Highmark Commercial Medical Policy - Pennsylvania


 
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Medical Policy: L-230-001
Topic: Ehlers Danlos Syndrome Testing
Section: Laboratory
Effective Date: July 1, 2018
Issue Date: July 2, 2018
Last Reviewed: March 2018

Ehlers-Danlos syndrome (EDS) is a heterogeneous group of connective tissue disorders. Although all types of EDS affect the joints and skin, additional features vary by type. An unusually large range of joint movement (hypermobility) occurs with most forms of EDS, and is especially prominent in the hypermobile type. Clinical genetic testing is available for most types of EDS, and is used to confirm the final diagnosis when it is clinically suspected.

This policy is designed to address medical guidelines that are appropriate for the majority of individuals with a particular disease, illness, or condition. Each person's unique clinical circumstances may warrant individual consideration, based on review of applicable medical records.

Policy Position Coverage is subject to the specific terms of the member’s benefit plan.

EDS Known Familial Mutation Analysis may be considered medically necessary when the following are met: 

  • Genetic Counseling:
    • Pre and post-test genetic counseling by an appropriate provider; and
  • Previous Genetic Testing:
    • No previous testing of the requested gene; and
  • Diagnostic Testing for an Autosomal Dominant EDS:
    • Known mutation identified in 1st degree biological relative. (Note: 2nd or 3rd degree relatives may be considered when 1st degree relatives are unavailable or unwilling to be tested); or
  • Carrier Screening for an Autosomal Recessive EDS:
    • Known mutation(s) identified in 1st, 2nd, or 3rd degree biologic relative(s); or
  • Prenatal Testing for At-Risk Pregnancies:
    • Family history of an autosomal dominant type of EDS with a known mutation identified in a previous child or either parent; or
    • Both parents carry a known mutation for an autosomal recessive type of EDS.
Procedure Codes
81403


EDS Gene Sequencing may be considered medically necessary when the following are met: 

  • Genetic Counseling:
    • Pre and post-test genetic counseling by an appropriate provider; and
  • Previous Genetic Testing:
    • No previous sequencing of the requested gene; and
  • The individual does not have a known genetic cause for their symptoms; and
  • The individual does not have a family history of a known EDS gene mutation; and
  • The individual meets the above 2017 minimal criteria suggestive for an EDS type associated with the requested gene test:
    • For COL5A1 and/or COL5A2 sequencing: criteria for classical EDS met; or
    • For TNXB sequencing: criteria for classical-like EDS met; or
    • For COL1A1* sequencing: criteria met for ONE of the following EDS types:
      • Classical EDS; or
      • Vascular EDS; or
      • Arthrochalasia EDS; or
      • Individual displays ONE or more of the following:
        • Arterial rupture at a young age; or
        • Spontaneous sigmoid colon perforation in the absence of known diverticular disease or other bowel pathology; or
        • Uterine rupture during the third trimester in the absence of previous C-section and/or severe peripartum perineum tears; or
    • For COL1A2* sequencing: criteria met for ONE of the following EDS types:
      • Cardiac valvular EDS; or
      • Arthrochalasia EDS; or
    • For COL3A1* sequencing: criteria for vascular EDS met; or
      • Member displays ONE or more of the following:
        • Arterial rupture at a young age; or
        • Spontaneous sigmoid colon perforation in the absence of known diverticula disease or other bowel pathology; or
        • Uterine rupture during the third trimester in the absence of previous C-section and/or severe peripartum perineum tears; or
        • Carotid-cavernous sinus fistula (CCSF) formation in the absence of trauma; or
    • For ADAMTS2 sequencing: criteria for dermatosparaxis EDS met; or
    • For PLOD1 and/or FKBP14 sequencing: criteria for kyphoscoliotic EDS met; or
    • For ZNF469 and/or PRDM5 sequencing: criteria for brittle cornea syndrome met; or
    • For B3GALT6, B4GALT7, and/or SLC39A13 sequencing: criteria for spondylodysplastic EDS met; or
    • For CHST14 and/or DSE sequencing: criteria for musculocontractural EDS met; or
    • For COL12A1 sequencing: criteria for myopathic EDS met; or
    • For C1R and/or C1S sequencing: criteria for periodontal EDS met.

