BlueCross and BlueShield of Montana Medical Policy/Codes
Genetic Testing for Facioscapulohumeral Muscular Dystrophy
Chapter: Genetic Testing
Current Effective Date: February 01, 2014
Original Effective Date: February 01, 2014
Publish Date: January 15, 2014
Description

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disease that typically presents before the age of 20 years with weakness of the facial muscles and the scapular stabilizer muscles; however, atypical presentations occur. The clinical course is usually of slowly progressive weakness, although the severity is highly variable. Approximately 95% of individuals with FSHD have contraction mutation of the D4Z4 locus.

Background

Description of the disease

Facioscapulohumeral muscular dystrophy (FSHD) is the third most common muscular dystrophy and involves progressive weakness and wasting of the facial muscles (facio), and shoulder and upper arm (scapulohumeral) muscles. The weakness is often most evident in the muscles of the face, resulting in difficulty smiling and whistling, and reduced facial expression. The weakness in the shoulder muscles causes the scapula to protrude from the back (“winging of the scapula”). The muscles are typically affected asymmetrically, and with progression, the lower extremities, both proximal and distal, become involved. (1) The severity of the disease is highly variable, ranging from mildly affected, asymptomatic individuals to severely affected, with approximately 20% of patients eventually requiring a wheelchair. Non-muscular manifestations include retinal vascular abnormalities which can result in significant loss of vision; however, only about 1% of patients with FSHD experience visual acuity loss. (1) Most people with FSHD will eventually develop high-frequency hearing loss, which is usually not noticeable, and only detected by audiogram. FSHD usually presents between the ages of 6 and 20 years, and life expectancy is not shortened. It is estimated that 4-5 people per 100,000 population have FSHD. FSHD affects males and females equally.

Clinical diagnosis of FSHD

FSHD is typically suspected in an individual with the following:

  • Weakness that predominantly involves the facial, scapular stabilizer, and foot dorsiflexor muscles without associated ocular or bulbar muscle weakness, and
  • Age of onset usually by 20 years of age (although mildly affected individuals show signs at a later age and some remain asymptomatic). (3)

FSHD has a characteristic distribution of muscle involvement that often can lead to targeted genetic testing without the need for a muscle biopsy. (2) However, atypical presentations have been reported, which include scapulohumeral dystrophy with facial sparing. (3) (4) A retrospective review of an academic center database of the period 1996 to 2011 determined that, of 139 genetically confirmed FSHD cases, 7 had atypical disease, including late age of onset of disease, focal weakness and dyspnea.(5)

Electromyography (EMG) and muscle biopsy to confirm the clinical diagnosis of FSHD has largely been supplanted by genetic testing. EMG usually shows mild myopathic changes, and muscle biopsy most often shows nonspecific chronic myopathic changes.

Genetics of FSHD

FSHD is likely to be caused by inappropriate expression of the gene DUX4 in muscle cells. DUX4 is a double homeobox-containing gene (a homeobox gene being one in a large family of genes that direct the formation of many body structures during early embryonic development). DUX4 lies in the macrosatellite repeat D4Z4, which is on chromosome 4q35. D4Z4 has a length of 11-100 repeat units on normal alleles. The most common form of FSHD (95%) is designated FSHD1, and these individuals have a D4Z4 allele of between 1 and 10 repeat units. (3) There is no linear and inverse correlation between residual repeat size and disease severity and onset; however, patients with repeat arrays of 1-3 units usually have an infantile onset and rapid progression, (1) The remaining 5% of patients who don’t have FSHD1 are designated as FSHD2, which is clinically indistinguishable from FSHD1. Patients with FSHD2 show loss of DNA methylation and heterochromatin markers at the D4Z4 repeat that are similar to patients with D4Z4 contractions (FSHD1), suggesting that a change in D4Z4 chromatin structure unifies FSHD1 and FSHD2. FSHD is inherited in an autosomal dominant manner. Approximately 70-90% of individuals inherit the disease-causing deletion from a parent, and 10-30% have FSHD as a result of a de novo deletion. (3)

Treatment of FSHD

There is currently no treatment or prevention of symptoms of FSHD, and clinical management is directed at surveillance to identify possible FSHD-related complications and to improve quality of life (e.g., assist devices, physical therapy, orthoses to improve mobility and prevent falls).

Commercially available testing for FSHD

The methodology for testing for FSHD uses pulsed field gel electrophoresis and Southern blot to detect deletions on chromosome 4q35. Testing is only available for FSHD1.

Laboratories that offer the test include Athena Diagnostics and the University of Iowa Diagnostic Laboratories.

Regulatory Status

No U.S. Food and Drug Administration (FDA)-cleared genotyping tests were found. Thus, genotyping is offered as a laboratory-developed test. Clinical laboratories may develop and validate tests in-house (“home-brew”) and market them as a laboratory service; such tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA).

