Anne Paepe - Academia.edu (original) (raw)

Papers by Anne Paepe

Clinical Dysmorphology, 2010

We report a 10-year-old male proband, born from consanguineous marriage, presenting with short st... more We report a 10-year-old male proband, born from consanguineous marriage, presenting with short stature, severe aortic root dilation, skin hyperextensibility, extreme joint laxity and craniofacial dysmorphism. Clinical, biochemical and molecular findings did not match any of the well-described connective tissue syndromes in the differential diagnosis for this specific combination of features. We presume that the phenotype presented in this patient may constitute a newly recognized syndrome of likely autosomal recessive inheritance.

International Journal of Cardiology, 2012

Background: Aortic root dilation, dissection and rupture are major clinical problems in Marfan sy... more Background: Aortic root dilation, dissection and rupture are major clinical problems in Marfan syndrome (MFS). Although β-blockers remain the standard of preventive treatment, preliminary results from animal studies and a selected group of severely affected MFS children show significant benefit from treatment with losartan, an angiotensin II receptor blocker with TGF-β inhibiting potential. Large-scale human trials are now needed to confirm these results. This trial aims to evaluate the combined effect of both drugs. Methods: We are conducting a prospective randomized placebo controlled double blind phase III study aiming to include 174 MFS patients (age ≥ 10 years and z-score ≥ 2). Patients already taking β-blockers are randomized for weight-adjusted treatment with losartan versus placebo. The primary endpoint is decrease in aortic root growth rate. Secondary endpoints are aortic dissection/surgery, progression of aortic/mitral regurgitation, arterial stiffness, left ventricular systolic/diastolic function, quality of life and genetic modifiers. Echocardiography, vascular echo-Doppler and quality of life assessment will be performed at baseline and at 6-monthly follow-ups for 3 years. MRI evaluation will be performed at baseline and at the end of the trial. Conclusion: This trial will study new therapeutic strategies for the prevention of serious cardiovascular complications in MFS. The uniqueness in our trial is that the additive effect of losartan and β-blocker will be evaluated in a large spectrum of disease severity. A combination of ultrasound and MRI will allow detailed evaluation of anatomic and functional properties of the aorta and left ventricle.

European Journal of Human Genetics, 2008

Journal of Investigative Dermatology, 2004

Ehlers-Danlos syndrome (EDS) type VIIC, or dermatosparactic type, is a recessively inherited conn... more Ehlers-Danlos syndrome (EDS) type VIIC, or dermatosparactic type, is a recessively inherited connective tissue disorder characterized, among other symptoms, by an extreme skin fragility resulting from mutations inactivating ADAMTS-2, an enzyme excising the aminopropeptide of procollagens type I, II, and III. All previously described mutations create premature stop codons leading to a marked reduction in the level of mRNA. In this study, we analyzed the ADAMTS2 cDNA sequences from five patients displaying clinical and/or biochemical features consistent with a diagnosis of either typical or potentially mild form of EDS type VIIC. Three different alterations were detected in the two patients with typical EDS type VIIC. The first patient was homozygous for a genomic deletion causing an in-frame skipping of exons 3-5 in the transcript. In the second patient, the allele inherited from the mother lacks exon 3, generating a premature stop codon, whereas the paternal allele has a genomic deletion resulting in an in-frame skipping of exons 14-16 at the mRNA level. Although the exons 3-5 or 14-16 encode protein domains that have not been previously recognized as crucial for ADAMTS-2 activity, the aminoprocollagen processing was strongly impaired in vitro and in vivo, providing evidence for the requirement of these domains for proper enzyme function. The three other patients with a phenotype with some resemblance to EDS type VIIC only had silent and functionally neutral variations also frequently found in a normal population.

Journal of medical …, 2010

The diagnosis of Marfan syndrome (MFS) relies on defined clinical criteria (Ghent nosology), outl... more The diagnosis of Marfan syndrome (MFS) relies on defined clinical criteria (Ghent nosology), outlined by international expert opinion to facilitate accurate recognition of this genetic aneurysm syndrome and to improve patient management and counselling. These Ghent criteria, comprising a set of major and minor manifestations in different body systems, have proven to work well since with improving molecular techniques, confirmation of the diagnosis is possible in over 95% of patients. However, concerns with the current nosology are that some of the diagnostic criteria have not been sufficiently validated, are not applicable in children or necessitate expensive and specialised investigations. The recognition of variable clinical expression and the recently extended differential diagnosis further confound accurate diagnostic decision making. Moreover, the diagnosis of MFSdwhether or not established correctlydcan be stigmatising, hamper career aspirations, restrict life insurance opportunities, and cause psychosocial burden. An international expert panel has established a revised Ghent nosology, which puts more weight on the cardiovascular manifestations and in which aortic root aneurysm and ectopia lentis are the cardinal clinical features. In the absence of any family history, the presence of these two manifestations is sufficient for the unequivocal diagnosis of MFS. In absence of either of these two, the presence of a bonafide FBN1 mutation or a combination of systemic manifestations is required. For the latter a new scoring system has been designed. In this revised nosology, FBN1 testing, although not mandatory, has greater weight in the diagnostic assessment. Special considerations are given to the diagnosis of MFS in children and alternative diagnoses in adults. We anticipate that these new guidelines may delay a definitive diagnosis of MFS but will decrease the risk of premature or misdiagnosis and facilitate worldwide discussion of risk and follow-up/management guidelines.

