Marfan Syndrome
Summary
Clinical characteristics.
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 (the most common ocular feature); 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 the 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 one of the following sets of findings:
- An FBN1 pathogenic variant known to be associated with Marfan syndrome AND one of the following:
- Aortic root enlargement (Z-score ≥2.0)
- Ectopia lentis
- Demonstration of aortic root enlargement (Z-score ≥2.0) and ectopia lentis OR a defined combination of features throughout the body yielding a systemic score ≥7
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). Scoliosis may require surgical stabilization; repair of pectus deformity is largely cosmetic. Orthotics and arch supports can lessen leg fatigue, joint pain, and muscle cramps associated with pes planus. Surgical repair of the aorta is indicated when the maximal measurement of the aortic root approaches 5.0 cm in adults or older children, the rate of increase of the aortic root diameter approaches 0.5-1.0 cm per year, or 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 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.
Prevention of primary manifestations: Medications that reduce hemodynamic stress on the aortic wall, such as use of beta blockers (β-blockers) or angiotensin receptor blockers (ARBs) together, are generally initiated at diagnosis or upon documentation of significant and/or progressive aortic dilatation. Other antihypertensive agents can be used if β-blockers and ARBs are not tolerated; however, evidence as to their efficacy and safety in Marfan syndrome is under investigation.
Prevention of secondary complications: Subacute bacterial endocarditis prophylaxis for dental work with the presence of mitral or aortic valve regurgitation.
Surveillance: Annual ophthalmologic examination; annual echocardiography to monitor the status of the ascending aorta when aortic dimensions are small and/or the rate of aortic dilation is slow; more frequent examinations are indicated when the aortic root diameter exceeds approximately 4.5 cm in adults, rates of aortic dilation exceed approximately 0.5 cm per year, and/or significant aortic regurgitation is present; intermittent surveillance of the entire aorta with CT or MRA scans beginning in young adulthood or after aortic root surgery in childhood.
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.
Evaluation of relatives at risk: It is recommended that the genetic status of at-risk relatives 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: Pregnant women with Marfan syndrome should be followed by a high-risk obstetrician both during pregnancy and through the immediate postpartum period.
In women with Marfan syndrome who anticipate pregnancy or become pregnant, β-blockers should be continued, but some other classes of medications such as ACE inhibitors or ARBs should be stopped because of the risk for fetal loss and birth defects. Cardiovascular imaging with echocardiography every two to three months during pregnancy to monitor aortic root size and growth is recommended. Monitoring should continue in the immediate postpartum period due to an increased risk for aortic dissection.
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. The offspring of an individual with Marfan syndrome are at a 50% risk of inheriting the FBN1 pathogenic variant. Once the FBN1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.
Diagnosis
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 National Marfan Foundation web site.
- Ectopia lentis; most reliably diagnosed by slit-lamp examination after maximal pupillary dilatation
- A systemic score ≥7 (see Table 1)
Table 1.
Calculation of the Systemic Score
| Feature | Value | Enter Value if Feature is Present |
|---|---|---|
| Wrist AND thumb sign | 3 | |
| Wrist OR thumb sign | 1 | |
| Pectus carinatum deformity | 2 | |
| Pectus excavatum or chest asymmetry | 1 | |
| Hindfoot deformity | 2 | |
| Plain flat foot (pes planus) | 1 | |
| Pneumothorax | 2 | |
| Dural ectasia | 2 | |
| Protrusio acetabulae | 2 | |
| Reduced upper segment / lower segment AND increased arm span/height ratios | 1 | |
| Scoliosis or thoracolumbar kyphosis | 1 | |
| Reduced elbow extension | 1 | |
| 3 of 5 facial features | 1 | |
| Skin striae | 1 | |
| Myopia | 1 | |
| Mitral valve prolapse | 1 | |
| Total | ||
A Systemic Score calculator and a complete description of each component evaluation can be found at the National Marfan Foundation web site.
Click here for a printable copy (pdf) of this table.
Family history. Consistent with autosomal dominant inheritance
Establishing the Diagnosis
The diagnosis of Marfan syndrome is established in a proband (by definition a person without a known family history of Marfan syndrome) who has [Loeys et al 2010a] an FBN1 pathogenic variant known to be associated with Marfan syndrome (see Table 2) and EITHER of the following:
- Aortic root enlargement (Z-score ≥2.0)
- Ectopia lentis
Note: Given that many manifestations of Marfan syndrome emerge with age, it is not advisable to establish definitive alternative diagnoses in individuals younger than age 20 years who have compatible but insufficient physical manifestations of Marfan syndrome. In this circumstance the author suggests the use of tentative diagnostic designations:
- 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 dilation (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 is 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 can include a combination of gene-targeted testing (single-gene testing or a multigene panel) and genomic testing (comprehensive genomic sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Although individuals with the distinctive findings of Marfan syndrome described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), 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).
