A heritable disorder of fibrous connective tissue, Marfan syndrome shows striking pleiotropism and clinical variability. The cardinal features occur in 3 systems--skeletal, ocular, and cardiovascular (McKusick, 1972; Pyeritz and McKusick, 1979; Pyeritz, 1993). It shares overlapping features with ... A heritable disorder of fibrous connective tissue, Marfan syndrome shows striking pleiotropism and clinical variability. The cardinal features occur in 3 systems--skeletal, ocular, and cardiovascular (McKusick, 1972; Pyeritz and McKusick, 1979; Pyeritz, 1993). It shares overlapping features with congenital contractural arachnodactyly (121050), which is caused by mutation in the FBN2 gene (612570). Gray and Davies (1996) gave a general review. They published Kaplan-Meier survival curves for a cohort of British Marfan syndrome patients demonstrating greater survivorship in females than in males; a similar result had been reported by Murdoch et al. (1972) and by Silverman et al. (1995). Gray and Davies (1996) also proposed a grading scale for clinical comparison of the Marfan syndrome patients. The authors provided criteria for each grade and suggested uniform use of these scales may facilitate clinicomolecular correlations.
The diagnosis of the Marfan syndrome is based on typical clinical features--skeletal, ocular, and cardiovascular--and a positive family history when available. The criteria established by Beighton et al. (1988) state that in the absence of an unequivocally affected ... The diagnosis of the Marfan syndrome is based on typical clinical features--skeletal, ocular, and cardiovascular--and a positive family history when available. The criteria established by Beighton et al. (1988) state that in the absence of an unequivocally affected first-degree relative, one should require involvement of the skeleton and at least 2 other systems with a minimum of 1 major manifestation (ectopia lentis, aortic dilatation/dissection, or dural ectasia). In the presence of an unequivocally affected first-degree relative, one requires only that 2 organ systems be involved. Schott (1992) questioned the usefulness of 'span greater than height' in the diagnosis of Marfan syndrome. He pointed out that equality of span and height, which allows man to be portrayed within a square, is a concept that dates from the Roman architect Vitruvius and was, of course, immortalized by Leonardo da Vinci. However, anthropometry shows that span exceeds height in most (59-78%) normal adult white males. Godfrey et al. (1993) reported prenatal diagnosis by the linkage method in a 4-generation Marfan kindred. The diagnosis was made using CVS material at 11 weeks' gestation. At birth the infant showed skeletal changes suggestive of the Marfan syndrome. The mutation involved a donor splice site in the FBN1 gene (134797.0014). In a pregnant affected female in a third generation, Rantamaki et al. (1995) succeeded in the prenatal diagnosis by chorionic villus sampling. De Paepe et al. (1996) proposed a revision of diagnostic criteria for Marfan syndrome and related conditions. Most notable were the following: more stringent requirements for diagnosis of Marfan syndrome in relatives of an unequivocally affected individual; skeletal involvement as a major criterion if at least 4 of 8 typical skeletal manifestations are present; potential contribution of molecular analysis to the diagnosis of Marfan syndrome; and delineation of initial criteria for diagnosis of other heritable conditions with partially overlapping phenotypes. Of most concern were the misdiagnoses of relatives that arose by relying solely on Berlin Nosology (Beighton et al., 1988) after unequivocal diagnosis of a first-degree relative (Pereira et al., 1994; Dietz et al., 1995). Molecular evidence showed that the criterion of a positive family history could produce a bias in favor of overdiagnosis. De Paepe et al. (1996) reproduced the diagrams for normal range of aortic root dimensions versus body surface area in children and adults, as reported by Roman et al. (1989). Rose et al. (2000) compared the Berlin (Beighton et al., 1988) and Ghent (de Paepe et al., 1996) nosologies. In a study at the NIH they found that 19% of patients diagnosed under the Berlin criteria failed to meet the Ghent standard. They also found that dural ectasia was the second most common major diagnostic manifestation, and that screening for dural ectasia established the diagnosis of Marfan syndrome in 23% of patients under the Ghent criteria. De Backer et al. (2006) assessed the prevalence of minor cardiovascular manifestations in Marfan syndrome to evaluate their usefulness in a diagnostic setting. Seventy-seven patients with Marfan syndrome, aged 4 months to 55 years, underwent echocardiography to assess the presence of mitral valve prolapse and the diameter of the main pulmonary artery. A subset of 29 adult patients with Marfan syndrome also underwent MRI evaluation of the diameters of the thoracoabdominal aorta. Mitral valve prolapse was encountered in 66% of patients with Marfan syndrome, with an equal distribution of classic and nonclassic mitral valve prolapse. The main pulmonary artery diameter was significantly larger in patients with Marfan syndrome at all ages when compared with controls. In the adult group (older than 14 years), De Backer et al. (2006) provided a cutoff value of 23 mm to define pulmonary artery dilatation. The descending aorta was enlarged, but with substantial overlap with controls, thus precluding the use of a cutoff value. De Backer et al. (2006) concluded that mitral valve prolapse and main pulmonary artery dilatation are common findings in Marfan syndrome patients at all ages and are easy to assess with echocardiography. De Backer et al. (2006) recommended echocardiographic evaluation of mitral valve prolapse and main pulmonary artery diameter in patients referred for cardiovascular diagnostic assessment for Marfan syndrome. Hennekam (2012) commented on 2 papers reviewing the distinction between the Ghent and revised Ghent nosologies for the diagnosis of Marfan syndrome, one by Aalberts et al. (2012) in a Dutch population and the other by Yang et al. (2012) in a Korean population, in which no significant differences were found in the diagnostic yield except for some slight improvement in specificity for mitral valve prolapse (see 157700) and MASS syndrome (604308), respectively.
