Bilateral infantile Frey syndrome mimicking food allergy: A case report

To the Editor: Localized facial erythema associated with eating is a common concern in infants and frequently raises the suspicion of immunoglobulin E (IgE)-mediated food allergy. However, when flushing consistently occurs at the same location without associated systemic allergic symptoms, Frey syndrome, also known as auriculotemporal syndrome, should be considered. Frey syndrome is characterized by transient flushing, with or without gustatory sweating, in the auriculotemporal region during eating. Although Frey syndrome is well recognized as a complication of parotid gland surgery in adults, pediatric cases are very rare and frequently misinterpreted as a food allergy.1 Most reported pediatric cases are unilateral and associated with a history of instrumental delivery. Bilateral cases without birth trauma or instrumental delivery are rare. We report a case of bilateral Frey syndrome in an infant without a history of birth trauma or surgery, highlighting the clinical features that differentiate Frey syndrome from food allergy and demonstrating the favorable natural course of this condition. A 10-month-old boy was referred to our Department of Allergy for the evaluation of recurrent facial flushing associated with food intake. Symptoms were first noted at 6 months of age shortly after the introduction of complementary foods. Sharply demarcated erythema appeared over both temporal regions and the lower eyelids within 3–5 min after starting to eat and resolved spontaneously within 30–45 min (Figure 1). The flushing occurred irrespective of skin contact with the food and spared the perioral area. No warmth or sweating accompanied the flushing. Various foods, including fruits (apples, bananas, strawberries, kiwi, and mango), dairy products (yogurt and cheese), bread, peanut butter, mashed potatoes, and tuna, were reported to provoke flushing, whereas beef, pork, bacon, carrots, pumpkin, and green beans were tolerated without symptoms. These episodes were not accompanied by pruritus, swelling, urticaria, respiratory distress, or gastrointestinal symptoms. The patient remained otherwise healthy throughout these episodes. Physical examination findings between episodes were unremarkable, and no signs of atopic dermatitis or urticaria were observed. The patient was born at term by cesarean section due to umbilical cord entanglement with a birth weight of 3270 g. Importantly, there was no history of instrumental delivery, facial trauma, or surgery. Growth and developmental milestones were appropriate for age. There was no family history of Frey syndrome or food allergies. Prior to referral, an oral antihistamine was prescribed at another clinic; however, it did not reduce the frequency, extent, or duration of flushing episodes. Because the patient was referred for an IgE-mediated food allergy and the family was worried about dietary restriction, we performed skin prick testing using the prick-to-prick technique with a bifurcated needle. All tests with suspected foods were negative, whereas the positive control (histamine) elicited an appropriate wheal response (Table S1). Based on the reproducible, sharply localized, food-triggered flushing and absence of systemic allergic manifestations, a diagnosis of bilateral infantile Frey syndrome was established. No specific treatment was initiated, and the parents were reassured of the benign nature of the condition. At the 4-month follow-up (age 14 months), the frequency of flushing episodes had decreased to approximately once per week despite the continued ingestion of previously triggered foods. At the 9-month follow-up (age 19 months), the symptoms were confined to a smaller periocular area (predominantly involving the lower eyelids) and were triggered by a narrower range of foods. At the 14-month follow-up (age 24 months), only tomatoes and tomato sauce consistently provoked flushing, and the duration of episodes decreased to approximately 5 min, suggesting ongoing spontaneous regression. Differential diagnoses for localized postprandial facial erythema in infants include IgE-mediated food allergy, contact dermatitis, early manifestations of atopic dermatitis, unilateral facial erythema (Harlequin syndrome), and chronic spontaneous urticaria. In our patient, several findings supported the diagnosis of Frey syndrome rather than IgE-mediated food allergy. First, symptoms were consistently induced by multiple foods, but were reproducibly confined to the same localized facial area. Second, there were no concurrent systemic allergic manifestations, and the child remained healthy during the episodes. Third, skin-prick tests (performed because the patient was referred with concern for IgE-mediated food allergy) were negative, making IgE-mediated sensitization less likely. However, this should not be interpreted as diagnostic evidence for Frey syndrome. Fourth, the antihistamine treatment was ineffective, and the symptoms resolved spontaneously without any intervention. The pathophysiology of Frey syndrome is not yet fully understood. In adults, it is most commonly observed following parotidectomy,2 and is thought to result from intraoperative damage to the auriculotemporal nerve (ATN). It is widely accepted that severed parasympathetic fibers may aberrantly