Marfan Syndrome AHS – M2144

Description of Procedure or Service

Definitions

Marfan Syndrome is a common autosomal dominant disorder of connective tissue most often caused by mutations in the extracellular matrix protein fibrillin (FBN1) gene (Hilhorst-Hofstee et al., 2010). Cardinal manifestations include proximal aortic aneurysm, dislocation of the ocular lens, and long-bone overgrowth (Judge & Dietz, 2005), however, clinical severity ranges from isolated features of MFS to neonatal presentation of severe and rapidly progressive disease involving multiple organ systems (Dietz, 2017).

***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician.

Policy

BCBSNC will provide coverage for genetic testing for marfan syndrome when it is determined to be medically necessary because the medical criteria and guidelines shown below are met.

Benefits Application

This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore member benefit language should be reviewed before applying the terms of this medical policy

When Genetic Testing for Marfan Syndrome is covered

1. Genetic testing (FBN1 mutation) for Marfan Syndrome is considered medically necessary for any of the following indications
   1. Marfan syndrome is suspected based on clinical features, but a definitive diagnosis cannot be made using established clinical diagnostic criteria (see Note 1 below)
   2. Testing of an asymptomatic individual who has an affected first-degree blood relative (i.e., parent, sibling, child) with a known mutation.
   3. 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, genetic testing for Loeys-Dietz Syndrome (TGFBR1 or TGFBR2 mutation) is considered medically necessary for any of the following indications
   1. To confirm or establish a diagnosis of LDS in an individual with character3istics of LDS (see Note 2 below)
   2. Testing of an asymptomatic individual who has an affected first-degree blood relative (i.e. parent, sibling, child) with a known mutation.

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 ≥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 (≤170 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.

When Genetic Testing for Marfan Syndrome is not covered

Panel gene testing for Marfan syndrome or other connective tissue disorders, including Ehlers-Danlos Syndrome is considered not medically necessary.

Policy Guidelines

Background

Marfan’s Syndrome (MFS) was first described more than 100 years ago by a Parisian professor of pediatrics, Antoine-Bernard Marfan. He was the first to report the association of long slender digits with other skeletal abnormalities in a 5-year-old girl (Radke & Baumgartner, 2014). It is a fairly common condition with an incidence of about 1 in 3000 to 5000 individuals (Wright & Connolly, 2018).

MFS is a systemic disorder of connective tissue with significant clinical variability, across a broad phenotypic continuum ranging from mild isolated features to severe and rapidly progressive neonatal multiorgan disease(Faivre et al., 2007). Historically defined by primary involvement the ocular, skeletal, and cardiovascular systems; ocular findings include myopia, ectopia lentis, and an increased risk for retinal detachment, glaucoma, and early cataracts. Skeletal system manifestations include bone overgrowth and joint laxity, disproportionately long extremities for the size of the trunk (dolichostenomelia), overgrowth of the ribs (pectus excavatum or pectus carinatum), and scoliosis. The major morbidity and early mortality in Marfan syndrome result from its effects on the cardiovascular system including aortic root dilatation and rupture, mitral valve, tricuspid valve prolapse, and enlargement of the proximal pulmonary artery. Severe and prolonged regurgitation of the mitral and/or aortic valve can lead to left ventricular dysfunction and heart failure. However, with careful management, life expectancy approximates that of the general population (H. Dietz, 2017; Pyeritz, 2017).

