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PubMed1998

Canadian Native Indians exhibit unique CYP2A6 and CYP2C19 mutant allele frequencies.

Many human cytochromes P450 (CYP) enzymes are polymorphically expressed, resulting in interindividual and interethnic differences in the metabolism of substrate drugs. Little is known about the genetic variation of CYP enzymes in Canadian Native Indians. We therefore determined the CYP2C19 and CYP2A6 mutant allele frequencies in 159 Canadian Native Indians and compared them with white and Asian subjects. Canadian Native Indians differed significantly from both white and Asian populations in allelic patterns of both CYP2C19 (19.1% CYP2C19*2 and 0% CYP2C19*3) and CYP2A6 (0.9% CYP2A6*2 and 13.9% CYP2A6*3). In addition, analysis of the Canadian Native Indian data suggested that there may be an association between the presence of the CYP2C19 and CYP2A6 mutant alleles such that the co-occurrence of these 2 alleles is higher than would be predicted on the basis of their individual frequencies in this population.

Alleles↗
PubMed1994

Alleles at D6S265 and D6S105 define a haemochromatosis-specific genotype.

Hereditary haemochromatosis is an HLA-linked, recessive disorder with HLA-A3 a strong marker for the gene. We have identified molecular markers for two serologically indistinguishable subtypes of HLA-A3 and examined these in 42 patients with haemochromatosis. The common HLA-A3 subtype HLA-A*0301 (highly correlated with allele 1 of D6S265) was a slightly better marker for haemochromatosis (RR = 10.1, Chi2 = 30) than the serologically recognized A3 antigen (RR = 9.1; Chi2 = 27.3). Allele 8 of the more telomeric locus D6S105 was also strongly associated with haemochromatosis (RR = 13.0; Chi2 = 21.1) but alleles at this locus were not in strong linkage disequilibrium with HLA-A alleles in the control subjects. The co-occurrence of D6S265-1 and D6S105-8 alleles yielded a higher risk (RR = 16.9; Chi2 = 44). Homozygosity for the haplotype including these markers was specific for haemochromatosis, i.e. did not occur in 376 healthy subjects but was observed in 21.4% of patients. These results refine the HLA-A3 association with haemochromatosis, suggest that the haemochromatosis gene is located on the telomeric side of HLA-A and define a possible haplotype in which the first mutation may have occurred.

Adolescent↗
PubMed2001

Didymosis aplasticosebacea: coexistence of aplasia cutis congenita and nevus sebaceus may be explained as a twin spot phenomenon.

BACKGROUND: Co-occurrence of aplasia cutis congenita and nevus sebaceus has sometimes been observed. OBJECTIVE: We propose a genetic mechanism that may explain this coexistence of two different congenital skin disorders. METHODS AND RESULTS: We review 15 cases as reported in the literature and present an additional case. To explain the temporal and spatial proximity of the two skin lesions we advance the concept of twin spotting for which we propose the term didymosis (Greek didymos = twin). In an embryo heterozygous for two different recessive mutations localized on either of a pair of homologous chromosomes, an event of somatic recombination would occur at an early developmental stage, giving rise to two different cell clones homozygous for either mutation. CONCLUSION: The concept of didymosis aplasticosebacea is so far hypothetical. Future molecular research may show whether this concept holds true.

Child↗
PubMed2001

Characteristic chromosomal aberrations in sporadic cerebellar hemangioblastomas revealed by comparative genomic hybridization.

