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Presentation

History

Classic Marfan syndrome (MFS1) is currently diagnosed using a criteria-based approach that includes an evaluation of family history, molecular data, and six organ systems. Diagnosis cannot be based on molecular analysis alone because molecular diagnosis is not generally available, mutation detection is imperfect, and not all FBN1 mutations are associated with MFS. As cited by the 1988 Berlin criteria, MFS was diagnosed on the basis of involvement of the skeletal system and two other systems, with the requirement of at least one major manifestation (ie, ectopia lentis, aortic dilatation or dissection, or dural ectasia).

In 1996, a group of the world's leading clinicians in MFS proposed a revised diagnostic criteria. The Ghent-1 criteria were intended to serve as an international standard for clinical and molecular studies and for investigations of genetic heterogeneity and genotype-phenotype correlations. The Ghent nosology identified major and minor diagnostic findings, which were based on clinical observation of various organ systems and on family history. A major criterion was defined as one that carried high diagnostic precision, because it was relatively infrequent in other conditions and in the general population. Clinical diagnosis in adults should be made using the Ghent criteria, which are considered not as reliable in children.

Further revision of the nosology was necessary, however, because, while the Berlin criteria did not provide for molecular studies and may have led to incorrect diagnoses in relatives of the proband, the Ghent-1 criteria may have been too stringent and hence have excluded MFS in affected patients. For example, 19% of patients whose disease was diagnosed based on the Berlin criteria did not meet the Ghent-1 criteria. Of those patients who were screened for dural ectasia, 23% were diagnosed with MFS by the Berlin criteria; however, these patients were not diagnosed with MFS when the Ghent-1 criteria were applied.^[16]

In 2010, an international expert panel revised the Ghent-1 criteria to the Ghent-2 criteria.^[17]Ghent-2 gave greater weight to cardiovascular manifestations (aortic aneurysm/dissection) and to molecular testing of the FBN1 gene, as well as other relevant genes, such as TGFβR1/2, COL3A1, and ACTA2. This new scoring system was designed to address systemic features. In the absence of family history, the presence of aortic root aneurysm and ectopia lentis is sufficient for the unequivocal diagnosis of MFS1. In the absence of either aortic aneurysm or ectopia lentis, the presence of an FBN1 mutation or a combination of systemic manifestations is required.

Application of the Ghent-2 criteria should help and support clinicians who are less knowledgeable of the Marfan phenotype. Indeed, even if the diagnosis of MFS is not reached, regular aortic follow-up is mandatory in every patient with a diagnosis of ectopia lentis syndrome, MASS, or mitral valve prolapse syndrome. Longitudinal studies of patient follow-up with such alternative diagnoses are required to determine the proportion of patients who will meet the criteria for MFS in later life.^[18]

Family history and results of molecular studies are part of the major criteria; hence the need to carefully obtain a complete family history and pedigree. Major criteria include the following:

A first-degree relative (parent, child, or sibling) who independently meets the diagnostic criteria.
Presence of an FBN1 mutation known to cause MFS.
Inheritance of an FBN1 haplotype known to be associated with unequivocally diagnosed MFS in the patient's family.
In family members, major involvement in one organ system and involvement in a second organ system.

If the family and genetic histories are noncontributory, major criteria in two different organ systems and involvement of a third organ system are required to make the diagnosis (organ system criteria are described in the Physical section).

Clinical presentations are as follows:

Delayed achievement of gross and fine motor milestones due to ligamentous laxity of the hips, knees, ankles, plantar arches, wrists, and fingers
A decrescendo diastolic murmur from aortic regurgitation
An ejection click at the apex followed by a holosystolic high-pitched murmur due to mitral prolapse and regurgitation
Dysrhythmia (a primary feature)
Abrupt onset of thoracic pain, which occurs in more than 90% of patients with aortic dissection
- Other signs of aortic dissection are syncope, shock, pallor, pulselessness, and paresthesia or paralysis in the extremities.
- Acute onset of hypotension may indicate aortic rupture.
Low back pain near the tailbone, burning sensation and numbness or weakness in the legs in severe dural ectasia
- Dural ectasia may cause headaches and neurologic deficits
- Dural ectasia is shown in the magnetic resonance imaging (MRI) scan below
  
  Dural ectasia in the lumbosacral region.
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Joint pain in older patients
Dyspnea, severe palpitations, and substernal pain in significant pectus excavatum
Breathlessness, often associated with chest pain, in spontaneous pneumothorax
Visual problems, such as vision impairment due to lens dislocation or retinal detachment
- Common refractory errors are myopia and amblyopia

Skeletal findings

Patients with Marfan syndrome (MFS) are usually taller and thinner than their family members. Their limbs are disproportionately long when compared with the trunk (dolichostenomelia). Arachnodactyly ("spider fingers," abnormally long and slender fingers) is a common feature. See the images below for examples.

