A Frank discussion about earlobe creases
By Warren R. Heymann, MD, FAAD
Dec. 14, 2022
Vol. 4, No. 49
A half-century has transpired since Sanders T. Frank reported: “All patients 60 years of age or younger who had a positive ear-lobe sign [characterized by a prominent crease in the lobule portion of the auricle] were studied in terms of personal and family history of premature cardiovascular disease and known risk factors. Among 20 patients with a positive sign seen in eight months, all but one had 1 or more risk factors for coronary heart disease.” (1) As a medical student I recall heated discussions questioning the validity of Frank’s observation.
Weidemann offered an important response to Frank’s publication: “I should like to emphasize that Frank’s ear-crease sign is an acquired feature of the earlobe found in older age groups. It is important to distinguish it from the congenital slit-like indentations of the earlobes (the so-called Kerbenohr) that are present at birth. These congenital, diagonal earlobe creases are a frequent and very characteristic symptom in Beckwith’s syndrome or “electromyogram” syndrome, but they also exist, although rarely, in healthy children and adults. (2) Most recently, earlobe creases (posterior > anterior) have been observed in the KBG syndrome (caused by haploinsufficiency of the ankyrin repeat domain-containing protein 11 gene [ANKRD11] and characterized clinically by its facial dysmorphology, range of intellectual disability, behavioral problems, and relatively short stature). (3)
Although still controversial in many aspects, diagonal earlobe creases (DEC) have been positively correlated with coronary artery disease (CAD) and peripheral vascular disease (PVD) and is considered an independent variable for CAD. The DEC (aka “Frank sign”) is a wrinkle that extends 45° backward from the tragus to the auricle hypothesized to be a predictor of atherosclerotic disease. (4) In a study of 655 patients with acute myocardial infarction, 442 (67.5%) showed a DEC grade 2/3 and 213 (32.5%) DEC grade 0/1. The median observation period was 3.06 years. Patients with DEC grade 2/3 had a 1.48-fold increased risk of death compared to the DEC grade 0/1 patient group. The fully adjusted model revealed a significant, 2.57-fold hazard ratio of death for the patients with DEC grade 2/3, allowing the authors to conclude that DEC is independently associated with 1-year AMI survival. (5) To assess the diagnostic accuracy of DEC for diagnosis of chronic and acute coronary syndromes in adults, 7 electronic databases were searched, with 13 cross-sectional studies evaluating 3951 patients, focusing on anatomically significant coronary stenosis. Invasive coronary angiography was used as a reference in most studies, except one which utilized computed tomography angiography. The sensitivity ranged from 26% to 90%, and specificity from 32% to 96%. Positive likelihood ratios varied from 1.11 to 7.03, but most results were below 2. Negative likelihood ratios were from 0.84 to 0.30, but most values exceeded 0.5. The authors concluded that the diagnostic accuracy of DEC for the detection of chronic coronary syndromes is insufficient. “It only slightly changes pre-test probability, and its mere presence or absence should not affect the clinical management of the patients. However, for its feasibility and easy interpretation, Frank’s sign could be considered as a part of physical examination.” (6)
Analogous to the myocardium, the earlobe has an end-artery pattern of microcirculation without collaterals; these vessels easily become anoxic when obstructed. The Frank sign is hypothesized to result from of a loss of the elastic fibers due to increased free-circulating radical oxidative stress and increased intimal blood vessel thickness with reduced blood flow. (7) In an autopsy study of earlobes of patients with the Frank sign, histopathology revealed myoelastofibrosis in an arterial vessel accompanied by diffuse fibrosis at the base of the crease and Wallerian-like degeneration in the peripheral nerves, suggesting a time-related progression of the crease-associated changes. (8)
Baboujian et al opine that the Frank sign “may facilitate prompt evaluation and early diagnoses of coronary atherosclerotic disease, especially in the presence of other concurrent risk factors, and help patients adapt a healthier lifestyle to help prevent the onset and progression of coronary disease.” It may be reasonable for dermatologists to mention this to patients to speak with their primary doctor when a DEC is noted, but should particular attention be paid in psoriatic patients who may be at risk for cardiovascular comorbidities? To date, only one study addresses this issue. DECs were appreciated in 153 psoriatic cases and 159 control subjects respectively. Age > 40 years and male subjects strongly related to bilateral DEC with statistical significance. Psoriasis tended to correlate with bilateral DEC without statistical significance. (9) Regardless, it may be prudent to refer psoriatic patients with DEC for an assessment of cardiovascular risk factors (hypertension, hyperlipidemia, metabolic syndrome, diabetes).
