Description of Procedure or Service

Definitions

Fanconi anemia (FA), is an inherited disorder that can lead to bone marrow failure (aplastic anemia), leukemia and/or solid tumors. FA is characterized by the following (Olson, 2016): “pancytopenia, predisposition to malignancy, and physical abnormalities including short stature, microcephaly, developmental delay, café-au-lait skin lesions, and malformations belonging to the VACTERL-H association.”

***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 fanconi anemia 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 is covered

1. Genetic counseling at the time of diagnosis of Fanconi Anemia and at various points throughout a patient’s life is considered medically necessary. 
2. Genetic testing for the diagnosis of Fanconi Anemia is considered medically necessary when any of the following criteria are met:
   1. Clinical signs and symptoms of Fanconi Anemia are present; OR
   2. A definitive diagnosis of Fanconi Anemia cannot be made after standard workup, i.e., non-diagnostic results on chromosome breakage analysis, OR
   3. Diagnostic results on chromosome breakage test is positive
3. Prenatal/carrier testing for Fanconi Anemia is considered medically necessary when any of the following criteria are met:
   1. The individual is of Ashkenazi Jewish descent; OR 
   2. Previous offspring with a diagnosis of Fanconi Anemia; OR 
   3. One parent is a known carrier of a Fanconi Anemia mutation; OR 
   4. One or both parents have a first or second-degree relative with a diagnosis of Fanconi Anemia. 
4. Preimplantation genetic testing for Fanconi Anemia is considered medically necessary when either of the following conditions is met:
   1. Both parents are known carriers of a pathogenic Fanconi Anemia mutation; OR 
   2. One parent has a diagnosis of Fanconi Anemia and the other parent is a known carrier of a pathogenic mutation.

When is not covered

Genetic testing for the diagnosis of Fanconi Anemia is considered not medically necessary when the above criteria are not met.

Genetic testing for Fanconi Anemia is considered investigational in all other conditions.

Policy Guidelines

Background

Fanconi anemia is rare, occurring in 1 in 100,000 to 250,000 births, with an increased incidence in Ashkenazi Jews and Afrikaner populations (Olsen, 2016).

Primarily inherited as an autosomal recessive disorder, FA is associated with known mutations causing FA identified in 19 genes. According to the Fanconi Anemia Research Fund (2016), “Mutations in FANCA, FANCC and FANCG are the most common and account for approximately 85% of FA patients worldwide. FANCD1, FANCD2, FANCE, FANCF and FANCL account for 10%, while the remaining FA genes, FANCB, FANCI, FANCJ, FANCM, FANCN, FANCO, FANCP, and FANCQ represent less than 5%.”

Applicable Federal Regulations

No U.S. Food and Drug Administration-cleared genetic tests for FA were found. Thus, these tests are offered as laboratory-developed tests. Clinical laboratories may develop and validate tests inhouse (“home-brew”) and market them as a laboratory service; such tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). The laboratory offering the service must be licensed by CLIA for high-complexity testing.

Guidelines and Recommendations

According to Fanconi Anemia Research Fund Guidelines for Diagnosis and Management, Fourth Edition, 2014 (Consensus Conference held by the Fanconi Anemia Research Fund in Herndon, Va., April 5-6, 2013. It replaces earlier editions published in 1999, 2003, and 2008), FA is a very rare genetic disorder and the understanding of interactions among molecular pathways has become increasingly complex and sophisticated. Genotype determination and mutation analysis for each patient bear directly on the appropriateness of some treatment choices and it is anticipated that this information will become increasing relevant to patient care. Accuracy in diagnosis is crucial and requires sophisticated expertise. The mode of inheritance is important for further genetic testing of siblings; finding matched donors; identification of genotype for purpose of predicting onset of symptoms and consequences; family planning (including PGD); selection of appropriate persons for FA gene therapy trials; and genetic counseling to the family. 