Hemangioblastomas (HBs) of the central nervous system are benign tumors and occur as sporadic (sp) tumors (75%) or as a manifestation of the von Hippel-Lindau (VHL) disease (25%). VHL-disease is an autosomal dominant disorder characterized by HBs of the central nervous system and retina, renal cell carcinoma (RCC), phaeochromocytoma (PHEO), islet tumors of the pancreas, and endolympatic sac tumors as well as cysts and cystadenoma in the kidney, pancreas and epididymis. In VHL patients a large spectrum of germline mutations in the VHL gene has been detected. In spHBs VHL alleles are reported to be inactivated in up to 50% of the tumors. To our knowledge the involvement of other genes in spHBs has not been investigated. To elucidate the oncogenesis of spHBs, we performed CGH on 10 spHBs to screen for chromosomal imbalances throughout the entire tumor genome. Aberrations most frequently detected are losses of chromosomes 3 (70%), 6 (50%), 9 (30%), and 18q (30%) and a gain of chromosome 19 (30%). Based on these frequencies and the co-occurrence of these aberrations in the analyzed tumors we hypothesize that loss of chromosome 3 (harboring the VHL gene) is an early event in the oncogenesis of spHBs, followed by loss of 6, and then losses of chromosomes 9, 18q and gain of chromosome 19. Comparison of the chromosomal imbalances in spHBs to those previously reported in RCCs and PHEOs reveals that the pathway of spHBs shows similarities to both the RCCs and PHEOs.

Adrenal Gland Neoplasms↗
PubMed2026

Co-occurrence of bronchiolar adenoma and lung adenocarcinoma: a study of nine cases revealing distinct clonal origins via integrated histologic, immunophenotypic and molecular analysis.

PURPOSE: This study sought to elucidate the possible biological association between BA and lung adenocarcinoma through an analysis of cases in which both lesions coexist within the same specimen. METHODS: In our cohort, the BA and lung cancer components of nine concurrent-type BAs were microdissected using the Millisect system and subjected to whole-exome sequencing (WES). Their histopathological, immunohistochemical, and genomic profiles were comparatively evaluated. RESULTS: Histopathologically, the BA regions of concurrent-type BAs exhibited a classic bilayered architecture, composed of continuous luminal and basal cell layers. The adjacent monolayered concurrent components were diagnosed as adenocarcinoma in situ (AIS, N = 4), minimally invasive adenocarcinoma (MIA, N = 2), and invasive adenocarcinoma (ADC, N = 3). Immunohistochemically, both luminal and basal cells in BA regions expressed thyroid transcription factor 1 (TTF1), albeit with more heterogeneous staining intensity compared to that observed in tumor components. Molecularly, EGFR mutations were the most frequently identified in either BA or tumor components, or in both (Case 9). In BA components, mutations included exon 19 p.S752F, exon 19 deletions (p.L747_T751delinsP and p.E746_T751delinsVP), and compound G719C/S768I mutations. Tumor components harbored exon 28 S1130C, exon 19 indel (p.E746_S752delins), and exon 18 p.G719C mutations. Notably, only three cases demonstrated limited overlap of mutations and copy number variations (CNVs) between the two components. Phylogenetic analysis revealed that six cases shared truncal alterations in genes including KMT2A, PIK3CA, SETD2, MITF, PBRM1, and SRSF3, one case harbored a shared canonical EGFR mutation (p.G719C), with an additional p.S768I alteration uniquely detected in the BA component. CONCLUSION: There is insufficient evidence to support BA as a premalignant lesion for lung adenocarcinoma base on morphological and molecular variables, and they may represent distinct pathological entities.

Concurrent-type bronchiolar adenoma↗
PubMedDate not supplied

An overview on peripheral vascular disease in blackfoot disease-hyperendemic villages in Taiwan.

