FGFR1, 2 or 3 mutation detection in 79 cases. Mutations preferentially occurred in exons 8 and 10 of FGFR2 encoding the third Ig loop of the receptor. Among the 74 FGFR2 mutations that we identified, four were novel including three missense substitutions causing CS and a 2 bp deletion creating a premature stop codon and producing JW phenotype. Five FGFR2 mutations were found in one of the two tyrosine kinase subdomains and one in the Ig I loop. Interestingly, two FGFR2 mutations creating cysteine residues (W290C and Y340C) caused severe forms of PS while conversion of the same residues into another amino-acid (W290G/R, Y340H) resulted in Crouzon phenotype exclusively. Our data provide conclusive evidence that the mutational spectrum of FGFR2 mutations in CS and PS is wider than originally thought. Genotype-phenotype analyses based on our cohort and previous studies further indicate that in spite of some overlap, PS and CS are preferentially accounted for by two distinct sets of FGFR2 mutations. A limited number of recurrent amino-acid changes (W290C, Y340C, C342R and S351C) is commonly associated with the most severe Pfeiffer phenotypes of poor prognosis.

Acrocephalosyndactylia↗
PubMed2005

The cystic fibrosis transmembrane conductance regulator gene and ion channel function in patients with idiopathic pancreatitis.

Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations are associated with cystic fibrosis (CF)-related monosymptomatic conditions, including idiopathic pancreatitis. We evaluated prospectively enrolled patients who had idiopathic recurrent acute pancreatitis or idiopathic chronic pancreatitis, healthy controls, CF heterozygotes, and CF patients (pancreatic insufficient or sufficient) for evidence of CFTR gene mutations and abnormalities of ion transport by sweat chloride and nasal potential difference testing. DNA samples from anonymous blood donors were controls for genotyping. At least one CFTR mutation or variant was carried in 18 of 40 patients (45%) with idiopathic chronic pancreatitis and in 6 of 16 patients (38%) with idiopathic recurrent acute pancreatitis but in only 11 of the 50 controls (22%, P=0.005). Most identified mutations were rare and would not be identified in routine genetic screening. CFTR mutations were identified on both alleles in six patient (11%). Ion transport measurements in patients with pancreatitis showed a wide range of results, from the values in patients with classically diagnosed CF to those in the obligate heterozygotes and healthy controls. In general, ion channel measurements correlated with the number and severity of CFTR mutations. Twelve of 56 patients with pancreatitis (21%) fulfilled current clinical criteria for the diagnosis of CF, but CFTR genotyping alone confirmed the diagnosis in only two of these patients. We concluded that extensive genotyping and ion channel testing are useful to confirm or exclude the diagnosis of CF in the majority of patients with idiopathic pancreatitis.

Adult↗
PubMed2006

Mosaicism for mitochondrial DNA polymorphic variants in placenta has implications for the feasibility of prenatal diagnosis in mtDNA diseases.

Women who have had a child with mitochondrial DNA (mtDNA) disease need to know the risk of recurrence, but this risk is difficult to estimate because mutant and wild-type (normal) mtDNA coexist in the same person (heteroplasmy). The possibility that a single sample may not reflect the whole organism both impedes prenatal diagnosis of most mtDNA diseases, and suggests radical alternative strategies such as nuclear transfer. We used naturally occurring mtDNA variants to investigate mtDNA segregation in placenta. Using large samples of control placenta, we demonstrated that the level of polymorphic heteroplasmic mtDNA variants is very similar in mother, cord blood and placenta. However, where placental samples were very small (< 10 mg) there was clear evidence of variation in the distribution of mtDNA polymorphic variants. We present the first evidence for variation in mutant load, that is, mosaicism for mtDNA polymorphic variants in placenta. This suggests that mtDNA mutants may segregate in placenta and that a single chorionic villous sample (CVS) may be unrepresentative of the whole placenta. Duplicates may be necessary where CVS are small. However, the close correlation of mutant load in maternal, fetal blood and placental mtDNA suggests that the average load in placenta does reflect the load of mutant mtDNA in the baby. Provided that segregation of neutral and pathogenic mtDNA mutants is similar in utero, our results are generally encouraging for developing prenatal diagnosis for mtDNA diseases. Identifying mtDNA segregation in human placenta suggests studies of relevance to placental evolution and to developmental biology.

