- Email: [email protected]
The mamey sapote fruit (Pouteria sapota) as a novel cause of IgE-mediated allergic reaction
352
Letters / Ann Allergy Asthma Immunol 114 (2015) 341e356
[2] Golden DB. Advances in diagnosis and management of insect sting allergy. Ann Allergy Asthma Immunol. 2013;111:84e89. [3] Köhler J, Blank S, Müller S, et al. Component resolution reveals additional major allergens in patients with honeybee venom allergy. J Allergy Clin Immunol. 2014;133:1383e1389. [4] WHO/IUIS Allergen Nomenclature Subcommittee. Allergen Nomenclature. http://www.allergen.org/search.php?allergenname¼&allergensource¼Apisþ mellifera&TaxSource¼&TaxOrder¼&foodallerg¼all&bioname¼. Accessed August 31, 2014. [5] Sanchez-Machin I, Moreno C, Gonzalez R, Iglesias-Souto J, Perez E, Matheu V. Safety of a 2-visit cluster schedule of venom immunotherapy in outpatients at risk of life-threatening anaphylaxis. J Investig Allergol Clin Immunol. 2010;20: 91e92.
[6] Müller U. Insect Sting Allergy Clinical: Clinical Picture, Diagnosis and Treatment. New York, NY: Gustav Fis. Stuttgart; 1990. [7] Incorvaia C, Frati F, Dell’Albani I, et al. Safety of hymenoptera venom immunotherapy: a systematic review. Expert Opin Pharmacother. 2011;12: 2527e2532. [8] Boyle RJ, Elremeli M, Hockenhull J, et al. Venom immunotherapy for preventing allergic reactions to insect stings. Cochrane Database Syst Rev. 2012; 10:CD008838. [9] Birnbaum J, Ramadour M, Magnan A, Vervloet D. Hymenoptera ultra-rush venom immunotherapy (210 min): a safety study and risk factors. Clin Exp Allergy. 2003;33:58e64. [10] Muller UR. Bee venom allergy in beekeepers and their family members. Curr Opin Allergy Clin Immunol. 2005;5:343e347.
The mamey sapote fruit (Pouteria sapota) as a novel cause of IgE-mediated allergic reaction The mamey sapote fruit (Pouteria sapota) is a round to ovoid fruit with a firm, leathery rind with salmon-pink to red flesh and 1 to 4 large spindle shaped seeds (Fig 1). It is commonly found in Central America, where it is generally consumed raw, although it also can be prepared into ice creams or jams. It is usually harvested in the spring through early autumn.1 To our knowledge, it has not previously been reported to cause allergic reactions of any type. A 65-year-old woman presented after having an adverse reaction associated with food. She ate dinner and then ate the flesh of a whole mamey sapote fruit. Approximately 15 minutes later, she noticed mouth and throat numbness, bilateral eyelid swelling, and pruritus of her palms and soles. Then, she noticed mild difficulty swallowing, with slight voice change and coughing. She selfmedicated with 50 mg of diphenhydramine and her symptoms gradually resolved. She denied shortness of breath, wheezing, dizziness, nausea, or vomiting at the time of the episode. During the following days, she tried her leftover food from dinner (pork ribs and vegetables) and did not notice a reaction. She denied consuming alcohol the day of the reaction. One week after the initial episode, she tried a small spoonful of the mamey sapote fruit and within 5 minutes had bilateral eyelid swelling without oral symptoms. She again took diphenhydramine, and her symptoms resolved. The last time she ate this fruit was approximately 1 year previously. On average, she eats them several times a year when they are in season. She denied a history of any symptoms with previous ingestion. She had no history of food allergy, although she did have a history of latex allergy. Five years previously, she was evaluated for several episodes of eyelid swelling and facial urticaria after eating at work. She worked as a dental assistant and was exposed to natural latex gloves at the time. Her latex specific IgE level was 0.47 kUA/L at the time. She avoided subsequent latex exposure and did not have any recurrence of symptoms in the 5-year interim. She did not have a history of urticaria or angioedema outside beyond these episodes or a history of asthma. She did have allergic rhinitis that was worse in the late spring and summer, which was controlled with oral antihistamines. Previous specific IgE testing showed positive reactions to grass, weeds, olive tree pollen, and elm tree pollen. Family history was negative for food or environmental allergies. After obtaining informed consent, allergy percutaneous skin testing was performed with prick-to-prick testing of fresh mamey sapote fruit pulp (whole fruit brought in by patient) and, given her history of latex allergy, an aliquot of natural rubber latex glove fragments soaked in sterile saline for 1 hour. The test reaction to
Disclosure: Authors have nothing to disclose.