Adult with Marfan syndrome. Note tall and thin build, disproportionately long arms and legs, and kyphoscoliosis.

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Arachnodactyly.

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Although most patients are diagnosed before the age of 10 years, few present with the four skeletal criteria, which tend to develop in later life.^[19]

Major skeletal criteria include the following:

Pectus excavatum (sunken or funnel chest) or pectus carinatum (keel-shaped or pigeon chest) that requires corrective surgery or intervention (See the image below.)

Pectus excavatum of moderate severity.
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Reduced upper-to-lower body segment ratio (0.85 vs 0.93) or arm span–to-height ratio greater than 1.05 - Arms and legs may be unusually long in proportion to the torso.
Positive wrist (Walker) and thumb (Steinberg) signs - Two simple maneuvers help demonstrate arachnodactyly. A positive wrist sign is identified if, when encircling the opposite wrist, the distal phalanges of the first and fifth digits of one hand overlap. A positive thumb sign is identified if the thumb extends past the ulnar border when completely opposed within the clenched hand. (See the images below.)
Positive wrist (Walker) sign.
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Positive thumb (Steinberg) sign.
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Scoliosis greater than 20° - More than 60% of patients have scoliosis. Progression is more likely with a curvature of more than 20° in growing patients (prior to puberty).
Reduced elbow extension (< 170°)
Medial displacement of the medial malleolus, resulting in pes planus (fallen arches or flat feet) - Pes planus is best diagnosed by examining the foot from the back side of the patient. A valgus deviation of the hindfoot indicates pes planus.
Protrusio acetabuli of any degree - This is a deformity of the hip joint in which the medial wall of the acetabulum invades the pelvic cavity with associated medial displacement of the femoral head. Radiography is used to diagnose protrusio acetabuli. Protrusio acetabuli affects 31-100% of patients with MFS to varying degrees.^[20] Clinical manifestations are hip joint stiffness and progressive limitation in activity as related to joint pain, a waddling gait, limited range of motion, flexion contracture, a pelvic tilt with a resulting hyperlordosis of the lumbar spine, and eventually osteoarthritic changes.^[21] Local progressive protrusion can lead to early hip pain and osteoarthritis.

Minor criteria are as follows:

Pectus excavatum of moderate severity
Scoliosis less than 20°
Thoracic lordosis
Joint hypermobility (See the image below.)

Hypermobility of finger joints.
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High arched palate
Dental crowding
Facial phenotype - Dolichocephaly, malar hypoplasia, enophthalmos, retrognathia, and down-slanting palpebral fissures

For the skeletal system to be involved, at least two major criteria or one major criterion plus two minor criteria must be present.

Ocular findings

The major criterion for the ocular system is ectopia lentis (the dislocation or displacement of the eye's natural crystalline lens). About 50% of patients have lens dislocation, with the dislocation position described as superior and temporal. Ectopia lentis may be present at birth or develop in childhood or adolescence.

Minor criteria for the ocular system are as follows:

Flat cornea (as measured by keratometry)
Increased axial length of the globe (as measured by ultrasonography)
Cataract, described as nuclear sclerotic (patients < 50 y)
Hypoplastic iris or hypoplastic ciliary muscle that causes decreased miosis
Nearsightedness (myopia), regardless of whether or not the lens is properly positioned - Myopia is the most common refraction error and is due to an elongated globe and amblyopia ("lazy eye").
Glaucoma (patients < 50 y)
Retinal detachment

At least 2 minor criteria must be present.

Cardiovascular findings

Cardiovascular involvement is the most serious problem associated with MFS.

