CAM 204129

Marfan Syndrome Testing

Category:Laboratory   Last Reviewed:April 2019
Department(s):Medical Affairs   Next Review:April 2020
Original Date:May 2017    

Description 
Marfan Syndrome is one of the most common inherited disorders of connective tissue. It is an autosomal dominant condition with an incidence of about 1 in 5,000 individuals. While most individuals with Marfan syndrome have an affected parent, approximately 25 percent of probands have Marfan Syndrome as the result of a de novo mutation.

Background 
The protein that plays a role in Marfan syndrome is called fibrillin-1. Fibrillin-1 is an important matrix component of both elastic and nonelastic tissues. It is the main constituent protein of extracellular microfibrils that are thought to contribute to the formation and maintenance of elastic fibers (UpToDate, 2017). Most patients with the typical Marfan phenotype have mutations involving the FBN1 gene that encodes fibrillin-1. FBN1 is a large gene (65 exons) located at chromosome 15q-21.1. In a minority of cases (<10 percent) with typical Marfan phenotype, no mutation in FBN1 is identified (UpToDate, 2017). This mutation results in an increase in a protein called transforming growth factor beta, or TGF-β. The increase in TGF-β causes problems in connective tissues throughout the body, which in turn creates the clinical features associated with Marfan syndrome.

At a molecular level, it is not well understood how FBN1 or transforming growth factor-beta receptor mutations lead to disease (UpToDate, 2017). Among the proposed mechanisms are alterations in: 

  • A structural role of microfibrils in coordinating tissue morphogenesis, homeostasis and/or response to hemodynamic stress 
  • Increased bioavailability of transforming growth factor (TGF)-beta

Symptoms
People with Marfan syndrome are born with it, but features of the disorder are not always present right away. Some people have a lot of Marfan features at birth or as young children – including serious conditions like aortic enlargement. Others have fewer features when they are young and don’t develop aortic enlargement or other signs of Marfan syndrome until they are adults. Some features of Marfan syndrome, like those affecting the heart and blood vessels, bones or joints, can get worse over time. Below are some details on major complications of Marfan Syndrome:

  • Skeletal Abnormalities: People with Marfan syndrome are typically very tall and slender with generalized joint hypermobility. They have disproportionately long extremities in comparison to the length of the trunk (dolichostenomelia), so the upper segment to lower segment (US/LS) ratio is decreased and the arm span to height ratio is increased (UpToDate, 2017). Other skeletal problems may include arachnodactyly, high arched palate, pectus deformities (pectus carinatum or pectus excavatum), hindfoot valgus, pes planus, acetabular protrusion and spinal deformities (kyphosis or scoliosis). Marfan syndrome patients could have one of the following facial features: dolichocephaly (reduced cephalic index or head width/length ratio), enophthalmos, downslanting palpebral fissures, malar hypoplasia and retrognathia.
  • Ocular Abnormalities: Ectopia lentis occurs in 50 to 80 percent people with Marfan syndrome. Other ocular abnormalities in Marfan syndrome include myopia, flat cornea, retinal detachment, glaucoma and early cataract formation. Retinal tears and detachment are commonly bilateral in MFS and may be associated with proliferative retinopathy (UpToDate, 2017).
  • Aortic Disease: Aortic root disease, leading to aneurysmal dilatation, aortic regurgitation and dissection, is the main cause of morbidity and mortality in Marfan syndrome (UpToDate, 2017). Approximately 50 percent of children and 60 to 80 percent of adults with Marfan syndrome have dilatation of the aortic root. Undiagnosed and untreated Marfan syndrome is frequently associated with aortic dissection. The dissection generally begins just above the coronary ostia and can extend the entire length of the aorta; it is a type I dissection in the DeBakey classification or a type A in the Dailey scheme. (UpToDate, 2017).
  • Cardiac Disease: Patients with Marfan syndrome frequently develop mitral valve prolapse, with many having mild mitral regurgitation. On echocardiography, the mitral leaflets have an elongated and redundant appearance and either or both leaflets may prolapse. Approximately 25 percent of patients with mitral valve prolapse have progressive disease as defined by the appearance or worsening of clinical symptoms of mitral regurgitation or worsening on echocardiography (UpToDate, 2017). Tricuspid valve prolapse may also occur in some patients.
  • Nervous system: Dural ectasia is a sensitive but not specific sign of Marfan syndrome and usually involves the lumbosacral spine. Dural ectasia results from enlargement of the spinal canal owing to progressive ectasia of dura and neural foramina and to erosion of vertebral bone (UpToDate, 2017).
  • Skin: Many people with Marfan syndrome develop stretch marks on their skin, even without any weight change. These stretch marks can occur at any age and can have an uncommon location such as the mid back, lumbar region, upper arm, axillary region or thigh.
  • Lungs: Some patients with Marfan syndrome develop emphysematous changes with lung bullae predominantly in the upper lobes, which can predispose to spontaneous pneumothorax (UpToDate, 2017). Rarely, people with Marfan syndrome may have sleep-related breathing disorders such as snoring or sleep apnea.