mamey sapote fruit was positive (7- 8-mm wheal, 25- 25-mm flare), whereas the test reaction to latex was negative (0-mm wheal, 5- 5-mm flare). The histamine control reaction produced an 8- 8-mm wheal and a 20- 25-mm flare, and the negative saline control reaction produced a 0-mm wheal and a 1- 1-mm flare. A control patient had a negative skin test reaction to the fruit pulp. To confirm the results, a slurry of fresh mamey sapote fruit pulp was biotinylated using the EZ-Link Sulfo-NHS-LC-Biotin kit according to the manufacturer’s instructions (Pierce Biotechnology, Thermo Scientific, Rockford, Illinois) and bound to a streptavidin ImmunoCAP assay (Phadia US Inc, Portage, Michigan) as previously described.2 This resulted in a serum specific IgE measurement of 0.11 kUA/L. The solution was concentrated further by centrifuging using an Amicon Ultra centrifugal filter (EMD Millipore, Billerica, Massachusetts) to separate the solution into a filtrated fraction consisting of proteins with a molecular weight of 1 to 5 kDa and an enriched fraction consisting of proteins with a molecular weight greater than 5 kDa. The filtrated fraction resulted in a specific IgE measurement lower than 0.10 kUA/L, and the enriched fraction had a specific IgE measurement of 0.39 kUA/L. Serum IgE testing to latex using a commercially available ImmunoCAP assay yielded a negative reaction (<0.10 kUA/L). To characterize the allergenic protein further, an immunoblot was performed with the mamey sapote fruit extract and the patient’s serum. Briefly, mamey sapote pulp crude extract was analyzed by electrophoresis on a 4% to 20% sodium
Figure 1. Mamey sapote fruit (Pouteria sapota) cut with view of interior (photograph by Angelina Crans Yoon, MD).
Letters / Ann Allergy Asthma Immunol 114 (2015) 341e356
dodecylsulfate polyacrylamide electrophoretic gel, transferred onto a nitrocellulose membrane, and incubated with the patient’s serum and then with horseradish peroxidaseeconjugated goat antihuman IgE antibody (Sigma-Aldrich, St Louis, Missouri). Then, Luminata horseradish peroxidase substrate (EMD Millipore) was used to develop the film. A putative protein was detected at 81 kDa. To assess for potential cross-reactivity, sensitization to PR-10 (measured by Ara h 8), lipid transfer protein (measured by Ara h 9), and profilin (measured by Bet v 2) by a commercially available ImmunoCAP assay yielded a level lower than 0.10 kUA/L. Interestingly, the patient’s history of similar reactions after exposure to latex provided a possible connection between mamey sapote allergy and latex allergy. However, because of the negative IgE and skin prick testing reactions to latex at the time of the mamey sapote reaction and negative reaction to profilin specific IgE, the reactions were less likely to be cross-allergenic in this case. In the same family Sapotaceae, Manilkara zapota, commonly known as the sapodilla, has been reported to cause oral allergy syndrome. Molecular studies have shown that it has basic thaumatin-like proteins 1 and 2, which match significantly with allergenic thaumatin-like proteins from olive, kiwi, bell pepper, and banana.3,4 Owing to the large size of the protein identified in our study, it is unlikely to have similar cross-reactivity because the thaumatin-like proteins previously identified were approximately 25 kDa.