Benefits to consider by an early/timely diagnosis, including: 

• Avoiding medical complications from unrecognized subtle congenital abnormalities 
• Ending the diagnostic odyssey that significant numbers of patients experience 
• Enabling appropriate monitoring and management of hematologic disease [aplastic anemia (AA), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML)] 
• Modifying radiation and chemotherapy protocols as needed to ameliorate the risk of severe side effects in patients where malignancies are the first clinical sign of FA 
• Providing an opportunity to make life-style modifications to reduce risks (e.g., avoiding smoking, sunlight, alcohol exposure, or unhealthy workplace environments) 
• Time to make family planning decisions in light of premature menopause and limited window of fertility (FARF, 2014).

The chromosome breakage test using peripheral blood T-lymphocytes is the accepted screening assay for FA. Primary skin fibroblasts have also been used as a readily available screening alternative, particularly if the T-cell analyses are ambiguous or do not give a clear result that the patient has FA, especially when there is a question of mosaicism. The cross-linking agents mitomycin C (MMC) and/or diepoxybutane (DEB; due to its toxicity as a carcinogen, DEB is not available everywhere) are used to induce chromosome breakage, and FA cells are more sensitive than normal cells to these agents. Either or both agents are acceptable.

When the chromosome breakage test is Positive: A patient is considered to have a positive test for FA if the lymphocytes display markedly increased chromosomal breakage and rearrangement after treatment with MMC and/or DEB. The patient and his or her family should be referred to a genetic counselor; follow-up testing should be performed to identify the patient’s disease-causing genetic mutation(s) using the molecular methods. All of the patient’s siblings should be tested for FA either by chromosome breakage analysis or, if his or her sibling’s disease-causing gene mutation(s) have been identified, by mutation analysis for FANCA, MLPA, Next generation sequencing for known FA genes, copy number evaluation for del/dup.

When the chromosome breakage test is Negative: A test result is considered to be negative if the patient’s lymphocytes do not show increased chromosomal breakage or rearrangement in response to MMC and/or DEB, and the types and rates of breakage are within the normal range of chromosome instability. Therefore, patients who have a negative chromosome breakage test but have some of the clinical features of FA should undergo DNA sequencing that includes the genes implicated in FA as well as genes relevant to the conditions.

When the chromosome breakage test is Equivocal: Test results are considered equivocal, or inconclusive, if the percentage of cells that display chromosomal breakage patterns characteristic of FA is much lower because of either there is mosaicism in patients peripheral blood. (Mosaicism is characterized by two distinct populations of lymphocytes in the blood), Or the patient has a condition other than FA that manifests with increased chromosomal breakage. Equivocal test should be followed with Next-generation sequencing or targeted mutation testing for other chromosome instability/DNA repair syndrome or Skin chromosome breakage study.

The benefits of genetic counseling and/or mutation identification

1. For the current patient: 
   • Understand appearance and consequences (genotype/phenotype) 
   • Suggest complications and provide nuanced discussion of therapeutic alternatives (genotype/outcome) 
   • Commence regular clinical review and surveillance 
   • Confirm a sibling stem cell transplantation (SCT) donor does not have FA 
2. For current family members: 
   • Identify undiagnosed affected siblings, who could be considered as SCT donors, who need genetic counseling and surveillance for complications of FA 
   • Identify carriers at risk for healthcare consequences, including cancer (e.g., Ashkenazi Jewish FANCC IVS5+4 A>T, FANCD1/BRCA2, FANCJ/BRIP1, FANCN/PALB2, FANCO/RAD51C, FANCP/SLX4, and FANCQ/XPF mutations) 
3. For future children in the family: 
   • Prenatal diagnosis of an established pregnancy 
   • In vitro fertilization (IVF) and preimplantation genetic diagnosis (PGD) to create an unaffected child or identify an HLA-matched, unaffected sibling hematopoietic stem cell donor.

Recommendations for clinical monitoring of bone marrow failure include the following:

For patients with normal counts and no cytogenetic clonal marrow abnormalities, a peripheral blood count and differential white blood cell count should be reviewed approximately every 3 to 4 months and a bone marrow aspirate and biopsy with cytogenetics considered yearly. A similar monitoring regimen is recommended for patients with mildly abnormal but stable peripheral blood counts without any associated clonal marrow abnormalities.

