Search PubMed⌕ Search

Biomedical subjects

C L Shovlin

Publications and source records attributed to C L Shovlin.

At least 19 recordsLinked to original sources
PubMed2005

A new locus for hereditary haemorrhagic telangiectasia (HHT3) maps to chromosome 5.

Patients with hereditary haemorrhagic telangiectasia (HHT, or Osler-Weber-Rendu syndrome) have variable presentation patterns and a high risk of preventable complications. Diagnostic tests for mutations in endoglin (HHT type 1) and ALK-1 (HHT type 2) are available. Some HHT patients are now known to have HHT-juvenile polyposis overlap syndrome due to Smad4 mutations. Families were ascertained following the presentation of probands for embolization of pulmonary arteriovenous malformations. Genome-wide linkage studies using over 700 polymorphic markers, and sequencing of candidate genes, were performed. In a previously described HHT family unlinked to endoglin or ALK-1, linkage to Smad4 was excluded, and no mutations were identified in the endoglin, ALK-1, or Smad4 genes. Two point LOD scores and recombination mapping identified a 5.4 cM HHT3 disease gene interval on chromosome 5 in which a single haplotype was inherited by all affected members of the pedigree. The remainder of the genome was excluded to a 2-5 cM resolution. We are currently studying a further family potentially linked to HHT3. We conclude that classical HHT with pulmonary involvement can result from mutations in an unidentified gene on chromosome 5. Identification of HHT3 should further illuminate HHT pathogenic mechanisms in which aberrant transforming growth factor (TGF)-beta signalling is implicated.

Chromosome Mapping↗
PubMed2003

Should asymptomatic patients with hereditary haemorrhagic telangiectasia (HHT) be screened for cerebral vascular malformations? Data from 22,061 years of HHT patient life.

BACKGROUND: The frequency of haemorrhage in individuals with hereditary haemorrhagic telangiectasia (HHT), 10% of whom will have cerebral arteriovenous (AV) malformations, could be high enough to justify screening. This would allow presymptomatic treatment to prevent early onset stroke in a condition that affects at least 1 in 8000 individuals. This is an important issue in view of the contrast between transatlantic management approaches, the worldwide dissemination of patient information, and the ethical implications of the diagnosis for the untreated patient. OBJECTIVES: To define the annual incidence of haemorrhagic stroke in individuals with HHT. METHODS: Retrospective study on stroke incidence in individuals with HHT and their immediate families (n = 674; 22,061 HHT patient years), specifically analysing patients under 46 years of age (17,515 patient years). The results were compared with stroke risk in the general population. RESULTS: In the majority of cases, the haemorrhage was the first significant neurological event. Overcorrecting for any bias towards overestimation that would be introduced in excluding non-penetrant family members, cerebral haemorrhages were more than 20 times more common in male HHT subjects under the age of 45 years than in the general population (standardised ratio 22.99; 95% confidence interval, 13.14 to 37.33). Haemorrhages were also six times more common in female HHT subjects (6.18; 2.27 to 13.45). The incidence ratio of cerebral haemorrhage in male patients (1.84; 1.05 to 2.99) yielded a haemorrhage rate in individuals with cerebral AV malformations of 1.4-2.0% per annum, comparable to figures in the non-HHT cerebral AV malformation population. CONCLUSIONS: These data contradict accepted wisdom in many countries that asymptomatic HHT patients are at a low (and acceptable) risk of haemorrhage. The data justify a more aggressive screening approach to identify small causative lesions amenable to treatment.

Adult↗
PubMed2003

Hereditary haemorrhagic telangiectasia (Osler-Weber-Rendu syndrome): a view from the 21st century.

Hereditary haemorrhagic telangiectasia (HHT) affects one in 5-8000, and no longer can be viewed as solely causing anaemia (due to nasal and gastrointestinal bleeding) and characteristic mucocutaneous telangiectasia. Arteriovenous malformations commonly occur, and in the pulmonary and cerebral circulations demand knowledge of risks and benefits of asymptomatic screening and treatment. HHT is inherited as an autosomal dominant trait and there is no age cut off when apparently unaffected offspring of an individual with HHT can be told they are unaffected. This review focuses on the evolving evidence base for HHT management, issues regarding pregnancy and prothrombotic treatments, and discusses the molecular and cellular changes that underlie this disease.

Arteriovenous Malformations↗
PubMed2002

Pulmonary arteriovenous malformations: effect of embolization on right-to-left shunt, hypoxemia, and exercise tolerance in 66 patients.

