Clinical characteristics.

FBN1-related Marfan syndrome (Marfan syndrome), a systemic disorder of connective tissue with a high degree of clinical variability, comprises a broad phenotypic continuum ranging from mild (features of Marfan syndrome in one or a few systems) to severe and rapidly progressive neonatal multiorgan disease. Cardinal manifestations involve the ocular, skeletal, and cardiovascular systems. Ocular findings include myopia (>50% of affected individuals); ectopia lentis (seen in approximately 60% of affected individuals); and an increased risk for retinal detachment, glaucoma, and early cataracts. Skeletal system manifestations include bone overgrowth and joint laxity; disproportionately long extremities for the size of the trunk (dolichostenomelia); overgrowth of the ribs that can push the sternum in (pectus excavatum) or out (pectus carinatum); and scoliosis that ranges from mild to severe and progressive. The major morbidity and early mortality in Marfan syndrome relate to the cardiovascular system and include dilatation of the aorta at the level of the sinuses of Valsalva (predisposing to aortic tear and rupture), mitral valve prolapse with or without regurgitation, tricuspid valve prolapse, and enlargement of the proximal pulmonary artery. Severe and prolonged regurgitation of the mitral and/or aortic valve can predispose to left ventricular dysfunction and occasionally heart failure. With proper management, the life expectancy of someone with Marfan syndrome approximates that of the general population.

Diagnosis/testing.

The diagnosis of Marfan syndrome is established in a proband (by definition a person without a known family history of Marfan syndrome) who has an FBN1 pathogenic variant known to be associated with Marfan syndrome and EITHER of the following:

• Aortic root enlargement (z score ≥2.0)
• Ectopia lentis

Management.

Treatment of manifestations: Comprehensive management by a multidisciplinary team including a clinical geneticist, cardiologist, ophthalmologist, orthopedist, and cardiothoracic surgeon is strongly recommended. Treatment typically includes spectacle correction for refractive errors and, sometimes, surgical removal of a dislocated lens with artificial lens implantation (preferably after growth is complete). Glaucoma, cataracts, and retinal detachment are treated in the standard fashion per an ophthalmologist. Scoliosis may require bracing or surgical stabilization; repair of pectus deformity is largely cosmetic. Functional deficits or pain associated with protusio acetabulae may respond to physical therapy, analgesics, or anti-inflammatory medications. Orthotics and arch supports can lessen leg fatigue, joint pain, and muscle cramps associated with pes planus. Dental crowding may be addressed through orthodontia and a palatal expander may be considered in some cases. Surgical repair of the aorta is indicated either when the maximal measurement of the aortic root approaches 5.0 cm in adults or older children, when the rate of increase of the aortic root diameter approaches 0.5-1.0 cm per year, or if there is progressive and severe aortic regurgitation. For younger children, aortic root surgery should be considered once: (1) the rate of increase of the aortic root diameter approaches 0.5-1.0 cm per year, or (2) there is progressive and severe aortic regurgitation. Severe and progressive mitral valve regurgitation with attendant ventricular dysfunction requires immediate attention of a cardiologist or cardiothoracic surgeon and is the leading indication for cardiovascular surgery in children with Marfan syndrome. Afterload-reducing agents can improve cardiovascular function when congestive heart failure is present. Standard treatment for hernias and pneumothorax is recommended. There are no known effective therapies for symptomatic dural ectasia.

Prevention of primary manifestations: Medications that reduce hemodynamic stress on the aortic wall, such as beta-blockers or angiotensin receptor blockers (ARBs), are routinely prescribed. This therapy should be managed by a cardiologist or clinical geneticist familiar with its use. Therapy is generally initiated at the time of diagnosis with Marfan syndrome at any age or upon appreciation of progressive aortic root dilatation even in the absence of a definitive diagnosis.