Most patients, more than 90%, with the typical Marfan phenotype have mutations involving the gene (FBN1) encoding the connective tissue protein fibrillin-1 (Loeys et al., 2004). Fibrillins are large glycoproteins that form extracellular microfibrils (Davis & Summers, 2012) which provide elasticity and structural support to tissues, modulate elastic fiber biogenesis and homeostatis, and regulate the bioavailability and activity of different growth factors (Grewal & Gittenberger-de Groot, 2018). Fibrillin-1 is an important matrix component of both elastic and nonelastic tissues (Wright & Connolly, 2018). Mutations lead to impaired fibrillin-1 protein synthesis, secretion and/ or incorporation in extracellular matrix, (Schrijver, Liu, Brenn, Furthmayr, & Francke, 1999; Whiteman & Handford, 2003), initiating the degeneration of the elastic microfibrillar architecture, loss of tissue homeostasis and ECM integrity (Grewal & Gittenberger-de Groot, 2018). This also gives rise to smooth muscle cell contractile dysfunction and a reduction in tensile strength of aortic tissue, thereby rendering the aorta maladapted/unfit to withstand the high pressures normally generated by the heart (Milewicz et al., 1996). Recent studies indicate a role for smooth muscle cell (SMA) phenotype in the pathogenesis of MFC. Early phenotypic switch resulting from FBN1 mutation appears to be associated with initiation of important metabolic changes in SMCs (Dale et al., 2017) that contribute to subsequent pathology. Lastly, mutation in FBN 1 has been shown to dysregulate the transforming growth factor-β (TGF-β) pathway (Bin Mahmood et al., 2017) as matrix sequestration of cytokines is crucial to their regulated activation and signaling(Neptune et al., 2003). The diagnosis of Marfan syndrome is now established by an FBN1 pathogenic variant known to be associated with Marfan syndrome AND one of the following: Aortic root enlargement (Z-score ≥2.0). Ectopia lentis. Demonstration of aortic root enlargement (Z-score ≥2.0) and ectopia lentis OR a defined combination of features throughout the body yielding a systemic score ≥7(H. Dietz, 2017).

As a result of the identification of FBN1 as the genetic basis for MFS and its downstream effects, the understanding of MFS as a structural disorder of the connective tissue has changed to that of a developmental abnormality with broad and complex effects on the morphogenesis and function of multiple organ systems (H. C. Dietz, Loeys, Carta, & Ramirez, 2005; Jensen & Handford, 2016). Importantly, this also introduced new biological targets for treatment strategies in MFS.

Current clinical studies have elucidated a medical regimen for patients with MFS to help control the progression of cardiovascular manifestations and resulting mortality. The standard of care for medical management includes the use of β-blockers with supplementation or replacement by angiotensin receptor blockers (ARBs)(Hiratzka et al., 2010), although this is a subject of ongoing research (Bin Mahmood et al., 2017).

However, a Chochrane review (Koo, Lawrence, & Musini, 2017) concluded that “Based on only one, low-quality RCT comparing long-term propranolol to no treatment in people with Marfansyndrome, we could draw no definitive conclusions for clinical practice. High-quality, randomised trials are needed to evaluate the long-term efficacy of beta-blocker treatment in people with Marfan syndrome. Future trials should report on all clinically relevant end points and adverse events to evaluate benefit versus harm of therapy.”

Sellers et al (Sellers et al., 2018) recently reported “Despite promising preclinical and pilot clinical data, a recent large-scale study using antihypertensive angiotensin II (AngII) receptor type 1 (ATR1) blocker losartan has failed to meet expectations at preventing MFS-associated aortic root dilation, casting doubts about optimal therapy.” Their mouse study suggested that, “increased protective endothelial function, rather than ATR1 inhibition or blood pressure lowering, might be of therapeutic significance in preventing aortic root disease in MFS.”

A minority of patients (up to 10%) with the Marfan phenotype have no identifiable mutation in the FBN1 gene, rather mutations in TGF-beta receptor 2 (TGFBR2) and TGFBR1 genes. It has been proposed that patients with the Marfan phenotype and TGFBR1 or TGFBR2 mutations be classified as having Loeys-Dietz syndrome to properly address the potential for more aggressive vascular disease than seen in MFS (Wright & Connolly, 2018).

Becerra-Munoz et al (2018)conducted a prospective cohort study to summarise variants in FBN-1 and establish the genotype-phenotype correlation. Genetic findings have importance not only in the diagnosis, but also in risk stratification and clinical management of patients with suspected MFS. Genotype-phenotype correlations have identified that patients with MFS and truncating variants in FBN-1 presented a higher proportion of aortic events, compared to a more benign course in patients with missense mutations.

