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THE DIAGNOSIS OF MARFAN SYNDROME (Revised 2010)

The diagnosis of Marfan syndrome is based on the systemic features (signs and symptoms in the organ systems). The revised method (2010) assigns points to relevant features and the final score for the patient is used to decide on the diagnosis.

Contents of this webpage (click on required section)

GENETICS AND CONNECTIVE TISSUE

Marfan syndrome is a genetic disorder of connective tissue. Fibrillin in elastin is faulty due to a mutation (alteration) in the FBN1 gene on chromosome15. Connective tissue, containing elastin, is found throughout the body and the effects of the faulty fibrillin are therefore found in all organ systems.

The disorder is an autosomal dominant genetic disorder, which means that it is passed from parent to child, without any unaffected carriers and it never skips a generation. Every child of a person with Marfan syndrome has a 50% chance of having it. It is very variable in both severity and in the features that are significant in a patient - even in one family. Sometimes there is a spontaneous mutation, where there is no sign of the disorder in the family. These patients are usually very seriously affected and can pass it on to their children by the usual autosomal dominant method.

The possible features of Marfan syndrome, including the family history and mutations of the gene for fibrillin, are listed below.

FEATURES OF MARFAN SYDROME

Some features common in Marfan syndrome are also found in other disorders and are therefore not used in the scoring for the diagnosis. (Brief descriptions of the features can be found on the Definitions page of this website. Click on the term in colour and underlined to go direct to the definition.)

Family and genetic history

• Having a parent, child or sibling who meets the diagnostic criteria independently.
• Presence of a mutation in FBN1 known to cause Marfan syndrome. (Technical information below.)

Criteria for causal FBN1 mutation (technical information about the mutation):

• Mutation previously shown to segregate in the Marfan family
• De novo (with proven paternity and absence of disease in parents) mutation in one of the following categories:
• Nonsense mutation.
• Inframe and out of frame deletion/insertion.
• Splice site mutations affecting canonical splice sequences or shown to alter splicing on mRNA/cDNA level.
• Missense affecting/creating cysteine residues.
• Missense affecting conserved residues of the EGF consensus sequence [(D/N)X(D/N)(E/Q)Xm(D/N)Xn(Y/F), m and n = variable number 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; or if no family history, absence in 400 ethnically matched control chromosomes.
• Linkage of haplotype for n≥6 meioses to the FBN1 locus.

Cardiovascular system

• Aortic root aneurysm or dissection
• Mitral valve prolapse
• Dilation or dissection of the descending thoracic or abdominal aorta (not included in scoring)
• Dilation of the main pulmonary artery (not included in scoring)
• Calcification of the mitral annulus below the age of 40 (not included in scoring)

Note for cardiologists: Aortic root aneurysm must be measured three times and corrected for age and body size and interpreted as a Z-score. (Z-score calculator at http://www.marfan.org/marfan/4647/2010-Revised-Ghent-Nosology----Z-Score-Calculation)

Ocular system

• Ectopia lentis
• Myopia - early onset, high severity, rapid progression
• Abnormally flat cornea (not included in scoring)
• Increased axial length of globe (not included in scoring)
• Hypoplastic iris or hypoplastic ciliary muscle (not included in scoring)
• Typical of Marfan syndrome: early cataracts, open angle glaucoma (not included in scoring)

SYSTEMIC CRITERIA

Skeletal system

• Wrist sign and thumb sign
• Pectus carinatum
• Pectus excavatum or chest asymmetry
• Acetabular protrusion (protrusio acetabulae)
• Hindfoot valgus
• Pes planus (flat foot)
• Reduced upper to lower segment ratio and armspan to height ratio greater than 1.05
• Scoliosis of +20° or exaggerated thoracolumbar kyphosis
• Reduced extension at elbows (<170°)
• Facial characteristics:
  • Dolichocephaly
  • Downward slanting palpebral fissures
  • Enophthalmos
  • Retrognathia
  • Malar hypoplasia
• Joint hypermobility (not included in scoring)
• Highly arched palate with crowding of teeth (not included in scoring)

Dura

• Lumbosacral dural ectasia

Pulmonary system

• Spontaneous pneumothorax
• Apical bullae (not included in scoring)

Dermal system and integument

• Striae atrophicae
• Recurrent or incisional herniae (not included in scoring)

SCORING OF SYSTEMIC FEATURES

The following are the points allocated to each feature or combination of features. The total score for a patient (if ≥7) can then be used for the final diagnosis - see Requirements 3 or 6 below.

DIAGNOSIS

Requirements for the diagnosis of Marfan syndrome.

The diagnosis of Marfan syndrome is positive if one of the following requirements is met:

        For the index case, i.e. in the absence of family history, one of:

1. Aortic root aneurysm (Z≥2 above 20 years, Z≥3 below 20 years), or aortic root dissection, AND ectopia lentis.
2. Aortic root aneurysm (Z≥2 above 20 years, Z≥3 below 20 years), or aortic root dissection, AND FBN1 mutation.
3. Aortic root aneurysm (Z≥2 above 20 years, Z≥3 below 20 years), or aortic root dissection, AND systemic points ≥7.
4. Ectopia lentis AND FBN1 mutation, WITH known aortic root aneurysm (Z<2 above 20 years, Z<3 below 20 years).

For a relative of an index case, i.e. presence of family history, one of:

5. Ectopia lentis AND family history of Marfan syndrome (as defined above).
6. Systemic points ≥7 AND family history of Marfan syndrome (as defined above).
7. Aortic root aneurysm (Z≥2 above 20 years, Z≥3 below 20 years), or aortic root dissection, AND family history of Marfan syndrome (as defined above).

Conditions to be differentiated from Marfan syndrome

The following disorders overlap, to varying extents, with Marfan syndrome:

• Loeys-Dietz syndrome
• Bicuspid aortic valve
• Familial thoracic aortic aneurysm
• Vascular Ehlers-Danlos syndrome
• Arterial tortuosity syndrome
• Ectopia lentis syndrome
• Weill-Marchesani syndrome
• Homocystinuria
• Stickler syndrome
• Shprintzen-Goldberg syndrome
• Congenital contractural arachnodactyly (Beals syndrome)
• MASS phenotype (myopia, mitral valve prolapse, mild aortic dilation, skin striae, and skeletal involvement)
• Mitral valve prolapse syndrome (Barlow syndrome)

Contact SAMSO for more information on the differential diagnosis of these disorders, or refer to "The revised Ghent nosology for the Marfan syndrome" by Loeys, Dietz, et al. Jour. Med Genetics (2010).

This summary was prepared by L P Higgs from "The revised Ghent nosology for the Marfan syndrome" by Loeys, Dietz, et al. Jour. Med Genetics (2010) - TEC/002 in the SAMSO catalogue.