Surveillance: Measurement of length/height/weight at each visit. Ophthalmologic examination annually or as clinically indicated. Clinical assessment for chest wall deformities and scoliosis at each visit until skeletal maturity, although severe scoliosis may require ongoing surveillance in adulthood. At least annual dental evaluation, including orthodontia, as indicated. Echocardiography annually when aortic dimensions are small and the rate of aortic dilatation is slow; more frequent than annual examinations are indicated when the aortic root diameter exceeds approximately 4.5 cm in adults, rates of aortic dilatation exceed approximately 0.3 cm per year, or significant aortic regurgitation is present. Intermittent surveillance of the entire aorta with CT or MRA scans beginning in young adulthood or at least annually in anyone with a history of aortic root replacement or dissection.

Agents/circumstances to avoid: Contact sports, competitive sports, and isometric exercise; activities that cause joint injury or pain; agents that stimulate the cardiovascular system, including decongestants and excessive caffeine; agents that cause vasoconstriction, including triptans; LASIK correction of refractive errors; breathing against resistance or positive pressure ventilation in those with a documented predisposition for pneumothorax; fluoroquinolone antibiotics, which may exacerbate the predisposition for aneurysm and dissection; classes of antihypertensive agents (e.g., calcium channel blockers, ACE inhibitors) where there is an absence of direct evidence for their efficacy or safety in individuals with Marfan syndrome.

Evaluation of relatives at risk: It is recommended that the genetic status of at-risk relatives of any age be clarified so that affected individuals can undergo routine surveillance for early detection of medically significant complications, particularly potentially life-threatening cardiac manifestations. Genetic status of at-risk relatives can be established EITHER:

• By molecular genetic testing if the FBN1 pathogenic variant in the family is known; OR
• In those with a rigorously defined family history of Marfan syndrome, by the presence of ONE OR MORE of the following:
  • Ectopia lentis
  • A systemic score ≥7
  • Aortic root dilatation (z score ≥2.0 for individuals age ≥20 years or z score ≥3.0 for those age <20 years)

Pregnancy management: An individual with Marfan syndrome should consider pregnancy only after appropriate counseling from a clinical geneticist or cardiologist familiar with this condition, a genetic counselor, and a high-risk obstetrician because of the risk of more rapid dilation of the aorta or aortic dissection during pregnancy, delivery, or in the immediate postpartum period. Cardiovascular imaging with echocardiography should be performed every two to three months during pregnancy to monitor aortic root size and growth. Monitoring should continue in the immediate postpartum period because of the increased risk for aortic dissection.

Individuals with Marfan syndrome who anticipate pregnancy or become pregnant should continue use of beta-blockers; however, some other classes of medications such as ARBs should be discontinued because of the increased risk for fetal loss, oligohydramnios, and abnormal development, often related to second- and third-trimester exposure.

Genetic counseling.

Marfan syndrome is inherited in an autosomal dominant manner. Approximately 75% of individuals with Marfan syndrome have an affected parent; approximately 25% have a de novo FBN1 pathogenic variant. Each child of an individual with Marfan syndrome has a 50% chance of inheriting the pathogenic variant and the disorder. Once the FBN1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

Marfan syndrome should be suspected in individuals with the following clinical findings and family history.

Clinical findings

• Aortic root enlargement (z score ≥2.0). Note: Aortic size must be standardized to age and body size for accurate interpretation. A z score ≥2.0 indicates a value at or above the 95th percentile, while a z score ≥3.0 indicates a value at or above the 99th percentile. References and calculators for this determination are available at the Marfan Foundation website.
• Ectopia lentis; most reliably diagnosed by slit-lamp examination after maximal pupillary dilation
• A systemic score ≥7 (Table 1)

Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history of Marfan syndrome does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of FBN1-related Marfan syndrome is established in a proband (by definition a person without a known family history of Marfan syndrome) who has an FBN1 pathogenic variant known to be associated with Marfan syndrome and EITHER of the following [Loeys et al 2010]:

• Aortic root enlargement (z score ≥2.0)
• Ectopia lentis

Note: Given that many manifestations of Marfan syndrome emerge with age, the author suggests the use of tentative diagnostic designations in individuals younger than age 20 years with suggestive findings who do not quite reach diagnostic thresholds:

• Nonspecific connective tissue disorder. If the systemic score is <7 and/or aortic root measurements are borderline (z score <3) (without an FBN1 pathogenic variant), use of this term is suggested until follow-up echocardiographic evaluation shows aortic root dilatation (z score ≥3).
• Potential Marfan syndrome. If an FBN1 pathogenic variant that has not previously been associated with aortic enlargement is identified in a person who represents a simplex case (i.e., a single occurrence in a family) and the aortic root z score is <3.0, this term should be used until the aorta reaches this threshold.

