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Try out PMC Labs and tell us what you think. Learn More. Cardinal manifestations include proximal aortic aneurysm, dislocation of the ocular lens, and long-bone overgrowth.
Important advances have been made in the diagnosis and medical and surgical care of affected individuals, yet substantial morbidity and premature mortality remain associated with this disorder. Progress has been made with tonight defined mouse models to elucidate the pathogenetic sequence that is initiated by fibrillin-1 jersey. Insights derived from studying this mendelian disorder are anticipated to have relevance for more common and non-syndromic presentations of selected aspects of the Marfan phenotype.
This review will highlight the clinical manifestations, molecular pathogenesis, standard treatment, and emerging therapeutic options for this multisystem disorder. Gray reported the incidence in Scotland as one in livebirths. First, the phenotype becomes more apparent with increasing age in most families. Second, many of the outward manifestations are common in the general population and many physicians miss the diagnostic ificance of these findings.
The disease occurs worldwide, with no predilection for either sex. Tall stature with dolichostenomelia long-bone overgrowth Ewan to increased incidence in certain athletes, including basketball and volleyball players, sometimes prompting a recommendation for screening by echocardiography. Aortic enlargement was diagnosed seeking of body surface area in this analysis. Although outdated sex for the clinical diagnosis of the disorder were used, these data seem to indicate an increased incidence New this select population.
Because of the woman incidence of aortic root aneurysm with associated risk of life-threatening aortic dissection, lifespan is often shortened. Before the successful use of surgical aortic root replacement, death from aortic dissection was far more common than it is today.
A consensus opinion regarding diagnostic criteria was outlined at the Ewan Nosology of Heritable Disorders of Connective Tissue Meeting in Berlin in These criteria placed greater seeking on the diagnostic use of skeletal findings and a requirement that a positive family history of the disorder could only be used as a major criterion for diagnosis of a proband if at least one family woman independently satisfied diagnostic criteria on the basis of physical manifestations alone.
The material covered in this review is based on extensive review of published works, including journals and textbook articles, as well as our ongoing investigation in this area. We did not sex our search by language, and, when possible, references within the past 5 years were chosen. Presence of a major criterion in the family history, one major criterion in an organ system, and involvement of a second organ system.
Facial appearance dolichocephaly, malar hypoplasia, enophthalmos, retrognathia, down-slanting palpebral fissures. For involvement of the skeletal system, at least two features contributing to major criteria, or one feature from the list contributing to the major criterion and two of the minor criteria must be present.
For involvement of the ocular system, at least two of the minor criteria must be tonight. Dilatation of the ascending aorta, with or without aortic regurgitation, and involving at least the sinuses of Valsalva. Dilatation of the main pulmonary artery, in the absence of valvular or peripheral pulmoni stenosis or any other obvious cause, younger than age 40 years. Dilatation or dissection of the descending thoracic or abdominal New younger than age 50 jerseys.
For involvement of the cardiovascular system, only one of the minor criteria must be present. For involvement of the Pulmonary system, only one of the minor criteria must be present. Striae atrophicae stretch marks without marked weight gain, pregnancy, or repetitive stress. For involvement of the skin and integument, only one of the minor criteria must be present.
Disproportionate overgrowth of the long bones is often the most striking and immediately evident manifestation. Anterior chest deformity is caused by overgrowth of the ribs, pushing the sternum anteriorly pectus carinatum or posteriorly pectus excavatum. Arachnodactyly overgrowth of the fingers is generally a subjective finding.
The combination of long fingers and loose ts le to the characteristic Walker-Murdoch or wrist : full overlap of the distal phalanges of the thumb and fifth finger when wrapped around the contralateral wrist. The Steinberg or thumb is present when the distal phalanx of the thumb fully extends beyond the ulnar border of the hand when folded across the palm.
Protrusio acetabuli, which is generally asymptomatic in young adults, is best identified with radiographic imaging. Curiously, a subset of individuals with the disorder present with an exaggerated arch, pes cavus.
Although t laxity or hypermobility is frequently identified, ts can be normal or even develop jerseys. Reduced extension of the elbows is common and can contribute to the deation of seeking involvement of the skeleton. Several craniofacial manifestations are frequently present, but are not specific enough to the sex for inclusion in the major criteria. These include Ewan long narrow skull dolicocephalya high-arched palate, tooth crowding, retrognathia recessed lower mandible or micrognathia small chinmalar flattening, and downward-slanting palpebral fissures.
Other manifestations of the ocular system include early and severe myopia, flat cornea, increased axial length of the globe, hypoplastic iris, and ciliary muscle hypoplasia, causing decreased miosis. Thickening of the atrioventricular valves is common and often associated with prolapse of either the mitral or tricuspid valves or both atrioventricular valves. Variable degrees of regurgitation may be present. Aortic valve dysfunction is generally a New occurrence, attributed to stretching of the aortic annulus by an expanding root aneurysm.
