Thompson & Thompson Genetics in Medicine, 8th Edition

Case 30. Marfan Syndrome (FBN1 Mutation, MIM 154700)

Autosomal Dominant


• Dominant negative mutations

• Variable expressivity

Major Phenotypic Features

• Age at onset: Early childhood

• Disproportionately tall stature

• Skeletal anomalies

• Ectopia lentis

• Mitral valve prolapse

• Aortic dilatation and rupture

• Spontaneous pneumothorax

• Lumbosacral dural ectasia

History and Physical Findings

J.L., a healthy 16-year-old high school basketball star, was referred to the genetics clinic for evaluation for Marfan syndrome. His physique was similar to that of his father. His father, a tall, thin man, had died during a morning jog; no other family members had a history of skeletal abnormalities, sudden death, vision loss, or congenital anomalies. On physical examination, J.L. had an asthenic habitus with a high arched palate, mild pectus carinatum, arachnodactyly, arm span–height ratio of 1.1, diastolic murmur, and stretch marks on his shoulders and thighs. He was referred for echocardiography, which showed dilatation of the aortic root with aortic regurgitation. An ophthalmological examination showed bilateral iridodonesis and slight superior displacement of the lenses. On the basis of his physical examination and testing results, the geneticist explained to J.L. and his mother that he had Marfan syndrome.


Disease Etiology and Incidence

Marfan syndrome (MIM 154700) is a panethnic, autosomal dominant, connective tissue disorder that results from mutations in the fibrillin 1 gene (FBN1, MIM 134797). This syndrome has an incidence of approximately 1 in 5000. Approximately 25% to 35% of patients have de novo mutations. Mutations leading to Marfan syndrome are scattered across the gene, and each mutation is usually unique to a family.


FBN1 encodes fibrillin 1, an extracellular matrix glycoprotein with wide distribution. Fibrillin 1 polymerizes to form microfibrils in both elastic and nonelastic tissues, such as the aortic adventitia, ciliary zonules, and skin.

Mutations affect fibrillin 1 synthesis, processing, secretion, polymerization, or stability. Studies of fibrillin 1 deposition and cell culture expression assays have generally suggested a dominant negative pathogenesis; that is, production of mutant fibrillin 1 inhibits formation of normal microfibrils by normal fibrillin 1 or stimulates inappropriate proteolysis of extracellular microfibrils. More recent evidence in mouse models of Marfan syndrome suggests that half-normal amounts of normal fibrillin 1 are insufficient to initiate effective microfibrillar assembly. Thus haploinsufficiency may also contribute to disease pathogenesis.

In addition to Marfan syndrome, mutations in FBN1 can cause other syndromes, including neonatal Marfan syndrome, isolated skeletal features, autosomal dominant ectopia lentis, and the MASS phenotype (marfanoid signs, including mitral valve prolapse or myopia, borderline and nonprogressive aortic enlargement, and nonspecific skeletal and skin findings). In general, the phenotypes are fairly consistent within a family, although the severity of the phenotype may vary considerably. To date, clear genotype-phenotype correlations have not emerged. The intrafamilial and interfamilial variability suggests that environmental and epigenetic factors play a significant role in determining the phenotype.

Recent evidence in mouse models suggests that fibrillin 1 is not simply a structural protein, and that Marfan syndrome is not the result of structural weakness of the tissues. Rather, fibrillin 1 microfibrils normally bind and reduce the concentration and activity of growth factors in the TGFβ superfamily. Loss of fibrillin 1 leads to an increase in the local abundance of unbound TGFβ and in local activation of TGFβ signaling. This increased signaling contributes significantly to the pathogenesis, as shown by the rescue by TGFβ antagonists of the pulmonary and vascular changes seen in fibrillin 1-deficient mice (see Chap. 13).

Phenotype and Natural History

Marfan syndrome is a multisystem disorder with skeletal, ocular, cardiovascular, pulmonary, skin, and dural abnormalities. The skeletal abnormalities include disproportionate tall stature (arm span–height ratio > 1.05; upper to lower segment ratio < 0.85 in adults), arachnodactyly, pectus deformities, scoliosis, joint laxity, and narrow palate. Ocular abnormalities associated with Marfan syndrome are ectopia lentis (Fig. C-30), flat corneas, and increased globe length causing axial myopia. The cardiovascular abnormalities include mitral valve prolapse, aortic regurgitation, and dilatation and dissection of the ascending aorta. Striae atrophicae and recurrent herniae are common, and lumbosacral dural ectasia may occur. Spontaneous pneumothorax and apical blebs can be seen in this disorder.


FIGURE C-30 Ectopia lentis. Slit-lamp view of the left eye of a patient with Marfan syndrome. The asterisk indicates the center of the lens that is displaced superior nasally; normally, the lens is in the center of the pupil. The arrows indicate the edge of the lens that is abnormally visible in the pupil. See Sources & Acknowledgments.