Molecular genetic testing approaches (see Table 2) can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings of Marfan syndrome described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those who do not have sufficiently discriminating features to consider the diagnosis of Marfan syndrome are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

FBN1-related Marfan syndrome (Marfan syndrome), a systemic disorder of connective tissue, is part of a broad phenotypic continuum associated with heterozygous FBN1 pathogenic variants that ranges from mild (features of Marfan syndrome in one or a few systems) to severe (rapidly progressive multiorgan disease in neonates). Cardinal manifestations of Marfan syndrome involving the ocular, skeletal, and cardiovascular systems have a high degree of clinical variability.

As a general rule, clinical manifestations run true within families, suggesting that the FBN1 pathogenic variant is the predominant determinant of phenotype.

Eye

• Myopia is a common ocular feature (>50% of affected individuals), often progressing rapidly during childhood.
• Displacement of the lens from the center of the pupil (ectopia lentis) is a hallmark feature of Marfan syndrome, and is seen in approximately 60% of affected individuals.
  While generally evident in early childhood, ectopia lentis can evolve later in life.
• The globe is often elongated and the cornea may be flat.
• Individuals with Marfan syndrome are at increased risk for retinal detachment, glaucoma, and early cataract formation.

Skeletal. The skeletal system is characterized by excessive linear growth of the long bones and joint laxity. All skeletal findings can develop in young children and tend to progress during periods of rapid growth. It is important to note that individuals with Marfan syndrome are not necessarily tall by population standards; they are taller than predicted for their family background [Erkula et al 2002].

• Paradoxically, some individuals can show reduced joint mobility, especially of the elbow and digits, and can have an exaggerated arch to the foot (pes cavus).
• The extremities are disproportionately long for the size of the trunk (dolichostenomelia), leading to an increase in the arm span to height ratio (>1.05 in adults) and a decrease in the upper to lower segment ratio <0.85 in adults).
• Overgrowth of the ribs can push the sternum in (pectus excavatum) or out (pectus carinatum).
• Scoliosis is also common and can be mild or severe and progressive (see Management).
• The combination of bone overgrowth and joint laxity leads to the characteristic thumb and wrist signs.
• Flat feet (pes planus) is common in Marfan syndrome and may be associated with inward rotation at the ankle (also known as hindfoot deformity), contributing to difficulty with ambulation, leg fatigue, and muscle cramps.
• The acetabulum can be abnormally deep and show accelerated erosion (protrusio acetabuli). This can lead to associated pain and functional limitations (see Management).

Craniofacial features include the following:

• A long and narrow face with deeply set eyes (enophthalmos)
• Downward slanting of the palpebral fissures
• Flat cheek bones (malar hypoplasia)
• Small and receding chin (micrognathia, retrognathia)
• Highly arched and narrow palate, often associated with tooth crowding

Cardiovascular. The major sources of morbidity and early mortality relate to the cardiovascular system. Cardiovascular manifestations include the following:

• Dilatation of the aorta at the level of the sinuses of Valsalva with a predisposition for aortic tear and rupture
  • Aortic dilatation tends to progress over time; however, the onset and rate of progression of aortic dilatation is highly variable.
  • Aortic dissection is exceedingly rare in early childhood.
  • In adults, a significant risk for aortic dissection or rupture occurs when the maximal dimension reaches approximately 5.0 cm. Histologic examination reveals fragmentation of elastic fibers, loss of elastin content, and accumulation of amorphous matrix components in the aortic media.
    These histologic findings do not distinguish Marfan syndrome from other causes of aortic aneurysm.
  • As an aneurysm enlarges, the aortic annulus can become stretched, leading to secondary aortic regurgitation.
• Mitral valve prolapse (MVP) with or without regurgitation
• Tricuspid valve prolapse with or without regurgitation
• Enlargement of the proximal pulmonary artery