The arsenic-related peripheral vascular disease found to be endemic along the southwestern coast of Taiwan is reviewed. In the early 20th century a strange disease involving the lower extremities characterized by typical clinical symptoms and signs of progressive arterial occlusion was reported in a confined area located along the southwestern coast of Taiwan. The disease was locally called "blackfoot disease" because of its gangrenous appearance involving the feet of the patients. The prevalence of this disease ranged from 6.51 to 18.85 per 1,000 population in different villages. Epidemiologic studies revealed that blackfoot disease was associated with the consumption of artesian well water containing high levels of arsenic. High co-occurrence of blackfoot disease and arsenic-related skin lesions such as hyperpigmentation, hyperkeratosis, and skin cancer was also observed. Recent studies also confirmed the association of preclinical peripheral vascular disease with arsenic exposure in a dose-response pattern. Subclinical arterial insufficiency and defects in cutaneous microcirculation can also be demonstrated in seemingly normal subjects living in the endemic villages. The incidence of clinical manifestation of blackfoot disease decreased dramatically after the implementation of tap water in these villages over the past 2-3 decades. The atherogenicity of arsenic could be associated with its effects on hypercoagulability, endothelial injury, smooth muscle cell proliferation, somatic mutation, oxidative stress, and apoptosis. However, its interaction with some trace elements and its association with hypertension and diabetes mellitus could also explain part of its higher risk of developing atherosclerosis.

Adult↗
PubMed2003

The nucleo-mitochondrial conflict in cytoplasmic male sterilities revisited.

Cytoplasmic male sterility (CMS) in plants is a classical example of genomic conflict, opposing maternally-inherited cytoplasmic genes (mitochondrial genes in most cases), which induce male sterility, and nuclear genes, which restore male fertility. In natural populations, this type of sex control leads to gynodioecy, that is, the co-occurrence of female and hermaphroditic individuals within a population. According to theoretical models, two conditions may maintain male sterility in a natural population: (1) female advantage (female plants are reproductively more successful than hermaphrodites on account of their global seed production); (2) the counter-selection of nuclear fertility restorers when the corresponding male-sterility-inducing cytoplasm is lacking. In this review, we re-examine the model of nuclear-mitochondrial conflict in the light of recent experimental results from naturally occurring CMS, alloplasmic CMS (appearing after interspecific crosses resulting from the association of nuclear and cytoplasmic genomes from different species), and CMS plants obtained in the laboratory and carrying mitochondrial mutations. We raise new hypotheses and discuss experimental models that would take physiological interactions between cytoplasmic and nuclear genomes into account.

DNA, Mitochondrial↗
PubMed2026

The Genomic Landscape of MYC-, MYCL-, and MYCN-Amplified Solid Tumors.

PURPOSE: MYC, MYCN, and MYCL amplifications are recurrent oncogenic events across solid tumors. Currently, no standardized selection biomarker is available to identify patients with MYC-dependent tumors. EXPERIMENTAL DESIGN: We analyzed copy-number alterations of MYC family genes and their features in more than 68,000 tumor-normal paired samples from pediatric and adult patients sequenced with MSK-IMPACT (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets) and annotated with FACETS (Fraction and Allele-Specific Copy Number Estimates from Tumor Sequencing). The relationship between amplification features and MYC mRNA expression levels were evaluated in more than 10,000 samples from The Cancer Genome Atlas (TCGA). RESULTS: Across MSK Cancer Center samples, MYC amplifications were most common, found in 2,949 samples compared with 310 in MYCL and 217 in MYCN. Although MYCN and MYCL amplifications were predominantly focal (<10 Mb, 79% and 93%, respectively), MYC amplifications were frequently broader (>10 Mb, 62%). Although most tumor types showed similar features between broad and focal amplifications of MYC, in select cancer types, we identified differing co-occurrence and mutual exclusivity patterns with other disease-specific drivers. Furthermore, although MYC-amplified TCGA samples showed higher mRNA expression than wild-type ones, the focality of MYC amplification was seen to have limited influence on expression levels. CONCLUSIONS: Our results suggest that MYC dependency likely depends on many factors, including, but not limited to, total copy number of the detected amplification, lineage-specific factors, concomitant presence or absence of additional oncogenic alterations, and in some cases amplification focality.

Humans↗
PubMed1998

An overview of the evolution of overproduced esterases in the mosquito Culex pipiens.