Major criteria include the following:

Aortic root dilatation at the level of the sinuses of Valsalva - The prevalence of aortic dilatation in MFS is 70-80%. It manifests at an early age and tends to be more common in men than women. A diastolic murmur over the aortic valve may be present.^[22]
Aortic dissections that involve the ascending aorta

Minor criteria are listed as follows:

Mitral valve prolapse (MVP) occurs in 55-69% of patients with MFS. Midsystolic clicks may be followed by a high-pitched late-systolic murmur. In severe cases of MVP, a holosystolic murmur is auscultated.
Dilatation of proximal main pulmonary artery, in the absence of peripheral pulmonic stenosis or another understood cause
Calcification of mitral annulus (patients < 40 y)
Dilatation of abdominal or descending thoracic aorta (patients < 50 y)

For the cardiovascular system to be involved, one minor criterion must be present.

Pulmonary findings

For the pulmonary system, only minor criteria are noted. If there is pulmonary system involvement, one minor criterion must be present.

Minor criteria include the following:

Spontaneous pneumothorax (seen in about 5% of patients)
Apical blebs on chest radiography

Integumentary findings

For integument system, only minor criteria are noted. If there is integument system involvement, one minor criterion must be present.

Minor criteria include the following:

Striae atrophicae (stretch marks) in the absence of marked weight changes, pregnancy, or repetitive dermatologic stress - Stretch marks are usually found on the shoulder, midback, and thighs. (See the image below.)
Stretch marks (striae atrophicae) in the lower back.
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Recurrent hernia or an incisional hernia (hernia due to an incompletely healed surgical wound)

Dural findings

For the dura, only one major criterion is defined: Dural ectasia must be present and confirmed using computed tomography (CT) scanning or MRI modalities. The characteristics of dural ectasia are as follows:

Dural ectasia is defined as a ballooning or widening of the dural sac, often associated with herniation of the nerve root sleeves out of the associated foramina.
Dural ectasia occurs most often in the region of the lumbosacral spine.
Dural ectasia is a common feature in patients with MFS, with an estimated prevalence of 65-92%.
Common clinical symptoms are low back pain, headache, weakness, loss of sensation above and below the affected limb, and occasional rectal pain and/or pain in the genital area. ^[23] These symptoms are aggravated mainly in the supine position and are relieved by lying on the back. ^[24]
Severity appears to increase with age, hence supporting the hypothesis that a weakened dural sac expands from the cumulative effect of increased intrathecal pressure at the spine base from upright posture. Less than 20% of patients with MFS are diagnosed with serious dural ectasia.
Dural ectasia is also associated with conditions such as Ehlers-Danlos syndrome, neurofibromatosis type 1, ankylosing spondylitis, trauma, scoliosis, and tumors.

Key issues in the assessment of Marfan syndrome

Diagnosis or exclusion of MFS in an individual should be based on the Ghent-2 diagnostic nosology.^[9]

Initial assessment should include a personal history, detailed family history, clinical examination and, specifically, an ophthalmologic examination and a transthoracic echocardiogram. For echocardiographic interpretation, the aortic diameter at the sinus of Valsalva should be related to normal values as based on age and body surface area.

The development of scoliosis and protrusio acetabuli is dependent on age, commonly occurring after periods of rapid growth. Radiography is indicated for these features, depending on age. A positive finding aids confirmation of the diagnosis of MFS.

A pelvic MRI scan to detect dural ectasia is indicated. A positive finding would confirm the diagnosis of MFS.

The Ghent-2 nosology cannot exclude MFS in children, because of the age-dependent penetrance of many clinical features. Young patients with a positive family history but with unsuccessful DNA testing and insufficient clinical features to fulfill the diagnostic criteria, and young patients with no family history who miss fulfilling the diagnostic criteria by one system, should have further clinical evaluations up to least age 18 years or until a diagnosis can be made.

Family history of aortic aneurysm may represent a disorder, such as familial thoracic aortic aneurysm, such that the use of the Ghent-2 nosology to assess risk in relatives is inappropriate.