reinnervate sympathetic effectors in the overlying skin.3 In children, unilateral Frey syndrome is closely associated with instrumental delivery, which may cause pressure on the temporal region of the face and result in nerve injury. The exact mechanism underlying this aberrant nerve regeneration remains unclear, but previous reports suggest a potential role for neurotrophic factors.4 In bilateral Frey syndrome, a history of ATN damage is rare. The condition is usually considered idiopathic; however, familial occurrence has been reported, and congenital nerve damage has been proposed as a potential underlying mechanism.5 In the present case, the absence of instrumental delivery, facial trauma, or parotid surgery makes an identifiable ATN injury unlikely. Therefore, this bilateral presentation without a clear precipitating event appears to be more consistent with an idiopathic or possibly congenital mechanism, consistent with previous pediatric reports. Although no family history was identified, congenital predisposition could not be excluded. Minor's starch–iodine test is useful for detecting gustatory sweating in the diagnosis of adult Frey syndrome,3, 6 but is rarely performed in infants, including our patient.1, 5 Pediatric Frey syndrome cases often lack sweating, possibly due to eccrine gland immaturity and differences in nerve regeneration following less traumatic injury mechanisms.1 In a French retrospective pediatric series, the diagnosis was primarily based on clinical history (and, in some cases, photographic documentation or provocation testing), and Minor's test was performed in none of the 48 cases.5 Given the clear clinical presentation and the distress associated with provocation testing in an infant, we prioritized a clinical diagnosis. Although the absence of an objective test is a limitation, pediatric Frey syndrome is generally a clinical diagnosis, and routine allergy testing is not required in typical presentations.1, 5, 7 Although the oral food challenge is the gold standard for diagnosing IgE-mediated food allergies, clinicians should recognize that ingestion of the same food can reproducibly provoke localized facial flushing in Frey syndrome, as seen in the present case. Therefore, if an oral food challenge is performed for suspected food allergy and elicits isolated, sharply demarcated flushing confined to a neurogenic distribution involving the temporal and adjacent periocular areas with sparing of the perioral region and no systemic manifestations, Frey syndrome should be considered. Allergy testing may be used selectively to assess IgE sensitization, but it is not mandatory to establish a diagnosis.1, 5, 7 Reported triggers for Frey syndrome include salivation-stimulating foods (e.g., sour, spicy, or sweet items) and foods requiring chewing; however, symptoms have also been reported with bread, eggs, and snack foods.7-9 In our patient, pork and beef, although requiring chewing, did not provoke flushing, whereas several other foods consistently triggered symptoms. This pattern suggests that gustatory salivary stimulation may have been more relevant than mastication itself in this case, although salivary stimulation was not measured directly. This interpretation is consistent with the recognized pathophysiology of Frey syndrome, in which gustatory stimuli may provoke flushing and sweating through aberrant parasympathetic reinnervation of the cutaneous sweat glands and vessels.3, 4 Among pediatric patients, bilateral Frey syndrome reportedly accounts for 17%–27% of cases.1, 5 In a national French pediatric case series, unilateral disease was more strongly associated with instrumental delivery than bilateral disease, and most children showed spontaneous regression or complete recovery.5 Consistent with this benign natural history, our patient demonstrated gradual spontaneous improvement over 14 months of follow-up, with fewer triggering foods and a shorter episode duration; however, complete resolution has not yet occurred, and continued follow-up is warranted. This case highlights the importance of recognizing pediatric Frey syndrome to avoid unnecessary dietary restrictions, undue concerns about anaphylaxis, and excessive allergy investigations that may result from the misdiagnosis of IgE-mediated food allergy. In a previous review, only 20% of children received a definitive diagnosis at the initial visit, and 21% were subjected to inappropriate dietary restrictions.5 Another systematic review reported that 45% of cases required more than 12 months to reach a diagnosis, and approximately half underwent unnecessary allergy testing.1 These data suggest that limited awareness of Frey syndrome contributes to diagnostic delay and potentially avoidable interventions. In our case, parental concern about food allergy initially raised the possibility of dietary restriction; counseling and reassurance regarding the benign course helped avoid unnecessary elimination and supported the continuation of a normal diet. This work was supported by JSPS KAKENHI (grant number 22K02174) and the Nipponham Foundation for the Future of Food. Written informed consent for the publication of this case report and accompanying images was obtained from the patient's parents. The authors declare no conflict of interest. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.