OBJECTIVE: This study assessed the effect and safety of percutaneous transcatheter coil embolization of pulmonary arteriovenous malformations. MATERIALS AND METHODS: In 58 (88%) of 66 patients, all malformations with feeding vessels greater than or equal to 3 mm in diameter were embolized with steel coils. Arterial oxygen saturation at rest and exercise, intrapulmonary right-to-left anatomic shunt fraction ((99m)Tc-macroaggregate injection), maximum exercise capacity (incremental work rate test), and pulmonary function were measured before and after embolization. Complications were analyzed. RESULTS: Three categories of patients were identified. Patients in group 1 (27%) had complete occlusion of all angiographically visible pulmonary arteriovenous malformations; patients in group 2 (61%) had complete occlusion of all malformations with feeding vessels greater than or equal to 3 mm in diameter, but with smaller lesions persisting; and patients in group 3 (12%) had incomplete embolization, with feeding vessels greater than or equal to 3 mm in diameter remaining. The mean right-to-left shunt after embolization was least in group 1 (7%), intermediate in group 2 (10%), and greatest in group 3 (19%). Arterial oxygen saturation and right-to-left shunt fraction returned to normal levels (>96% and <3.5%, respectively) in 33% of patients. A significant improvement occurred after embolization in carbon monoxide diffusing capacity per unit of alveolar volume and in exercise capacity in 16 and 10 patients, respectively. In 93 procedures, 12 complications (13%) occurred. CONCLUSION: Coil embolization of pulmonary arteriovenous malformations is effective in reducing right-to-left anatomic shunt fraction and in improving arterial oxygenation. Coil embolization of pulmonary arteriovenous malformations is well tolerated and has a low complication rate.

Adolescent↗
PubMed2001

Alveolar macrophage activity and the pulmonary complications of haematopoietic stem cell transplantation.

BACKGROUND: The success of haematopoietic (bone marrow or peripheral blood) stem cell transplantation (SCT) is compromised by pulmonary complications. We hypothesised that a proinflammatory alveolar microenvironment, reflected in alveolar macrophage (AM) cytokine production, would predispose to such complications. METHODS: AM were isolated from adult SCT recipients by bronchoalveolar lavage before SCT (n=32) and during post-transplant pancytopenia (n=23). Concentrations of tumour necrosis factor (TNF)alpha, granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin (IL)-1 beta, IL-6, and IL-8 in 24 hour AM culture medium were measured by enzyme linked immunosorbent assay and compared with both the occurrence of post-SCT lung disease and with subjects' previous respiratory histories. RESULTS: Eleven subjects developed lung disease within 6 months of SCT. These subjects had higher median pre-transplant AM TNFalpha (8 (IQR 1-8) v 2 (1-5) ng/10(6)AM, p=0.01, median difference (D) = 3, 95% CI 0.1 to 7), GM-CSF (5 (0.7-8) v 0.2 (0.1-0.8), p=0.006, D = 4, 95% CI 0.5 to 7), and IL-6 (0.5 (0.1-1) v 0.1 (0.02-0.3), p=0.049, D = 0.3, 95% CI 0.0002 to 1) production than remaining subjects; IL-1 beta and IL-8 did not differ. During pancytopenia high AM GM-CSF production again predicted later lung disease (1 (0.7-9) v 0.1 (0.06-0.3), p=0.01, D = 1, 95% CI 0.1 to 6). A history of recent chest disease was associated with high AM TNFalpha and GM-CSF production and with post-SCT lung disease. Pre-SCT lung function was unrelated to post-SCT lung disease. CONCLUSIONS: Recent respiratory disease and persistent proinflammatory AM behaviour detectable before transplantation are associated with lung disease following SCT. These associations may prove useful in pre-transplant risk assessment.

Adolescent↗
PubMed2000

Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome).

Hereditary Hemorrhagic Telangiectasia (HHT) is easily recognized in individuals displaying the classical triad of epistaxis, telangiectasia, and a suitable family history, but the disease is more difficult to diagnosis in many patients. Serious consequences may result if visceral arteriovenous malformations, particularly in the pulmonary circulation, are unrecognized and left untreated. In spite of the identification of two of the disease-causing genes (endoglin and ALK-1), only a clinical diagnosis of HHT can be provided for the majority of individuals. On behalf of the Scientific Advisory Board of the HHT Foundation International, Inc., we present consensus clinical diagnostic criteria. The four criteria (epistaxes, telangiectasia, visceral lesions and an appropriate family history) are carefully delineated. The HHT diagnosis is definite if three criteria are present. A diagnosis of HHT cannot be established in patients with only two criteria, but should be recorded as possible or suspected to maintain a high index of clinical suspicion. If fewer than two criteria are present, HHT is unlikely, although children of affected individuals should be considered at risk in view of age-related penetration in this disorder. These criteria may be refined as molecular diagnostic tests become available in the next few years.

