Inherited Connective Tissue Diseases

CHAPTER 76

Inherited Connective Tissue Diseases

Marfan Syndrome

INTRODUCTION/ETIOLOGY/EPIDEMIOLOGY

• The estimated prevalence of Marfan syndrome (MFS) is 1 in 5,000 to 1 in 10,000 individuals.

• MFS is an autosomal-dominant condition with high penetrance and variable expressivity, affecting cardiovascular, ocular, and skeletal systems.

• A pathogenic variant in the gene FBN1 results in a reduction in the functional amount of fibrillin-1 protein, which is one of the building blocks for the microtubules that provide strength and flexibility to connective tissues.

• Approximately 25% of individuals present without family history, suggesting a de novo mutation.

SIGNS AND SYMPTOMS

• Tall, thin body habitus

• Arachnodactyly (thin extremities with disproportionately long distal extremities)

• Joint hypermobility (see Table 4-1 and Figure 4-2 in Chapter 4, Physical Examination)

• Pectus deformities (of the carinatum or excavatum)

• Scoliosis

• Kyphosis

• Narrowed, high-arched palate with dental crowding

• Skin striae distensae without rapid change in body shape or weight

• Myopia and astigmatism

• Recurrent spontaneous pneumothorax should also raise suspicion of MFS.

DIFFERENTIAL DIAGNOSIS

• See Box 76–1.

Box 76-1. Differential Diagnosis of Marfan Syndrome

For a tall, young person with marfanoid body habitus

• Beals syndrome (ie, congenital contractual arachnodactyly)

• Ehlers-Danlos syndrome (vascular, valvular, kyphoscoliotic types)

• Familial thoracic aortic aneurysms and dissection syndromes (also with bicuspid valve or patent ductus arteriosus)

• Fragile X syndrome

• Klinefelter syndrome

• Homocystinuria

• Lujan-Fryns syndrome

• MASS phenotype: myopia, mitral valve prolapse, borderline and nonprogressive aortic enlargement, and nonspecific skin and skeletal features

• Mitral valve prolapse syndrome

• Shprintzen-Goldberg syndrome

• Stickler syndrome

Other disorders that overlap with the clinical findings of Marfan syndrome

• Arterial tortuosity syndrome

• Familial ectopia lentis

• Loeys-Dietz syndrome

• Weill-Marchesani syndrome

Box 76-2. Revised Ghent Criteria for Diagnosis of Marfan Syndrome and Related Conditions

Criteria to diagnose MFS for an individual in the absence of family history

1. Aortic root^a (Z score ≥ 2) and ectopia lentis

2. Aortic root (Z score ≥ 2) and FBN1 mutation

3. Aortic root (Z score ≥ 2) and systemic score ≥ 7 points

4. Ectopia lentis and FBN1 associated with previously identified aortic root aneurysm

Criteria to diagnose MFS for an individual with positive family history (individual independently diagnosed according to above criteria)

1. Ectopia lentis

2. Systemic score ≥ 7 points

3. Aortic root (Z score ≥ 2 for individual ≥ 20 y, ≥ 3 for individual < 20 y) and ectopia lentis

Criteria to diagnose MFS for an individual in the absence of family history

1. Ectopia lentis with or without systemic score ≥ 7 points and with FBN1 not associated with aortic root aneurysm/dilation or without FBN1: ectopia lentis syndrome

2. Aortic root (Z score < 2) and systemic score ≥ 5 points (with at least one skeletal feature) without ectopia lentis: MASS^b

3. Mitral valve prolapse and aortic root (Z score < 2) and systemic score ≥ 5 points without ectopia lentis: MVPS

Abbreviations: MASS, mitral valve prolapse, aortic root diameter at upper limits of normal for body size, stretch marks of the skin, and skeletal conditions similar to Marfan syndrome; MFS, Marfan syndrome; MVPS, mitral valve prolapse syndrome.

^a Measurement of aortic root dilation uses a Z score that is standardized for age and body size.

^b MASS is caused by a mutation in the FBN1 gene, which encodes fibrillin-1.

DIAGNOSTIC CONSIDERATIONS

• A multidisciplinary assessment is essential in making the diagnosis.

• A thorough personal history, family history, and clinical examination of the cardiovascular, skeletal, and ocular systems is required.

• Dilated ophthalmologic examination to screen for possible lens dislocation

• Transthoracic echo with 4-point aortic root measurements at the aortic valve annulus, sinuses of Valsalva, supra-aortic ridge, and proximal ascending aorta should be performed.

• The revised Ghent nosology (Box 76-2) emphasizes cardiovascular manifestations and identifies 2 cardinal features: aortic root aneurysm or dissection and ectopia lentis.

• To correctly diagnose MFS in the absence of any family history, the revised criteria require (1) the 2 cardinal features; (2) 1 cardinal feature and identification of a bona fide FBN1 mutation; or (3) 1 cardinal feature and other organ manifestations that contribute to a systemic score of 7 or higher (Box 76-3).

• Individuals who have a positive documented family history of MFS (ie, a family member’s MFS was independently diagnosed using the Ghent nosology) require the presence of 1 criterion to receive proper diagnoses (see Box 76-2) (Figure 76-1).

Box 76-3. Scoring of Systemic Features for the Diagnosis of Marfan Syndrome

• Wrist^a and thumb sign^b: 3 (wrist or thumb sign: 1)

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

• Hindfoot deformity: 2 (flexible pes planus: 1)

• Pneumothorax: 2

• Dural ectasia: 2

• Protrusio acetabuli: 2

• Reduced US/LS^c and increased arm span/height^d and no severe scoliosis: 1

• Scoliosis or thoracolumbar kyphosis: 1

• Reduced elbow extension: 1

• Facial features (3 out of 5): 1 (dolichocephaly, enophthalmos, down-slanting palpebral fissures, malar hypoplasia, retrognathia)

• Skin striae: 1