For patients with a cytogenetic clonal marrow abnormality (in the absence of morphologic MDS) together with normal or mildly low, but stable, blood counts, more frequent surveillance of counts and bone marrow examinations should be considered (as indicated by the patient’s clinical status) to monitor for progression to MDS or leukemia. It would be reasonable to examine the blood counts every 1 to 2 months and the bone marrow every 1 to 6 months initially to determine if the blood counts are stable or progressively changing. Cytogenetic abnormalities and marrow morphologic changes should be similarly monitored. If the blood counts are stable, then the interval between bone marrow exams may be increased.

Patients with progressively changing blood counts without a clinically apparent underlying cause (e.g., transient response to an acute infection or suppression secondary to medication) require immediate evaluation with a complete blood count and bone marrow examination with cytogenetics. Rising peripheral blood counts can be due to either the development of MDS/AML (for which stem cell transplantation would be a potential urgent undertaking) or, rarely, reversion of a germ-line mutation in a stem cell, which repopulates the marrow with normal cells (somatic stem cell mosaicism). Such patients warrant continued close monitoring with complete blood counts at least every 1 to 2 months and a marrow exam with cytogenetics every 1 to 6 months.

The guidelines for chromosome analysis for acquired abnormalities are specified in the 2009 (revised January 2010) edition of the Standards and Guidelines for Clinical Genetics Laboratories by the American College of Medical Genetics specifically, the guidelines state that:

• At least 20 different cells in the metaphase stage of the cell cycle should be analyzed using G-banding, with follow-up and screening of additional cells as necessary. 
• The chromosomes from normal and abnormal cells should be documented with karyograms (digital images or photographs of the chromosomes, with each pair of the chromosomes aligned in numerical order from 1 – 22, XX or XY). 
  • The results should be summarized using the standard nomenclature found in the most recent version of the International Standards for Cytogenetic Nomenclature (ISCN). 

The American College of Obstetricians and Gynecologist issued a 2009 Committee Opinion on carrier screening for genetic diseases in individuals of Eastern European and Jewish descent (ACOG, 2009). The opinion made the following 7 recommendations:

1. The family history of individuals considering pregnancy, or who are already pregnant, should determine whether either member of the couple is of Eastern European (Ashkenazi) Jewish ancestry or has a relative with one or more of the genetic conditions. 
2. Carrier screening for TSD [Tay-Sachs disease], Canavan disease, cystic fibrosis, and familial dysautonomia should be offered to Ashkenazi Jewish individuals before conception or during early pregnancy so that a couple has an opportunity to consider prenatal diagnostic testing options. If the woman is already pregnant, it may be necessary to screen both partners simultaneously so that the results are obtained in a timely fashion to ensure that prenatal diagnostic testing is an option. 
3. Individuals of Ashkenazi Jewish descent may inquire about the availability of carrier screening for other disorders. Carrier screening is available for mucolipidosis IV, Niemann-Pick disease type A, Fanconi Anemia group C, Bloom syndrome, and Gaucher disease. Patient education materials can be made available so that interested patients can make an informed decision about having additional screening tests. Some patients may benefit from genetic counseling. 
4. When only one partner is of Ashkenazi Jewish descent, that individual should be screened first. If it is determined that this individual is a carrier, the other partner should be offered screening. However, the couple should be informed that the carrier frequency and the detection rate in non-Jewish individuals are unknown for all of these disorders, except for TSD and cystic fibrosis. Therefore, it is difficult to accurately predict the couple's risk of having a child with the disorder. 
5. Individuals with a positive family history of one of these disorders should be offered carrier screening for the specific disorder and may benefit from genetic counseling. 
6. When both partners are carriers of one of these disorders, they should be referred for genetic counseling and offered prenatal diagnosis. Carrier couples should be informed of the disease manifestations, range of severity, and available treatment options. Prenatal diagnosis by DNA based testing can be performed on cells obtained by chorionic villus sampling and amniocentesis. 
7. When an individual is found to be a carrier, his or her relatives are at risk for carrying the same mutation. The patient should be encouraged to inform his or her relatives of the risk and the availability of carrier screening. The provider does not need to contact these relatives because there is no provider–patient relationship with the relatives, and confidentiality must be maintained.

Committee Opinion on Carrier Screening for Genetic Conditions (ACOG, 2017).