Insecticide resistance genes have developed in a wide variety of insects in response to heavy chemical application. Few of these examples of adaptation in response to rapid environmental change have been studied both at the population level and at the gene level. One of these is the evolution of the overproduced esterases that are involved in resistance to organophosphate insecticides in the mosquito Culex pipiens. At the gene level, two genetic mechanisms are involved in esterase overproduction, namely gene amplification and gene regulation. At the population level, the co-occurrence of the same amplified allele in distinct geographic areas is best explained by the importance of passive transportation at the worldwide scale. The long-term monitoring of a population of mosquitoes in southern France has enabled a detailed study to be made of the evolution of resistance genes on a local scale, and has shown that a resistance gene with a lower cost has replaced a former resistance allele with a higher cost.

Alleles↗
PubMed2004

Interleukin-10 and interleukin-6 gene polymorphisms as risk factors for Alzheimer's disease.

In the pathogenesis of Alzheimer disease (AD), it has been proposed that the anti-inflammatory interleukins such as IL-10 regulate beta-amyloid-induced microglial inflammatory responses inhibiting the proinflammatory cytokine IL-6. Since the promoters of the IL-10 and IL-6 genes show single nucleotide polymorphisms (SNPs) (IL-10: -1082 G --> A; IL-6: -174 G --> C), we investigated these SNPs and cytokine production by peripheral blood mononuclear cells in 65 AD patients and 65 controls (HC). In AD there was a significant increase of the -1082A IL-10 allele (P=0.009) and a decrease of -1082GG genotype (P=0.019). The frequency of the GG IL-6 genotype in AD was lower and the C allele significantly higher (P <0.005). The co-occurrence of IL-10 A and IL-6 C alleles significantly raised the odds ratio (OR 11.2, confidence interval: CI 1.3-97.3; P <0.05) independently of apolipoprotein E4 (adjusted OR 10.3, CI 1-108; P <0.05). Only amyloid-stimulated IL-10 production differed between the groups (P=0.023). These results raise questions regarding the inflammatory theory in AD, pointing to a pivotal role of IL-10 and IL-6 and a selective alteration in this network.

Aged↗
PubMed2001

Evolution and the molecular basis of somatic hypermutation of antigen receptor genes.

Somatic hypermutation of immunoglobulin genes occurs in many vertebrates including sharks, frogs, camels, humans and mice. Similarities among species reveal a common mechanism and these include the AGC/T sequence hot spot, preponderance of base substitutions, a bias towards transitions and strand bias. There are some differences among species, however, that may unveil layers of the mechanism. These include a G:C bias in frog and shark IgM but not in nurse shark antigen receptor (NAR), a high frequency of doublets in NAR hypermutation, and the co-occurrence of somatic hypermutation with gene conversion in some species. Here we argue that some of the similarities and differences among species are best explained by error-prone DNA synthesis by the translesion synthesis DNA polymerase zeta (Pol zeta) and, as suggested by others, induction of DNA synthesis by DNA breaks in antigen receptor variable genes. Finally, targeting of the variable genes is probably obtained via transcription-related elements, and it is the targeting phase of somatic hypermutation that is the most likely to reveal molecules unique to adaptive immunity.

Animals↗
PubMed2003

Genomic scan of 254 hereditary prostate cancer families.

Hereditary prostate cancer (HPC) is a genetically heterogeneous disease, complicating efforts to map and clone susceptibility loci. We have used stratification of a large dataset of 254 HPC families in an effort to improve power to detect HPC loci and to understand what types of family features may improve locus identification. The strongest result is that of a dominant locus at 6p22.3 (heterogeneity LOD (HLOD) = 2.51), the evidence for which is increased by consideration of the age of PC onset (HLOD = 3.43 in 214 families with median age-of-onset 56-72 years) and co-occurrence of primary brain cancer (HLOD = 2.34 in 21 families) in the families. Additional regions for which we observe modest evidence for linkage include chromosome 7q and 17p. Only weak evidence of several previously implicated HPC regions is detected. These analyses support the existence of multiple HPC loci, whose presence may be best identified by analyses of large, including pooled, datasets which consider locus heterogeneity.