Applicable Federal Regulations

N/A

Guidelines and Recommendations

The American College of Cardiology, published recommendations that include:

1. An echocardiogram is recommended at the time of diagnosis of Marfan syndrome to determine the aortic root and ascending aortic diameters and 6 months thereafter to determine the rate of enlargement of the aorta.
2. Annual imaging is recommended for patients with Marfan syndrome if stability of the aortic d iameter is documented. If the maximal aortic diameter is 4.5 cm or greater, or if the aortic diameter shows significant growth from baseline, more frequent imaging should be considered.
3. 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.
4. Sequencing of other genes known to cause familial thoracic aortic aneurysms and/or dissection (TGFBR1, TGFBR2, MYH11) may be considered in patients with a family history and clinical features associated with mutations in these genes.

Billing/Coding/Physician Documentation Information

This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page.

Applicable service codes: 81405, 81408, 81410, 81411

BCBSNC may request medical records for determination of medical necessity. When medical records are requested, letters of support and/or explanation are often useful, but are not sufficient documentation unless all specific information needed to make a medical necessity determination is included.

Scientific Background and Reference Sources

Becerra-Munoz, V. M., Gomez-Doblas, J. J., Porras-Martin, C., Such-Martinez, M., Crespo-Leiro, M. G., Barriales-Villa, R., Cabrera-Bueno, F. (2018). The importance of genotype-phenotype correlation in the clinical management of Marfan syndrome. Orphanet J Rare Dis, 13(1), 16. doi:10.1186/s13023-017-0754-6

Bin Mahmood, S. U., Velasquez, C. A., Zafar, M. A., Saeyeldin, A. A., Brownstein, A. J., Ziganshin, B. A., Mukherjee, S. K. (2017). Medical management of aortic disease in Marfan syndrome. Ann Cardiothorac Surg, 6(6), 654-661. doi:10.21037/acs.2017.11.09

Dale, M., Fitzgerald, M. P., Liu, Z., Meisinger, T., Karpisek, A., Purcell, L. N., . . . Xiong, W. (2017). Premature aortic smooth muscle cell differentiation contributes to matrix dysregulation in Marfan Syndrome. PLoS One, 12(10), e0186603. doi:10.1371/journal.pone.0186603

Davis, M. R., & Summers, K. M. (2012). Structure and function of the mammalian fibrillin gene family: implications for human connective tissue diseases. Mol Genet Metab, 107(4), 635-647. doi:10.1016/j.ymgme.2012.07.023

Dietz, H. (2017). Marfan Syndrome. In M. P. Adam, H. H. Ardinger, R. A. Pagon, S. E. Wallace, L. J. H. Bean, K. Stephens, & A. Amemiya (Eds.), GeneReviews((R)). Seattle (WA): University of Washington, SeattleUniversity of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved. Retrieved from http://dx.doi.org/.

Dietz, H. C., Loeys, B., Carta, L., & Ramirez, F. (2005). Recent progress towards a molecular understanding of Marfan syndrome. Am J Med Genet C Semin Med Genet, 139c(1), 4-9. doi:10.1002/ajmg.c.30068

Faivre, L., Collod-Beroud, G., Loeys, B., Child, A., Binquet, C., Gautier, E., Boileau, C. (2007). Effect of Mutation Type and Location on Clinical Outcome in 1,013 Probands with Marfan Syndrome or Related Phenotypes and FBN1 Mutations: An International Study. Am J Hum Genet, 81(3), 454-466.