Revised Ghent criteria (Ghent-2) for the diagnosis of MFS and related conditions

Abbreviations are as follows:

Ao - Aortic diameter at the sinuses of Valsalva above indicated Z-score or aortic root dissection
EL - Ectopia lentis
ELS - Ectopia lentis syndrome
FBN1 - Fibrillin-1 mutation
FBN1 not known with Ao - FBN1 mutation that has not previously been associated aortic root aneurysm/dissection
FBN1 with known Ao - FBN1 mutation that has been identified in an individual with aortic aneurysm
FH - Family history
MASS - Myopia, mitral valve prolapse, borderline (Z< 2) aortic root dilatation, striae, skeletal findings phenotype
MFS - Marfan syndrome
MVPS - Mitral valve prolapse syndrome
Syst - Systemic score
Z - Z-score

According to the 2010 revised Ghent nosology (Ghent-2), the diagnosis of MFS depends on the following seven rules^{[17, 18]}:

In the absence of family history:

Aortic root dilatation Z score ≥ 2 and EL = MFS (Ao [ Z ≥ 2] and EL = MFS). The diagnosis of MFS is confirmed when the patient demonstrates aortic root dilatation (Z ≥ 2 when standardized to age and body size) or dissection and ectopia lentis, regardless of whether or not systemic features exist (except in cases in which systemic features indicate the presence of Shprintzen-Goldberg syndrome, Loeys-Dietz syndrome, or vascular Ehlers-Danlos syndrome).
Aortic root dilatation Z score ≥ 2 and FBN1 = MFS (Ao [ Z ≥ 2] and FBN1 = MFS). Even in the absence of ectopia lentis, the diagnosis of MFS can be confirmed by aortic root dilatation (Z ≥ 2) or dissection and the identification of a bona fide FBN1 mutation. 
Aortic root dilatation Z score ≥ 2 and systemic score ≥ 7pts = MFS (Ao [ Z ≥ 2] and Syst (≥7 points) = MFS. Sufficient systemic findings can confirm the diagnosis of MFS when aortic root dilatation (Z ≥ 2) or dissection is present but ectopia lentis is not and the FBN1 status is either unknown or negative (≥ 7 points, according to a scoring system). However, it is necessary to exclude findings indicative of Shprintzen-Goldberg syndrome, Loeys-Dietz syndrome, and vascular Ehlers-Danlos syndrome; also, appropriate alternative genetic testing (eg, TGF β R1/2, SMAD3, TGF β 2, TGF β 3, collagen biochemistry, COL3A1) should be carried out.
EL and FBN1 with known aortic root dilatation = MFS (EL and FBN1 with known Ao = MFS). If ectopia lentis is present but aortic root dilatation/dissection is not, the diagnosis of MFS can only be confirmed by the identification of an aortic disease–associated FBN1 mutation.

In the presence of family history (FH):

EL and FH of MFS = MFS (EL and FH of MFS = MFS). MFS can be diagnosed based on the presence of ectopia lentis and a family history of MFS.
A systemic score ≥ 7 points and FH of MFS = MFS ( Syst [≥7 points] and FH of MFS = MFS). MFS can be diagnosed based on a systemic score of greater than or equal to 7 points and a family history of MFS. However, it is necessary to exclude findings indicative of Shprintzen-Goldberg syndrome, Loeys-Dietz syndrome, and vascular Ehlers-Danlos syndrome; also, appropriate alternative genetic testing (eg, TGF β R1/2, SMAD3, TGF β 2, TGF β 3, collagen biochemistry, COL3A1) should be carried out.
Aortic root dilatation (Z score ≥ 2 above age 20 y, ≥ 3 below age 20 y) + FH of MFS = MFS (Ao [ Z ≥ 2 above age 20 y, ≥3 below age 20 y] + FH of MFS = MFS). MFS can be diagnosed based on the presence of aortic root dilatation (Z ≥ 2 above age 20 y, ≥ 3 below age 20 y) and a family history of MFS. However, it is necessary to exclude findings indicative of Shprintzen-Goldberg syndrome, Loeys-Dietz syndrome, and vascular Ehlers-Danlos syndrome; also, appropriate alternative genetic testing (eg, TGF β R1/2, SMAD3, TGF β 2, TGF β 3, collagen biochemistry, COL3A1) should be carried out.

Systemic score list (maximum total = 20 points; score ≥7 indicates systemic involvement)

Wrist (Walker) AND thumb (Steinberg) sign - 3 (wrist OR thumb sign - 1)
Pectus carinatum deformity - 2 (pectus excavatum or chest asymmetry - 1)
Hindfoot deformity - 2 (only pes planus - 1)
Pneumothorax - 2
Dural ectasia - 2
Protrusio acetabuli - 2
Reduced US/LS AND increased arm/height AND no severe scoliosis - 1
Scoliosis or thoracolumbar kyphosis - 1
Reduced elbow extension - 1
Facial features (3 out of 5; dolichocephaly, enophthalmos, down-slanting palpebral fissures, malar hypoplasia, retrognathia) - 1
Skin striae - 1
Myopia > 3 diopters - 1
Mitral valve prolapse (all types) - 1

Causes

Marfan syndrome (MFS) is caused by mutations in the FBN1 gene located on chromosome 15 at band q21.1. Mutations in TGFβR1 or TGFβR2 genes, located on chromosome 9q22.33 and on chromosome 3p24.2-p25, respectively, are typically associated with Loeys-Dietz syndrome, and there is marked phenotypic overlap with MFS. If the patient has ectopia lentis (dislocation of the lens), this is a more specific finding to MFS versus the other syndromes.