Aged↗
PubMed2026

Hereditary Diffuse Gastric Cancer With Poorly Differentiated Gallbladder Adenocarcinoma: A Case Report Suggesting Carcinogenesis in the Stomach and Gallbladder Caused by a Pathogenic Germline Variant in CDH1.

BACKGROUND/AIM: Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome primarily characterized by a high lifetime risk of diffuse gastric cancer and lobular breast cancer. It is predominantly caused by inactivating germline variants in the tumor suppressor gene CDH1. While the association between HDGC and these two specific malignancies is well-established, the co-occurrence of extra-gastric malignancies in other organs remains exceptionally rare. In particular, the clinical and genetic relationship between HDGC and gallbladder adenocarcinoma has not been previously clarified. CASE REPORT: We present the case of a 67-year-old female initially referred for surgical management of gallbladder cancer (GBC) following an initial cholecystectomy for progressive wall thickening. Pathological examination of the gallbladder revealed a de novo, poorly differentiated adenocarcinoma invading the subserosal layer with reduced E-cadherin expression. Given the atypical histopathology and a significant family history-her father and brother both died of gastric cancer at young ages-a preoperative gastric endoscopy was performed. The endoscopy identified multiple faded mucosal lesions, which biopsy confirmed as signet-ring cell carcinoma. The patient subsequently underwent total gastrectomy and gallbladder bed resection. Postoperative pathology identified 22 distinct malignant gastric lesions, predominantly signet-ring cell carcinoma (pT1a), showing variable or lost E-cadherin expression. Germline genetic testing via direct sequencing identified a pathogenic frameshift mutation in exon 5 of the CDH1 gene. CONCLUSION: This represents the first reported case of synchronous HDGC and primary gallbladder adenocarcinoma associated with a germline CDH1 mutation. Our findings suggest that pathogenic CDH1 variants may contribute to the carcinogenesis of poorly differentiated gallbladder adenocarcinoma. Clinicians should consider the possibility of extra-gastric malignancies in HDGC patients.

Humans↗
PubMed2000

A first molecular approach towards CGG repeat expansion in FMR1 gene in systemic lupus erythematosus and in Sjögren's syndrome: a preliminary report.

Co-occurrent autoimmune disease and fragile X syndrome has been reported in the literature and we have therefore studied the expansion of Cytosine-Guanine-Guanine (CGG) repeat in FMR1 gene in a series of females with autoimmune diseases such as systemic lupus erythematosus and Sjögren's syndrome, with PCR and Southern blot methods. The average length of trinucleotide repeat was not increased in these female patients as compared with controls. These preliminary data on a short series of patients suggest a possible absence of trinucleotide repeat expansion abnormality associated with autoimmune diseases such as systemic lupus erythematosus and Sjögren's syndrome.

Adult↗
PubMed1999

UDP-glucuronosyltransferase (UGT1A1*28 and UGT1A6*2) polymorphisms in Caucasians and Asians: relationships to serum bilirubin concentrations.

