Alport syndrome with a Novel COL4A3 Gene Alteration presenting with recurrent vertebral artery dissections: Case report and Literature Review
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical-Adult
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Secondary Categories:
- Clinical-Adult & Pediatric
Introduction
Alport syndrome typically presents with hematuria, proteinuria, and progressive kidney failure, often accompanied by sensorineural hearing impairment and ocular problems. Alport syndrome (autosomal dominant inheritance) is the most common form and associated with COL4A3 and COL4A4 gene defects. Autosomal Dominant Alport syndrome’ even though their kidney disease is typically more mild and deafness is typically absent or occurs much later in life, they have a greater risk than the general population of developing proteinuria and hypertension. The expanded phenotypic spectrum of AS may present with focal segmental glomerulosclerosis, idiopathic chronic kidney disease, steroid-resistant nephrotic syndrome, familial IgA nephropathy, and kidney cysts. More, AS can make blood vessels more vulnerable due to type IV collagen abnormalities. Here we describe a patient with a novel COL4A3 gene alteration and history of recurrent vertebral artery dissections.
Case Presentation
A 44-year-old female presented for a genetics evaluation with clinical diagnoses of two vertebral artery dissections, early onset hypertension, hyper cholesterolemia, gestational DM, endometriosis, interstitial cystitis, longstanding history of kidney stones, benign hemangioma, PCOS, Hashimoto's thyroiditis, psoriasis, diverticulitis, positive titer for RA/lupus.
Diagnostic Workup
Whole genome analysis revealed a heterozygous uncertain significant variant in the COL4A3 gene (c.2968G>A, p.Ala990Thr) that was associated with Alport sydnrome. Panel testing did not reveal any variants in the connective tissue or vascular genes.
ECHO 11/30/2023:
Left ventricle: The cavity size is normal. Normal thickness is present.
There are no regional wall motion abnormalities present. The left
ventricular ejection fraction is normal. Left ventricular ejection
fraction is 55-60%. E/e' ratio is suggestive of normal left atrial
pressure. The left ventricular filling pattern is abnormal from impaired
relaxation. Diastolic dysfunction is present.
2. Right ventricle: Calculated right ventricular systolic pressure is
estimated to be 22 mmHg.
3. Mitral valve: There is trace mitral valve regurgitation.
4. Aortic valve: Limited image resolution does not allow for distinction of
all leaflets. There is no aortic stenosis. There is no valvular aortic
regurgitation.
5. Tricuspid valve: There is trace tricuspid valve regurgitation.
6. Pericardium, extracardiac: There is no pericardial effusion.
Treatment and Management
None
Outcome and Follow-Up
None
Discussion
There are reports of aortic, coronary, and cervical dissections, but few reports of intracranial dissections in patients with Alport syndrome. Vogt et al. reported a poor prognosis for aortic dissection in young patients with chronic hypertension; all their patients had hypertension associated with chronic renal failure. Patients with Alport syndrome are thought to be more prone to aortic disease because of the combination of renal hypertension and vascular fragility. In Alport syndrome, protective strategies for renal function are determined to be clinically important, and therapeutic interventions are often performed for renal hypo function and hearing loss, but screening for aortic and other vascular disease is rarely performed.
Conclusion
This highlights the need for further investigation into the relationship between Alport syndrome and vascular fragility and should alert clinicians to the possibility of intracranial dissection in patients with AS
Alport syndrome typically presents with hematuria, proteinuria, and progressive kidney failure, often accompanied by sensorineural hearing impairment and ocular problems. Alport syndrome (autosomal dominant inheritance) is the most common form and associated with COL4A3 and COL4A4 gene defects. Autosomal Dominant Alport syndrome’ even though their kidney disease is typically more mild and deafness is typically absent or occurs much later in life, they have a greater risk than the general population of developing proteinuria and hypertension. The expanded phenotypic spectrum of AS may present with focal segmental glomerulosclerosis, idiopathic chronic kidney disease, steroid-resistant nephrotic syndrome, familial IgA nephropathy, and kidney cysts. More, AS can make blood vessels more vulnerable due to type IV collagen abnormalities. Here we describe a patient with a novel COL4A3 gene alteration and history of recurrent vertebral artery dissections.
Case Presentation
A 44-year-old female presented for a genetics evaluation with clinical diagnoses of two vertebral artery dissections, early onset hypertension, hyper cholesterolemia, gestational DM, endometriosis, interstitial cystitis, longstanding history of kidney stones, benign hemangioma, PCOS, Hashimoto's thyroiditis, psoriasis, diverticulitis, positive titer for RA/lupus.
Diagnostic Workup
Whole genome analysis revealed a heterozygous uncertain significant variant in the COL4A3 gene (c.2968G>A, p.Ala990Thr) that was associated with Alport sydnrome. Panel testing did not reveal any variants in the connective tissue or vascular genes.
ECHO 11/30/2023:
Left ventricle: The cavity size is normal. Normal thickness is present.
There are no regional wall motion abnormalities present. The left
ventricular ejection fraction is normal. Left ventricular ejection
fraction is 55-60%. E/e' ratio is suggestive of normal left atrial
pressure. The left ventricular filling pattern is abnormal from impaired
relaxation. Diastolic dysfunction is present.
2. Right ventricle: Calculated right ventricular systolic pressure is
estimated to be 22 mmHg.
3. Mitral valve: There is trace mitral valve regurgitation.
4. Aortic valve: Limited image resolution does not allow for distinction of
all leaflets. There is no aortic stenosis. There is no valvular aortic
regurgitation.
5. Tricuspid valve: There is trace tricuspid valve regurgitation.
6. Pericardium, extracardiac: There is no pericardial effusion.
Treatment and Management
None
Outcome and Follow-Up
None
Discussion
There are reports of aortic, coronary, and cervical dissections, but few reports of intracranial dissections in patients with Alport syndrome. Vogt et al. reported a poor prognosis for aortic dissection in young patients with chronic hypertension; all their patients had hypertension associated with chronic renal failure. Patients with Alport syndrome are thought to be more prone to aortic disease because of the combination of renal hypertension and vascular fragility. In Alport syndrome, protective strategies for renal function are determined to be clinically important, and therapeutic interventions are often performed for renal hypo function and hearing loss, but screening for aortic and other vascular disease is rarely performed.
Conclusion
This highlights the need for further investigation into the relationship between Alport syndrome and vascular fragility and should alert clinicians to the possibility of intracranial dissection in patients with AS