353
We report a systemic allergic reaction from mamey sapote fruit. As more tropical fruits are consumed in the United States, it is important to be aware that they can cause IgE-mediated adverse reactions. Angelina Crans Yoon, MD* C.K. Lin, PhDy Javed Sheikh, MD* *Department of Allergy/Clinical Immunology y Clinical Allergy/Immunology Laboratory Kaiser Permanente Los Angeles Medical Center Los Angeles, California [email protected]
References [1] Morton J. “Sapote.” Fruits of Warm Climates. Miami, FL: Julia F. Morton; 1987, pp 398e402. [2] Erwin EA, Custis NJ, Satinover SM, et al. Quantitative measurement of IgE antibodies to purified allergens using streptavidin linked to a high-capacity solid phase. J Allergy Clin Immunol. 2005;115:1029e1035. [3] Hegde VL, Ashok Kumar HG, Sreenath K, Hegde ML, Venkatesh YP. Identification and characterization of a basic thaumatin-like protein (TLP 2) as an allergen in sapodilla plum (Manilkara zapota). Mol Nutr Food Res. 2014;58:894e902. [4] Ashok Kumar HG, Venkatesh YP. In silico analyses of structural and allergenicity features of sapodilla (Manilkara zapota) acidic thaumatin-like protein in comparison with allergenic plant TLPs. Mol Immunol. 2014;57:119e128.
Expanding the spectrum: chronic urticaria and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy Chronic urticaria (CU) affects approximately 1% of the general population and occurs most frequently in adult women, usually presenting in the third to fifth decade of life.1 Current research suggests a link between CU and autoimmune disease supported in part by the detection of anti-FCεRI autoantibodies and positive autologous serum skin test reactions in many patients with CU.2e5 Despite the numerous autoimmune features of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), this rare primary immunodeficiency disorder has not been linked with CU. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy occurs as a result of a mutation in the AIRE gene that regulates central tolerance in the thymus through medullary thymic epithelial cells and thymic dendritic cells.6 Clinical manifestations identified to date include hypoparathyroidism, adrenal failure, diabetes mellitus, parietal cell atrophy, hypothyroidism, ovarian failure, testicular failure, candidiasis, alopecia, vitiligo, keratopathy, hepatitis, intestinal malabsorption, enamel hypoplasia, tympanic membrane calcification, and nail dystrophy. An acute urticarial-like rash also has been reported in 9% of patients in a Finnish cohort and appeared in association with recurrent fevers up to 4 to 5 times monthly.5,7 Given the suspected autoimmune etiology of up to 25% to 60% of patients with CU and the strong autoimmune character of APECED, a high incidence of CU in this population might be predicted.2e5 An extensive review of the literature yielded only 1 incompletely characterized case report of CU in an 18-month-old male patient with APECED in Northern Ireland.8 We present 2 cases Disclosure: Authors have nothing to disclose. Disclaimer: The views expressed are those of the authors and do not reflect the official policy of the Department of the Army, Department of the Navy, Department of Defense, or the US government.
of APECED that developed refractory CU in early adolescence and were successfully treated with omalizumab. In case 1, APECED was diagnosed when the patient was 3 years old after she presented with blepharospasm, keratoconjunctivitis, and severe hypocalcemia in the setting of intermittent chronic diarrhea. Subsequent genetic testing showed a 13-bp deletion in exon 8 of AIRE, the most common mutation among those of white British ancestry.9 Other clinical features included alopecia, vitiligo, tooth enamel hypoplasia, hypothyroidism, and premature ovarian failure. At 12 years of age, she developed CU unassociated with fever and refractory to 180 mg of fexofenadine and 10 mg cetirizine twice daily, 150 mg ranitidine twice daily, 10 mg of montelukast daily, and up to 100 mg of doxepin nightly. Serology demonstrated the presence of anti-FCεRI autoantibodies and positive histamine release assay results (Table 1). Notably, there were no flares or significant changes in the autoimmune processes previously noted and no associated fevers. Treatment with 150 mg of omalizumab administered subcutaneously every 4 weeks and later extended to every 12 weeks resulted in resolution of her symptoms. Omalizumab was discontinued; however, this resulted in a relapse that required continued treatment with omalizumab every 6 weeks to maintain control of the patient’s symptoms. In case 2, APECED was diagnosed at 9 years of age after the patient presented acutely with severe tetany and hypocalcemia in the setting of recurrent candidiasis and chronic intermittent diarrhea. Genetic testing showed that the patient was compound heterozygous with AIRE mutations R257X and c.967_979del13. Additional clinical manifestations included adrenal insufficiency, gonadal failure, vitiligo, tooth enamel hypoplasia, and dystrophic nails. At 13 years of age, she developed CU without fever that was refractory to 180 mg fexofenadine and 10 mg cetirizine twice daily, 150 mg of ranitidine twice daily, and 10 mg of montelukast daily.