Many features of Marfan syndrome develop with age. Skeletal anomalies such as anterior chest deformity and scoliosis worsen with bone growth. Subluxation of the lens is often present in early childhood but can progress through adolescence. Retinal detachment, glaucoma, and cataracts show increased frequency in Marfan syndrome. Cardiovascular complications manifest at any age and progress throughout life.

The major causes of premature death in patients with Marfan syndrome are heart failure from valve regurgitation and aortic dissection and rupture (see Fig. 13-6). As surgical and medical management of the aortic dilatation have improved, so has survival. Between 1972 and 1993, the median age of mortality in Marfan patients rose from 49 to 74 years for women and from 41 to 70 years for men.


Marfan syndrome is a clinical diagnosis based upon the recognition of characteristic features in the ocular, skeletal, and cardiovascular systems and the integument. Aortic root dilatation and ectopia lentis carry disproportionate weight in the diagnostic criteria, given their relative specificity for this disorder. Although molecular confirmation of an FBN1 mutation is not a requirement for diagnosis, it can play a pivotal role in children with emerging clinical manifestations or in atypically mild presentations of disease. FBN1 gene sequencing lacks full specificity or sensitivity for Marfan syndrome and therefore cannot substitute for a comprehensive clinical evaluation. It can be of particular importance, however, for prenatal and presymptomatic diagnosis and in the discrimination of Marfan syndrome from other entities in the differential diagnosis, some of which require different treatment protocols.

There is presently no cure for Marfan syndrome; treatment therefore focuses on prevention and symptomatic management. Ophthalmological management includes frequent examinations, correction of the myopia and, often, lens replacement. Orthopedic management includes bracing or surgery for scoliosis. Pectus deformity repair is largely cosmetic. Physical therapy or orthotics can compensate for joint instability. Cardiovascular management includes a combination of medical and surgical therapy. Medical therapy attempts to prevent or to slow progression of aortic dilatation by reducing heart rate, blood pressure, and ventricular ejection force historically with β-adrenergic blockers. Recent work using mouse models of Marfan syndrome documents remarkable protection from aortic aneurysm and dissection with the use of angiotensin receptor blockers such as losartan, which work through a combination of reduction of hemodynamic stress and antagonism of the transforming growth β signaling cascade. Clinical trials of losartan in Marfan syndrome are on-going. Cardiovascular protection is also achieved through restriction of participation in contact sports, competitive sports, and isometric exercise. Prophylactic replacement of the aortic root is recommended when aortic dilatation or aortic regurgitation becomes sufficiently severe. Most patients now receive a valve-sparing aortic root replacement that eliminates the need for chronic anticoagulation.

Pregnancy can precipitate progressive aortic enlargement or dissection. The aortic dissections are believed to be secondary to the hormonal, blood volume, and cardiac output changes associated with pregnancy and parturition. Current evidence suggests that there is a high risk for dissection in pregnancy if the aortic root measures more than 4 cm at conception. Women can elect to undergo valve-sparing aortic replacement before pregnancy.

Inheritance Risk

Patients with Marfan syndrome have a 50% risk for having a child affected with Marfan syndrome. In families segregating Marfan syndrome, at-risk individuals can be identified by detecting the mutation (if known in the family) or by clinical evaluation. Prenatal diagnosis is available for families in which the FBN1 mutation has been identified.

Questions for Small Group Discussion

1. Homocystinuria has many overlapping features with Marfan syndrome. How can these two disorders be distinguished by medical history? by physical examination? by biochemical testing?

2. What are dominant negative mutations? What are gain-of-function mutations? Contrast the two. Why are dominant negative mutations common in connective tissue disorders?

4. If one wished to design a curative treatment for a disorder caused by dominant negative mutations, what must the therapy accomplish at a molecular level? How is this different from treatment of a disease caused by loss-of-function mutations?


Bolar N, Van Laer L, Loeys BL. Marfan syndrome: from gene to therapy. Curr Opin Pediatr. 2012;24:498–504.

Cook JR, Ramirez F. Clinical, diagnostic, and therapeutic aspects of the Marfan syndrome. Adv Exp Med Biol. 2014;802:77–94.

Dietz HC. Marfan syndrome. [2001 [Updated 2014]. Available from]

Lacro RV, Guey LT, Dietz HC, et al. Characteristics of children and young adults with Marfan syndrome and aortic root dilation in a randomized trial comparing atenolol and losartan therapy. Am Heart J. 2013;165:828–835.

Yim ES. Aortic root disease in athletes: aortic root dilation, anomalous coronary artery, bicuspid aortic valve, and Marfan's syndrome. Sports Med. 2013;43:721–732.