Increased height, disproportionately long limbs and digits, anterior chest deformity, mild to moderate joint laxity, vertebral column deformity (scoliosis and thoracic lordosis), and a narrow, highly arched palate with crowding of the teeth are frequent skeletal features. Sponseller ... Increased height, disproportionately long limbs and digits, anterior chest deformity, mild to moderate joint laxity, vertebral column deformity (scoliosis and thoracic lordosis), and a narrow, highly arched palate with crowding of the teeth are frequent skeletal features. Sponseller et al. (1995) evaluated spinal deformity in 113 patients with Marfan syndrome, 82 of whom were skeletally immature. Scoliosis was found in 52 of the 82 patients, with equal prevalence for the sexes. The thoracic portion of the curve was convex to the right in all but 2 patients. Westling et al. (1998) quantitated the craniofacial morphology through evaluation of dental casts and lateral cephalograms in 76 Marfan patients. About 70% of the patients had been referred for orthodontic treatment, mostly because of crowded teeth or extreme maxillary overjet (overbite). The appearance of the palatal vault, crowded teeth, and overbite were illustrated. Myopia, increased axial globe length, corneal flatness, and subluxation of the lenses (ectopia lentis) are ocular findings. Mitral valve prolapse, mitral regurgitation, dilatation of the aortic root, and aortic regurgitation are cardiovascular features. The major life-threatening cardiovascular complications--aneurysm of the aorta and aortic dissection--were reported in single cases by Baer et al. (1943) and Etter and Glover (1943). About one-third of affected persons have mitral valve prolapse, aortic root enlargement, or both on echocardiography, despite normal auscultatory findings on cardiac examination (Brown et al., 1975; Pyeritz and McKusick, 1979). Other common or peculiar manifestations include striae distensae, pulmonary blebs (which predispose to spontaneous pneumothorax), and spinal arachnoid cysts or diverticula (Weir, 1973; Newman and Tilley, 1979; Cilluffo et al., 1981). By CT scanning, Pyeritz et al. (1988) found widening of the lumbosacral spinal canal (dural ectasia) in 36 of 57 patients with the Marfan syndrome and in none of 57 age- and sex-matched non-Marfan control patients. Severe changes were present in 13 patients, 2 of whom had associated neurologic signs, and included meningoceles or near-total erosion of a pedicle. Yellin et al. (1991) described a father and 2 sons with multiple and bilateral episodes of pneumothorax. Fattori et al. (1999) studied the frequency of dural ectasia in the Marfan syndrome, this feature having been classified as a major diagnostic criterion by Beighton et al. (1988) and De Paepe et al. (1996). MRI studies of the thoracic aorta and lumbosacral spine were performed in 83 patients with Marfan syndrome; 12 patients were younger than 18 years. The control group consisted of 100 individuals who underwent MRI of the lumbar spine for routine clinical indications; none of them had any potential causes for dural ectasia. Dural ectasia was identified in 76 (92%) patients and none of the control group. The severity of dural ectasia was related to age; the mean (SD) age of patients with mild dural ectasia was 26 years (14), whereas that of those with severe disease (meningocele) was 36 years (9) (p = 0.038). Dural ectasia was present in 11 of 12 patients younger than 18 years. No association was found between aortic dilatation and dural ectasia. Ahn et al. (2000) studied dural ectasia in 32 volunteers with Marfan syndrome as diagnosed by the Ghent criteria (De Paepe et al., 1996). They concluded that MRI and CT diagnosed dural ectasia with high specificity and sensitivity, and suggested criteria for the diagnosis in adult Marfan patients. Van den Berg et al. (1996) surveyed 135 patients with Marfan syndrome and found none that presented with the symptomatic intracranial aneurysm. Morse et al. (1990) reported experience with 22 severely affected infants in whom the diagnosis of the Marfan syndrome was made in the first 3 months of life and reviewed the cases of 32 previously reported infants. They pointed out that serious cardiac abnormalities as well as congenital contractures may be present at birth. The most severely affected cases appear to be due to sporadic mutation; familial cases have milder manifestations which render them more difficult to detect during infancy. Buntinx et al. (1991) described severe Marfan syndrome in a neonate with aortic dilatation and cardiac valve insufficiency who died from heart failure at 20 hours of age. Cardiomegaly and aortic dilatation had been noted at 35 weeks' gestation by means of routine