You are in: eMedicine Specialties > Orthopedic Surgery > PEDIATRICS Marfan SyndromeArticle Last Updated: Feb 21, 2008AUTHOR AND EDITOR INFORMATIONSection 1 of 11
  Author: Khalid Channell, MD, Staff Physician, Department of General Surgery, Division of Orthopedic Surgery, King Drew Medical Center Coauthor(s): Eleby R Washington III, MD, FACS, Associate Professor, Department of Surgery, Division of Orthopedics, Charles R Drew University of Medicine and Science Editors: Charles T Mehlman, DO, MPH, Director, Musculoskeletal Outcomes Research, Associate Professor, Division of Pediatric Orthopaedic Surgery, Cincinnati Children's Hospital Medical Center; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; George H Thompson, MD, Professor of Orthopedic Surgery and Pediatrics, Department of Pediatric Orthopedic Surgery, Case Western Reserve University; Director, Rainbow Babies and Children's Hospital; Dinesh Patel, MD, FACS, Associate Clinical Professor of Orthopedic Surgery, Harvard Medical School; Chief of Arthroscopic Surgery, Department of Orthopedic Surgery, Massachusetts General Hospital; Dennis P Grogan, MD, Clinical Professor, Department of Orthopedic Surgery, University of South Florida College of Medicine; Chief of Staff, Department of Orthopedic Surgery, Shriners Hospital for Children of Tampa Author and Editor Disclosure Synonyms and related keywords: MFS, Marfan's syndrome, arachnodactyly, long and thin digits, dolichostenomelia, long limbs, pectus deformities, pectus excavatum, pectus carinatum, thoracolumbar scoliosis, aortic dilatation, aortic regurgitation, aortic dissection, aneurysm, mitral valve prolapse, myopia, cataracts, retinal detachment, superior lens dislocation INTRODUCTIONSection 2 of 11
  Marfan syndrome (MFS) is a spectrum disorder caused by a heritable genetic defect of connective tissue that has an autosomal dominant mode of transmission.1, 2, 3, 4 The defect itself has been isolated to the FBN1 gene on chromosome 15, which codes for the connective tissue protein fibrillin.1, 5 Abnormalities in this protein cause a myriad of distinct clinical problems, of which the musculoskeletal, cardiac, and ocular system problems predominate.2, 6, 7 The skeleton of patients with MFS typically displays multiple deformities including arachnodactyly (ie, abnormally long and thin digits), dolichostenomelia (ie, long limbs relative to trunk length), pectus deformities (ie, pectus excavatum and pectus carinatum), and thoracolumbar scoliosis.8, 9 History of the ProcedureBernard Marfan was born in Castelnaudary, Aude, France on June 23, 1858. In 1892, he was appointed assistant professor of pediatrics in the Paris faculty. Marfan described the disease that still bears his name at a meeting of the Medical Society of Paris in 1896. He presented the case of a 5-year-old girl named Gabrielle, who had disproportionately long limbs. ProblemThe abnormality of the connective tissue protein fibrillin causes a variety of problems in the affected individual. The most severe problems include aortic root dilatation and dissection, which have historically been the causative factors in early patient demise.10 Skeletal deformities such as thoracolumbar scoliosis, thoracic lordosis, and pectus excavatum, may lead to pulmonary difficulties that include restrictive airway disease and cor pulmonale if the deformities are progressive and untreated. Finally, blindness may result from unrecognized and untreated glaucoma, retinal detachment, and cataracts. FrequencyThe estimated incidence of MFS ranges from 1 in 5,000 to 2-3 in 10,000 persons.1 The mutation in the fibrillin gene causes pleiotropic effects; thus, a wide range of phenotypic features is derived from a single gene mutation. Several other diseases have presentations similar to MFS, making it exceedingly difficult to determine the exact incidence. EtiologyMutations in the FBN1 locus of the fibrillin gene on chromosome 15 have been linked to MFS and other distinct clinical entities with similar findings. PathophysiologyOver many years, several investigators have studied various molecules found in the extracellular matrix in attempts to elucidate the cause of MFS. These molecules have included collagen, elastin, hyaluronic acid, and, more recently, fibrillin. Sakai et al identified fibrillin, a 350-kd protein, by using monoclonal antibodies raised against myofibrils.11 Immunofluorescence studies were then used to compare the reactivity in both healthy subjects and those with MFS. During this period, similar technology was used to construct a genetic exclusion map that led to the localization of the defect to chromosome 15 (bands q15-q23). Several point mutations have now been identified in the fibrillin gene, most of which affect cysteine residues within the microfibril. Thus, these mutations are thought to cause defective fibrillin to be produced. Fibrillin's structure and function are altered by abnormal protein folding due to the alteration of bonding between cysteine residues, which in turn causes defective microfibril production. ClinicalNo single sign is pathognomic for MFS, given its variable expressivity. The diagnosis is made on clinical grounds based upon typical abnormalities. The cardiac, skeletal, and ocular systems are generally more focused upon for MFS diagnostic criteria; however, other tissues, including skeletal muscle, fat, skin, fascia, and the respiratory tract, may be affected in this condition as well. The following list describes the most common clinical findings and the revised Berlin criteria (1986) for diagnosis of MFS. The Ghent criteria (1996) updated the previous guidelines to include greater emphasis on the skeletal findings, as well as those of the family and genetic history.12, 13 (See also the eMedicine article Marfan Syndrome in the Pediatrics section for a more detailed description of the Ghent criteria.) Skeletal system For the skeletal system involvement to be used as criteria for the diagnosis, at least 2 major criteria or 1 major criterion plus 2 minor criteria must be present.
