Periorbital purpura has been described as a presenting sign in a patient with hereditary transthyretin amyloidosis (hATTR). The case report is published in Annals of Internal Medicine: Clinical Cases.

Amyloidosis is associated with deposits of misfolded precursor protein into extracellular tissues in the body, leading to organ dysfunction. Among more than 30 different amyloidogenic proteins, 11 that affect the heart have been described.

More than 95% of all cases of cardiac amyloidosis can be categorized into 2 major subtypes with varying prognoses and phenotypic differences: immunoglobulin light chain amyloidosis and transthyretin (ATTR) amyloidosis. Among individuals with the ATTR subtype of the disease, bilateral periorbital purpura has been reported very rarely.

The current case report describes a 68-year-old Brazilian man with a family history of cardiac amyloidosis. The patient presented to the Cleveland Clinic Amyloid Heart Disease Department in June 2020 for assessment of periorbital purpura that had persisted for 5 years. He reported no history of trauma to the area. He had consulted with both a dermatologist and a hematologist, with no definitive diagnosis being rendered.

At his initial clinic presentation, the patient reported a history of medically treated endocarditis associated with nonrheumatic mitral valve insufficiency 7 years earlier. Additional history included prostate cancer, for which he had undergone transurethral resection of the prostate, and carpal tunnel syndrome of the right hand, for which carpal tunnel release surgery had been performed.

An electrocardiogram revealed low voltage throughout the limb leads and an anterior pseudoinfarct pattern. His echocardiogram showed mild left ventricular wall thickness with moderate thickening of the mitral valve leaflets, a restrictive mitral valve inflow pattern, and decreased global longitudinal strain. Coronary angiography revealed mild nonobstructive coronary artery disease, and serum laboratory testing confirmed a minimal elevation in the kappa/lambda ratio. Transthyretin (TTR) genetic testing verified heterozygosity for an Ala19Asp (p.Ala39Asp) variant, which confirmed a diagnosis of hATTR.

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At hATTR diagnosis, treatment with tafamidis—a TTR stabilizer—was initiated. The patient’s cardiomyopathy continued to progress, however, requiring many hospitalizations for decompensated heart failure. Ultimately developing end-stage amyloid cardiomyopathy, he needed to undergo heart transplantation. Additionally, cystoscopy revealed diffuse hemorrhagic changes in this bladder wall, with amyloid deposition confirmed on biopsy.

ATTR amyloidosis presents as either a wild-type form of the disease (ATTRwt), which is typically observed in elderly patients, or as a hereditary variant (ATTRv). More than 150 unique variants in the TTR gene have been reported, leading to “a spectrum of penetrance and phenotypic presentation.” Both ATTRwt and ATTRv amyloidosis can be associated with the propensity for cardiac or neurologic manifestations.

The ALA19Asp variant reported in the current patient, who was from Brazil, recently (2006 to 2021) was shown to be responsible for approximately 3.5% of all cases of ATTRv amyloidosis at a Brazilian referral center. The patient presented with a predominantly cardiac phenotype without notable neuropathy but with significant involvement of the bladder. His periorbital purpura was attributed to vascular fragility.

“Here we describe this exceedingly rare presentation as an index sign in a patient found to have hereditary ATTR cardiac amyloidosis,” the authors wrote. “It is important for clinicians to be aware of this sign to avoid unnecessary diagnosis and treatment delay.”


Katzianer DS, James K, Hanna M. Periorbital purpura as a presenting sign of hereditary transthyretin amyloidosis. AIMCC. Published online March 7, 2023. doi:10.7326/aimcc.2022.0878