Option 1
When the clinical findings suggest the diagnosis of Marfan syndrome, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:
- Single-gene testing. Sequence and deletion/duplication analysis of FBN1 are performed.
- A multigene Marfan syndrome/Loeys-Dietz syndrome/familial thoracic aortic aneurysms and dissections panel that includes FBN1 as well as a number of other genes associated with disorders that include aortic aneurysms and dissections (see Differential Diagnosis) may be offered by clinical laboratories. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the phenotype is indistinguishable from other inherited disorders with features observed in Marfan syndrome, molecular genetic testing approaches can include comprehensive genomic testing (exome sequencing and genome sequencing).
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 2.
Molecular Genetic Testing Used in Marfan Syndrome
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| FBN1 | Sequence analysis 3 | ~90%-93% 4 |
| Gene-targeted deletion/duplication analysis 5 | ~5% 6 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
In individuals with classic Marfan syndrome an FBN1 pathogenic variant was identified by sequence analysis in 86 (93%) of 93 [Loeys et al 2004] and 76 (91%) of 87 individuals [Baetens et al 2011]. Subsequently, a number of these individuals have subsequently were found to have FBN1 deletions that had not been detected by sequencing [Bart Loeys, personal communication].
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
Deletions and duplications ranging in size from one to multiple exons as well as full-gene deletions have been described (www
.hgmd.cf.ac.uk, www .umd.be/FBN1). In one systematic study, 4/86 individuals with classic Marfan syndrome had a large deletion or duplication [Baetens et al 2011].
Clinical Characteristics
Clinical Description
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. Ocular findings include myopia (the most common ocular feature); 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, a predisposition for aortic tear and rupture, mitral valve prolapse with or without regurgitation, tricuspid valve prolapse, and enlargement of the proximal pulmonary artery.
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 the most common ocular feature and often progresses rapidly during childhood.
Displacement of the lens from the center of the pupil (ectopia lentis) is a hallmark feature of Marfan syndrome, but is only seen in approximately 60% of affected individuals.
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. The extremities are disproportionately long for the size of the trunk (dolichostenomelia), leading to an increase in the arm span-to-height ratio and a decrease in the upper-to-lower segment ratio. 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. Inward rotation of the medial aspect of the ankle can result in flat feet (pes planus). 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 acetabulum can be abnormally deep and show accelerated erosion (protrusio acetabuli). All skeletal findings can develop in young children and tend to progress during periods of rapid growth.
The facial features include a long and narrow face with deeply set eyes (enophthalmos), downward slanting of the palpebral fissures, flat cheek bones (malar hypoplasia), and a small and receding chin (micrognathia, retrognathia). The palate can be highly arched and narrow, often associated with tooth crowding.
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 [Erkula et al 2002].
Cardiovascular. The major sources of morbidity and early mortality relate to the cardiovascular system.
Cardiovascular manifestations include dilatation of the aorta at the level of the sinuses of Valsalva, a predisposition for aortic tear and rupture, mitral valve prolapse (MVP) with or without regurgitation, tricuspid valve prolapse, and enlargement of the proximal pulmonary artery.
Aortic dilatation in the Marfan syndrome tends to progress over time. Histologic examination reveals fragmentation of elastic fibers, loss of elastin content, and accumulation of amorphous matrix components in the aortic media. This picture of "cystic medial necrosis" does not distinguish Marfan syndrome from other causes of aortic aneurysm. In adults, a significant risk for aortic dissection or rupture occurs when the maximal dimension reaches approximately 5.0 cm. The onset and rate of progression of aortic dilatation is highly variable. Aortic dissection is exceedingly rare in early childhood. As an aneurysm enlarges, the aortic annulus can become stretched, leading to secondary aortic regurgitation.
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 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 recent study of 50 individuals with Marfan syndrome identified enlarged pulmonary artery root in 74% [Nollen & Mulder 2004].
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].
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 CSF from a dural sac can cause postural drop in CSF pressure and headache [Foran et al 2005].
Skin. Manifestations in the skin and integument include hernias and skin stretch marks (striae distensae). Individuals can show a paucity of muscularity and fat stores despite adequate 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 [Giske et al 2003].
Pregnancy can be dangerous for women with Marfan syndrome, especially if the aortic root exceeds 4.0 cm. Complications include rapid progression of aortic root enlargement and aortic dissection or rupture during pregnancy, delivery, and the postpartum period.
Self-image. The vast majority of affected individuals older than age 13 years report a positive general self-image [De Bie et al 2004].
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.
Genotype-Phenotype Correlations
Few genotype-phenotype correlations exist in the Marfan syndrome; none is definitive [Dietz & Pyeritz 2001]. Identification of an FBN1 pathogenic variant in a proband thus has little prognostic value and has not been proven to reliably guide individual management.
