Marfan Syndrome

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Chapter 693 Marfan Syndrome

Marfan syndrome (MFS) is an autosomal dominant disorder caused by mutations in the gene encoding the extracellular matrix (ECM) protein fibrillin-1. It is primarily associated with skeletal, cardiovascular, and ocular pathology, displaying near-complete penetrance but variable expression. Diagnosis is based on clinical findings, some of which are age dependent.

Epidemiology

The incidence of this disorder is about 1/5,000-10,000 births. About 30% of cases are sporadic, due to de novo mutations; new mutations often associate with advanced paternal age.

Pathogenesis

MFS is associated with abnormal biosynthesis of fibrillin-1, a 350-kd ECM protein that is the major constituent of microfibrils. The fibrillin-1 (FBN1) locus resides on the long arm of chromosome 15 (15q21), and the gene is composed of 65 exons. More than 1,000 mutations distributed throughout FBN1 have been identified, many being unique to a given family. With the exception of an early-onset and severe presentation of MFS associated with some mutations in exons 26-27 and 31-32, no clear phenotype-genotype correlation has been identified. There is considerable intrafamily variability, suggesting that epigenetic, modifier gene, environmental, or other unidentified factors might influence expression of the disease.

MFS was traditionally considered to result from a structural deficiency of connective tissues. Reduced fibrillin-1 was thought to lead to a primary derangement of elastic fiber deposition, because both skin and aorta from affected patients show decreased elastin, along with elastic fiber fragmentation. In response to stress (such as hemodynamic forces in the proximal aorta), affected organs were thought to manifest this structural insufficiency with accelerated degeneration. However, it was difficult to reconcile certain manifestations of the disease with this structural deficiency model (i.e., bony overgrowth is more suggestive of excess cell proliferation than structural insufficiency).

Additional research has identified a cytokine-regulatory role for fibrillin-1 that appears to have important implications for MFS. Fibrillin-1 shares significant homology with the latent transforming growth factor β (TGF-β) binding proteins (LTBPs). TGF-β is secreted from cells as part of a large latent complex (LLC) that includes the mature cytokine (TGF-β), a dimer of its processed amino-terminal pro-peptide called latency associated peptide (LAP), and one of three LTBPs. Mice heterozygous for a mutation in the fibrillin-1 gene typical of those that cause MFS in humans (C1039G) display many of the classic features of MFS, including progressive aortic root dilatation. TGF-β signaling has been shown to be increased in the aortas of these mice, as well as the aortic wall from patients with MFS, suggesting that failed ECM sequestration of the LLC by fibrillin-1 leads to increased TGF-β signaling in MFS. Neutralizing antibodies to TGF-β have been shown to reduce the aortic size and improve the aortic wall architecture in these mice.

Aberrant TGF-β signaling might also play a role in the wider spectrum of manifestations of MFS. Increased TGF-β signaling has been observed in many tissues in MFS mice, including the developing lung, skeletal muscle, mitral valve, and dura. Treatment of these mice with agents that antagonize TGF-β signaling attenuates or prevents pulmonary emphysema, skeletal muscle myopathy, and myxomatous degeneration of the mitral valve. Patients with heterozygous mutations in TGF-β receptors 1 and 2 (TGFβR1 and TGFβR2) have MFS-like manifestations yet normal fibrillin-1. Paradoxically, these mutations also appear to result in increased TGF-β signaling in tissues of these patients. The resulting Loeys-Dietz syndrome (LDS) has much phenotypic overlap with MFS, but it also has many discriminating features (see Differential Diagnosis).

Clinical Manifestations

MFS is a multisystem disorder, with cardinal manifestations in the skeletal, cardiovascular, and ocular systems.

Skeletal System

Disproportionate overgrowth of the long bones is often the most striking and immediately evident manifestation of MFS. Anterior chest deformity is caused by overgrowth of the ribs, pushing the sternum anteriorly (pectus carinatum) or posteriorly (pectus excavatum). Overgrowth of arms and legs can lead to an arm span >1.05 times the height or a reduced upper to lower segment ratio (in the absence of severe scoliosis). Arachnodactyly (overgrowth of the fingers) is generally a subjective finding. The combination of long fingers and loose joints leads to the characteristic Walker-Murdoch or wrist sign: full overlap of the distal phalanges of the thumb and fifth finger when wrapped around the contralateral wrist (Fig. 693-1). The Steinberg or thumb sign is present when the distal phalanx of the thumb fully extends beyond the ulnar border of the hand when folded across the palm (Fig. 693-2), with or without active assistance by the patient or examiner.

Figure 693-1 Wrist sign. When the wrist is grasped by the contralateral hand, the thumb overlaps the terminal phalanx of the 5th digit.

(From McBride ART, Gargan M: Marfan syndrome, Curr Orthop 20:418–423, 2006.)

Figure 693-2 Thumb sign. When the hand is clenched without assistance, the entire thumbnail projects beyond the border of the hand.

(From McBride ART, Gargan M: Marfan syndrome, Curr Orthop 20:418–423, 2006.)

Thoracolumbar scoliosis is commonly present and can contribute to the systemic score of the diagnosis (Table 693-1). Protrusio acetabuli (inward bulging of the acetabulum into the pelvic cavity), which is generally asymptomatic in young adults, is best identified with radiographic imaging. Pes planus (flat feet) is commonly present and varies from mild and asymptomatic to severe deformity, wherein medial displacement of the medial malleolus results in collapse of the arch and often reactive hip and knee disturbances. Curiously, a subset of patients with the disorder present with an exaggerated arch (pes cavus). Although joint laxity or hypermobility is often identified, joints can be normal or even develop contractures. Reduced extension of the elbows is common and can contribute to the systemic score of the diagnosis (see Table 693-1). Contracture of the fingers (camptodactyly) is commonly observed, especially in children with severe and rapidly progressive MFS. Several craniofacial manifestations are often present and can contribute to the diagnosis (Fig. 693-3). These include a long narrow skull (dolicocephaly), recession of the eyeball within the socket (enophthalmos), recessed lower mandible (retrognathia) or small chin (micrognathia), malar hypoplasia (malar flattening), and downward-slanting palpebral fissures.