There is a new wrinkle in the earlobe crease realm — it may serve as a proxy for the presence of facial edema when differentiating DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome from other serious drug eruptions. Gilkey et al performed a retrospective case-control study in which dermatologists evaluated the presence of an oblique earlobe crease in photographs of patients diagnosed with DRESS syndrome compared to unmatched controls with morbilliform drug reactions, Stevens–Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) or acute generalized exanthematous pustulosis (AGEP). Seventeen out of 37 (46%) DRESS patients had an ear image in their chart compared to 10 out of 91 (11%) and 18 out of 346 (5.2%) SJS/TEN/AGEP and low-risk morbilliform patients, respectively (P < 0.0001). When comparing DRESS versus all eruptions (low-risk morbilliform, SJS/TEN, and AGEP), the presence of an oblique earlobe crease had a sensitivity of 81%, specificity of 71%, and positive predictive value (PPV) of 68% for the diagnosis of DRESS (P < 0.0001). The authors suggest: “The presence of an oblique earlobe crease in a patient with a suspected drug eruption is a strong indication to proceed with additional laboratory testing to complete a validated DRESS scoring assessment.” A prospective study is recommended to confirm these findings. Please note that the eponym “Frank sign” should not be used in this context. The next time I am evaluating a patient with a severe drug eruption, I will look at the earlobes.
Frankly speaking, earlobe creases may be very revealing — they may be normal, part of a syndrome, reflect cardiovascular disease (Frank sign), or be indicative of DRESS syndrome. DWI&I readers of a certain age will recall Carol Burnett ending her shows by tugging on her left earlobe (meant to be a signal to her grandmother). Earlobes may be sending astute dermatologists a signal worth reading.
Point to Remember: Depending on the context, diagonal earlobe creases may reflect an increased risk of cardiovascular disease (the Frank sign) or may be indicative of facial edema in DRESS syndrome.
Our expert’s viewpoint
Ben Kaffenberger, MD, MS, FAAD
Ohio State Department of Dermatology
Although multiple algorithms are available for the validated diagnosis of drug-reaction with eosinophilia and systemic symptoms (DRESS) are available (11-13), I have struggled to provide a consistent answer to our trainees on when it is necessary to use one of these diagnostic systems. Must it be done with every patient presenting with a morbilliform eruption? Similarly, should every patient with a morbilliform eruption have a complete blood count with differential, peripheral blood smear, and hepatic function test?
To answer these questions, our group has been focused on physical examination signs that can distinguish and guide the additional evaluation of patients presenting with morbilliform eruptions (thank you Dermatology Foundation and everyone who has supported its mission).
The oblique earlobe crease is intended to be one such tool that a dermatologist may walk into a room and immediately know that the pre-test probability is high for DRESS syndrome and that algorithmic confirmation and laboratory work-up ought to be performed. While it is not perfect, we believe it is more specific than our data shows. Namely, our study relied on clinical images showing the auricle in patient clinical records; these were infrequent especially in our patients with what we term “low-risk” morbilliform drug eruptions. We suspect this was because there was no rash to document on the face or ear, yet we only included the ones who had images. This non-random enrollment likely lowered our specificity, especially in comparing DRESS syndrome to low-risk morbilliform drug eruptions.
There is a second benefit of the oblique ear lobe crease sign. In obese patients, it can be difficult to ascertain whether the patient’s face is edematous. Our experience is that in this situation, again, look to the earlobes!
Dr. Heymann astutely recognized the similarities with Frank’s sign, or the diagonal earlobe crease sign, but I would like to emphasize a difference in morphology: the previously described diagonal earlobe crease is characterized by an atrophic crease (Figure 1A), whereas the oblique earlobe crease is one that is often so edematous that it is folding over itself (Figure 1B).
Ultimately, our goal was never to replace an algorithm with a single physical examination sign; rather, we hope that this will be utilized as a rapid, inexpensive test, to differentiate and guide the evaluation and work-up of patients presenting with morbilliform eruptions.