In March 2017, ACOG have issued a Committee Opinion on Carrier Screening for Genetic Conditions. They recommended carrier screening and counseling ideally before pregnancy. Their recommendations were very similar to those issued in previous numbers. For genetic conditions in individuals of Eastern and Central European Jewish descent, ACOG still recommends offering screening for four conditions in the Ashkenazi population: Canavan disease, Cystic Fibrosis, Familial dysautonomia and Tay-Sachs disease. In addition, some experts propose that carrier screening should offer a more comprehensive panel for which screening should be considered in individuals of Ashkenazi descent. Their suggested list of autosomal recessive conditions included Fanconi anemia and other nine conditions (Bloom syndrome, Familial hyperinsulinism, Gaucher disease, Glycogen storage disease type I, Joubert syndrome, Maple syrup urine disease, Mucolipidosis, Niemann-Pick disease and Usher syndrome).

U.S. Preventive Services Task Force Recommendations

No U.S. Preventive Services Task Force recommendations for genetic testing for FA have been identified.

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. 

Scientific Background and Reference Sources

Alter BP, MD, MPH, FAAP, Kupfer G, MD. Fanconi Anemia, Gene Reviews [Internet], 2013. Accessed August 27, 2014.

Ameziane N, Errami A, Leveille F, et al. Genetic subtyping of Fanconi Anemia by comprehensive mutation screening. Hum Mutat. Jan 2008;29(1):159-166. 

Committee Opinion on Carrier Screening for Genetic Conditions. American College of Obstetricians and Gynecologists, Committee Opinion Number 691, March 2017. Carrier screening for genetic diseases in individuals of Eastern European and Jewish descent. American College of Obstetricians and Gynecologists, Committee. Published October, 2009. Accessed November, 2016.

Chandrasekharappa SC, Lach FP, Kimble DC, et al. Massively parallel sequencing, aCGH, and RNA-Seq technologies provide a comprehensive molecular diagnosis of Fanconi Anemia. Blood. May 30 2013; 121(22): e138-148.

Chrzanowska KH, Gregorek H, Dembowska-Bagińska B, Kalina MA, Digweed M. Nijmegen breakage syndrome (NBS). Orphanet J Rare Dis. 2012; 7:13.

De Rocco D, Bottega R, Cappelli E, et al. Molecular analysis of Fanconi Anemia: the experience of the Bone Marrow Failure Study Group of the Italian Association of Pediatric OncoHematology. Haematologica. Jun 2014; 99(6): 1022-1031.

Frohnmayer D, Frohnmayer L, Guinan E, Kennedy T, Larsen K, Editors. Fanconi Anemia Guidelines for Diagnosis and Management. Fanconi Anemia Research Fund. 4th ed. Eugene, OR:

Fanconi Anemia Research Fund. 2014

Fanconi Anemia Research Fund. (2017). Fanconi anemia and diagnosis. Retrieved March 7, 2017

Khincha PP, Savage SA. Genomic characterization of the inherited bone marrow failure syndromes. Semin Hematol. Oct 2013; 50(4):333-347.

Mehta Fanconi Anemia, Genereviews, Parinda A Mehta, MD and Jakub Tolar, MD, PhD, Last Update: September 22, 2016. 

Olson, T. (2016). Clinical manifestation and diagnosis of Fanconi anemia. 

Rosenberg Philip, Hannah Tamary and Blanche P. Alter, How high are carrier frequencies of rare recessive syndromes? Contemporary estimates for Fanconi Anemia in the United States and Israel, American Journal of Human Genetics 155A(8): 1877-83, 7 July 2011.

Sakaguchi H, Nakanishi K, Kojima S. Inherited bone marrow failure syndromes in 2012, Int J Hematol, Jan 2013; 97(1):20-29.

What is Fanconi Anemia? Fanconi Anemia Research Fund. N.D. Accessed October, 2016.

Zhang MY, Keel SB, Walsh T, et al. Genomic analysis of bone marrow failure and myelodysplastic syndromes reveals phenotypic and diagnostic complexity, Haematologica, Sep 19 2014.

Policy Implementation/Update Information

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