Table 693-1 Diagnostic Criteria for Marfan Syndrome (MFS)

In the absence of a family history of MFS, a diagnosis can be reached in 1 of 4 scenarios:

1 Aortic diameter at Sinuses of Valsalva Z-score ≥2 AND Ectopia Lentis = MFS *

2 Aortic diameter at Sinuses of Valsalva Z-score ≥2 AND FBN1 mutation = MFS

3 Aortic diameter at Sinuses of Valsalva Z-score ≥2 AND Systemic Score ≥7 = MFS *

4 Ectopia Lentis AND FBN1 mutation known to associate with aortic aneurysm = MFS

In the absence of a family history of MFS, alternative diagnoses to MFS include:

1 Ectopia Lentis ± Systemic Score AND FBN1 mutation not known to associate with aortic aneurysm or no FBN1 mutation = Ectopia Lentis syndrome

2 Aortic diameter at Sinuses of Valsalva Z-score <2 AND Systemic Score ≥5 (with at least one skeletal feature) without Ectopia Lentis = MASS phenotype

3 Mitral Valve Prolapse AND Aortic diameter at Sinuses of Valsalva Z-score <2 AND Systemic Score <5 without Ectopia Lentis = Mitral Valve Prolapse syndrome

In the presence of a family history of MFS, a diagnosis can be reached in 1 of 3 scenarios:

1 Ectopia Lentis AND Family History of MFS = MFS

2 Systemic Score ≥7 AND Family History of MFS = MFS *

3 Aortic diameter at Sinuses of Valsalva Z-score ≥2 if older than 20 yr or ≥3 if younger than 20 yr AND Family History of MFS = MFS *

SCORING OF SYSTEMIC FEATURES (IN POINTS)^†

Wrist AND thumb sign = 3 (wrist OR thumb sign = 1)

Pectus carinatum deformity = 2 (pectus excavatum or chest asymmetry = 1)

Hindfoot deformity = 2 (plain 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 (3/5) = 1 (dolichocephaly, enophthalmos, downslanting palpebral fissures, malar hypoplasia, retrognathia)

Skin striae = 1

Myopia >3 diopters = 1

Mitral valve prolapse (all types) = 1

CRITERIA FOR CAUSAL FBN1 MUTATION

Mutation previously shown to segregate in a Marfan family

Any one of the following de novo mutations (with proven paternity and absence of disease in parents):

Nonsense mutation

In-frame and out-of-frame deletion/insertion

Splice site mutations affecting canonical splice sequence or shown to alter splicing on mRNA/cDNA level

Missense mutation affecting/creating cysteine residues

Missense mutation affecting conserved residues of the EGF consensus sequence [(D/N)X(D/N)(E/Q)Xm(D/N)Xn(Y/F), with m and n representing variable number of residues; D, aspartic acid; N, asparagine; E, glutamic acid; Q, glutamine; Y, tyrosine; F, phenylalanine]

Other missense mutations: segregation in family, if possible, + absence in 400 ethnically matched control chromosomes; if no family history, absence in 400 ethnically matched control chromosomes

Linkage of haplotype for n≥6 meioses to the FBN1 locus

US/LS, upper segment/lower segment ratio.

* Without discriminating features of SGS, LDS, or vEDS (as defined in Table 693-2) and after TGFBR1/2, collagen biochemistry, COL3A1 testing if indicated. Other conditions/genes will emerge with time.

† Maximum total: 20 points; score ≥7 indicates systemic involvement.

From Loeys BL, Dietz HC, Braverman AC, et al: The revised Ghent nosology for the Marfan syndrome, J Med Genet 47:476–485, 2010.

Figure 693-3 Marfan syndrome. Note the elongated facies, droopy lids, apparent dolichostenomelia, and mild scoliosis.

Cardiovascular System

Manifestations of MFS in the cardiovascular system are conveniently divided into those affecting the heart and those affecting the vasculature. Within the heart, the atrioventricular (AV) valves are most often affected. Thickening of the AV valves is common and often associated with prolapse of the mitral and/or tricuspid valves. Variable degrees of regurgitation may be present. In children with early onset and severe MFS, insufficiency of the mitral valve can lead to congestive heart failure, pulmonary hypertension, and death in infancy; this manifestation represents the leading cause of morbidity and mortality in young children with the disorder (Chapter 422.3). Aortic valve dysfunction is generally a late occurrence, attributed to stretching of the aortic annulus by an expanding root aneurysm. Both the aortic and AV valves seem to be more prone to calcification in persons with MFS.

Ventricular dysrhythmia has been described in children with MFS (Chapter 429). In association with mitral valve dysfunction, supraventricular arrhythmia (e.g., atrial fibrillation or supraventricular tachycardia) may be seen. There is also an increased prevalence of prolonged QT interval on electrocardiographic surveys of patients with MFS. Dilated cardiomyopathy, beyond that explained by aortic or mitral valve regurgitation, seems to occur with increased prevalence in patients with MFS, perhaps implicating a role for fibrillin-1 in the cardiac ventricles. However, the incidence seems to be low, and the occurrence of mild to moderate ventricular systolic dysfunction is often attributed to mitral or aortic insufficiency or to the use of β-adrenergic receptor blockade.

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