Chorionic Villi Sampling↗
PubMed2025

Rapid replacement of blaKPC variant in ST11 carbapenem-resistant and hypervirulent Klebsiella pneumoniae contributed to ceftazidime/avibactam resistance during severe in vivo infection.

OBJECTIVES: Hypervirulent ceftazidime/avibactam (CAZ/AVI)-resistant Klebsiella pneumoniae (Kp) has emerged; however, its dynamic within-host evolution and competitive features are uncharacterized. This study aimed to clarify the systematic microevolution characteristics of the rapid transformation of blaKPC variants during long-term infection. METHODS: Thirty-nine Kp strains were isolated from a single patient with severe recurrent osteomyelitis during a 2-year period. Whole-genome sequencing and in vitro evolution assay was performed. Microbiological characteristics were examined through antimicrobial susceptibility testing, plasmid stability, growth curve, in vitro competition and Galleria mellonella larvae lethality assays. RESULTS: Among all the clinical Kp isolates, 37 were carbapenem-resistant Kp (CRKP), including 25 CAZ-/AVI-resistant Kp. All isolates belonged to the ST11-K47. During in vivo evolution, the blaKPC variant and its amplification emerged. Twenty-four isolates (24/39, 61.5%) harboured a novel blaKPC variant, blaKPC-144. All five Kp isolates carried blaKPC-2 in 2021. Surprisingly, 24 blaKPC-144-harbouring isolates (70.6%, 24/34) and 10 blaKPC-2-harboring isolates were identified in 2023, indicating rapid changing of blaKPC. Kp4 carried two copies of blaKPC-2, and Kp10-1 exhibited a 1.94-fold increase in the blaKPC-144 copy number. Similarly, in vitro, the blaKPC copy number increased upon exposure to low CAZ/AVI concentrations. However, at higher concentrations (4/1&#x2005;mg/L), the blaKPC copy number increased significantly, and blaKPC mutations emerged simultaneously. The competition assay indicated that the blaKPC-144-harboring isolates exhibited a superior competitive capacity. CONCLUSIONS: The blaKPC amplification and mutation emerged simultaneously or sequentially during in vivo and in vitro evolution. Kp isolates harbouring blaKPC-144, conferring resistance to CAZ/AVI, exhibited a competitive advantage, promoting the rapid replacement of blaKPC-2.

Klebsiella pneumoniae↗
PubMed2026

Long-Read Haplotype Phasing Resolves Allelic Configuration as a Missing Layer of Precision Oncology.

Conventional short-read sequencing cannot determine whether co-occurring variants within a cancer gene reside on the same allele (cis) or on opposing alleles (trans), a distinction with direct biological and therapeutic consequences. Trans configurations confirm biallelic tumor suppressor inactivation and inform therapy selection, while cis configurations generate compound oncogenic alleles with enhanced activity. We analyzed 768 patients with prostate, breast, or ovarian cancers in the PROBLEM cohort, using mutational signatures to nominate cryptic genomic instability cases where the causative biallelic event was not apparent from short-read sequencing. Long-read nanopore sequencing resolved 32 of 46 cryptic cases (69.6%), leveraging its unique advantages in direct methylation detection, long insertion resolution, and complex structural variant characterization, confirming trans biallelic inactivation in all resolved tumor suppressor cases. Systematic analysis of 4,496 MiOncoSeq samples identified 17,519 multi-hit gene pairs, of which 78.7% exceeded the 500 bp short-read phasing limit. Long-read phasing further revealed recurrent compound cis oncogenic alleles in NOTCH1, PIK3CA, PDGFRB, and KIT with functionally synergistic activity. Haplotype phasing resolves a systematically overlooked gap in cancer variant interpretation and warrants broader integration into precision oncology workflows.

Journal Article↗
PubMed2001

Nodular presentation of eosinophilic cellulitis (Wells' syndrome).