American Journal of Medical Genetics Part A, 2008

We report on a 3-year-old child who presented a de novo rearrangement of chromosome 4, detected o... more We report on a 3-year-old child who presented a de novo rearrangement of chromosome 4, detected on GTG banding and characterized by array CGH and FISH, as a complex intrachromosomal rearrangement with three deletions: del(q32.1q32.2), del(q33q34.1), del(q35.2), one tandem duplication dup(q34.3q35.1) and short normal regions in between. The study of karyotype-phenotype correlations in this and other patients with deletions of 4q suggests 4q33q34.1 as a candidate region for 4q-syndrome and for craniofacial development.

Journal of medical genetics, 2000

International Journal of Cardiology, 2012

Background: Aortic root dilation, dissection and rupture are major clinical problems in Marfan sy... more Background: Aortic root dilation, dissection and rupture are major clinical problems in Marfan syndrome (MFS). Although β-blockers remain the standard of preventive treatment, preliminary results from animal studies and a selected group of severely affected MFS children show significant benefit from treatment with losartan, an angiotensin II receptor blocker with TGF-β inhibiting potential. Large-scale human trials are now needed to confirm these results. This trial aims to evaluate the combined effect of both drugs. Methods: We are conducting a prospective randomized placebo controlled double blind phase III study aiming to include 174 MFS patients (age ≥ 10 years and z-score ≥ 2). Patients already taking β-blockers are randomized for weight-adjusted treatment with losartan versus placebo. The primary endpoint is decrease in aortic root growth rate. Secondary endpoints are aortic dissection/surgery, progression of aortic/mitral regurgitation, arterial stiffness, left ventricular systolic/diastolic function, quality of life and genetic modifiers. Echocardiography, vascular echo-Doppler and quality of life assessment will be performed at baseline and at 6-monthly follow-ups for 3 years. MRI evaluation will be performed at baseline and at the end of the trial. Conclusion: This trial will study new therapeutic strategies for the prevention of serious cardiovascular complications in MFS. The uniqueness in our trial is that the additive effect of losartan and β-blocker will be evaluated in a large spectrum of disease severity. A combination of ultrasound and MRI will allow detailed evaluation of anatomic and functional properties of the aorta and left ventricle.

The American Journal of Human Genetics, 2007

Mutations in the fibrillin-1 (FBN1) gene cause Marfan syndrome (MFS) and have been associated wit... more Mutations in the fibrillin-1 (FBN1) gene cause Marfan syndrome (MFS) and have been associated with a wide range of overlapping phenotypes. Clinical care is complicated by variable age at onset and the wide range of severity of aortic features. The factors that modulate phenotypical severity, both among and within families, remain to be determined. The availability of international FBN1 mutation Universal Mutation Database (UMD-FBN1) has allowed us to perform the largest collaborative study ever reported, to investigate the correlation between the FBN1 genotype and the nature and severity of the clinical phenotype. A range of qualitative and quantitative clinical parameters (skeletal, cardiovascular, ophthalmologic, skin, pulmonary, and dural) was compared for different classes of mutation (types and locations) in 1,013 probands with a pathogenic FBN1 mutation. A higher probability of ectopia lentis was found for patients with a missense mutation substituting or producing a cysteine, when compared with other missense mutations. Patients with an FBN1 premature termination codon had a more severe skeletal and skin phenotype than did patients with an inframe mutation. Mutations in exons 24-32 were associated with a more severe and complete phenotype, including younger age at diagnosis of type I fibrillinopathy and higher probability of developing ectopia lentis, ascending aortic dilatation, aortic surgery, mitral valve abnormalities, scoliosis, and shorter survival; the majority of these results were replicated even when cases of neonatal MFS were excluded. These correlations, found between different mutation types and clinical manifestations, might be explained by different underlying genetic mechanisms (dominant negative versus haploinsufficiency) and by consideration of the two main physiological functions of fibrillin-1 (structural versus mediator of TGFb signalling). Exon 24-32 mutations define a high-risk group for cardiac manifestations associated with severe prognosis at all ages.