Inheritance pattern
Marfan Syndrome is inherited in an autosomal dominant pattern. Approximately 25 percent of probands have Marfan Syndrome as the result of a de novo mutation and occur in people with no history of the disorder in their family.

Genetic changes
Mutations in the FBN1 gene cause Marfan syndrome. Fibrillin-1 is an important matrix component of both elastic and nonelastic tissues. It is the main constituent protein of extracellular microfibrils that are thought to contribute to the formation and maintenance of elastic fibers (UpToDate, 2017). A mutation in the FBN1 gene can reduce the amount of functional fibrillin-1 that is available to form microfibrils, which leads to decreased microfibril formation. As a result, excess growth factors are released and elasticity in many tissues is decreased, leading to overgrowth and instability of tissues.

Diagnosis of Marfan Syndrome
Marfan syndrome is a clinical diagnosis based on family history and the observation of characteristic findings in multiple organ systems. Ectopia lentis and aortic aneurysm are given special significance in the diagnosis of Marfan syndrome because of their relative specificity or frequency and clinical significance, respectively.

Loeys-Dietz syndrome has several characteristics that overlap with those of Marfan syndrome. Most patients with a TGFBR1 or TGFBR2 mutation have Loeys-Dietz syndrome, which is often characterized by hypertelorism, a split uvula or cleft palate, tortuous arteries and aortic aneurysms. Associated findings may include premature fusion of the skull, cervical spine deformity and instability, structural heart disease and aneurysms affecting vessels other than the aorta (UpToDate, 2017). When making a diagnosis, it is important to distinguish between the two disorders: Loeys-Dietz is more likely to cause fatal aortic aneurysms, and treatment for the two is different.

Diagnostic Criteria
The revised diagnostic criteria for Marfan syndrome [Loeys et al., 2010] integrate information from multiple sources, including family history, personal medical history, physical examination, slit lamp evaluation and echocardiography or other forms of cardiovascular imaging.

Revised Ghent nosology — The 2010 revised Ghent nosology puts greater weight on aortic root dilatation/dissection and ectopia lentis as the cardinal clinical features of MFS and on testing for mutations in FBN1 (UpToDate 2016).

  • In the absence of family history of MFS, the presence of one of any of the following criteria is diagnostic for MFS:
    • Aortic criterion (aortic diameter Z ≥ 2 or aortic root dissection) and ectopia lentis*
    • Aortic criterion (aortic diameter Z ≥ 2 or aortic root dissection) and a causal FBN1 mutation
    • Aortic criterion (aortic diameter Z ≥ 2 or aortic root dissection) and a systemic score ≥ 7 points*
    • Ectopia lentis and a causal FBN1 mutation that has been identified in an individual with aortic aneurysm
  • In the presence of family history of MFS (as defined by the above criteria), the presence of one of any of the following criteria is diagnostic for MFS:
    • Ectopia lentis
    • Systemic score ≥ 7 points*
    • Aortic criterion (aortic diameter Z ≥ 2 above 20 years old, Z ≥ 3 below 20 years or aortic root dissection)* 

For criteria with an asterisk (*), the diagnosis of MFS can be made only in the absence of discriminating features of Shprintzen-Goldberg syndrome, Loeys-Dietz syndrome or vascular Ehlers-Danlos syndrome and after TGFBR1/2, collagen biochemistry or COL3A1 testing if indicated.

Systemic score — The revised Ghent nosology includes the following scoring system for systemic features (UpToDate 2016):

  • Wrist AND thumb sign: 3 points
  • Wrist OR thumb sign: 1 point
  • Pectus carinatum deformity: 2 points
  • Pectus excavatum or chest asymmetry: 1 point
  • Hindfoot deformity: 2 points
  • Plain pes planus: 1 point
  • Pneumothorax: 2 points
  • Dural ectasia: 2 points
  • Protrusio acetabuli: 2 points
  • Reduced upper segment/lower segment ratio AND increased arm span/height AND no severe scoliosis: 1 point
  • Scoliosis or thoracolumbar kyphosis: 1 point
  • Reduced elbow extension (≤ 70 degrees with full extension): 1 point
  • Facial features (at least three of the following five features: dolichocephaly, malar hypoplasia, enophthalmos, downslanting palpebral fissures, retrognathia): 1 point
  • Skin striae: 1 point
  • Myopia >3 diopters: 1 point
  • Mitral valve prolapse: 1 point

Molecular Genetic Testing
FBN1 is the only gene in which pathogenic variants are known to cause classic Marfan syndrome.

