Dermal fibroblasts from a 13-yr-old boy with isolated skeletal features of the Marfan syndrome were used to study fibrillin synthesis and processing. Only one half of the secreted profibrillin was proteolytically processed to fibrillin outside the cell and deposited into the extracellular matrix. Electron microscopic examination of rotary shadowed microfibrils made by the proband's fibroblasts were indistinguishable from control cells. Sequencing of the FBN1 gene revealed a heterozygous C to T transition at nucleotide 8176 resulting in the substitution of a tryptophan for an arginine (R2726W), at a site immediately adjacent to a consensus sequence recognized by a cellular protease. Six other individuals in the proband's family had the FBN1 mutation that segregated with tall stature. None of the affected individuals have cardiac or ocular manifestations of the Marfan syndrome. This mutation identifies a putative site for profibrillin to fibrillin processing, and is associated with isolated skeletal features of the Marfan syndrome, indicating that the FBN1 gene is one of the genes that determines height in the general population. The cellular effect of the mutation may be equivalent to a "null" FBNJ allele and may define the phenotype associated with FBNI "null" alleles. (J. Clin.

Objective To determine the effects of creation of a systemic to pulmonary venous atrial level communication (fenestration) at the time of the Fontan procedure on late outcomes. Background Fenestrations are frequently performed during Fontan procedures but late consequences are not well described. Methods Patient characteristics were compared between those with and without surgical fenestration among 536 subjects (mean 11.9 years) enrolled in the Pediatric Heart Network Fontan Cross-sectional Study. The status of the fenestration and the association of a currently patent fenestration with health status and measures of ventricular performance were investigated. Results Fenestration was performed in 361 patients (67%) and frequency differed by year and center (p<0.001 for each). After adjustment for center, age at Fontan, year of Fontan and prior superior cavopulmonary surgery, the fenestrated group had shorter length of Fontan hospital stay. At time of cross-sectional testing 8±3 years after Fontan, the fenestration remained open in 19% of subjects. Among those with confirmed fenestration closure, 59% were by catheter intervention, 1% by surgical intervention, and 40% had apparent spontaneous closure. Compared to those without evidence of a fenestration, subjects with a current fenestration were taking more medications (p=0.02) and had lower resting oxygen saturation (median 89 vs. 95%, p<.001). Functional health status, exercise performance, echocardiographic variables, prevalence of post Fontan stroke or thrombosis, and growth did not differ by current fenestration status. Discussion Surgical fenestration is associated with well demonstrated early postoperative benefits. This cross-sectional study found few associations between a persistent fenestration and deleterious later outcomes.

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