Eosinophilic cellulitis is a rare condition of unknown aetiology. The classical presentation is of a tender or mildly pruritic cellulitis-like eruption, that has typical histology characterized by tissue eosinophilia, oedema and "flame" figures. Other reported clinical presentations include papular and nodular eruptions. It may be recurrent, and preceded at a variable time by a pruritic papular eruption. We describe a patient with the rare nodular variant of eosinophilic cellulitis affecting the palms of the hands, which occurred 2 years after a nonspecific pruritic papular eruption, without an obvious precipitant and in the absence of the more typical cellulitis-like plaques.

Adult↗
PubMed2001

Venous thromboembolism in young patients from western India: a study.

The goal of this article is to study the association of known markers of thrombophilia with venous thrombosis in young patients (< 45 years) from the Western part of India. A prospective study of 432 patients (252 males and 180 females, age 1-45 years) was conducted between 1994 and 2000 (6 years). The diagnosis was confirmed in all the patients by ultrasound with Doppler or by a computed tomograph (CT) scan of the brain with or without contrast depending on the case. Detailed clinical examination, and family history was taken to establish recurrent thrombosis and familial occurrence of thrombosis. The markers studied were protein C, protein S, antithrombin (AT) III, factor V Leiden mutation, prothrombin gene G20210A polymorphism, and the thermolabile MTHFR variant C677T polymorphism, using appropriate techniques. Lupus inhibitor was tested in the first 72 patients using Dilute Russel Viper Venom Time (DRVVT) test, and anticardiolipin antibodies were tested by enzyme-linked immunosorbent assay. Protein C, protein S, and AT III deficiency was detected in 9.5%, 6.5%, and 2.6%, respectively, among the patients. Anticardiolipin antibody was present in 9.9% of the patients, whereas lupus anticoagulant was present in 8.3% of patients; factor V Leiden mutation was detected in 3% of patients; thermolabile variant of MTHFR C677T polymorphism was present in 14.9% of patients with 1.2% homozygotes. Prothrombin G20210A polymorphism was not detected in any sample in this population. One hundred and four patients of 432 (24.9%) had recurrent attacks of thrombosis without any proximate precipitating cause, whereas 7.5 % of the patients had another close member of the family with a history of deep venous thrombosis. Eighty-six members from 28 families (out of 32 families giving family history of thrombosis) were investigated and found to have protein C and protein S deficiency in seven each; factor V Leiden was present in 6, and MTHFR C677T polymorphism was present in 5 cases. Hence, 25 of 86 members (28%) from the family of patients with familial history deep venous thrombosis had positive markers for thrombophilia. Thus, we could show that in young patients presenting with thrombosis, at least 34% of them had a demonstrable cause for thrombophilia. Prothrombin gene polymorphism G20210A seems to be nonexistent in our population and AT III deficiency also appears to be low compared to other markers of thrombophilia. There is a high prevalence of variant MTHFR C677T in our series, but the incidence of MTHFR C677T in our general population is also high. Hence, the significance of this finding in our cases of deep venous thrombosis remains to be seen, but we did not see any homozygotes when we tested 70 randomly selected asymptomatic persons, whereas in the present series, 1.8% of the patients had homozygosity for the MTHFR C677T polymorphism.

Adolescent↗
PubMed2004

Identification of variants in cyclin D1 ( CCND1) and B-Cell CLL/lymphoma 2 ( BCL2).

CCND1 is an important cell-cycle regulatory protein associated with cell proliferation, poor prognosis and recurrence in cancer, while BCL2 is an important anti-apoptotic protein that plays a vital role in the regulation of the life span by controlling the rate of apoptosis. Recent studies have shown that CCND1 and BCL2 may be responsible for the body mass and the regulation of various metabolic processes. In an effort to discover additional polymorphism(s), we scrutinized the genetic polymorphisms in the CCND1 and BCL2. By direct DNA sequencing in 24 individuals, we identified 22 sequence variants within the 16 kb of whole CCND1 gene: one in exon 4, 17 in introns and four in the 3' UTR region. We also found eight sequence variants within 7.5 kb exon-intron boundaries of BCL2 gene: one in promoter, three in exon 1, and four in the 3' UTR region. Haplotypes, their frequencies and linkage disequilibrium coefficients (| D'| and r(2)), among polymorphisms were estimated. Among identified variants, seven and six variants of CCND1 and BCL2 were genotyped in a larger series of subjects ( n=320). Statistical analyses of CCND1 and BCL2 polymorphisms with two metabolic phenotypes revealed no significant association. The information concerning genetic polymorphisms of CCND1 and BCL2 might provide valuable information for future genetic studies of diseases.

