Ades, L. C. et al. FBN1, TGFBR1, and the Marfan-craniosynostosis/mental retardation disorders revisited. Am. J. Med. Genet. A 140, 1047-1058
The recent identification of TGFBR2 mutations in Marfan syndrome II (MFSII) [Mizuguchi et al. (2004); Nat Genet 36:855-860] and of TGFBR1 and TGFBR2 mutations in Loeys-Dietz aortic aneurysm syndrome (LDS) [Loeys et al. (2005); Nat Genet 37:275-281] [OMIM 609192] has provided direct evidence of abnormal signaling in transforming growth factors beta (TGF-beta) in the pathogenesis of Marfan syndrome (MFS). In light of this, we describe the phenotypes and genotypes of five individuals. Patient 1 had MFS and abnormal cranial dura. Patient 2 had severe early onset MFS and an abnormal skull. Patients 3 and 4 had probable Furlong syndrome (FS). Patient 5 had marfanoid (MD) features, mental retardation (MR), and a deletion of chromosome 15q21.1q21.3. All patients had a condition within the MFS, MD-craniosynostosis (CS) or MD-MR spectrum. The names of these entities may become redundant, and instead, come to be considered within the spectrum of TGF-beta signaling pathway disorders. Two recurrent heterozygous FBN1 mutations were found in Patients 1 and 2, and an identical novel heterozygous de novo TGFBR1 mutation was found in Patients 3 and 4, in whom altered fibrillin-1 processing was demonstrated previously [Milewicz et al. (2000); Am J Hum Genet 67:279]. A heterozygous FBN1 deletion was found in Patient 5. These findings support the notion that perturbation of extracellular matrix homeostasis and/or remodeling caused by abnormal TGF-beta signaling is the core pathogenetic mechanism in MFS and related entities including the MD-CS syndromes.
Available from: Christopher S Graffeo
- "On a molecular level, abnormalities in transforming growth factor beta (TGFβ) are implicated in the relationship between HCTD and weak connective tissue. Loeys–Dietz syndromes types 2A and 2B arise from mutations in the TGFβ receptor gene TGFBR1 and TGFBR2, leading to fibroblast signaling abnormalities, while TGFβ dysregulation and overexpression have been observed in Marfan syndrome pathogenesis. Marfan and Loeys–Dietz syndromes are associated with high rates of dural ectasia (DE) and SIH. "
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ABSTRACT: Spontaneous intracranial hypotension is an uncommon clinical entity. Heritable connective tissue disorders (HCTD), such as Marfan syndrome, are frequently implicated as an underlying cause, due to dural structural weaknesses that predispose patients to spontaneous cerebrospinal fluid (CSF) leak. Due to the high prevalence of multi-system disease in HCTD, diagnosis and treatment are often complicated.
We present a 58-year-old female with Marfan syndrome on anticoagulation for a mechanical aortic valve replacement who came to medical attention with severe, acute-onset headache following a straining episode. Noninvasive magnetic resonance (MR) myelography confirmed thoracic CSF extravasations and multiple lumbar diverticula. The patient was treated conservatively and her symptoms resolved.
We discuss the common presentation, diagnostic tools, and treatment options for spontaneous CSF leaks in patients with Marfan syndrome or related HCTD with an emphasis on noninvasive modalities and a review of the major radiographic criteria used to diagnose dural abnormalities, such as dural ectasia.
Available from: Ana Dutra
- "To our best knowledge, there are only six reports in the literature describing deletions of the whole FBN1 gene detected by molecular techniques, and only in five of them this gene deletion was associated with classical MFS [2,7-11]. The patients described by Adès et al.  and Hutchinson et al.  had clinical features of the MFS spectrum and mental retardation, but the size of their deletions was not determined. The patient described by Faivre et al.  had a 2.97 Mb deletion and some features of MFS but no mental retardation. "
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ABSTRACT: The majority of Marfan syndrome (MFS) cases is caused by mutations in the fibrillin-1 gene (FBN1), mapped to chromosome 15q21.1. Only few reports on deletions including the whole FBN1 gene, detected by molecular cytogenetic techniques, were found in literature.
We report here on a female patient with clinical symptoms of the MFS spectrum plus craniostenosis, hypothyroidism and intellectual deficiency who presents a 1.9 Mb deletion, including the FBN1 gene and a complex rearrangement with eight breakpoints involving chromosomes 6, 12 and 15.
This is the first report of MFS with a complex chromosome rearrangement involving a deletion of FBN1 and contiguous genes. In addition to the typical clinical findings of the Marfan syndrome due to FBN1 gene haploinsufficiency, the patient presents features which may be due to the other gene deletions and possibly to the complex chromosome rearrangement.
Available from: Whitney Wooderchak-Donahue
- "Three additional patients with 15 q deletions that included and extended beyond FBN1 were previously reported [19,21,22]. Their phenotype was characterized by marfanoid features predominantly affecting the skeletal system, with absent or mild aortic involvement. "
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ABSTRACT: Connective tissue diseases characterized by aortic aneurysm, such as Marfan syndrome, Loeys-Dietz syndrome and Ehlers Danlos syndrome type IV are heterogeneous and despite overlapping phenotypes, the natural history, clinical manifestations and interventional course for each diagnosis can be quite unique. The majority of mutations involved in the etiology of these disorders are missense and nonsense mutations. However, large deletions and duplications undetected by sequencing may be implicated in their pathogenesis, and may explain the apparent lack of genotype-phenotype correlation in a subset of patients. The objective of this study was to search for large pathogenic deletions and/or duplications in the FBN1, TGFβR1, and TGFβR2 genes using multiplex-ligation dependent probe amplification (MLPA) in patients with aortopathy, in whom no mutations in the FBN1, TGFβR1, and TGFβR2 genes were identified by sequencing.
The study included 14 patients from 11 unrelated families with aortic aneurysm. Of those, six patients (including 3 first-degree relatives), fulfilled the revised Ghent criteria for Marfan syndrome, and eight had predominantly aortic aneurysm/dilatation with variable skeletal and craniofacial involvement. MLPA for FBN1, TGFβR1, and TGFβR2 was carried out in all patients. A 385 K chromosome 15 specific array was used in two patients with a deletion of the entire FBN1 in order to define its size and boundaries.
We identified two novel large deletions in the FBN1 gene in four patients of two unrelated families who met clinical diagnostic criteria for Marfan syndrome. One patient was found to have a FBN1 deletion encompassing exons 1-5. The other three patients had a 542 Kb deletion spanning the whole FBN1 gene and five additional genes (SLC24A5, MYEF2, CTXN2, SLC12A1, DUT) in the chromosome 15.
Our findings expand the number of large FBN1 deletions, and emphasize the importance of screening for large genomic deletions in connective tissue disorders featuring aortopathies, especially for those with classic Marfan phenotype.
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