Spontaneous spinal cerebrospinal fluid leaks and minor skeletal features of Marfan syndrome: a microfibrillopathy

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  • 1 Howard Hughes Medical Institute and the Departments of Genetics and Pediatrics, Stanford University School of Medicine, Stanford, California; Cedars—Sinai Neurosurgical Institute, Los Angeles, California; Department of Pediatrics and Center for Human Molecular Genetics, University of Nebraska Medical Center, Omaha, Nebraska; and Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota
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Object. Spontaneous spinal cerebrospinal fluid (CSF) leaks are increasingly recognized as a cause of postural headaches. The authors examined a group of patients suffering from spontaneous spinal CSF leaks who also had minor skeletal features of Marfan syndrome for abnormalities of fibrillin-containing microfibrils.

Methods. Patients with spontaneous CSF leaks were evaluated for the clinical characteristics of connective tissue disorders. Skin biopsies were obtained in three patients with skeletal manifestations that constitute part of the Marfan syndrome phenotype. Cultured fibroblasts were studied for fibrillin-1 synthesis and incorporation into the extracellular matrix (ECM) by performing quantitative metabolic labeling and immunohistochemical analysis. Among 20 consecutive patients found to have spinal CSF leaks, four (20%) exhibited minor skeletal features of Marfan syndrome, but lacked any ocular or cardiovascular abnormalities. The mean age of these patients (30 years) was lower than that of the 16 patients without skeletal abnormalities (44 years; p = 0.01). Abnormalities in fibrillin metabolism and immunostaining were detected in all three patients with the skeletal abnormalities who underwent examination, but not in a control patient without these skeletal manifestations.

Conclusions. Twenty percent of patients who experience spontaneous spinal CSF leaks have minor skeletal features of Marfan syndrome. The authors demonstrated abnormalities in fibrillin-1 protein deposition in all patients examined, but only one person was found to have a fibrillin-1 abnormality typically found in classic Marfan syndrome. The results indicate that there is a heterogeneous involvement of other components of ECM microfibrils at the basis of this cerebrospinal manifestation. In addition, the authors identified a connective-tissue etiological factor in a group of disorders not previously classified as such.

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