5' Untranslated Regions↗
PubMed2005

Strong evidence that the common variant S384F in BRCA2 has no pathogenic relevance in hereditary breast cancer.

INTRODUCTION: Unclassified variants (UVs) of unknown clinical significance are frequently detected in the BRCA2 gene. In this study, we have investigated the potential pathogenic relevance of the recurrent UV S384F (BRCA2, exon 10). METHODS: For co-segregation, four women from a large kindred (BN326) suffering from breast cancer were analysed. Moreover, paraffin-embedded tumours from two patients were analysed for loss of heterozygosity. Co-occurrence of the variant with a deleterious mutation was further determined in a large data set of 43,029 index cases. Nature and position of the UV and conservation among species were evaluated. RESULTS: We identified the unclassified variant S384F in three of the four breast cancer patients (the three were diagnosed at 41, 43 and 57 years of age). One woman with bilateral breast cancer (diagnosed at ages 32 and 50) did not carry the variant. Both tumours were heterozygous for the S384F variant, so loss of the wild-type allele could be excluded. Ser384 is not located in a region of functional importance and cross-species sequence comparison revealed incomplete conservation in the human, dog, rodent and chicken BRCA2 homologues. Overall, the variant was detected in 116 patients, five of which co-occurred with different deleterious mutations. The combined likelihood ratio of co-occurrence, co-segregation and loss of heterozygosity revealed a value of 1.4 x 10-8 in favour of neutrality of the variant. CONCLUSION: Our data provide conclusive evidence that the S384F variant is not a disease causing mutation.

Adult↗
PubMed1981

Malignant fibrous histiocytoma, myxoid variant metastatic to the oral cavity. Report of a case and review of the literature.

Primary and metastatic malignant fibrous histiocytoma (MFH) of the oral cavity is exceedingly rare. A review of the literature yielded only nine cases of primary MFH and no reports of MFH metastatic to this area. We report a case of recurrent malignant fibrous histiocytoma of the myxoid type arising in the soft tissue of the lower extremity and metastasizing to the gingiva as the typical storiform fibrous variant.

Cytoplasm↗
PubMed1981

Treatment of Prinzmetal's variant angina. Role of medical treatment with nifedipine and surgical coronary revascularization combined with plexectomy.

This study describes three forms of treatment of Prinzmetal's variant angina. Coronary spasm, frequently found at coronary arteriography in patients with Prinzmetal's variant angina, can be treated with intravenous or intracoronary injection of nitroglycerin as well as of nifedipine. Nifedipine (0.2 mg) was injected directly into the involved artery in 12 patients and suppressed spasm in 9; in 3 patients, nifedipine increased coronary sinus flow, which had been decreased by spasm in one of the branches of the left coronary artery. Patients with Prinzmetal's variant angina who have spasm superimposed on atherosclerotic lesions can benefit from coronary arterial bypass grafting combined with partial denervation of the heart. This combination yielded acceptable results (83.4 percent favorable outcome); recurrence of attacks occurred in only 6.7 percent of this group. In those forms of angina in which spasm occurs in angiographically normal coronary arteries, therapy is essentially medical. In 13 patients treated with oral nifedipine (30 to 40 mg/day), suppression of attacks was achieved in 11 instances. During the period of treatment, the methergine provocative test, which had been consistently positive before treatment, converted to negative in 12 patients. Transient withdrawal of nifedipine caused recurrence of pain in two patients.

Adult↗
PubMed1979

Neurotropic melanoma. A variant of desmoplastic melanoma.