Even in the presence of an FBN1 mutation, the diagnosis of MFS relies on fulfillment of clinical diagnostic criteria. Genetic testing, however, may be beneficial in the following circumstances (UpToDate, 2017):

  • Identification of FBN1 mutation will change medical management of the affected patient
  • Identification of FBN1 mutation will change follow-up frequency of the affected patient
  • Identification of FBN1 mutation will help identify potentially affected family members
  • Identification of FBN1 mutation will facilitate prenatal diagnostic testing
  • Identification of another disorder (e.g., Loeys-Dietz or familial aortic aneurysmal disease) will change medical or surgical management or follow-up for the affected patient.

Table 1: Summary of Molecular Genetic Testing Used in Marfan syndrome (Dietz, 2014)  

Gene Test Method Proportion of Probands with a Pathogenic Variant Detectable by this Method
FBN1 Sequence analysis ~70%-93%
Deletion/duplication analysis Unknown
Linkage analysis Not applicable

Policy 

  1. Genetic testing (FBN1 mutation) for Marfan Syndrome is MEDICALLY NECESSARY for any of the following indications:
    • Marfan syndrome is suspected based on clinical features, but a definitive diagnosis cannot be made using established clinical diagnostic criteria (see Note 1 below)
    • Testing of an asymptomatic individual who has an affected first-degree blood relative (i.e,. parent, sibling, child) with a known mutation.
    • The prenatal diagnosis or PGD of Marfan syndrome in the offspring of patients with known disease-causing variants.
  2. If FBN1 mutation testing is negative, Avalon considers genetic testing for Loeys-Dietz Syndrome (TGFBR1 or TGFBR2 mutation) MEDICALLY NECESSARY for any of the following indications:
    • a) To confirm or establish a diagnosis of LDS in an individual with characteristics of LDS (see Note 2 below)
    • b) Testing of an asymptomatic individual who has an affected first-degree blood relative (i.e., parent, sibling, child) with a known mutation.
  3. Panel gene testing for Marfan Syndrome or other connective tissue disorders, including Ehlers-Danlos Syndrome, is considered NOT MEDICALLY NECESSARY.

Note 1: Clinical Diagnostic Criteria for Marfan Syndrome is as follows:

Revised Ghent nosology — The 2010 revised Ghent nosology puts greater weight on aortic root dilatation/dissection and ectopia lentis as the cardinal clinical features of MFS and on testing for mutations in FBN1 (UpToDate 2016).

  • In the absence of family history of MFS, the presence of one of any of the following criteria is diagnostic for MFS:
    • Aortic criterion (aortic diameter Z ≥ 2 or aortic root dissection) and ectopia lentis*
    • Aortic criterion (aortic diameter Z ≥ 2 or aortic root dissection) and a causal FBN1 mutation
    • Aortic criterion (aortic diameter Z ≥ 2 or aortic root dissection) and a systemic score ≥ 7 points*
    • Ectopia lentis and a causal FBN1 mutation that has been identified in an individual with aortic aneurysm
  • In the presence of family history of MFS (as defined by the above criteria), the presence of one of any of the following criteria is diagnostic for MFS:
    • Ectopia lentis
    • Systemic score ≥ 7 points*
    • Aortic criterion (aortic diameter Z ≥ above 20 years old, Z ≥ below 20 years or aortic root dissection)*

For criteria with an asterisk (*), the diagnosis of MFS can be made only in the absence of discriminating features of Shprintzen-Goldberg syndrome, Loeys-Dietz syndrome or vascular Ehlers-Danlos syndrome and after TGFBR1/2, collagen biochemistry, or COL3A1 testing if indicated.

Systemic score — The revised Ghent nosology includes the following scoring system for systemic features (UpToDate 2016):

  • Wrist AND thumb sign: 3 points
  • Wrist OR thumb sign: 1 point
  • Pectus carinatum deformity: 2 points
  • Pectus excavatum or chest asymmetry: 1 point
  • Hindfoot deformity: 2 points
  • Plain pes planus: 1 point
  • Pneumothorax: 2 points
  • Dural ectasia: 2 points
  • Protrusio acetabuli: 2 points
  • Reduced upper segment/lower segment ratio AND increased arm span/height AND no severe scoliosis: 1 point
  • Scoliosis or thoracolumbar kyphosis: 1 point
  • Reduced elbow extension (≤70 degrees with full extension): 1 point
  • Facial features (at least three of the following five features: dolichocephaly, malar hypoplasia, enophthalmos, downslanting palpebral fissures, retrognathia): 1 point
  • Skin striae: 1 point
  • Myopia >3 diopters: 1 point
  • Mitral valve prolapse: 1 point

Note 2: Clinical features of Loeys-Dietz Syndrome: aortic/arterial aneurysms/tortuosity, arachnodactyly, bicuspid aortic valve and patent ductus arteriosus, blue sclerae, camptodactyly, cerebral, thoracic or abdominal arterial aneurysms and/or dissections, cleft palate/bifid uvula, club feet, craniosynostosis, easy bruising, joint hypermobility, ocular hypertelorism, pectus carinatum or pectus excavatum, scoliosis, talipes equinovarus, thin skin with atrophic scars, velvety and translucent skin, widely spaced eyes.