Valvular dysfunction can lead to volume overload with secondary left ventricular dilatation and failure. Indeed, MVP with congestive heart failure is the leading cause of cardiovascular morbidity and mortality – and the leading indication for cardiovascular surgery – in young children with severe features of Marfan syndrome. The majority of individuals with Marfan syndrome and MVP have a tolerable degree of mitral regurgitation that shows slow, if any, progression with age. A study of 87 individuals with Marfan syndrome identified enlarged pulmonary artery root in 54% [Lundby et al 2012].

Other

• Dura. Stretching of the dural sac in the lumbosacral region (dural ectasia) can lead to bone erosion and nerve entrapment.
  • Symptoms include low back pain, proximal leg pain, weakness and numbness above and below the knees, and genital/rectal pain.
  • Leaking of cerebrospinal fluid (CSF) from a dural sac can cause postural drop in CSF pressure and headache.
• Skin and integument manifestations include hernias and skin stretch marks (striae distensae). Individuals can show a paucity of muscularity and fat stores despite adequate exercise and caloric intake.
• Lung bullae can develop, especially of the upper lobes, and can predispose to spontaneous pneumothorax. Increased total and residual lung volume and reduced peak oxygen uptake have been demonstrated, with reduced aerobic capacity.
• Pregnancy can be dangerous for women with Marfan syndrome, especially if the aortic root exceeds 4.0 cm (see Pregnancy Management). Complications include rapid progression of aortic root enlargement and aortic dissection or rupture during pregnancy, delivery, and the postpartum period. Pregnancy-associated dissection can occur in the ascending or descending segments of the aorta.
• Self-image. The vast majority of affected individuals older than age 13 years report a positive general self-image.
• Learning disability and/or hyperactivity has been suggested as a rare manifestation of Marfan syndrome, but may simply occur in this context at a frequency observed in the general population.

Prognosis. With proper management of the cardiovascular manifestations, the life expectancy of someone with Marfan syndrome approximates that of the general population [Silverman et al 1995].

Genotype-Phenotype Correlations

Few genotype-phenotype correlations exist in FBN1-related Marfan syndrome; none is definitive [Dietz & Pyeritz 2001].

• As a general rule, a variant that causes the in-frame loss or gain of central coding sequence through deletions, insertions, or splicing errors is associated with more severe disease.
• Pathogenic variants that create a premature termination codon (PTC) have been associated with clinical presentations that range from mild (not meeting clinical diagnostic criteria for Marfan syndrome) to classic Marfan syndrome. Ectopia lentis is less common in individuals with haploinsufficiency of FBN1.
• Some, but not all, studies have suggested that pathogenic variants that create a PTC can be associated with more frequent aortic events including dissection, surgery, and death in adults with Marfan syndrome [Arnaud et al 2021] or an improved response to treatment with angiotensin receptor blockers [Franken et al 2015].
• Other studies have emphasized a significant enrichment of in-frame pathogenic variants in a central region of FBN1 among young children with severe, early-onset, and rapidly progressive Marfan syndrome and worse clinical outcomes.

In general, identification of the precise FBN1 pathogenic variant in a proband has limited prognostic value and has not been proven to reliably guide individual management.

Penetrance

Although intrafamilial clinical variability can be extensive, FBN1-related Marfan syndrome shows high clinical penetrance.

Nomenclature

Outdated terms used in the description of Marfan syndrome include the following:

• Neonatal Marfan syndrome. Although many have used the term "neonatal Marfan syndrome" to describe the earliest and most severe presentation of Marfan syndrome, in reality, this term does not adequately represent a discrete subset of individuals with truly distinguishing characteristics and its use should be abandoned. The terms "early onset" and "rapidly progressive" are adequate to describe the clinical course in these children.
• Marfan syndrome type 2. This term is no longer in use. It was used by Mizuguchi et al [2004] in a report of individuals with a phenotype that resembled Marfan syndrome but is now known to be Loeys-Dietz syndrome (see Differential Diagnosis).