More than 500 fibrillin gene mutations have been identified. Almost all of these mutations are unique to an affected individual or family. Different fibrillin mutations are responsible for genetic heterogeneity. Phenotypic variability in the presence of the same fibrillin mutation suggests the importance of other, yet-to-be-identified factors that affect the phenotype.

Despite intensive international efforts, genotype-phenotype correlations have not been made, with the exception of an apparent clustering of mutations in patients diagnosed with neonatal MFS. Neonatal MFS represents the most severe end of the clinical spectrum of the fibrillinopathies and is associated with FBN1 gene mutation on chromosome 15q21.1 in exons 24–32.^[25]Affected individuals are generally diagnosed at birth or shortly thereafter. Unique features include joint contractures, "crumpled" external ears, and loose skin. Congestive heart failure associated with mitral and tricuspid regurgitation is the main cause of death. Aortic dissection is uncommon in neonatal MFS, and survival beyond 24 months is rare.^[26] A study by Ágg et al suggests that for patients with MFS, there are extracardiac predictors of aortic dissection: elevated TGFβ, increased matrix metalloproteinase 3 (MMP3) gene expression in peripheral blood mononuclear cells, and a greater frequency of striae atrophicae.^[27]

Genotype-phenotype correlations in MFS have been complicated by the large number of unique mutations reported, as well as by the degree of clinical heterogeneity among individuals with the same mutation.

Mutations in the FBN1 gene have also been found in patients with other fibrillinopathies. Identifying a given mutation is currently of limited value in establishing a phenotype or providing a prognosis in MFS.

MFS is known as an autosomal dominant connective tissue disorder. However, a family was reported to have homozygosity for an FBN1 missense mutation and demonstrated molecular evidence for recessive MFS.^[28]This case report has significant implications for genetic counseling and for interpretation of molecular diagnoses.