Polymorphisms that alter UDP-glucuronosyltransferase (UGT) activities have been identified. Mutations in the promoter of the UGT1A1 gene (UGT1A1*28), resulting in 5, 7 or 8, instead of 6 thymine-adenine (TA) repeats, alter bilirubin conjugation. Two missense mutations on one allele of UGT1A6 (UGT1A6*2) result in T181A and R184S amino acid substitutions and reduced activity against phenolics, such as 4-nitrophenol, 4-hydroxycoumarin and butylated hydroxy anisole. We determined the frequency of these polymorphisms in 245 healthy men and women, aged 20-40 years and examined the relationship between TA repeat number and serum bilirubin concentrations in a subset of 24 Asians and 169 Caucasians. The frequencies of the UGT1A1*28 genotypes were 0.537, 0.348, 0.098, 0.008 and 0.008 for promoter TA repeats 6/6, 6/7, 7/7, 5/6 and 6/8, respectively. Both allele and genotype frequencies varied by race (P < 0.02), with 11% of the Caucasians and none of the Asians having the 7/7 genotype. Within both ethnic groups, serum bilirubin increased with increased numbers of UGT1A1 promoter TA repeats (P = 0.0001). However, a strong ethnic group-by-UGT1A1 genotype interaction suggests that additional ethnic differences in bilirubin metabolism contribute to observed bilirubin concentrations. Genotype frequencies for UGT1A6*2 were 0.478, 0.392, 0.029, 0.090, 0.012 for wild-type (wt)/wt, wt/T181A + R184S, wt/R184S, T181A + R184S/T181A + R184S and T181A + R184S/R184S, respectively. The co-occurrence of polymorphisms in UGT1A1 and UGT1A6 differed from that expected (P < 0.0001): individuals homozygous wild-type for UGT1A1 and UGT1A6 were observed at twice the expected frequency; individuals homozygous variant for both genes were ten-fold more frequent and individuals homozygous wild-type for one gene and homozygous variant for the other were ten-fold less frequent than expected. Overall, 8% were homozygous variant for both UGT1 polymorphisms and 43% had at least one variant allele for both UGT1A1*28 and UGT1A6*2. These highly prevalent polymorphisms, which result in modified expression and activity of UGTs, may influence susceptibility to cancers associated with altered metabolism of endogenous and xenobiotic compounds.

Asian People↗
PubMed2025

Molecular analysis of lung adenocarcinomas from the SAFIR02-Lung cohort reveals new metastasis-associated copy-number alterations including frequent mutant-specific KRAS-allelic imbalance and identifies CDKN2A homozygous deletions as an independent biomarker of poor prognosis.

BACKGROUND: Identifying molecular alterations specific to advanced lung adenocarcinomas could provide insights into tumour progression and dissemination mechanisms. METHOD: We analysed tumour samples, either from locoregional lesions or distant metastases, from patients with advanced lung adenocarcinoma from the SAFIR02-Lung trial by targeted sequencing of 45 cancer genes and comparative genomic hybridisation array and compared them to early tumours samples from The Cancer Genome Atlas. RESULTS: Differences in copy-number alterations frequencies suggest the involvement in tumour progression of LAMB3, TNN/KIAA0040/TNR, KRAS, DAB2, MYC, EPHA3 and VIPR2, and in metastatic dissemination of AREG, ZNF503, PAX8, MMP13, JAM3, and MTURN. Conversely, no meaningful difference was found in pathogenic single-nucleotide variant frequencies, reinforcing the notion that they are early events in tumorigenesis. CDKN2A homozygous deletion was linked to poor clinical outcome in patients with early tumours (overall survival hazard ratio 2.17, 95% CI: 1.43-3.28, corrected p-value&#x2009;=&#x2009;0.01). Furthermore, we found that KRAS mutant allele specific imbalance, i.e. focal amplification of the mutant allele, is more prevalent in locoregional or distant samples of metastatic patients than in early lesions (8.4%, 13% and 2.8% respectively). This observation was replicated in three public cohorts. Tumours with KRAS mutant allele specific imbalance show specific patterns of co-occurrence and mutual exclusion with alterations in key cancer genes like CDKN2A, TP53, STK11 and NKX2-1, often in a tumour type dependent manner. CONCLUSION: Advanced LUAD tumours exhibit higher copy-number alteration burden, with distinct alterations associated with tumour progression and metastasis. CDKN2A homozygous deletions predict poor prognosis in early disease, while KRAS mutant allele-specific imbalance is enriched in advanced tumours.

Humans↗
PubMed2001

Hypothesis. Bystanders or bad seeds? Many autoimmune-target cells may be transforming to cancer and signalling "danger" to the immune system.