Letters / Ann Allergy Asthma Immunol 114 (2015) 341e356
[2] Golden DB. Advances in diagnosis and management of insect sting allergy. Ann Allergy Asthma Immunol. 2013;111:84e89. [3] Köhler J, Blank S, Müller S, et al. Component resolution reveals additional major allergens in patients with honeybee venom allergy. J Allergy Clin Immunol. 2014;133:1383e1389. [4] WHO/IUIS Allergen Nomenclature Subcommittee. Allergen Nomenclature. http://www.allergen.org/search.php?allergenname¼&allergensource¼Apisþ mellifera&TaxSource¼&TaxOrder¼&foodallerg¼all&bioname¼. Accessed August 31, 2014. [5] Sanchez-Machin I, Moreno C, Gonzalez R, Iglesias-Souto J, Perez E, Matheu V. Safety of a 2-visit cluster schedule of venom immunotherapy in outpatients at risk of life-threatening anaphylaxis. J Investig Allergol Clin Immunol. 2010;20: 91e92.
[6] Müller U. Insect Sting Allergy Clinical: Clinical Picture, Diagnosis and Treatment. New York, NY: Gustav Fis. Stuttgart; 1990. [7] Incorvaia C, Frati F, Dell’Albani I, et al. Safety of hymenoptera venom immunotherapy: a systematic review. Expert Opin Pharmacother. 2011;12: 2527e2532. [8] Boyle RJ, Elremeli M, Hockenhull J, et al. Venom immunotherapy for preventing allergic reactions to insect stings. Cochrane Database Syst Rev. 2012; 10:CD008838. [9] Birnbaum J, Ramadour M, Magnan A, Vervloet D. Hymenoptera ultra-rush venom immunotherapy (210 min): a safety study and risk factors. Clin Exp Allergy. 2003;33:58e64. [10] Muller UR. Bee venom allergy in beekeepers and their family members. Curr Opin Allergy Clin Immunol. 2005;5:343e347.
The mamey sapote fruit (Pouteria sapota) as a novel cause of IgE-mediated allergic reaction The mamey sapote fruit (Pouteria sapota) is a round to ovoid fruit with a firm, leathery rind with salmon-pink to red flesh and 1 to 4 large spindle shaped seeds (Fig 1). It is commonly found in Central America, where it is generally consumed raw, although it also can be prepared into ice creams or jams. It is usually harvested in the spring through early autumn.1 To our knowledge, it has not previously been reported to cause allergic reactions of any type. A 65-year-old woman presented after having an adverse reaction associated with food. She ate dinner and then ate the flesh of a whole mamey sapote fruit. Approximately 15 minutes later, she noticed mouth and throat numbness, bilateral eyelid swelling, and pruritus of her palms and soles. Then, she noticed mild difficulty swallowing, with slight voice change and coughing. She selfmedicated with 50 mg of diphenhydramine and her symptoms gradually resolved. She denied shortness of breath, wheezing, dizziness, nausea, or vomiting at the time of the episode. During the following days, she tried her leftover food from dinner (pork ribs and vegetables) and did not notice a reaction. She denied consuming alcohol the day of the reaction. One week after the initial episode, she tried a small spoonful of the mamey sapote fruit and within 5 minutes had bilateral eyelid swelling without oral symptoms. She again took diphenhydramine, and her symptoms resolved. The last time she ate this fruit was approximately 1 year previously. On average, she eats them several times a year when they are in season. She denied a history of any symptoms with previous ingestion. She had no history of food allergy, although she did have a history of latex allergy. Five years previously, she was evaluated for several episodes of eyelid swelling and facial urticaria after eating at work. She worked as a dental assistant and was exposed to natural latex gloves at the time. Her latex specific IgE level was 0.47 kUA/L at the time. She avoided subsequent latex exposure and did not have any recurrence of symptoms in the 5-year interim. She did not have a history of urticaria or angioedema outside beyond these episodes or a history of asthma. She did have allergic rhinitis that was worse in the late spring and summer, which was controlled with oral antihistamines. Previous specific IgE testing showed positive reactions to grass, weeds, olive tree pollen, and elm tree pollen. Family history was negative for food or environmental allergies. After obtaining informed consent, allergy percutaneous skin testing was performed with prick-to-prick testing of fresh mamey sapote fruit pulp (whole fruit brought in by patient) and, given her history of latex allergy, an aliquot of natural rubber latex glove fragments soaked in sterile saline for 1 hour. The test reaction to
Disclosure: Authors have nothing to disclose.