Differential Diagnoses

Esfandiari H, Ansari S, Mohammad-Rabei H, Mets MB. Management Strategies of Ocular Abnormalities in Patients with Marfan Syndrome: Current Perspective. J Ophthalmic Vis Res. 2019 Jan-Mar. 14 (1):71-7. [QxMD MEDLINE Link]. [Full Text].
Niwa K. Aortic dilatation in complex congenital heart disease. Cardiovasc Diagn Ther. 2018 Dec. 8 (6):725-38. [QxMD MEDLINE Link]. [Full Text].
Benke K, Agg B, Szilveszter B, et al. The role of transforming growth factor-beta in Marfan syndrome. Cardiol J. 2013. 20 (3):227-34. [QxMD MEDLINE Link]. [Full Text].
Bolar N, Van Laer L, Loeys BL. Marfan syndrome: from gene to therapy. Curr Opin Pediatr. 2012 Aug. 24(4):498-504. [QxMD MEDLINE Link].
Salik I, Rawla P. Marfan Syndrome. StatPearls. 2018 Jan. [QxMD MEDLINE Link]. [Full Text].
Renner S, Schuler H, Alawi M, et al. Next-generation sequencing of 32 genes associated with hereditary aortopathies and related disorders of connective tissue in a cohort of 199 patients. Genet Med. 2019 Jan 24. [QxMD MEDLINE Link].
Dietz HC, Pagon RA, Adam MP, et al. Marfan Syndrome. GeneReviews. 1993. [QxMD MEDLINE Link]. [Full Text].
von Kodolitsch Y, Robinson PN. Marfan syndrome: an update of genetics, medical and surgical management. Heart. 2007 Jun. 93(6):755-60. [QxMD MEDLINE Link].
Dean JC. Marfan syndrome: clinical diagnosis and management. Eur J Hum Genet. 2007 May 9. [QxMD MEDLINE Link]. [Full Text].
Benarroch L, Aubart M, Gross MS, et al. Reference Expression Profile of Three FBN1 Transcript Isoforms and Their Association with Clinical Variability in Marfan Syndrome. Genes (Basel). 2019 Feb 11. 10 (2):[QxMD MEDLINE Link]. [Full Text].
Loeys BL, Chen J, Neptune ER, et al. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet. 2005 Mar. 37(3):275-81. [QxMD MEDLINE Link].
Lee B, Godfrey M, Vitale E, et al. Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genes. Nature. 1991. 352:337-339.
Pyeritz RE. The Marfan syndrome. Annu Rev Med. 2000. 51:481-510. [QxMD MEDLINE Link].
Behr CA, Denning NL, Kallis MP, et al. The incidence of Marfan syndrome and cardiac anomalies in patients presenting with pectus deformities. J Pediatr Surg. 2018 Dec 27. [QxMD MEDLINE Link].
Vanem TT, Geiran OR, Krohg-Sorensen K, Roe C, Paus B, Rand-Hendriksen S. Survival, causes of death, and cardiovascular events in patients with Marfan syndrome. Mol Genet Genomic Med. 2018 Nov. 6 (6):1114-23. [QxMD MEDLINE Link]. [Full Text].
Rose PS, Levy HP, Ahn NU, et al. A comparison of the Berlin and Ghent nosologies and the influence of dural ectasia in the diagnosis of Marfan syndrome. Genet Med. 2000 Oct. 2(5):278-82. [QxMD MEDLINE Link].
Loeys BL, Dietz HC, Braverman AC, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010 Jul. 47(7):476-85. [QxMD MEDLINE Link].
Faivre L, Collod-Beroud G, Ades L, et al. The new Ghent criteria for Marfan syndrome: what do they change?. Clin Genet. 2012 May. 81(5):433-42. [QxMD MEDLINE Link].
Van de Velde S, Fillman R, Yandow S. Protrusio acetabuli in Marfan syndrome. History, diagnosis, and treatment. J Bone Joint Surg Am. 2006 Mar. 88(3):639-46. [QxMD MEDLINE Link].
Jones KB, Sponseller PD, Erkula G, et al. Symposium on the musculoskeletal aspects of Marfan syndrome: meeting report and state of the science. J Orthop Res. 2007 Mar. 25(3):413-22. [QxMD MEDLINE Link].
Avivi E, Arzi H, Paz L, Caspi I, Chechik A. Skeletal manifestations of Marfan syndrome. Isr Med Assoc J. 2008 Mar. 10(3):186-8. [QxMD MEDLINE Link]. [Full Text].
Wozniak-Mielczarek L, Sabiniewicz R, Drezek-Nojowicz M, et al. Differences in Cardiovascular Manifestation of Marfan Syndrome Between Children and Adults. Pediatr Cardiol. 2019 Feb. 40 (2):393-403. [QxMD MEDLINE Link]. [Full Text].
Altman A, Uliel L, Caspi L. Dural ectasia as presenting symptom of Marfan syndrome. Isr Med Assoc J. 2008 Mar. 10(3):194-5. [QxMD MEDLINE Link]. [Full Text].