Penetrance
Although intrafamilial clinical variability can be extensive, 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, an autosomal dominant disorder caused by a heterozygous pathogenic variant in either TGFBR1 or TGFBR2 (see Differential Diagnosis).
Prevalence
The estimated prevalence of Marfan syndrome is 1:5,000-1:10,000.
There is no apparent enrichment in any ethnic or racial group and no gender preference.
Differential Diagnosis
Loeys-Dietz syndrome (LDS) is an autosomal dominant condition that includes many features of Marfan syndrome (long face, downslanted palpebral fissures, highly arched palate, malar hypoplasia, micrognathia, retrognathia, pectus deformity, scoliosis, arachnodactyly, joint laxity, dural ectasia, and aortic root aneurysm with dissection). Some features of Marfan syndrome are either less common or prominent (dolichostenomelia) or absent (ectopia lentis). Unique features can include widely spaced eyes, broad or bifid uvula, cleft palate, hydrocephalus (rare), Chiari I malformation, blue sclerae, exotropia, craniosynostosis, cervical spine instability, talipes equinovarus, soft and velvety skin, translucent skin, easy bruising, generalized arterial tortuosity and aneurysms, and dissection throughout the arterial tree. Individuals with LDS are at risk for cervical spine malformation and/or instability, food allergy, asthma, eosinophilic esophagitis, and inflammatory bowel disease (rare).
Aortic aneurysms behave very differently from those in Marfan syndrome, with frequent dissection and rupture at small dimensions and in early childhood.
LDS results from a heterozygous pathogenic variant in one of five genes (see Table 4).
Table 4.
Loeys-Dietz Syndrome: Associated Genes and Subtypes
| Gene | LDS Subtype 1 | Comment | Reference |
|---|---|---|---|
| TGFBR1 | LDS1 2 | Loeys et al [2005], Loeys et al [2006] | |
| TGFBR2 | LDS2 2 | ||
| SMAD3 | LDS3 | Strong predisposition for osteoarthritis | van de Laar et al [2011] |
| TGFB2 | LDS4 | Lindsay et al [2012], Bertoli-Avella et al [2015] | |
| TGFB3 | LDS5 |
- 1.
Subtypes are ordered from most to least severe.
- 2.
Note: LDS1 and LDS2 are equal in severity.
Hemizygous loss-of-function pathogenic variants in the X-linked gene BGN are characterized by early-onset thoracic aortic aneurysm and dissection, as well as hypertelorism, pectus deformity, joint hypermobility, contractures, and mild skeletal dysplasia [Meester et al 2017].
Other connective tissue disorders. Many of the skeletal features of Marfan syndrome are common in the general population. When severe and found in combination, such findings usually indicate a disorder of connective tissue, including the following:
- Congenital contractural arachnodactyly (CCA), an autosomal dominant disorder characterized by a Marfan-like appearance and long, slender fingers and toes, is caused by a heterozygous pathogenic variant in FBN2 (encoding fibrillin-2). Most affected individuals have "crumpled" ears, with a folded upper helix, and most have contractures of knees and ankles at birth that usually improve with time. The proximal interphalangeal joints also have flexion contractures (i.e., camptodactyly), as do the toes. Hip contractures, adducted thumbs, and clubfoot may occur. Kyphosis/scoliosis, present in approximately half of all affected individuals, begins as early as infancy and is progressive. The majority of affected individuals have muscular hypoplasia. Mild dilatation of the aorta is present in rare cases. Rare infants have been observed with a severe/lethal form characterized by multiple cardiovascular and gastrointestinal anomalies in addition to the typical skeletal findings.
- Heritable thoracic aortic disease (HTAD) refers to thoracic aortic disease caused by mutation of a gene that confers a high risk for thoracic aortic aneurysms and aortic dissections (TAAD). Up to 20% of individuals with TAAD who do not have features of Marfan syndrome, vascular Ehlers Danlos syndrome, or Loeys-Dietz syndrome have a family history of TAAD. Approximately 30% of families with HTAD who do not have a clinical diagnosis of Marfan syndrome or another syndrome have a causative pathogenic variant in one of the 13 known HTAD-related genes. HTAD is primarily inherited in an autosomal dominant manner.
- Ehlers-Danlos syndrome (EDS) is a group of disorders that have joint hypermobility as a common feature.
- EDS, classic type is an autosomal dominant disorder characterized by skin hyperextensibility, abnormal wound healing, smooth, velvety skin, and joint hypermobility. Approximately 50% of individuals with classic EDS have an identifiable heterozygous pathogenic variant in COL5A1 or COL5A2.