Policy

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply.  If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coverage

Genetic testing for facioscapulohumeral muscular dystrophy (FSHD) may be considered medically necessary to confirm a diagnosis in a patient with clinical signs of the disease.

FSHD is typically suspected in an individual with the following:

  • Weakness that predominantly involves the facial, scapular stabilizer, and foot dorsiflexor muscles without associated ocular or bulbar muscle weakness, and
  • Age of onset usually by 20 years of age (although mildly affected individuals show signs at a later age and some remain asymptomatic).

Genetic testing for facioscapulohumeral muscular dystrophy is considered experimental, investigational and/or unproven for all other indications.

Policy Guidelines

As of November, 2013:

Tier 2 CPT code 81404: 

FSHMD1A (facioscapulohumeral muscular dystrophy 1A) [evaluation for abnormal alleles, and/or characterization of haplotype(s)]

Rationale

Literature Review

This policy is based on a search of the MEDLINE database through June 2013. Literature that describes the analytic validity, clinical validity, and clinical utility of testing for facioscapulohumeral muscular dystrophy (FSHD) was sought.

Analytic validity (technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent)

According to one laboratory, Southern blotting diagnostic methods enable the identification of FSHD1 in about 95% of cases. (6)

Clinical validity (diagnostic performance of the test [sensitivity, specificity, positive and negative predictive values] in detecting clinical disease)

According to a large reference laboratory, the identification of a characteristic 4q35 deletion is more than 90% specific for the disease. (7)

There are reports of a correlation between the degree of the mutation of the D4Z4 locus and the age at onset of symptoms, age at loss of ambulation, and muscle strength as measured by quantitative isometric myometry. Some reports in the literature describe individuals with a large contraction of the D4Z4 locus having earlier-onset disease and more rapid progression than those with smaller contractions of the D4Z4 locus, although other reports have not been able to confirm a correlation between disease severity and degree of D4Z4 contraction mutations. (3)

On average, de novo mutations are associated with larger contractions of D4Z4 compared to the degree of D4Z4 contraction mutations observed segregating in families, and individuals with de novo mutations tend to have findings at the more severe end of the phenotypic spectrum. (3)

Clinical utility (how the results of the diagnostic test will be used to change management of the patient and whether these changes in management lead to clinically important improvements in health outcomes)

Individual

The clinical utility for patients with suspected FSHD depends on the ability of genetic testing to make a definitive diagnosis and for that diagnosis to lead to management changes that improve outcomes. There is no direct evidence for the clinical utility of genetic testing in these patients as no studies were identified that described how a molecular diagnosis of FSHD changed patient management.

However, for patients who are diagnosed with FSHD by identifying a D4Z4 contraction mutation, the clinical utility of molecular genetic testing for FSHD includes:

  • Establishing the diagnosis and initiating/directing treatment, such as evaluation for physical therapy and the need for assistive devices, assessment for hearing loss, ophthalmologic examination for the presence of retinal telangiectasias and continued ophthalmologic surveillance, and possible orthopedic intervention;
  • Distinguishing from other disorders that are similar clinically to FSHD, especially the limb-girdle muscular dystrophies and scapuloperoneal muscular dystrophy syndromes;
  • Avoidance of a muscle biopsy in the majority of cases.

Treatment after a confirmed diagnosis of FSHD includes physical therapy and rehabilitation, exercise, pain management, ventilator support for those with hypoventilation, therapy for hearing loss, orthopedic intervention (ankle/foot orthoses; surgical fixation of the scapula to the chest wall to improve range of motion) and ophthalmologic management including lubricants or taping the eyes shut at night for exposure keratitis.

For those with a confirmed diagnosis of FSHD, the following surveillance applies (3) (8):

  • Regular assessment of pain;
  • Routine screening for hypoventilation in those with moderate to severe disease, and yearly forced vital capacity (FVC) measurements for all affected individuals who are wheelchair bound, have pelvic girdle weakness and superimposed pulmonary disease, and/or have moderate to severe kyphoscoliosis, lumbar hyperlordosis, or chest wall deformities;
  • Hearing loss assessment in children as routinely performed as part of school-based testing. In severe infantile onset forms of FSHD, hearing screens are important as hearing loss can result in delayed language acquisition. Adults should have a formal hearing evaluation based on symptoms;
  • Annual dilated ophthalmoscopy in childhood is indicated. In adults, a dilated retinal exam should be performed at the time of diagnosis, and if vascular disease is absent, follow-up exams are only necessary if visual symptoms develop.