We report a group of neuroid, cutaneous tumors that are usually associated with, or preceded by a melanocytic dysplasia. For this clinicopathologic entity we have chosen the term neurotropic melanoma. The neurotropic melanoma is a cutaneous fibrous tumor whose clinical course is characterized by local infiltration, multiple recurrences, and commonly by metastases. Its microscopic picture is characterized by atypical "neuroma-like" patterns, by poorly defined margins, and by neurotropism. Its early or precursory melanocytic dysplasias include lentigo maligna (actinic or lentigo maligna variant), and a melanoma with borderline cytologic characteristics (minimal deviation variant). A third type is not preceded by a recognizable melanocytic dysplasia: it has "neuroma-like" qualities at its inception (de novo variant). In our 22 cases, the preponderant sites were the head, neck, and lip. The patients were fair-faced, and 18 of the patients were over 40 years old. Seventeen patients had one or more recurrences. Of 16 patients with follow-up, nine died with evidence of disease, five are alive with active disease, and seven are apparently free of disease.

Adult↗
PubMed2001

Possible contribution of CD44 variant 6 and nuclear beta-catenin expression to the formation of budding tumor cells in patients with T1 colorectal carcinoma.

BACKGROUND: In an earlier study, the authors demonstrated that tumor budding was useful for predicting lymph node metastasis in patients with early invasive (T1) colorectal carcinoma. This study was undertaken to clarify the associations between tumor budding, E-cadherin-catenin complex, and CD44 variant 6 abnormalities. METHODS: In 51 T1 colorectal carcinomas, tumor budding (the number of dedifferentiation units at the invasive margin) on hematoxylin and eosin-stained slides was counted under light microscopy. Immunostaining for E-cadherin, alpha-catenin, beta-catenin, and CD44 variant 6 was performed on formalin fixed, paraffin embedded sections. The associations between locoregional failure (lymph node metastasis or local recurrence) and tumor budding and clinicopathologic parameters and immunoreactivity were examined statistically. RESULTS: In univariate analysis, tumor budding and nuclear beta-catenin expression were associated significantly with locoregional failure (P = 0.004, 0.01). Multivariate analysis showed that tumor budding alone was associated significantly with locoregional failure (P = 0.02), and the association between nuclear beta-catenin expression and locoregional failure was marginally significant (P = 0.07). Analysis of variance showed that lymphatic invasion alone was associated significantly with tumor budding (P = 0.02), and there was a significant interaction effect for tumor budding between CD44 variant 6 expression and nuclear beta-catenin expression (P = 0.01). There was a significant correlation between expression patterns of these two molecules and locoregional failure (P = 0.01). CONCLUSIONS: The current results suggest that the up-regulation of CD44 variant 6 through nuclear beta-catenin activation may contribute to the formation of tumor budding, and immunostaining of these two adhesion molecules may be useful in identifying those at high-risk for locoregional failure among patients with T1 colorectal carcinoma.

Adult↗
PubMed1996

Oncogenic osteomalacia associated with a meningeal phosphaturic mesenchymal tumor. Case report.

A 60-year-old woman suffered from hypophosphatemic osteomalacia secondary to a frontal intracranial tumor. Oral administration of phosphate and 1-alpha-hydroxyvitamin D3 provided only temporary symptomatic relief. A computerized tomography (CT) scan of the patient's head revealed a large subfrontal tumor attached to the dura. Following removal of the tumor, the patient's hypophosphatemia subsided; her level of 1,25-dihydroxyvitamin D3, which was undetectable preoperatively, returned to normal, and she had symptomatic improvement. Three years later, decreasing levels of phosphate and 1,25-dihydroxyvitamin D3 indicated tumor recurrence, before it was detected by CT scan. Histological examination of the tumor provided the diagnosis of "mixed connective tissue variant of phosphaturic mesenchymal tumor." The characteristic histological features of this relatively rare entity are discussed. This is the first report of a surgically treated intracranial phosphaturic mesenchymal tumor that caused oncogenic osteomalacia.

Craniotomy↗