ultrasonography. While the occurrence of contractures in the severe neonatal form raised a question about the distinctness of congenital contractural arachnodactyly (CCA; 121050) from Marfan syndrome, CCA has now been linked to the gene encoding fibrillin-2 (612570) on chromosome 5. The contractures tend to resolve with time. Hanseus et al. (1995) described a case very similar to that of Buntinx et al. (1991): a newborn girl with extreme cardiomegaly discovered by fetal ultrasound at 34 gestational weeks. The girl died at the age of 10 hours. Postmortem examination showed cardiovascular lesions typical of Marfan syndrome. Immunofluorescence studies of cultured fibroblasts from the patient showed decreased amounts of immunostained fibrillin, supporting the clinical diagnosis of severe Marfan syndrome. Ruiz et al. (1996) described acute dissection of the aorta in a 5-year-old girl with Marfan syndrome. Surgical repair was successful. The patient's father had Marfan syndrome with previous surgery for aortic dissection. The mother made the diagnosis of acute dissection in her daughter. The trisomy 8 syndrome (Pai et al., 1979) simulates the Marfan syndrome in its skeletal features. However, it does not show the ocular and aortic characteristics of the Marfan syndrome and does show unusual creases of the palms and soles and mental retardation which are not found in the Marfan syndrome. Most, if not all, cases of trisomy 8 have been mosaic, thus accounting for the relatively mild manifestations of trisomy of a large chromosome. James and Jacobs (1996) determined the parental origin in 8 cases of constitutional trisomy 8. In all 4 cases of spontaneous abortion, the additional chromosome was maternal in origin and there was evidence for nullichiasmate meiosis I as the basis of the trisomy. In contrast, all 4 cases of liveborn trisomy 8 studied appeared to have arisen by a mechanism consistent with the postzygotic mitotic gain of the additional chromosome, a mechanism consistent with mosaicism. In a survey of adult genetic skeletal dysplasias in the Museum of Pathological Anatomy in Vienna, Beighton et al. (1993) pictured the skeleton of a man who died of pulmonary tuberculosis at the age of approximately 35 years. A detailed appraisal of the skeleton had been published in the pathology literature in 1904 as an example of macrosomia. The height was 191 cm, the hand length was 20 cm, and the upper segment/lower segment ratio was 0.82. The diagnosis was clearly Marfan syndrome. Cistulli and Sullivan (1995) suggested that the Marfan syndrome is associated with a high prevalence of obstructive sleep apnea. They measured upper airway closing pressures during sleep in 12 patients and 6 age-, height-, and weight-matched controls. Obstructive sleep apnea was found in 10 of the patients. All 12 patients with the Marfan syndrome, including the 2 without obstructive sleep apnea, demonstrated increased upper airway collapsibility during sleep. In contrast, only 2 control subjects demonstrated upper airway closure, and that only at significantly higher suction pressures. Verbraecken et al. (1995) reported obstructive sleep hypopnea syndrome in a 35-year-old woman who had Marfan syndrome. They commented that 'such findings are not obvious because Marfan patients have a rather low weight and a tall and slender neck.' They presumed that an increased laxity of the pharyngeal wall was responsible for the complication. Verbraecken et al. (2003) described a patient with Marfan syndrome and coexistent obstructive sleep hypopnea and restrictive lung disease, complicated by respiratory insufficiency. Successful treatment with nasal intermittent positive airway pressure and oxygen appeared to 'attenuate' the progressive dilatation of the aortic root, but did not reverse it. Verbraecken et al. (2003) hypothesized that a decrease of nocturnal intrathoracic pressures could at least partially explain the observation. Murdoch et al. (1972) reported that life span in patients affected with the Marfan syndrome is markedly shortened and that most deaths are cardiovascular. Silverman et al. (1995) reported a study of survival in 417 patients from 4 referral centers with a definite diagnosis of the Marfan syndrome. They concluded that life expectancy had increased more than 25% since 1972 and suggested that the reasons for the increase might include (1) an overall improvement in population life expectancy; (2) benefits arising from cardiovascular surgery; (3) a greater proportion of mild cases due to increased frequency of diagnosis; and (4) medical therapy, including beta-blockers. Gray et al. (1998) studied 206 Marfan syndrome patients ascertained through genetics clinics in Wales and Scotland during the period 