- EDS, kyphoscoliotic form (previously known as EDS VI) is an autosomal recessive disorder characterized by friable, hyperextensible skin, thin scars, and easy bruising; generalized joint laxity; severe muscular hypotonia at birth; progressive scoliosis, present at birth or within the first year of life; and scleral fragility with increased risk of rupture of the globe. Intelligence is normal; life span may be normal, but affected individuals are at risk for rupture of medium-sized arteries and respiratory compromise if kyphoscoliosis is severe. EDS kyphoscoliotic form is caused by deficient activity of the enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1, resulting from biallelic pathogenic variants in PLOD1.
- EDS, vascular type (previously known as EDS IV) is an autosomal dominant disorder characterized by joint laxity (often limited to small joints), translucent skin with easily visible underlying veins, easy bruising, wide and dystrophic scars, characteristic facies (prominent eyes and a tight or "pinched" appearance), organ rupture (spleen, bowel, gravid uterus), and a tendency for aneurysm and/or dissection of any medium to large muscular artery throughout the body. Unlike in Marfan syndrome, there is no particular tendency for involvement of the aortic root, although this location is not spared from risk. The tissues can be extremely friable, often contributing to surgical catastrophe. EDS, vascular type is caused by a heterozygous pathogenic variant in COL3A1.
- Homocystinuria caused by cystathionine β-synthase deficiency, an autosomal recessive disorder, is characterized by variable intellectual disability, ectopia lentis and/or severe myopia, skeletal abnormalities (including excessive height and limb length), and a tendency for intravascular thrombosis and thromboembolic events. Overlap with Marfan syndrome can be extensive and includes an asthenic (long and lean) body habitus, pectus deformity, scoliosis, mitral valve prolapse, highly arched palate, hernia, and ectopia lentis. Thromboembolic events can be life threatening. Approximately half of affected individuals are responsive to pharmacologic doses of vitamin B6, highlighting the need to consider this diagnosis. Biallelic pathogenic variants in CBS are causative.
- Stickler syndrome can include ocular findings of myopia, cataract, and retinal detachment; hearing loss that is both conductive and sensorineural; midfacial hypoplasia and cleft palate (either alone or as part of the Robin sequence); and mild spondyloepiphyseal dysplasia and/or precocious arthritis. The diagnosis of Stickler syndrome is clinically based. Stickler syndrome caused by a heterozygous pathogenic variant in COL2A1, COL11A1, or COL11A2 is inherited in an autosomal dominant manner; Stickler syndrome caused by biallelic pathogenic variants in COL9A1, COL9A2, or COL9A3 is inherited in an autosomal recessive manner.
- Fragile X syndrome is an X-linked disorder characterized by moderate intellectual disability in affected males and mild intellectual disability in affected females. Males may have a characteristic appearance (large head, long face, prominent forehead and chin, protruding ears) and connective tissue findings (joint laxity) that suggest the Marfan syndrome phenotype. They also have large testes (postpubertally). Behavior abnormalities, sometimes including autism spectrum disorder, are common. More than 99% of individuals with fragile X syndrome have a full mutation in FMR1 caused by an increased number of CGG trinucleotide repeats (>200 typically) accompanied by aberrant methylation of FMR1.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Marfan syndrome, the following evaluations are recommended, if they have not already been completed:
- Evaluation by an ophthalmologist with expertise in Marfan syndrome, including:
- Slit lamp examination through a maximally dilated pupil for evidence of lens subluxation
- Refraction and correction of refractive errors, especially in young children at risk for amblyopia
- Specific assessment for glaucoma and cataract
- Evaluation for skeletal manifestations that may require immediate attention by an orthopedist (e.g., severe scoliosis)
- Echocardiography
- Aortic root measurements must be interpreted based on consideration of normal values for age and body size. Click here for a calculator.
- Selected findings may require the immediate attention of a cardiologist or cardiothoracic surgeon (e.g., severe valve dysfunction, severe aortic dilatation, congestive heart failure, history or evidence suggestive of arrhythmia).
- Consultation with a clinical geneticist and/or genetic counselor
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.
Eye
- The ocular manifestations should be managed by an ophthalmologist with expertise in Marfan syndrome.
- Most often, refractive errors can be adequately controlled with spectacle correction alone.
- Lens dislocation can require surgical aphakia (removal of lens) if the lens is freely mobile or the margin of the lens obstructs vision. An intraocular lens can be implanted after puberty (i.e., once growth is complete). While intraocular lens implants are currently considered quite safe when performed in specialized centers, major complications including retinal detachment can occur.
- Prompt and aggressive assessment and correction of refractive error are mandatory in young children at risk for amblyopia.
Skeletal
- Bone overgrowth and ligamentous laxity can lead to severe problems (including progressive scoliosis) and should be managed by an orthopedist; surgical stabilization of the spine may be required.
- Pectus excavatum can be severe; in rare circumstances, surgical intervention is indicated for medical (rather than cosmetic) reasons.
- Protusio acetabulae can be associated with pain or functional limitations. Surgical intervention is rarely indicated