Humans↗
PubMed2000

A hereditary haemorrhagic telangiectasia family with pulmonary involvement is unlinked to the known HHT genes, endoglin and ALK-1.

BACKGROUND: Pulmonary arteriovenous malformations (PAVMs) occur in over 25% of patients with the autosomal dominant disorder hereditary haemorrhagic telangiectasia (HHT). Mutations in two genes, endoglin and ALK-1, are known to cause HHT. Each encodes a protein expressed on vascular endothelial cells and involved in signalling by members of the transforming growth factor (TGF)-beta superfamily. To date, PAVMs have not been detected in ALK-1 families. There is evidence from a single HHT family without pulmonary involvement that a third HHT gene may exist. To establish the existence of a further HHT gene responsible for PAVMs, linkage analyses were performed on an expanded PAVM-HHT family in which HHT did not result from endoglin mutations. METHODS: Family members were assessed clinically to assign HHT disease status and were screened for PAVMs. DNA was extracted from blood obtained from 20 individuals of known disease status. Short tandem repeat polymorphic markers spanning the intervals containing the endoglin and ALK-1 genes were amplified by the polymerase chain reaction using (33)P-labelled oligonucleotide primers, separated by denaturing polyacrylamide gel electrophoresis (PAGE), and the resultant autoradiographs were examined for allele sizes. Linkage analyses were performed using MLINK and GENEHUNTER. RESULTS: Twelve members spanning four generations were affected with HHT. Two had proven PAVMs, one with a classical appearance, the other exhibiting microscopic PAVMs exacerbated by pregnancy. Two point lod and multipoint lod scores significantly excluded linkage to endoglin and ALK-1 in this pedigree. CONCLUSIONS: This study confirms the existence of a third HHT locus that accounts for disease in some HHT patients with pulmonary involvement.

Activin Receptors↗
PubMed1998

Glaxo/MRS Young Investigator Medal. Molecular studies on adenosine deaminase deficiency and hereditary haemorrhagic telangiectasia.

1. This manuscript describes two different strategies to progress from the clinical assessment of patients to the identification of disease-causing mutations. In the first disease, recognition of a metabolic abnormality allowed direct molecular analysis of the causal gene. In contrast, localization of the second disease gene by linkage analysis was critical to implicate a gene with a previously unsuspected disease role. 2. Two sisters with chronic respiratory disease and recurrent infections were identified as the first cases of adult onset immunodeficiency due to adenosine deaminase deficiency. Autosomal recessive inheritance of two mutations in the adenosine deaminase gene was demonstrated. Enzyme replacement therapy improved the patients' immunological and clinical status. 3. Individuals with pulmonary arteriovenous malformations were used to identify families with hereditary haemorrhagic telangiectasia (HHT, Rendu-Osler-Weber Syndrome). Linkage studies mapped the HHT disease gene in some families to chromosome 9, and demonstrated genetic heterogeneity. The chromosome 9 disease interval was refined, and several candidate genes were assessed. Following the first description of disease-segregating mutations, a complete analysis of the endoglin gene (which encodes an endothelial cell transforming growth factor-beta receptor) identified seven novel mutations. Two mutations did not produce mutant mRNA, and disease severity was comparable between families, indicating that HHT results from stoichiometric insufficiency of endoglin. 4. Each study has implications extending beyond the relatively rare disease analysed. The adenosine-deaminase-deficient patients highlight a treatable cause of HIV-negative CD4+ lymphopenia in adults, perhaps accounting for further cases of 'non-HIV AIDS'. The HHT studies have illuminated a novel area of vascular pathophysiology, with potential relevance to further disease states.

Adenosine Deaminase↗
PubMed1997

Characterization of endoglin and identification of novel mutations in hereditary hemorrhagic telangiectasia.

To identify mutations that cause hereditary hemorrhagic telangiectasia (HHT, or Rendu-Osler-Weber syndrome), clinical evaluations and genetic studies were performed on 32 families. Linkage studies in four of eight families indicated an endoglin (ENG) gene mutation. ENG sequences of affected members of the four linked families and probands from the 24 small families were screened for mutations, by Southern blot analyses and by cycle sequencing of PCR-amplified DNA. Seven novel mutations were identified in eight families. Two mutations (a termination codon in exon 4 and a large genomic deletion extending 3' of intron 8) did not produce a stable ENG transcript in lymphocytes. Five other mutations (two donor splice-site mutations and three deletions) produce altered mRNAs that are predicted to encode markedly truncated ENG proteins. Mutations in other families are predicted to lie in ENG-regulatory regions or in one of the additional genes that may cause HHT. These data suggest that the molecular mechanism by which ENG mutations cause HHT is haploinsufficiency. Furthermore, because the clinical manifestation of disease in these eight families was similar, we hypothesize that phenotypic variation of HHT is not related to a particular ENG mutation.