Lacassie HJ, Millar S, Leithe LG, et al. Dural ectasia: a likely cause of inadequate spinal anaesthesia in two parturients with Marfan's syndrome. Br J Anaesth. 2005 Apr. 94(4):500-4. [QxMD MEDLINE Link].
Frydman M. The Marfan syndrome. Isr Med Assoc J. 2008 Mar. 10(3):175-8. [QxMD MEDLINE Link]. [Full Text].
Tiecke F, Katzke S, Booms P, et al. Classic, atypically severe andneonatal Marfan syndrome: twelve mutations and genotype-phenotypecorrelations in FBN1 exons 24-40. Eur J Hum Genet. 2001. 9:13-21. [QxMD MEDLINE Link]. [Full Text].
Agg B, Benke K, Szilveszter B, et al. Possible extracardiac predictors of aortic dissection in Marfan syndrome. BMC Cardiovasc Disord. 2014 Apr 11. 14:47. [QxMD MEDLINE Link]. [Full Text].
de Vries BB, Pals G, Odink R, Hamel BC. Homozygosity for a FBN1 missense mutation: clinical and molecular evidence for recessive Marfan syndrome. Eur J Hum Genet. 2007 Sep. 15(9):930-5. [QxMD MEDLINE Link].
Pyeritz RE. Evaluation of the adolescent or adult with some features of Marfan syndrome. Genet Med. 2012 Jan. 14(1):171-7. [QxMD MEDLINE Link].
Nee J, Kilaru S, Kelley J, et al. Prevalence of Functional GI Diseases and Pelvic Floor Symptoms in Marfan Syndrome and Ehlers-Danlos Syndrome: A National Cohort Study. J Clin Gastroenterol. 2019 Jan 21. [QxMD MEDLINE Link].
Callewaert B, Malfait F, Loeys B, De Paepe A. Ehlers-Danlos syndromes and Marfan syndrome. Best Pract Res Clin Rheumatol. 2008 Mar. 22(1):165-89. [QxMD MEDLINE Link].
Zhu L, Vranckx R, Khau Van Kien P, et al. Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus. Nat Genet. 2006 Mar. 38(3):343-9. [QxMD MEDLINE Link].
Loeys BL, Schwarze U, Holm T, et al. Aneurysm syndromes caused by mutations in the TGF-betareceptor. New Engl J Med. 2006. 355:788-798.
Glesby MJ, Pyeritz RE. Association of mitral valve prolapse and systemic abnormalities of connective tissue. A phenotypic continuum. JAMA. 1989 Jul 28. 262(4):523-8. [QxMD MEDLINE Link].
Montgomery RA, Geraghty MT, Bull E, Gelb BD, Johnson M, McIntosh I, et al. Multiple molecular mechanisms underlying subdiagnostic variants of Marfan syndrome. Am J Hum Genet. 1998 Dec. 63(6):1703-11. [QxMD MEDLINE Link].
Lieberman ER, Gomperts ED, Shaw KN, Landing BH, Donnell GN. Homocystinuria: clinical and pathologic review, with emphasis on thrombotic features, including pulmonary artery thrombosis. Perspect Pediatr Pathol. 1993. 17:125-47. [QxMD MEDLINE Link].
Sood S, Eldadah ZA, Krause WL, McIntosh I, Dietz HC. Mutation in fibrillin-1 and the Marfanoid-craniosynostosis (Shprintzen-Goldberg) syndrome. Nat Genet. 1996 Feb. 12(2):209-11. [QxMD MEDLINE Link].
Raymond FL, Tarpey PS, Edkins S, et al. Mutations in ZDHHC9, which encodes a palmitoyltransferase of NRAS and HRAS, cause X-linked mental retardation associated with a Marfanoid habitus. Am J Hum Genet. 2007 May. 80(5):982-7. [QxMD MEDLINE Link].
Schwartz CE, Tarpey PS, Lubs HA, et al. The original Lujan syndrome family has a novel missense mutation (p.N1007S) in the MED12 gene. J Med Genet. 2007 Jul. 44(7):472-7. [QxMD MEDLINE Link].
Summers KM, West JA, Peterson MM, et al. Challenges in the diagnosis of Marfan syndrome. Med J Aust. 2006 Jun 19. 184(12):627-31. [QxMD MEDLINE Link].
Weigang E, Ghanem N, Chang XC, et al. Evaluation of three different measurement methods for dural ectasia in Marfan syndrome. Clin Radiol. 2006 Nov. 61(11):971-8. [QxMD MEDLINE Link].
Faivre L, Masurel-Paulet A, Collod-Béroud G, Callewaert BL, Child AH, Stheneur C, et al. Clinical and molecular study of 320 children with Marfan syndrome and related type I fibrillinopathies in a series of 1009 probands with pathogenic FBN1 mutations. Pediatrics. 2009 Jan. 123(1):391-8. [QxMD MEDLINE Link].
Frobel AK, Hulpke-Wette M, Schmidt KG, Laer S. Beta-blockers for congestive heart failure in children. Cochrane Database Syst Rev. 2009 Jan 21. CD007037. [QxMD MEDLINE Link].
