Is the 81408 - Molecular Pathology (MOPATH) procedure level 9 medically necessary for a patient with suspected Hypermobile Ehlers-Danlos Syndrome (hEDS) or Hypermobile Spectrum Disorder (HSD)?

Medical Necessity of CPT 81408 (MOPATH Level 9) for Suspected hEDS/HSD

Genetic testing with CPT 81408 is NOT medically necessary for this patient with suspected hypermobile Ehlers-Danlos syndrome (hEDS) or Hypermobility Spectrum Disorder (HSD), as no causative genes have been identified for hEDS and diagnosis remains purely clinical. 1

Why Genetic Testing is Not Indicated

The American Gastroenterological Association explicitly advises against routine genetic testing for hEDS, as no causative genes have been identified. 1 This patient's clinical presentation—with joint hypermobility, skin manifestations, GI symptoms, and autonomic dysfunction—is consistent with hEDS/HSD, but these diagnoses are made using the 2017 clinical diagnostic criteria, not genetic testing. 2, 1

Critical Exception: When Genetic Testing IS Appropriate

Genetic testing becomes medically necessary only when vascular EDS or other monogenic connective tissue disorders must be excluded. 1, 3 This is a life-or-death distinction, as vascular EDS carries significant mortality risk from arterial or organ rupture. 1

In this specific case, genetic testing may be justified because:

• A recent 2025 study found that 26.4% of patients meeting clinical hEDS criteria had an alternative or additional genetic diagnosis requiring distinct management strategies 3
• The patient has features that could suggest other EDS subtypes: easy bruising, fragile skin, delayed wound healing, spontaneous wound reopening, and abnormal scarring 3
• Family history includes cardiovascular complications (uncle with heart valve replacement, grandfather with heart valve problems) that could suggest vascular EDS 1

The Appropriate Diagnostic Approach

Step 1: Apply Clinical Diagnostic Criteria First

• Use the 2017 diagnostic criteria for hEDS (available at https://www.ehlers-danlos.com/wp-content/uploads/2017/05/hEDS-Dx-Criteria-checklist-1.pdf) to determine if patient meets clinical criteria 1, 4
• Assess joint hypermobility using the Beighton score (≥5 required for hEDS diagnosis) 1
• Document skin hyperextensibility, fragility, and scarring patterns 1

Step 2: Screen for Features Requiring Genetic Testing

Order genetic testing ONLY if any of these red flags are present:

• Vascular complications: arterial rupture, aneurysms, or unexplained vascular events 1
• Severe skin findings: atrophic scarring, skin fragility beyond typical hEDS 3
• Family history of sudden death or arterial complications 1
• Features overlapping with classical EDS or vascular EDS 3

Step 3: If Genetic Testing is Pursued

Multi-gene panel testing is the most efficient approach when EDS subtype is unclear, covering COL3A1 (vascular EDS), COL5A1, COL5A2 (classical EDS), TGFBR1, TGFBR2, PLOD1, and other arteriopathy genes. 1 This is more appropriate than single-gene testing when the clinical picture is ambiguous.

Essential Workup INSTEAD of Genetic Testing

For this patient, the following evaluations are medically necessary and should be completed before or instead of genetic testing:

Cardiovascular Assessment

• Echocardiogram to evaluate for aortic root dilation (occurs in 25-33% of hEDS patients) 1, 4
• Postural vital signs with active stand test: heart rate increase ≥30 beats/min within 10 minutes of standing suggests POTS 1, 4

Gastrointestinal Evaluation

• Celiac disease serological testing should be performed early, as risk is elevated in hEDS patients (up to 20% prevalence) 1, 4
• Consider anorectal manometry, balloon expulsion test, or defecography given her constipation and high prevalence of pelvic floor dysfunction (up to 50% in hEDS) 4
• Consider gastric emptying studies given her GI symptoms and likely POTS (abnormal gastric emptying occurs in up to 30% of hEDS patients with POTS) 4

Mast Cell Activation Syndrome Screening

• Baseline serum tryptase level only if she has episodic multisystem symptoms involving ≥2 physiological systems (flushing, urticaria, wheezing) 1, 4
• Do NOT perform routine MCAS testing for isolated GI symptoms 1

Autonomic Function

• Tilt table testing if POTS is suspected based on postural vital signs 1

Common Pitfalls to Avoid

1. Ordering genetic testing reflexively for all hypermobile patients: This is not evidence-based and wastes resources, as hEDS has no identified genetic markers 1, 5

2. Missing vascular EDS: This is the critical error—failure to recognize vascular EDS carries significant mortality risk 1. The patient's skin findings (easy bruising, fragile skin, delayed wound healing, spontaneous wound reopening) warrant careful consideration of whether multi-gene panel testing is needed to exclude vascular EDS 3

3. Failing to coordinate multidisciplinary care: Medical geneticists should be consulted when clinical features suggest EDS, family history shows autosomal dominant inheritance, or when arteriopathy is suspected 1

Clinical Recommendation for This Case

Given this patient's concerning skin findings and family history of cardiovascular complications, referral to medical genetics for evaluation is appropriate. 1 The geneticist can determine whether multi-gene panel testing (which would include CPT 81408 or similar codes) is warranted to exclude vascular EDS or other monogenic connective tissue disorders. 1, 3

However, if the clinical presentation is clearly consistent with hEDS without features suggesting vascular or classical EDS, then genetic testing remains unnecessary and the diagnosis should be made clinically using the 2017 criteria. 2, 1, 5

The key distinction is that genetic testing is not for confirming hEDS (which has no genetic test), but for excluding other dangerous EDS subtypes that require different management. 1, 3