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Novel COL4A1-related phenotype: generalized hypermobility in a patient with heterozygous missense mutation at NM_001845.6(COL4A1): c.4006G>A (p. Val1336Ile)

Journal: The AAO Journal Date: 2025/06, 35(2):Pages: 8-9. doi: Subito , type of study: case report

Full text    (https://aaoj.kglmeridian.com/view/journals/aaoj/35/2/article-p5.xml)

Keywords:

case report [708]
COL4A1 [1]
female [597]
genes [16]
hypermobility [10]
OMT [3751]
osteopathic manipulative treatment [3771]
women [553]

Abstract:

Introduction: Type 4 collagen is a major constituent of the basement membrane, providing mechanical support for the body’s tissues. Pathogenic mutations in COL4A1 usually result from substitution of a glycine residue, resulting in varied neurological disorders including infantile hemiparesis, migraine with aura, porencephaly, and seizures. We present a case of novel COL4A1-related hypermobility in a patient refractory to treatment with osteopathic manipulative treatment (OMT). Case: A 34-year-old female sought osteopathic management for chronic pain affecting the hips, back, and neck. History included back pain since age 11, recurrent subluxations and dislocations of the shoulders and hips, postural orthostatic tachycardia (POTS), and mast cell activation (MAS). On presentation, Beighton score was 5/9, indicating generalized hypermobility. Significant somatic dysfunctions (SD) of head, C-spine, T-spine, ribs, abdomen, and extremities were treated with MFR, BLT, ST, CS, and OCMM. Results: The patient’s SD was refractory after OMT administered once every 4-8 weeks for 22 months. Mean pain severity was 4 +- 1 on the 11-point Numeric Rating Scale. Beighton score remained 5/9 despite concurrent physical therapy. Genetic analysis identified N=1 mutation on a 92-gene panel of connective tissue disorders. The patient was heterozygous for NM_001845.6(COL4A1):c.4006G>A(p.Val1336lle) and ClinVar query did not identify a corresponding hypermobile-type trait or pathogenic classification. Discussion: We present the first known case of generalized hypermobility in a patient with COL4A1 mutation. The patient’s SD was refractory to OMT potentially due to increased musculoskeletal elasticity, suggesting a novel COL4A1-related syndrome further comprising POTS and MAS. If future research confirms causality, genotyping of COL4A1 may be indicated in the workup of hitherto undifferentiated cases of generalized hypermobility, including hypermobile Ehlers-Danlos Syndrome.


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