Frank ST. Aural sign of coronary-artery disease. N Engl J Med. 197 3 Aug 9;289(6):327-8. doi: 10.1056/nejm197308092890622. PMID: 4718047.
Wiedemann HR. Ear-lobe creases, congenital and acquired. N Engl J Med. 1979 Jul 12;301(2):111. doi: 10.1056/nejm197907123010220. PMID: 449943.
Ashraf T, Harrison M, Irving M. Ear lobe creases: A novel phenotypic feature in KBG syndrome. Am J Med Genet A. 2022 May;188(5):1618-1622. doi: 10.1002/ajmg.a.62675. Epub 2022 Feb 17. PMID: 35175682.
Baboujian A, Bezwada P, Ayala-Rodriguez C. Diagonal Earlobe Crease, a Marker of Coronary Artery Disease: A Case Report on Frank's Sign. Cureus. 2019 Mar 11;11(3):e4219. doi: 10.7759/cureus.4219. PMID: 31106102; PMCID: PMC6506272.
Thilo C, Meisinger C, Heier M, von Scheidt W, Kirchberger I. Diagonal earlobe crease and long-term survival after myocardial infarction. BMC Cardiovasc Disord. 2021 Dec 16;21(1):597. doi: 10.1186/s12872-021-02425-4. PMID: 34915852; PMCID: PMC8679982.
Więckowski K, Gallina T, Surdacki A, Chyrchel B. Diagonal Earlobe Crease (Frank's Sign) for Diagnosis of Coronary Artery Disease: A Systematic Review of Diagnostic Test Accuracy Studies. J Clin Med. 2021 Jun 25;10(13):2799. doi: 10.3390/jcm10132799. PMID: 34202100; PMCID: PMC8268092.
Elawad OAMA, Albashir AAD. 'Frank's sign: dermatological marker for coronary artery disease'. Oxf Med Case Reports. 2021 Sep 20;2021(9):omab089. doi: 10.1093/omcr/omab089. PMID: 34557307; PMCID: PMC8451276.
Stoyanov GS, Dzhenkov D, Petkova L, Sapundzhiev N, Georgiev S. The Histological Basis of Frank's Sign. Head Neck Pathol. 2021 Jun;15(2):402-407. doi: 10.1007/s12105-020-01205-4. Epub 2020 Jul 25. PMID: 32712879; PMCID: PMC8134579.
Honma M, Shibuya T, Iwasaki T, Iinuma S, Takahashi N, Kishibe M, Minami-Hori M, Ishida-Yamamoto A. Prevalence of coronary artery calcification in Japanese patients with psoriasis: A close correlation with bilateral diagonal earlobe creases. J Dermatol. 2017 Oct;44(10):1122-1128. doi: 10.1111/1346-8138.13895. Epub 2017 May 2. PMID: 28464401.
Gilkey TW, Amigo MA, Himed S, Rojek NW, Milani-Nejad N, Korman AM, Trinidad JC, Kaffenberger BH. Oblique earlobe crease as a novel physical examination finding in drug reaction with eosinophilia and systemic symptoms: a retrospective study. J Eur Acad Dermatol Venereol. 2022 Sep;36(9):e739-e740. doi: 10.1111/jdv.18270. Epub 2022 Jun 3. PMID: 35617202.
Bocquet H, Bagot M, Roujeau JC. Drug-induced pseudolymphoma and drug hypersensitivity syndrome (Drug Rash with Eosinophilia and Systemic Symptoms: DRESS). Semin Cutan Med Surg. Dec 1996;15(4):250-7. doi:10.1016/s1085-5629(96)80038-1
Shiohara T, Iijima M, Ikezawa Z, Hashimoto K. The diagnosis of a DRESS syndrome has been sufficiently established on the basis of typical clinical features and viral reactivations. Br J Dermatol. May 2007;156(5):1083-4. doi:10.1111/j.1365-2133.2007.07807.x
Kardaun SH, Sidoroff A, Valeyrie-Allanore L, et al. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist? Br J Dermatol. Mar 2007;156(3):609-11. doi:10.1111/j.1365-2133.2006.07704.x
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