Prevalence

The estimated prevalence of FBN1-related Marfan syndrome is 1:5,000-1:10,000.

There is no apparent enrichment in any ethnic or racial group. Males and females are affected with equal frequency.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with FBN1-related Marfan syndrome, the evaluations summarized in Table 7 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Management is most effectively accomplished through the coordinated input of a multidisciplinary team of specialists including a clinical geneticist, cardiologist, ophthalmologist, orthopedist, and cardiothoracic surgeon.

Prevention of Primary Manifestations

Medications that reduce hemodynamic stress on the aortic wall, such as beta-blockers or angiotensin receptor blockers (ARBs), are routinely prescribed. This therapy should be managed by a cardiologist or clinical geneticist familiar with its use. Therapy is generally initiated at the time of diagnosis of Marfan syndrome at any age or upon appreciation of progressive aortic root dilatation even in the absence of a definitive diagnosis.

The confluence of data from clinical trials of beta-blockers or ARBs suggests that both classes of medication can be effective at reducing aortic root growth rate and are safe and well tolerated. A meta-analysis of seven studies and more than 1,500 individuals with Marfan syndrome documented that ARBs significantly reduce normalized aortic root and ascending aortic growth rate when compared to placebo [Al-Abcha et al 2020] or when added to pre-existing therapy with a beta-blocker [Al-Abcha et al 2020, Wang et al 2022].

General principles applied by the author include:

• Initiation of therapy at the time of diagnosis with Marfan syndrome. This would include children without aortic enlargement if there is a family history of Marfan syndrome with aortic involvement or the identified pathogenic variant has previously been associated with significant aortic involvement in unrelated individuals.
• Targeting of high dosing (as tolerated) irrespective of blood pressure in recognition that benefit likely relates to desirable biochemical effects in the aortic wall that do not strictly correlate with hemodynamic parameters
• Dose optimization of one agent (e.g., an ARB) before consideration of adding another (e.g., a beta-blocker)
• Avoidance of ARBs in pregnant individuals or if pregnancy is imminently anticipated
• Avoidance of other classes of antihypertensive agents (e.g., calcium channel blockers, ACE inhibitors) in the absence of direct evidence for their efficacy or safety in individuals with Marfan syndrome

Surveillance

Agents/Circumstances to Avoid

The following should be avoided:

• Contact sports, competitive sports, and isometric exercise. Note: Individuals can and should remain active with aerobic activities performed in moderation.
• Activities that cause joint injury or pain
• Agents that stimulate the cardiovascular system including routine use of decongestants. Caffeine can aggravate a tendency for arrhythmia.
• Agents that cause vasoconstriction, including triptans
• LASIK eye surgery to correct refractive errors
• For individuals at risk for recurrent pneumothorax, breathing against resistance (e.g., playing a brass instrument) or positive pressure ventilation (e.g., SCUBA diving)
• Fluoroquinolone antibiotics due to the considerable evidence suggesting exacerbation of predisposition for aneurysm and dissection
• Avoidance of classes of antihypertensive agents (e.g., calcium channel blockers, ACE inhibitors) where there is an absence of direct evidence for their efficacy or safety in individuals with Marfan syndrome

Evaluation of Relatives at Risk

It is recommended that the genetic status of relatives of any age at risk for Marfan syndrome be clarified either by molecular genetic testing or by clinical examination so that affected individuals can undergo routine surveillance for early detection of medically significant complications, particularly potentially life-threatening cardiac manifestations. Approaches include the following:

• If the FBN1 pathogenic variant has been identified in an affected relative, molecular genetic testing can be used.
• In the presence of a rigorously defined family history of Marfan syndrome, clinical examination can establish the clinical diagnosis of Marfan syndrome in a first-degree relative of an affected individual who has any one of the following three findings [Loeys et al 2010]:
  • Ectopia lentis
  • Systemic score ≥7 (See Suggestive Findings.)
  • Aortic root enlargement (z score ≥2.0 in those age ≥20 years or ≥3.0 in those age <20 years) (see Suggestive Findings). Note: (1) Echocardiography of relatives is indicated upon appreciation of any suspicious signs of Marfan syndrome, and even in apparently unaffected individuals if findings are subtle in the index case. (2) It is generally appropriate to delay echocardiography for infants and toddlers until they can cooperate with the examination without needing sedation. Exceptions include those with evidence of valve dysfunction and/or congestive heart failure. (3) All first-degree relatives of an individual with apparent isolated aortic enlargement should be evaluated by echocardiography when they are old enough to cooperate with the exam. Earlier evaluation may be indicated based on a particularly aggressive family history or a worrisome clinical finding such as a murmur, dyspnea, or poor weight gain.

See Genetic Counseling for issues related to evaluation of at-risk relatives for genetic counseling purposes.

Pregnancy Management

It is recommended that an individual with Marfan syndrome consider pregnancy only after appropriate counseling from a clinical geneticist or cardiologist familiar with this condition, a genetic counselor, and a high-risk obstetrician because of the risk of more rapid dilation of the aorta or aortic dissection during pregnancy, delivery, or in the immediate postpartum period. This is especially relevant to individuals who begin pregnancy with a maximal aortic dimension that exceeds 4.0 cm. Note: Some individuals with Marfan syndrome and aortic root dilatation opt for elective aortic repair with a valve-sparing procedure prior to reaching a conventional threshold for surgical intervention (i.e., at a root dimension <5.0 cm) before becoming pregnant. While this is thought to decrease the risk for ascending aortic dissection in association with pregnancy, it will not lessen risk for descending aortic dissection or other potential cardiovascular manifestations of Marfan syndrome.

Pregnant individuals with Marfan syndrome should be followed by a high-risk obstetrician both during pregnancy and through the immediate postpartum period.

Individuals with Marfan syndrome who anticipate pregnancy or become pregnant should continue use of beta-blockers; however, some other classes of medications such as ARBs should be discontinued because of the increased risk for fetal loss, oligohydramnios, and abnormal development, often related to second- and third-trimester exposure.

See MotherToBaby for further information on medication use during pregnancy.

Efforts should be made to minimize cardiovascular stress through pregnancy and delivery.

Cardiovascular imaging with echocardiography should be performed every two to three months during pregnancy to monitor aortic root size and growth. Monitoring should continue in the immediate postpartum period because of the increased risk for aortic dissection.

The choice between a controlled vaginal delivery and cesarean section remains controversial and should be tailored to the specific clinical context.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

FBN1-related Marfan syndrome (Marfan syndrome) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Approximately 75% of individuals diagnosed with Marfan syndrome have an affected parent.
• Approximately 25% of individuals diagnosed with Marfan syndrome have the disorder as the result of a de novo pathogenic variant.
• If the proband appears to represent a simplex case (i.e., the only family member known to have Marfan syndrome), it is appropriate to evaluate both parents of the proband for manifestations of Marfan syndrome by performing a comprehensive clinical examination and echocardiogram. Molecular genetic testing for the FBN1 pathogenic variant identified in the proband is recommended for the parents to confirm their genetic status and to facilitate reliable recurrence risk counseling.
• If the FBN1 pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. *
    Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
    * A parent with somatic and germline mosaicism for an FBN1 pathogenic variant may be mildly/minimally affected.
• The family history of some individuals diagnosed with Marfan syndrome may appear to be negative because of failure to recognize the disorder in family members or early death of the parent before the onset of symptoms. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. Sibs who inherit an FBN1 pathogenic variant from a parent will have Marfan syndrome, although the severity cannot be predicted.
• If the FBN1 pathogenic variant identified in the proband cannot be detected in parental leukocyte DNA and both parents are clinically unaffected, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental mosaicism.