Autoimmune-target cells in autoimmune disease (AID) are usually construed as constitutionally normal healthy cells. A related assumption is that other cells in the body of AID patients, except for certain immunocytes, are healthy cells. An implication of that view is that any systemic pathology in organ-specific AID is related to metabolic derangements secondary to tissue destruction. However, much data on target and other cells in AID suggest widespread primary cellular defects. In insulin-dependent diabetes mellitus (IDDM), for example, many "complications" such as atherosclerosis, premature arterial stiffening, senescence of fibroblasts in vitro, and exuberant growth of smooth muscle and mesangial cells in vivo are not strictly attributable to glucose elevation. Also unexplained is the similar appearance of IDDM beta-cells and cells from insulinoma and why the prodromal phase of IDDM has many insulinoma-like features. While AID target cells have often been likened to neoplastic cells, investigators have rarely explored the possibility that autoimmunity in AID is fundamentally antineoplastic. This is likely because the dominant ideas in oncology and immunology-somatic mutation and clonal deletion, respectively-have prevented explanations for how normal immunity could detect transforming cells not expressing non-self antigens. New and less conventional theories of cancer and immunity have facilitated such an explanation. I use Rubin's "epigenetic" aging model of carcinogenesis and Matzinger's "danger" model of immunity to integrate the immunological and oncological sides of AID. In particular, I postulate that individuals suffering from AID have inherited many foci of prematurely aging cells. Those inherently damaged cells adapt to in vivo challenges by beginning to transform into cancer cells. However, as long as those stressed cells have not fully transformed, they will continue to signal "danger" to the innate immune system. The clinical outcome of that struggle between incipient neoplasia and immunity will vary depending upon the degree of tumor-proneness and resistance of the individual. Borrowing from cancer geneticist Henry Lynch, I postulate that tumor-resistance is inherited as a quantitative polygenic trait in direct proportion to tumor-proneness. I further contend that tumor-proneness and immunity are linked polygenic traits such that the greater one's tumor-proneness, the more powerful his/her antitumor immunity. I point to the shared DNA repair deficiency of certain cancer-prone syndromes and HLA-linked AID, their occasional co-occurrence, and their demonstrably exceptional immunity against solid tumors. I propose that HLA-linked AID constitute "chronic hypersensitivity syndromes" due to immunity's largely hidden battle to suppress multiple incipient neoplastic microfoci. Much of the physiopathology of AID is explicable as a sustained systemic response to threatened neoplastic transformation.

Animals↗
PubMed2000

Co-occurrence of autosomal dominant polycystic kidney disease and Marfan syndrome in a kindred.

Several reports exist of the co-occurrence of autosomal dominant polycystic kidney disease (ADPKD) and Marfan syndrome, including a report of ADPKD and "overlap" connective tissue disorder in a family with linkage to the PKD1 locus. We report the results of clinical and linkage investigations of an ADPKD family in whom several affected subjects also had aortic vascular complications as well as features of Marfan syndrome. Detailed clinical assessment and linkage analysis were performed with polymorphic microsatellite markers closely linked to the PKD1 and FBN1 loci. Survival data were compared with 10 geographically matched PKD1 families. Although several subjects had features of both ADPKD and Marfan syndrome, detailed clinical examination of the extended family indicated that the two conditions had converged within the kindred. For those with ADPKD, linkage was established to the PKD1 locus (lod score, 6.04). Among those with features of Marfan syndrome, linkage was confirmed to the FBN1 locus (lod score, 1.87). Five of six subjects with both ADPKD and the high-risk FBN1 haplotype had associated vascular complications. In contrast, among the remaining nine individuals with PKD1 alone, seven had aortic assessments, and none were found to have aortic complications. Our experience suggests that when prominent features of connective tissue disease or vascular complications are found in ADPKD patients, alternative additional diagnoses should be considered, including the possibility of a coinherited FBN1 mutation responsible for Marfan syndrome or, alternatively, an associated milder FBN1 phenotype in the absence of sufficient other clinical features to allow Marfan syndrome to be diagnosed.

Adult↗