Adult↗
PubMed1997

Molecular defects in rare bleeding disorders: hereditary haemorrhagic telangiectasia.

Vascular diseases may mimic coagulopathies by presenting as a haemorrhagic state. The archetypal example of an inherited disorder resulting in haemorrhage from dilated vessels of the microvasculature (telangiectasia) is Hereditary Haemorrhagic Telangiectasia (HHT, Rendu-Osler-Weber syndrome). This autosomal dominant disorder is characterised by haemorrhage from nasal, mucocutaneous and gastrointestinal telangiectasia, in addition to vascular anomalies in other organs, particularly in the pulmonary, hepatic and cerebral circulations. Linkage analyses have indicated there are at least three HHT loci, including the genes for endoglin on chromosome 9, and activin-like receptor kinase (ALK1) on chromosome 12. Mutations in these genes, together with recent data on the normal function of the encoded proteins highlight the role of TGF-b family members in the pathogenesis of HHT. Complimentary information from other telangiectatic states indicates potential precipitants, and indicate a critical role for TGF-beta ligand-receptor interactions in vascular homeostasis.

Activin Receptors↗
PubMed1996

Genetic analysis of susceptibility to experimental autoimmune encephalomyelitis in a cross between SJL/J and B10.S mice.

Experimental autoimmune encephalomyelitis (EAE), a model for human multiple sclerosis, is a T cell-mediated autoimmune disease that can be induced in experimental animals by immunization with myelin Ags. Inbred strains of mice show varying degrees of susceptibility to EAE, indicating that susceptibility is an inherited trait. To define the genetic factors that control susceptibility to EAE, we performed linkage analysis on the first backcross (BC1) between highly susceptible SJL/J mice and resistant B10.S mice, both of which are of the H-2s haplotype. Mice were immunized for disease with encephalitogenic myelin proteolipid protein peptide 139 to 151, and analysis was performed on 68 backcross mice showing the severe disease phenotype (disease score > or = 3)and 68 backcross mice of the resistant phenotype (no clinical or histologic signs of disease) using microsatellite markers covering >98% of the genome. We found the strongest linkage (p = 0.001) with clinical disease at two loci: one at the telomeric end of chromosome 2, and another near the center of chromosome 3. In addition, several other regions showing some evidence of linkage (p < or = 0.05) with clinical disease were found.

Animals↗
PubMed1996

Inherited diseases of the vasculature.

This review focuses on a spectrum of inherited disorders in which recent genetic advances have made a significant contribution to our understanding of vascular pathology and homeostasis. They are discussed according to the type of blood vessel affected and the compounded physiological processes that include angiogenesis, vascular development, and defects in the structure and regulation of the mature vessel. Vascular malformations, arterial aneurysms and dissection, telangiectasia, infiltrative vascular disease, and inherited tumors and disorders of neovascularization are discussed in a variety of settings. Disease roles for endoglin, tissue inhibitor of metalloproteinases 3 (TIMP3), and vascular endothelial growth factor (VEGF) dysregulation are highlighted (175 references).

Animals↗
PubMed1995

Medical complications of pregnancy in hereditary haemorrhagic telangiectasia.

Hereditary haemorrhagic telangiectasia (HHT) displays significant variation in severity between affected individuals in the same family, ranging from relatively trivial epistaxis and telangiectasia to gastrointestinal, cerebral and pulmonary involvement. Evidence for successful therapy of HHT-related haemorrhage with oestrogens and progesterones, and recent case reports outlining pulmonary complications of pregnancy in HHT, prompted us to review the outcome of 161 pregnancies in 47 affected women. HHT-related maternal complications developed in eleven patients, ten in the subgroup of 23 pregnancies in which pulmonary arteriovenous malformations (PAVMs) were present at the outset, or documented in the two years following pregnancy. We present six cases of intrapulmonary shunt deterioration, two cases of fatal pulmonary haemorrhage and three cerebrovascular accidents related to pregnancy. A predisposition towards PAVMs in females was observed. Following the recent discovery of mutations in the endoglin gene in this disease, our data support a hypothesis of hormonal modification of the HHT phenotype. In addition, a significant excess of affected offspring are present in HHT families. We consider contributary aetiological factors, and discuss implications for patient management.

Abortion, Spontaneous↗