Clinical Dysmorphology, 2010

Clinical Dysmorphology, 2010

We report a 10-year-old male proband, born from consanguineous marriage, presenting with short st... more We report a 10-year-old male proband, born from consanguineous marriage, presenting with short stature, severe aortic root dilation, skin hyperextensibility, extreme joint laxity and craniofacial dysmorphism. Clinical, biochemical and molecular findings did not match any of the well-described connective tissue syndromes in the differential diagnosis for this specific combination of features. We presume that the phenotype presented in this patient may constitute a newly recognized syndrome of likely autosomal recessive inheritance.

International Journal of Cardiology, 2012

Background: Aortic root dilation, dissection and rupture are major clinical problems in Marfan sy... more Background: Aortic root dilation, dissection and rupture are major clinical problems in Marfan syndrome (MFS). Although β-blockers remain the standard of preventive treatment, preliminary results from animal studies and a selected group of severely affected MFS children show significant benefit from treatment with losartan, an angiotensin II receptor blocker with TGF-β inhibiting potential. Large-scale human trials are now needed to confirm these results. This trial aims to evaluate the combined effect of both drugs. Methods: We are conducting a prospective randomized placebo controlled double blind phase III study aiming to include 174 MFS patients (age ≥ 10 years and z-score ≥ 2). Patients already taking β-blockers are randomized for weight-adjusted treatment with losartan versus placebo. The primary endpoint is decrease in aortic root growth rate. Secondary endpoints are aortic dissection/surgery, progression of aortic/mitral regurgitation, arterial stiffness, left ventricular systolic/diastolic function, quality of life and genetic modifiers. Echocardiography, vascular echo-Doppler and quality of life assessment will be performed at baseline and at 6-monthly follow-ups for 3 years. MRI evaluation will be performed at baseline and at the end of the trial. Conclusion: This trial will study new therapeutic strategies for the prevention of serious cardiovascular complications in MFS. The uniqueness in our trial is that the additive effect of losartan and β-blocker will be evaluated in a large spectrum of disease severity. A combination of ultrasound and MRI will allow detailed evaluation of anatomic and functional properties of the aorta and left ventricle.

European Journal of Human Genetics, 2008

Journal of Investigative Dermatology, 2004

Ehlers-Danlos syndrome (EDS) type VIIC, or dermatosparactic type, is a recessively inherited conn... more Ehlers-Danlos syndrome (EDS) type VIIC, or dermatosparactic type, is a recessively inherited connective tissue disorder characterized, among other symptoms, by an extreme skin fragility resulting from mutations inactivating ADAMTS-2, an enzyme excising the aminopropeptide of procollagens type I, II, and III. All previously described mutations create premature stop codons leading to a marked reduction in the level of mRNA. In this study, we analyzed the ADAMTS2 cDNA sequences from five patients displaying clinical and/or biochemical features consistent with a diagnosis of either typical or potentially mild form of EDS type VIIC. Three different alterations were detected in the two patients with typical EDS type VIIC. The first patient was homozygous for a genomic deletion causing an in-frame skipping of exons 3-5 in the transcript. In the second patient, the allele inherited from the mother lacks exon 3, generating a premature stop codon, whereas the paternal allele has a genomic deletion resulting in an in-frame skipping of exons 14-16 at the mRNA level. Although the exons 3-5 or 14-16 encode protein domains that have not been previously recognized as crucial for ADAMTS-2 activity, the aminoprocollagen processing was strongly impaired in vitro and in vivo, providing evidence for the requirement of these domains for proper enzyme function. The three other patients with a phenotype with some resemblance to EDS type VIIC only had silent and functionally neutral variations also frequently found in a normal population.

Journal of medical …, 2010

The diagnosis of Marfan syndrome (MFS) relies on defined clinical criteria (Ghent nosology), outl... more The diagnosis of Marfan syndrome (MFS) relies on defined clinical criteria (Ghent nosology), outlined by international expert opinion to facilitate accurate recognition of this genetic aneurysm syndrome and to improve patient management and counselling. These Ghent criteria, comprising a set of major and minor manifestations in different body systems, have proven to work well since with improving molecular techniques, confirmation of the diagnosis is possible in over 95% of patients. However, concerns with the current nosology are that some of the diagnostic criteria have not been sufficiently validated, are not applicable in children or necessitate expensive and specialised investigations. The recognition of variable clinical expression and the recently extended differential diagnosis further confound accurate diagnostic decision making. Moreover, the diagnosis of MFSdwhether or not established correctlydcan be stigmatising, hamper career aspirations, restrict life insurance opportunities, and cause psychosocial burden. An international expert panel has established a revised Ghent nosology, which puts more weight on the cardiovascular manifestations and in which aortic root aneurysm and ectopia lentis are the cardinal clinical features. In the absence of any family history, the presence of these two manifestations is sufficient for the unequivocal diagnosis of MFS. In absence of either of these two, the presence of a bonafide FBN1 mutation or a combination of systemic manifestations is required. For the latter a new scoring system has been designed. In this revised nosology, FBN1 testing, although not mandatory, has greater weight in the diagnostic assessment. Special considerations are given to the diagnosis of MFS in children and alternative diagnoses in adults. We anticipate that these new guidelines may delay a definitive diagnosis of MFS but will decrease the risk of premature or misdiagnosis and facilitate worldwide discussion of risk and follow-up/management guidelines.

