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Molecular Diagnosis Actively and Immediately Changes Treatment Plan in Patients Clinically Diagnosed with Congenital or Idiopathic Spinal Deformities

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical Genetics
  • Secondary Categories:
    • Clinical Genetics
Introduction:
Patients with syndromic spinal deformities lacking typical features are likely to be misdiagnosed with congenital or idiopathic spinal deformities, the most common deformity types without clear etiologies or diagnostic molecular testing. Recently, molecular testing has increasingly been used to tailor management plans. However, in spinal surgeries, surgical and non-surgical treatment decisions still primarily depend on clinically observable spinal and additional features.

Methods:
We retrospectively reviewed the medical records of patients clinically diagnosed with congenital or idiopathic spinal deformities visited or referred to Peking Union Medical College Hospital. Deep phenotyping was integrated with exome, genome sequencing (ES/GS) and/or RNA sequencing during molecular testing. Patients and family members with disease-causing variants were included. We identified “active changes in treatment plans” informed by molecular diagnosis, including: 1) changes in surgical plans; 2) new findings requiring immediate medical attention; or 3) revisions to existing management plans. Initiation or continuation of long-term management without urgent issues identified were not considered active changes.

Results:
Molecular testing provided positive results for 253 patients, leading to corrected diagnoses and appropriate managements. The diagnostic rate was 12.05% (176/1461) for congenital and 5.37% (77/1433) for idiopathic cases, with TBX6-associated congenital scoliosis (108/176) and Marfan syndrome (26/77) being the most common diagnoses. We identified 13 cases with active and immediate changes in treatment plans, classified into five categories.

 

1. Modification of surgical strategy

Patient 1, a 4-year-old male with “congenital kyphoscoliosis”, underwent standard surgery but developed coronal imbalance. Biallelic disease-causing variants in B3GALT6 were identified, prompting an extension of the lowest instrumented vertebra during revision surgery considering the clinical hallmark of joint laxity. A similar surgical approach was applied to Patient 2 with B3GALT6-related disorder diagnosed preoperatively. No complications occurred. Patient 3 was referred with severe idiopathic kyphoscoliosis. High-level osteotomy is the standard practice but carries higher risks. Classical Ehlers-Danlos syndrome (cEDS) was revealed through deep phenotyping and GS. Due to cEDS-associated joint hypermobility and skin fragility, high-level osteotomy was avoided, and special attention was given to prevent joint dislocations and skin injuries. The curves were successfully corrected without complications.

 

2. Cancellation of planned surgery

Patient 4 also had cEDS, but with prominent vascular fragility. His surgery was postponed. His scoliosis was managed conservatively. Patient 5, referred for vertebral fusion surgery, had extensive cervical fusion and heterotopic ossifications. Rapid GS confirmed fibrodysplasia ossificans progressiva, and invasive procedures trigger soft tissue ossifications. Her surgery was canceled, and she was referred for physical therapy and clinical trial assessment.

 

3. Identification of hidden anomalies requiring immediate medical attention.

Patient 6, presented with minimal Marfan-like features, found to have Marfan syndrome inherited from her “asymptomatic” father. Patient 8 was diagnosed with Marfan syndrome after a further RNA sequencing. Echocardiogram reported urgent cardiovascular complications in all three individuals, prompting immediate referrals to cardiology.

 

4. Alteration in diagnosis and referral decision

Patient 9 was clinically diagnosed with idiopathic scoliosis, showing Marfan-like cardiovascular features and short stature. ES revealed Noonan syndrome, enabling growth hormone therapy with endocrinologists. Patient 10 experienced similar changes.

 

5. Discontinuation of unnecessary surveillance

Patient 11, diagnosed with idiopathic scoliosis and Marfan-like features, had undergone nine years of post-operative Marfan surveillance. GS revealed Trisomy X, leading to the discontinuation of unnecessary Marfan monitoring, alleviating her emotional burden, and enabling consultations with reproductive specialists. Patients 12 and 13, diagnosed with Trisomy X and 1p34.3 deletion, experienced similar changes.

Conclusion:
Patients with genetic disorders may be misdiagnosed with congenital or idiopathic spinal deformities. Molecular diagnosis can also be actionable in spinal care, from initiation of multidisciplinary management plan to active and immediate adjustments in surgical and non-surgical treatments for both patients and family members, advancing toward precision orthopedics.

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