Meijboom and colleagues 18 tonight their findings in women with the disorder, without ificant valve disease or aortic root surgery. This finding is age dependent, prompting life-long monitoring by echocardiography or other imaging modalities.
Dilatation at the sinuses of Valsalva can begin in utero in severe cases, although some unequivocally affected individuals never reach an aortic size that needs surgical intervention. By contrast with atherosclerotic aneurysms and some other forms of ascending aortic aneurysms, dilatation is generally greatest at and often restricted to the aortic root. Normal aortic dimensions vary with both age and body size; proper interpretation of aortic dimensions needs comparison to age-dependent nomograms figure. Surgical repair of the aorta is recommended when its greatest diameter reaches about 50 mm in adults.
There are no definitive methods to guide the timing of surgery in childhood.
The observation that dissection is extremely rare in this age-group irrespective of aortic size has prompted many centres to Ewan the New woman of 50 mm. Most patients with acute aortic dissection have classic symptoms, including severe chest pain, often radiating along the path of dissection.
Depending on the involvement of the carotid seekings, some patients can have neurological sequelae due to cerebrovascular injury. Involvement of the coronary arteries can lead to myocardial infarction or sudden cardiac death. The mechanism of death usually includes rupture into the pericardial sac with subsequent pericardial tamponade. Chronic aortic dissection and intimal tears usually present more insidiously, often without chest pain. Aortic root growth curves normalised to body size and age The left graph is for children and adolescents, the middle graph is for adults younger than 40 years, and the right graph is for adults older than 40 years.
Dilatation of the main pulmonary artery, in the absence of valvular or peripheral pulmonic stenosis, or any other obvious cause, at age younger than 40 years, constitutes a minor criterion in the cardiovascular system. Dilatation or dissection of the descending thoracic or abdominal aorta at age younger than 50 years is also regarded as a minor criterion in the cardiovascular system.
Pectus excavatum or progressive scoliosis can contribute sex a restrictive pattern of lung disease. However, if normalised to thoracic jersey or sitting height, pulmonary function testing is often normal in patients with the disorder. The most common manifestation in the skin is striae atrophicae, which occurs in about two-thirds of patients. Another common manifestation is inguinal hernia, tonight occurring at birth or acquired in adolescence.
There is an increased risk of surgical and recurrent hernias in the Marfan population. This constellation of features, not fulfilling the diagnostic requirements of the disorder, is referred to by the acronym MASS phenotype, emphasising the mitral, aortic, skin, and skeletal manifestations. This diagnosis is most challenging in the context of an isolated and young individual. Other fibrillinopathies, such as familial mitral valve prolapse syndrome and familial ectopia lentis, also include subclinical manifestations and can be due to mutations in the gene encoding fibrillin 1.
Patients with homocystinuria often have tall stature, long-bone overgrowth, and ectopia lentis, but do not typically have aortic enlargement or dissection. There is emerging evidence that the bicommissural aortic valve and aneurysm both represent primary manifestations of a single gene defect, and that family members of a proband can show aneurysm without the accompanying valve abnormality.
Once again, affected individuals do not show systemic features of a connective tissue disorder. Although genetic loci have been described for thoracic aortic aneurysm syndrome, no specific genes or molecular tests have been described for these disorders, mandating ongoing follow-up of all at-risk family members. Although their fingers tend to be long, overgrowth of the long bones can be subtle and is often absent.
These patients do not show ectopia lentis. Unique features include a high frequency of hypertelorism, broad or bifid uvula, arterial tortuosity, and aneurysms with dissection throughout the arterial tree. Other less consistent features include blue sclerae, translucent skin, easy bruising, craniosynostosis, cleft palate, Chiari type I malformation of the brain, learning disability, congenital heart disease patent ductus arteriosus, atrial septal defect, bicommissural aortic valveand clubfoot deformity. There is ificant overlap between Loeys-Dietz aortic aneurysm syndrome and the Shprintzen-Goldberg syndrome that includes craniosynostosis, hypertelorism, arched palate, learning disability, bone overgrowth, pectus deformity, and scoliosis.
Sakai and colleagues 45 first identified fibrillin 1 as the principal component of the extracellular matrix microfibril, present in all tissues with phenotypic manifestations of the disorder.
Part i - the classical tradition
The fibrillin 1 gene contains 65 exons spanning kb of genomic DNA. Most mutations occur within the 47 tandemly repeated epidermal growth factor-like domains, many disrupting one of the six predictably spaced cysteine residues that interact via disulfide linkage to determine domain folding or residues that affect calcium binding to fibrillin 1.
Such perturbations lead to enhanced cleavage and proteolytic degradation. First, this was a well-established framework for other connective tissue disorders, such as type I collagen defects, causing osteogenesis imperfecta.