<i>FBN1</i>, <i>TGFBR1</i>, and the Marfan‐craniosynostosis/mental retardation disorders revisited

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<jats:title>Abstract</jats:title><jats:p>The recent identification of <jats:italic>TGFBR2</jats:italic> mutations in Marfan syndrome II (MFSII) [Mizuguchi et al. (2004); Nat Genet 36:855–860] and of <jats:italic>TGFBR1</jats:italic> and <jats:italic>TGFBR2</jats:italic> 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 β (TGF‐β) 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‐β signaling pathway disorders. Two recurrent heterozygous <jats:italic>FBN1</jats:italic> mutations were found in Patients 1 and 2, and an identical novel heterozygous de novo <jats:italic>TGFBR1</jats:italic> 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 <jats:italic>FBN1</jats:italic> deletion was found in Patient 5. These findings support the notion that perturbation of extracellular matrix homeostasis and/or remodeling caused by abnormal TGF‐β signaling is the core pathogenetic mechanism in MFS and related entities including the MD‐CS syndromes. © 2006 Wiley‐Liss, Inc.</jats:p>

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