1970 to 1990. Median survival was 53 years for males and 72 years for females. Mean age at death was 45.3 +/- 16.5 years. Severity was the best independent indicator of survival. The study was not able to assess the efficacy of beta-blockade. Parida et al. (1997) described an infant with neonatal Marfan syndrome and a large hiatus/paraesophageal hernia with pronounced gastroesophageal reflux. Whitelaw et al. (2004) reported 2 unrelated infant girls with neonatal Marfan syndrome and primary trabeculodysgenesis; FBN1 mutations were confirmed in both cases. Tekin et al. (2007) identified a heterozygous mutation in the FBN1 gene (134797.0046) in a male infant with severe neonatal Marfan syndrome. Two older brothers were similarly affected, and all 3 sibs died at ages 2 to 4 months of cardiorespiratory insufficiency. Mosaicism for the mutation was identified in somatic cells and germ cells of the clinically unaffected father. Tekin et al. (2007) stated that this was the first report of familial neonatal Marfan syndrome. Voermans et al. (2009) evaluated 10 patients with Marfan syndrome specifically for neuromuscular features. Four older patients had muscle weakness, 5 had mild to moderate reduction in vibration sense, and all older patients mentioned mild functional impairment compared to controls. Neurophysiologic studies showed axonal neuropathy in 4, and myopathic and neurologic changes in all. Imaging showed lumbosacral dural ectasia in 7 patients. Voermans et al. (2009) emphasized that neuromuscular features may be present in Marfan syndrome, particularly in older patients, and noted that muscle hypoplasia and myopathy had been reported by Marfan himself as a feature of the syndrome. Lundby et al. (2012) found that 47 of 87 (54%) patients with Marfan syndrome had widening of the trunk of the pulmonary artery (30 mm or more) as determined by magnetic resonance or computed tomography imaging. Of these 47, 15% had no sign of disease of the ascending aorta.
Attias et al. (2009) compared clinical features and outcomes of 71 patients with TGFBR2 (190182) mutations to those of 243 patients with FBN1 mutations. Aortic dilation was present in a similar proportion of patients in both the TGFBR2 ... Attias et al. (2009) compared clinical features and outcomes of 71 patients with TGFBR2 (190182) mutations to those of 243 patients with FBN1 mutations. Aortic dilation was present in a similar proportion of patients in both the TGFBR2 and FBN1 groups (78% and 79%, respectively) but was highly variable; the incidence and average age for thoracic aortic surgery and aortic dissection were also similar in the 2 groups. Mitral valve involvement was less frequent in the TGFBR2 than in the FBN1 group (p less than 0.05 for myxomatous valve, prolapse, or mitral regurgitation). Aortic dilation, dissection, or sudden death was the index event leading to genetic diagnosis in 65% of families with TGFBR2 mutations versus 32% with FBN1 mutations (p = 0.002). The rate of death was greater in TGFBR2 families before diagnosis, but similar once the disease was recognized. Most pregnancies were uneventful in both groups. Seven (10%) of the 71 patients with TGFBR2 mutations fulfilled the Ghent criteria for Marfan syndrome, including 2 with ectopia lentis, compared with 140 (58%) of 243 patients in the FBN1 group (p less than 0.0001); 3 patients in the TGFBR2 group fulfilled the diagnostic criteria for both Loeys-Dietz (see 610168) and Marfan syndromes. Noting that clinical outcomes were similar between treated patients from both groups, Attias et al. (2009) concluded that prognosis depends on clinical disease expression and treatment rather than simply the presence of a TGFBR2 mutation. Using DNA samples from 300 patients with clinical features of MFS or a related phenotype that had been previously screened by DHPLC with no mutations found in the FBN1 gene, Hilhorst-Hofstee et al. (2011) performed multiplex ligation-dependent probe amplification (MLPA) and identified 9 patients from 5 families with deletion of 1 entire FBN1 allele. A tenth patient with complete deletion of FBN1 was identified by cytogenetic analysis and array CGH. All of the patients had facial and skeletal features of MFS, and 7 of the 10 patients fulfilled the Ghent criteria; the 3 patients who did not present the full clinical picture of MFS were young (5, 8, and 13 years of age, respectively). Aortic root dilation was present in 6 patients, 2 of whom underwent surgical repair at relatively young ages. Hilhorst-Hofstee et al. (2011) concluded that complete loss of 1 FBN1 allele does not predict a mild phenotype, and that their findings support the hypothesis that true haploinsufficiency can lead to the classic phenotype of Marfan syndrome.