 * For non-EDS indications, refer to any available disorder-specific guidelines or general guidelines:

  • L-232, Hereditary Connective Tissue Disorder Testing
  • L-111, Genetic Testing for Non-Cancer Conditions

COL1A1 and COL1A2 are also associated with osteogenesis imperfecta, Caffey disease, and skeletal dysplasias. COL3A1 is also associated with familial thoracic aortic aneurysm and dissection (TAAD).

Panel testing is addressed in the guideline: L-232 Hereditary Connective Tissue Disorder Testing.

Procedure Codes
81408, 81479


EDS Gene Deletion/Duplication Analysis may be considered medically necessary when ALL of the following are met: 

  • The individual meets criteria (see Table Attachment) for sequencing of the requested gene; and
  • Sequencing failed to identify a causative mutation (or, in the case of an autosomal recessive EDS, no more than one causative mutation was identified); and
  • No previous deletion/duplication analysis of the requested gene.
Procedure Codes
81479


The following are non-covered indications for EDS gene sequencing and deletion/duplication analysis:

  • Hypermobile EDS or the related clinical entity, “joint hypermobility syndrome”
  • Nonsyndromic joint hypermobility, including both asymptomatic and symptomatic forms (e.g., “hypermobility spectrum disorders”)
Procedure Codes
81479

Professional Statements and Societal Positions

  • An expert-authored review (updated in 2016) states the following regarding hEDS: “If a patient’s personal or family history is suggestive of one of the other types of EDS or another hereditary disorder of connective tissue or arterial fragility syndrome, analysis of an associated gene or multi-gene connective tissue disease panel may be appropriate. Failure to identify a pathogenic variant with such multiple gene testing reduces the likelihood of an arterial fragility syndrome, but does not completely rule it out, especially in the setting of a positive personal or family history of arterial fragility. Negative testing for an arterial fragility syndrome also does not confirm a diagnosis of EDS, hypermobility type. Therefore, such testing is not recommended in the absence of specific suggestive signs, symptoms, or family history.”
  • According to the International Consortium on the Ehlers-Danlos Syndromes (2017):
    • “In view of the vast genetic heterogeneity and phenotypic variability of the EDS subtypes, and the clinical overlap between many of these subtypes, but also with other hereditary connective tissue disorders, the definite diagnosis relies for all subtypes, except hEDS, on molecular confirmation with identification of (a) causative variant(s) in the respective gene.”
    • “Molecular diagnostic strategies should rely on NGS technologies, which offer the potential for parallel sequencing of multiple genes. Targeted resequencing of a panel of genes…is a time- and cost-effective approach for the molecular diagnosis of the genetically heterogeneous EDS. When no mutation (or in case of an autosomal recessive condition only one mutation) is identified, this approach should be complemented with a copy number variant (CNV) detection strategy to identify large deletions or duplications, for example Multiplex Ligation-dependent Probe Amplification (MLPA), qPCR, or targeted array analysis.”
    • “The diagnosis of hEDS remains clinical as there is yet no reliable or appreciable genetic etiology to test for in the vast majority of patients.”

Note: See Table Attachment for 2017 International Criteria


Place of Service: Outpatient

Ehlers Danlos syndrome is typically an outpatient procedure which is only eligible for coverage as an inpatient procedure in special circumstances, including, but not limited to, the presence of a co-morbid condition that would require monitoring in a more controlled environment such as the inpatient setting.


The policy position applies to all commercial lines of business


Denial Statements

Services that do not meet the criteria of this policy will not be considered medically necessary. A network provider cannot bill the member for the denied service unless: (a) the provider has given advance written notice, informing the member that the service may be deemed not medically necessary; (b) the member is provided with an estimate of the cost; and (c) the member agrees in writing to assume financial responsibility in advance of receiving the service. The signed agreement must be maintained in the provider’s records.

A network provider can bill the member for the non-covered service.

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Medical policies do not constitute medical advice, nor are they intended to govern the practice of medicine. They are intended to reflect Highmark's reimbursement and coverage guidelines. Coverage for services may vary for individual members, based on the terms of the benefit contract.

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