Family members

Most individuals diagnosed with FSHD have a parent with clinical findings of FSHD and one D4Z4 allele with a contraction mutation (70-90% of individuals with FSHD), although 10-30% of probands with FSHD have the disorder as a result of a D4Z4 de novo contraction mutation. (3) Evaluation of at risk relatives may determine that they may be affected but escaped previous diagnosis because of a milder phenotypic presentation. However, for this population, no evidence was identified that compared outcomes in family members tested for genetic mutations compared to family members not tested for genetic mutations, and conclusions cannot be made on whether genetic testing of asymptomatic family members of a patient with known FSHD improves outcomes.

Summary

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disease that typically presents before the age of 20 years with weakness of the facial muscles and the scapular stabilizer muscles; however, atypical presentations occur. The clinical course is usually of slowly progressive weakness, although the severity is highly variable. Approximately 95% of individuals with FSHD have contraction mutation of the D4Z4 locus.

The clinical utility of genetic testing for FSHD is that it leads to a definitive diagnosis and can distinguish FSHD from other myopathies, with possible avoidance of a muscle biopsy. Changes in clinical management include supportive management involving physical therapy and rehabilitation, exercise, pain control and orthopedic interventions. Other issues include increased surveillance for potential pulmonary, ophthalmologic, and auditory problems related to FSHD. Therefore, genetic testing for FSHD may be considered medically necessary when a presumptive diagnosis of FSHD has been made based on clinical signs. Genetic testing for facioscapulohumeral muscular dystrophy is considered experimental, investigational and/or unproven for all other indications.

Practice Guidelines and Position Statements

In a report from the 171st European Neuromuscular Centre International Workshop Standards of Care and Management of FSHD held in January 2010, it is stated that when a physician concludes facioscapulohumeral syndrome based on clinical findings, the odds are in favor of FSHD, and genetic testing is the preferred diagnostic choice. (9)

Coding

Disclaimer for coding information on Medical Policies

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.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps. 

ICD-9 Codes
359.1
ICD-10 Codes
G71.0
Procedural Codes: 81404
References
  1. van der Maarel SM, Tawil R, Tapscott SJ. Facioscapulohumeral muscular dystrophy and DUX4: breaking the silence. Trends in molecular medicine 2011; 17(5):252-8.
  2. Menezes MP, North KN. Inherited neuromuscular disorders: pathway to diagnosis. Journal of paediatrics and child health 2012; 48(6):458-65.
  3. Lemmers R, Miller DG, van der Maarel SM. Facioscapulohumeral Muscular Dystrophy. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT, Stephens K, eds. GeneReviews. Seattle (WA) 1993.
  4. Pastorello E, Cao M, Trevisan CP. Atypical onset in a series of 122 cases with FacioScapuloHumeral Muscular Dystrophy. Clinical neurology and neurosurgery 2012; 114(3):230-4.
  5. Hassan A, Jones LK, Jr., Milone M et al. Focal and other unusual presentations of facioscapulohumeral muscular dystrophy. Muscle & nerve 2012; 46(3):421-5.
  6. Facioscapulohumeral Muscular Dystrophy. GTR: Genetic Testing Registry. GTR Test ID: GTR000219919.4. National Center for Biotechnology Information, U.S. National Library of Medicine (June 25, 2013) Available at http://www.ncbi.nlm.nih.gov (Accessed November 7, 2013).
  7. Facioscapulohumeral Dystrophy (FSHD) Information. Department of Pathology, University of Iowa Diagnostic Laboratories (UIDL) (June 2008) Available at http://www.healthcare.uiowa.edu (Accessed November 7, 2013).
  8. Tawil R, van der Maarel S, Padberg GW et al. 171st ENMC international workshop: Standards of care and management of facioscapulohumeral muscular dystrophy. Neuromuscular disorders: NMD 2010; 20(7):471-5.
  9. Lemmers RJ, O'Shea S, Padberg GW et al. Best practice guidelines on genetic diagnostics of Facioscapulohumeral muscular dystrophy: workshop 9th June 2010, LUMC, Leiden, The Netherlands. Neuromuscular disorders: NMD 2012; 22(5):463-70.
  10. Genetic Testing for Facioscapulohumeral Muscular Dystrophy. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (August 2013) Medicine 2.04.105.
History
February 2014  New medical document. 1) Genetic testing for facioscapulohumeral muscular dystrophy may be considered medically necessary to confirm a diagnosis in a patient with clinical signs of the disease. FSHD is typically suspected in an individual with the following: a) Weakness that predominantly involves the facial, scapular stabilizer, and foot dorsiflexor muscles without associated ocular or bulbar muscle weakness, and b) Age of onset usually by 20 years of age (although mildly affected individuals show signs at a later age and some remain asymptomatic); 2) Genetic testing for facioscapulohumeral muscular dystrophy is considered experimental, investigational and/or unproven for all other indications.
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Genetic Testing for Facioscapulohumeral Muscular Dystrophy