Policy Guidelines 
The National Institute of Arthritis and Musculoskeletal and Skin Disease states that "after a clinical diagnosis of a family member, a genetic study might identify the specific mutation for which a test can be performed to determine if other family members are affected."

According to American College of Cardiology, if a mutant gene (FBN1, TGFBR1, TGFBR2, COL3A1, ACTA2, MYH11) associated with aortic aneurysm and/or dissection is identified in a patient, first-degree relatives should undergo counseling and testing (Hiratzka et al., 2010).

References 

  1. Genetic Home Reference – National Library of Medicine (2017). Marfan Syndrome. Retrieved January 21, 2017, from https://ghr.nlm.nih.gov/condition/marfan-syndrome#genes
  2. Medline Plus (2016. Marfan Syndrome. Accessed online on Nov 12, 2016, from https://medlineplus.gov/ency/article/000418.htm
  3. Dietz, H. (2001). Marfan syndrome. 2001 Apr 18 [Updated 2017 Feb 2]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
  4. Hiratzka, L.F., Bakris, G.L., Beckman, J.A., et al. (2010). Guidelines for the diagnosis and management of patients with thoracic aortic disease. Retrieved December, 2016, from http://circ.ahajournals.org/content/121/13/e266.short
  5. Loeys BL, Dietz HC, Braverman AC, Callewaert BL, De Backer J, Devereux RB, Hilhorst-Hofstee Y, Jondeau G, Faivre L, Milewicz DM, Pyeritz RE, Sponseller PD, Wordsworth P, De Paepe AM (2010). The revised Ghent nosology for the Marfan syndrome. J Med Genet;47:476–85.
  6. Marfan Foundation. Marfan and related disorders. Retrieved November 21, 2016, from https://www.marfan.org/about/marfan
  7. National Institute of Arthritis and Musculoskeletal and Skin Disease-NIH (2015). Questions and answers about Marfan Syndrome. Retrieved January 30, 2017, from https://www.niams.nih.gov/health_info/marfan_syndrome/#4

Coding Section 

Code Number Description
CPT  81405  Molecular pathology procedure, Level 6    Genes:  TGFBR1 (transforming growth factor, beta receptor 1) (eg, Marfan syndrome), full gene sequence. TGGFBR2 (transforming growth factor, beta receptor 2) (eg, marfan syndrome), full gene sequence 
  81408  Molecular pathology procedure, Level 9  Genes: FBN1 (fibrillin 1) (eg, Marfan syndrome), full gene sequence 
  81410 Aortic dysfunction or dilation (eg, Marfan syndrome, Loeys Dietz syndrome, Ehler Danlos syndrome type IV, arterial tortuosity syndrome)
  81411 Aortic dysfunction or dilation (eg, Marfan syndrome, Loeys Dietz syndrome, Ehler Danlos syndrome type IV, arterial tortuosity syndrome)
ICD-10-CM H52.1 codes Myopia
  I34.1 Nonrheumatic mitral (valve) prolapse
  I71.1-I71.9 codes Aortic aneurysm
  J93 codes Pneumothorax and air leak
  L90.6 Striae atrophicae
  M21.41 – M21.42 Flat foot (pes planus)
  M21.6X1 – M21.6X2 codes Other acquired deformities of foot
  M24.7 Protrusio acetabuli
  M35.7 Hypermobility syndrome
  M40 codes Kyphosis and lordosis
  M41 codes Scoliosis
  Q12.1 Congenital displaced lens
  Q23.1 Congenital malformations of aortic and mitral valves
  Q25.0 Patent ductus arteriosus
  Q35 Cleft palate
  Q35.7 Cleft uvula
  Q66.0 Congenital talipes equinovarus
  Q66.8 Other congenital deformities of feet
  Q66.51 and Q66.52 Congenital pes planus
  Q67.6 Pectus excavatum
  Q67.7 Pectus carinatum
  Q75.0 Craniosynostosis
  Q75.2 Hypertelorism
  Q87.4 Marfan's syndrome

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each Policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology© American Medical Association.  All Rights Reserved" 

History From 2017 Forward     

04/01/2019 

Annual review, no change to policy intent. 

06/26/2018 

Updated Policy criteria with adding Number 3 criteria. No other changes made. 

06/07/2018 

Updated Z scores. No other change made.  

04/17/2018 

Annual review, no change to policy intent. 

04/03/2018

Updated background section to add z score values. No other changes made. 

04/27/2017

New Policy

 


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