Minor skeletal system criteria are as follows:
Related Medscape topic:
For ocular system involvement to be used as diagnostic criteria, the major criterion or at least 2 minor criteria must be present. Minor ocular system criteria are as follows:
Related Medscape topics: For cardiovascular system involvement to be considered diagnostic criteria, only one of the major or minor criteria must be present.
Minor cardiovascular system criteria are as follows:
Related eMedicine topics: For pulmonary system involvement to be considered diagnostic criteria, one of the minor criteria must be present. Minor pulmonary system criteria are as follows:
Related Medscape topics: For skin and integument involvement to be considered diagnostic criteria, the major criteria or one of the minor criteria must be present. The minor skin and integument criteria are as follows:
For the family history to be considered contributory to a diagnosis of MFS, one of the major criteria must be present.
No minor family history criteria exist. Related Medscape topic:
INDICATIONSSection 3 of 11
No specific surgical procedure exists to cure this systemic disease. Rather, specific medical and surgical interventions may ameliorate certain aspects of MFS. System-specific treatment options are discussed in the Treatment section. RELEVANT ANATOMYSection 4 of 11
MFS is a systemic disease with various clinically significant abnormalities that require the medical and surgical intervention described in the Treatment section. The disease is not specific to one anatomic location. CONTRAINDICATIONSSection 5 of 11
Any evidence of aortic dilatation must be treated medically or surgically, before any spinal reconstruction is attempted for scoliosis. Any evidence of imminent cardiac compromise would preclude surgical intervention until that issue is addressed. WORKUPSection 6 of 11
Lab Studies
Imaging Studies
Other Tests
TREATMENTSection 7 of 11
Medical therapyThe majority of medical therapy as it relates to MFS has been targeted at preventing cardiovascular compromise, which is the most likely cause of demise in this patient population.10 Beta-blockers and afterload reduction agents are used to reduce stress on the aortic and mitral valves and the aortic root.14 Beta blockade is used because it is believed to reduce both inotropy and chronotropy and thus reduce the stress on the aortic root. Nitroprusside reduces overall systemic vascular resistance, which serves to reduce overall afterload and stress on the heart. Whether these effects translate into decreased morbidity and mortality at this time is unclear, as no long-term studies have been preformed yet. Calcium channel blockers (eg, verapamil) are being investigated to assess their effects on cardiovascular physiology in patients with MFS. Scoliosis is the most common major skeletal deformity encountered in patients with MFS that requires intervention. No specific medicinal intervention exists to treat scoliosis. Nonoperative means of treatment (eg, bracing) may be attempted but are usually unsuccessful. Scoliosis occurs in approximately 50-70% of patients with MFS and differs from idiopathic adolescent scoliosis with regard to curve pattern, progression, and symptoms. The double right thoracic–left lumbar curve is the most common type among patients with MFS, whereas a single pattern is usually seen in the idiopathic type. Pelvic obliquity is uncommon in both types, however. Unfortunately, these patients often have an earlier onset of scoliosis with severely rigid, painful, and deforming curves, as well as have a high incidence of curve progression. The curve progression may average 7-10° per year after the onset of scoliosis, and the curve often progresses rapidly in the early adolescent period during maximal vertebral growth. This is also in contrast to the idiopathic type, which is typically not painful and is not as progressively deforming as the scoliosis in patients with MFS. Scoliosis, in combination with poor musculature and chest deformities, can cause significant respiratory compromise, which mandates early detection and prevention, if possible, in this patient population. Nonoperative intervention for the scoliosis typically involves observation followed by the use of a thoracolumbosacral orthosis (TLSO) if the curve is mild and reveals signs of progression. Bracing is controversial; many surgeons believe that the bulk of curves in patients with MFS progress regardless of bracing and thus require operative intervention to prevent worsening deformity. Surgical therapyMitral valve regurgitation may become so severe that medical therapy must be replaced with surgical