Grewal, N., & Gittenberger-de Groot, A. C. (2018). Pathogenesis of aortic wall complications in Marfan syndrome. Cardiovasc Pathol, 33, 62-69. doi:10.1016/j.carpath.2018.01.005

Hilhorst-Hofstee, Y., Rijlaarsdam, M. E., Scholte, A. J., Swart-van den Berg, M., Versteegh, M. I., van der Schoot-van Velzen, I., . . . Pals, G. (2010). The clinical spectrum of missense mutations of the first aspartic acid of cbEGF-like domains in fibrillin-1 including a recessive family. Hum Mutat, 31(12), E1915-1927. doi:10.1002/humu.21372

Hiratzka, L. F., Bakris, G. L., Beckman, J. A., Bersin, R. M., Carr, V. F., Casey, D. E., Jr., . . . Williams, D. M. (2010). 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with Thoracic Aortic Disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine. Circulation, 121(13), e266-369. doi:10.1161/CIR.0b013e3181d4739e

Jensen, S. A., & Handford, P. A. (2016). New insights into the structure, assembly and biological roles of 10-12 nm connective tissue microfibrils from fibrillin-1 studies. Biochem J, 473(7), 827-838. doi:10.1042/bj20151108

Judge, D. P., & Dietz, H. C. (2005). Marfan's syndrome. Lancet, 366(9501), 1965-1976. doi:10.1016/s0140-6736(05)67789-6

Koo, H. K., Lawrence, K. A., & Musini, V. M. (2017). Beta-blockers for preventing aortic dissection in Marfan syndrome. Cochrane Database Syst Rev, 11, Cd011103. doi:10.1002/14651858.CD011103.pub2

Loeys, B., De Backer, J., Van Acker, P., Wettinck, K., Pals, G., Nuytinck, L., De Paepe, A. (2004). Comprehensive molecular screening of the FBN1 gene favors locus homogeneity of classical Marfan syndrome. Hum Mutat, 24(2), 140-146. doi:10.1002/humu.20070

Milewicz, D. M., Michael, K., Fisher, N., Coselli, J. S., Markello, T., & Biddinger, A. (1996). Fibrillin-1 (FBN1) mutations in patients with thoracic aortic aneurysms. Circulation, 94(11), 2708-2711.

Neptune, E. R., Frischmeyer, P. A., Arking, D. E., Myers, L., Bunton, T. E., Gayraud, B., . . . Dietz, H. C. (2003). Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat Genet, 33(3), 407-411. doi:10.1038/ng1116

Pyeritz, R. E. (2017). Etiology and pathogenesis of the Marfan syndrome: current understanding. Ann Cardiothorac Surg, 6(6), 595-598. doi:10.21037/acs.2017.10.04

Radke, R. M., & Baumgartner, H. (2014). Diagnosis and treatment of Marfan syndrome: an update. Heart, 100(17), 1382-1391. doi:10.1136/heartjnl-2013-304709

Schrijver, I., Liu, W., Brenn, T., Furthmayr, H., & Francke, U. (1999). Cysteine substitutions in epidermal growth factor-like domains of fibrillin-1: distinct effects on biochemical and clinical phenotypes. Am J Hum Genet, 65(4), 1007-1020. doi:10.1086/302582

Sellers, S. L., Milad, N., Chan, R., Mielnik, M., Jermilova, U., Huang, P. L., Bernatchez, P. (2018). Inhibition of Marfan Syndrome Aortic Root Dilation by Losartan: Role of Angiotensin II Receptor Type 1-Independent Activation of Endothelial Function. Am J Pathol, 188(3), 574-585. doi:10.1016/j.ajpath.2017.11.006

Whiteman, P., & Handford, P. A. (2003). Defective secretion of recombinant fragments of fibrillin-1: implications of protein misfolding for the pathogenesis of Marfan syndrome and related disorders. Hum Mol Genet, 12(7), 727-737.

Wright, M., & Connolly, H. (2018). Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders - UpToDate. In H. Dietz (Ed.), UpToDate. Retrieved from https://www.uptodate.com/contents/genetics-clinical-features-and-diagnosis-of-marfan-syndrome-and-related-disorders?search=marfan&source=search_result&selectedTitle=1~125&usage_type=default&display_rank=1#H559172.

Policy Implementation/Update Information

1/1/2019 BCBSNC will provide coverage for genetic testing for marfan syndrome when it is determined to be medically necessary because criteria and guidelines are met. Medical Director review 1/1/2019. Policy noticed 1/1/2019 for effective date 4/1/2019. (jd)