American Journal of Medical Genetics Part A, 2008

We report on a 3-year-old child who presented a de novo rearrangement of chromosome 4, detected o... more We report on a 3-year-old child who presented a de novo rearrangement of chromosome 4, detected on GTG banding and characterized by array CGH and FISH, as a complex intrachromosomal rearrangement with three deletions: del(q32.1q32.2), del(q33q34.1), del(q35.2), one tandem duplication dup(q34.3q35.1) and short normal regions in between. The study of karyotype-phenotype correlations in this and other patients with deletions of 4q suggests 4q33q34.1 as a candidate region for 4q-syndrome and for craniofacial development.

Journal of medical genetics, 2000

International Journal of Cardiology, 2012

Background: Aortic root dilation, dissection and rupture are major clinical problems in Marfan sy... more Background: Aortic root dilation, dissection and rupture are major clinical problems in Marfan syndrome (MFS). Although β-blockers remain the standard of preventive treatment, preliminary results from animal studies and a selected group of severely affected MFS children show significant benefit from treatment with losartan, an angiotensin II receptor blocker with TGF-β inhibiting potential. Large-scale human trials are now needed to confirm these results. This trial aims to evaluate the combined effect of both drugs. Methods: We are conducting a prospective randomized placebo controlled double blind phase III study aiming to include 174 MFS patients (age ≥ 10 years and z-score ≥ 2). Patients already taking β-blockers are randomized for weight-adjusted treatment with losartan versus placebo. The primary endpoint is decrease in aortic root growth rate. Secondary endpoints are aortic dissection/surgery, progression of aortic/mitral regurgitation, arterial stiffness, left ventricular systolic/diastolic function, quality of life and genetic modifiers. Echocardiography, vascular echo-Doppler and quality of life assessment will be performed at baseline and at 6-monthly follow-ups for 3 years. MRI evaluation will be performed at baseline and at the end of the trial. Conclusion: This trial will study new therapeutic strategies for the prevention of serious cardiovascular complications in MFS. The uniqueness in our trial is that the additive effect of losartan and β-blocker will be evaluated in a large spectrum of disease severity. A combination of ultrasound and MRI will allow detailed evaluation of anatomic and functional properties of the aorta and left ventricle.

The American Journal of Human Genetics, 2007

Mutations in the fibrillin-1 (FBN1) gene cause Marfan syndrome (MFS) and have been associated wit... more Mutations in the fibrillin-1 (FBN1) gene cause Marfan syndrome (MFS) and have been associated with a wide range of overlapping phenotypes. Clinical care is complicated by variable age at onset and the wide range of severity of aortic features. The factors that modulate phenotypical severity, both among and within families, remain to be determined. The availability of international FBN1 mutation Universal Mutation Database (UMD-FBN1) has allowed us to perform the largest collaborative study ever reported, to investigate the correlation between the FBN1 genotype and the nature and severity of the clinical phenotype. A range of qualitative and quantitative clinical parameters (skeletal, cardiovascular, ophthalmologic, skin, pulmonary, and dural) was compared for different classes of mutation (types and locations) in 1,013 probands with a pathogenic FBN1 mutation. A higher probability of ectopia lentis was found for patients with a missense mutation substituting or producing a cysteine, when compared with other missense mutations. Patients with an FBN1 premature termination codon had a more severe skeletal and skin phenotype than did patients with an inframe mutation. Mutations in exons 24-32 were associated with a more severe and complete phenotype, including younger age at diagnosis of type I fibrillinopathy and higher probability of developing ectopia lentis, ascending aortic dilatation, aortic surgery, mitral valve abnormalities, scoliosis, and shorter survival; the majority of these results were replicated even when cases of neonatal MFS were excluded. These correlations, found between different mutation types and clinical manifestations, might be explained by different underlying genetic mechanisms (dominant negative versus haploinsufficiency) and by consideration of the two main physiological functions of fibrillin-1 (structural versus mediator of TGFb signalling). Exon 24-32 mutations define a high-risk group for cardiac manifestations associated with severe prognosis at all ages.

Clinical Dysmorphology, 2010