intervention. The mitral valve is often found to have a dilated annulus, redundant and flaccid cusps, and ruptured chordae tendineae. Mitral valve repair is undertaken if possible, to delay the eventual mitral valve replacement; this is done because these patients often present at a young age and may require further reconstructive surgery later. Surgical repair also preserves papillary muscle function and obviates chronic anticoagulation, unlike artificial valve replacement. The ascending aorta (aortic root) or the incompetent aortic valve may also require repair. Either a composite graft or a valve-sparing technique is performed.15 The valve-sparing technique is usually performed in patients whose aorta has dilated to approximately 50 mm. Patients with widely dilated aortic roots or significantly attenuated aortic cusps typically undergo a composite graft repair. This is also the procedure of choice in the case of an acute aortic root dissection. Some surgeons advocate prophylactic composite grafting in patients who have a history of increasing aortic dilatation and a family history of sudden cardiovascular death. The major indication for surgery for the musculoskeletal system involves progression of moderate to severe scoliosis. Chest-wall deformities may also be so severe that they impact cardiopulmonary mechanics; these can be surgically corrected as well. In the past, patients with MFS did not have these chest-wall deformities addressed, and most died at an early age due to intrinsic cardiovascular disease. The advent of successful aortic root surgery as well as aortic and mitral valve replacement has changed the overall long-term outlook for patients with the disease. Adequate treatment should be provided for those with scoliosis to reduce pain, to improve overall cosmetic appearance, and, most importantly, to improve pulmonary mechanics through reduction of spinal and chest-wall deformities. As previously described, bracing can be considered in patients with mild curves (see the Medical therapy section). However, most patients with MFS will have significant curve progression that eventually warrants surgical intervention. Patients with curves greater than 40-50º or with associated abnormal sagittal curvature deformities require surgery. Posterior spinal fusion and segmental spinal instrumentation, along with autogenous bone grafting, are the mainstay of treatment. Most authors agree that scoliosis can be corrected with this approach; however, the overall incidence of complications varies in different series. Pseudoarthrosis and loss of correction can occur and are problematic; the incidence rates range from 12-40%. Most authors recommend aggressive bone grafting, rigid internal fixation, and adequate patient surveillance postoperatively to diagnose complications early in the clinical course. Sagittal malalignment (kyphotic deformity) may require an anterior fusion (excision of discs) followed by posterior spinal fusion and segmental spinal instrumentation to achieve satisfactory correction of the sagittal alignment. Preoperative detailsThe most important aspect in the preoperative evaluation of patients with MFS is to rule out any imminent cardiac compromise. A complete cardiac workup, including electrocardiography followed by echocardiography, is mandatory. It is well known that aortic dilatation and subsequent rupture can develop throughout these patients' childhood and adult life; thus, one must be diligent to exclude these entities before any surgical undertaking. Any evidence of aortic dilatation must be treated medically or surgically before any spinal reconstruction is attempted. COMPLICATIONSSection 8 of 11
See Surgical therapy. OUTCOME AND PROGNOSISSection 9 of 11
Recent strides in the management of the cardiovascular manifestations of MFS have led to a significant decrease in the morbidity and mortality that are associated with this condition. Before the advent of pharmacologic and surgical therapy for aortic root and valvular disease, the life expectancy for patients with MFS was about two thirds that of the healthy population. Aortic dissection and congestive heart failure due to aortic and mitral valvular anomalies accounted for over 90% of the known causes of death. FUTURE AND CONTROVERSIESSection 10 of 11
Many new areas of investigation into the etiology and effects of MFS exist. Some are ongoing, whereas others will likely come to the forefront as the disease is more readily understood.
Although many discoveries have been made since the original description of MFS in 1896, much investigation is still needed. REFERENCESSection 11 of 11
Article Last Updated: Feb 21, 2008 |