Offspring of a proband

• Each child of an individual with FBN1-related Marfan syndrome has a 50% chance of inheriting the pathogenic variant and the disorder.
• The penetrance of FBN1 pathogenic variants is reported to be 100%; thus, offspring who inherit an FBN1 pathogenic variant from a parent will have Marfan syndrome, although the severity cannot be predicted.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Predictive testing for at-risk asymptomatic family members requires prior identification of the FBN1 pathogenic variant in the family.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.

Prenatal Testing and Preimplantation Genetic Testing

Once the FBN1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Fibrillin-1 is an extracellular matrix protein that contributes to large structures called microfibrils that are found in both elastic and non-elastic tissues. They participate in the formation and homeostasis of the elastic matrix, in matrix-cell attachments, and in the regulation of selected growth factors.

The pathogenesis of Marfan syndrome is complex. Abnormal forms of fibrillin-1 are believed to have dominant-negative activity. In affected individuals, the residual level of protein is generally far below the 50% level predicted by the presence of a wild type copy of FBN1. A hallmark feature of Marfan syndrome is a severe reduction of microfibrils in explanted tissues and in the matrix deposited by cultured dermal fibroblasts.

Studies in animal models of Marfan syndrome have demonstrated that microfibrils regulate the matrix sequestration and activation of the growth factor TGFβ. Excess TGFβ signaling has been observed in the developing lung, the mitral valve, the skeletal muscle, the dura, and the ascending aorta [Neptune et al 2003, Ng et al 2004, Jones et al 2005, Loeys et al 2005, Habashi et al 2006, Cohn et al 2007]. TGFβ antagonism in vivo has been shown to attenuate or prevent pulmonary emphysema, myxomatous changes of the mitral valve, skeletal muscle myopathy, and progressive aortic enlargement seen in fibrillin-1-deficient mice. Further evidence suggests the particular relevance of specific cellular signaling events including activation of the extracellular signal-regulated kinase cascade [Habashi et al 2011, Holm et al 2011]. The relevance of this mechanism to other manifestations of Marfan syndrome is currently being explored. Other studies have highlighted the potential role of matrix-degrading enzymes in the pathogenesis of aortic disease in Marfan syndrome [Bunton et al 2001, Booms et al 2005].

Mechanism of disease causation. Both dominant-negative effects and haploinsufficiency have been implicated in the pathogenesis of Marfan syndrome.

Missense changes associated with disease include:

• Missense variant that creates or destroys a cysteine residue;
• Missense variant affecting conserved residues in the EGF-like domain consensus sequence (D/N)X(D/N)(E/Q)Xm(D/N)Xn(Y/F) (m and n represent variable numbers of residues).

FBN1-specific laboratory technical considerations. Three exons at the extreme 5' end of the gene are alternatively utilized and do not appear to contribute to the coding sequence. For a detailed summary of gene and protein information, see Table A, Gene. Additionally, high evolutionary conservation of intronic sequence at the 5' end of the gene suggests the presence of intronic regulatory elements, but these have not been implicated in the etiology of Marfan syndrome.

Author Notes

Harry (Hal) Dietz is the Victor A McKusick Professor of Medicine and Genetics in the Institute of Genetic Medicine at the Johns Hopkins University School of Medicine and an Investigator in the Howard Hughes Medical Institute. He serves on the Professional Advisory Board of the Marfan Foundation. His research focuses on the development of rational therapeutic strategies for Marfan syndrome and related conditions through elucidation of disease pathogenesis using animal models of disease. He directs a multidisciplinary clinic for the diagnosis and management of Marfan syndrome and other connective tissue disorders affecting the cardiovascular system.

Revision History

• 17 February 2022 (ma) Comprehensive update posted live
• 12 October 2017 (bp) Comprehensive update posted live
• 12 June 2014 (me) Comprehensive update posted live
• 1 December 2011 (me) Comprehensive update posted live
• 30 June 2009 (me) Comprehensive update posted live
• 26 October 2005 (me) Comprehensive update posted live
• 22 September 2003 (me) Comprehensive update posted live
• 18 April 2001 (pb) Review posted live
• January 2001 (hd) Original submission

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