Williams A, Davies S, Stuart AG, Wilson DG, Fraser AG. Medical treatment of Marfan syndrome: a time for change. Heart. 2008 Apr. 94(4):414-21. [QxMD MEDLINE Link].
Pyeritz RE. Marfan syndrome: 30 years of research equals 30 years of additional life expectancy. Heart. 2009 Mar. 95(3):173-5. [QxMD MEDLINE Link].
Yetman AT, Bornemeier RA, McCrindle BW. Usefulness of enalapril versus propranolol or atenolol for prevention of aortic dilation in patients with the Marfan syndrome. Am J Cardiol. 2005 May 1. 95(9):1125-7. [QxMD MEDLINE Link].
Ahimastos AA, Aggarwal A, D'Orsa KM, et al. Effect of perindopril on large artery stiffness and aortic root diameter in patients with Marfan syndrome: a randomized controlled trial. JAMA. 2007 Oct 3. 298(13):1539-47. [QxMD MEDLINE Link].
Chung AW, Yang HH, Radomski MW, van Breemen C. Long-term doxycycline is more effective than atenolol to prevent thoracic aortic aneurysm in marfan syndrome through the inhibition of matrix metalloproteinase-2 and -9. Circ Res. 2008 Apr 25. 102(8):e73-85. [QxMD MEDLINE Link]. [Full Text].
Chung AW, Au Yeung K, Sandor GG, Judge DP, Dietz HC, van Breemen C. Loss of elastic fiber integrity and reduction of vascular smooth muscle contraction resulting from the upregulated activities of matrix metalloproteinase-2 and -9 in the thoracic aortic aneurysm in Marfan syndrome. Circ Res. 2007 Aug 31. 101(5):512-22. [QxMD MEDLINE Link].
Kharrazi FD, Rodgers WB, Coran DL, Kasser JR, Hall JE. Protrusio acetabuli and bilateral basicervical femoral neck fractures in a patient with Marfan syndrome. Am J Orthop. 1997 Oct. 26(10):689-91. [QxMD MEDLINE Link].
[Guideline] Harris EJ, Vanore JV, Thomas JL, et al. Diagnosis and treatment of pediatric flatfoot. J Foot Ankle Surg. 2004 Nov-Dec. 43(6):341-73. [QxMD MEDLINE Link].
Habashi JP, Judge DP, Holm TM, et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science. 2006 Apr 7. 312(5770):117-21. [QxMD MEDLINE Link]. [Full Text].
Brooke BS, Habashi JP, Judge DP, Patel N, Loeys B, Dietz HC 3rd. Angiotensin II blockade and aortic-root dilation in Marfan's syndrome. N Engl J Med. 2008 Jun 26. 358(26):2787-95. [QxMD MEDLINE Link]. [Full Text].
Pees C, Laccone F, Hagl M, Debrauwer V, Moser E, Michel-Behnke I. Usefulness of losartan on the size of the ascending aorta in an unselected cohort of children, adolescents, and young adults with Marfan syndrome. Am J Cardiol. 2013 Nov 1. 112 (9):1477-83. [QxMD MEDLINE Link].
Lacro RV, Dietz HC, Sleeper LA, et al. Atenolol versus losartan in children and young adults with Marfan's syndrome. N Engl J Med. 2014 Nov 27. 371 (22):2061-71. [QxMD MEDLINE Link]. [Full Text].
Chen H. Genetic Diagnosis and Counseling. 2nd ed. New York, NY: Springer; 2012. Vol 2: 1309-26.
Stout M. The Marfan syndrome: implications for athletes and their echocardiographic assessment. Echocardiography. 2009 Oct. 26(9):1075-81. [QxMD MEDLINE Link].
Van Lam H, Groth M, Mir T, et al. Impact of chest wall deformity on cardiac function by CMR and feature-tracking strain analysis in paediatric patients with Marfan syndrome. Eur Radiol. 2020 Dec 23. [QxMD MEDLINE Link]. [Full Text].
Milewicz DM, Dietz HC, Miller DC. Treatment of aortic disease in patients with Marfan syndrome. Circulation. 2005 Mar 22. 111 (11):e150-7. [QxMD MEDLINE Link]. [Full Text].

Media Gallery

Adult with Marfan syndrome. Note tall and thin build, disproportionately long arms and legs, and kyphoscoliosis.
Positive wrist (Walker) sign.
Positive thumb (Steinberg) sign.
Arachnodactyly.
Pectus excavatum of moderate severity.
Hypermobility of finger joints.
Stretch marks (striae atrophicae) in the lower back.
Dural ectasia in the lumbosacral region.
Typical face seen in a girl with Marfan syndrome characterized by dolichocephaly, malar hypoplasia, enophthalmos, retrognathia, and down-slanting palpebral fissures.