mamey sapote fruit was positive (7- 8-mm wheal, 25- 25-mm flare), whereas the test reaction to latex was negative (0-mm wheal, 5- 5-mm flare). The histamine control reaction produced an 8- 8-mm wheal and a 20- 25-mm flare, and the negative saline control reaction produced a 0-mm wheal and a 1- 1-mm flare. A control patient had a negative skin test reaction to the fruit pulp. To confirm the results, a slurry of fresh mamey sapote fruit pulp was biotinylated using the EZ-Link Sulfo-NHS-LC-Biotin kit according to the manufacturer’s instructions (Pierce Biotechnology, Thermo Scientific, Rockford, Illinois) and bound to a streptavidin ImmunoCAP assay (Phadia US Inc, Portage, Michigan) as previously described.2 This resulted in a serum specific IgE measurement of 0.11 kUA/L. The solution was concentrated further by centrifuging using an Amicon Ultra centrifugal filter (EMD Millipore, Billerica, Massachusetts) to separate the solution into a filtrated fraction consisting of proteins with a molecular weight of 1 to 5 kDa and an enriched fraction consisting of proteins with a molecular weight greater than 5 kDa. The filtrated fraction resulted in a specific IgE measurement lower than 0.10 kUA/L, and the enriched fraction had a specific IgE measurement of 0.39 kUA/L. Serum IgE testing to latex using a commercially available ImmunoCAP assay yielded a negative reaction (<0.10 kUA/L). To characterize the allergenic protein further, an immunoblot was performed with the mamey sapote fruit extract and the patient’s serum. Briefly, mamey sapote pulp crude extract was analyzed by electrophoresis on a 4% to 20% sodium
Figure 1. Mamey sapote fruit (Pouteria sapota) cut with view of interior (photograph by Angelina Crans Yoon, MD).
Letters / Ann Allergy Asthma Immunol 114 (2015) 341e356
dodecylsulfate polyacrylamide electrophoretic gel, transferred onto a nitrocellulose membrane, and incubated with the patient’s serum and then with horseradish peroxidaseeconjugated goat antihuman IgE antibody (Sigma-Aldrich, St Louis, Missouri). Then, Luminata horseradish peroxidase substrate (EMD Millipore) was used to develop the film. A putative protein was detected at 81 kDa. To assess for potential cross-reactivity, sensitization to PR-10 (measured by Ara h 8), lipid transfer protein (measured by Ara h 9), and profilin (measured by Bet v 2) by a commercially available ImmunoCAP assay yielded a level lower than 0.10 kUA/L. Interestingly, the patient’s history of similar reactions after exposure to latex provided a possible connection between mamey sapote allergy and latex allergy. However, because of the negative IgE and skin prick testing reactions to latex at the time of the mamey sapote reaction and negative reaction to profilin specific IgE, the reactions were less likely to be cross-allergenic in this case. In the same family Sapotaceae, Manilkara zapota, commonly known as the sapodilla, has been reported to cause oral allergy syndrome. Molecular studies have shown that it has basic thaumatin-like proteins 1 and 2, which match significantly with allergenic thaumatin-like proteins from olive, kiwi, bell pepper, and banana.3,4 Owing to the large size of the protein identified in our study, it is unlikely to have similar cross-reactivity because the thaumatin-like proteins previously identified were approximately 25 kDa.
353
We report a systemic allergic reaction from mamey sapote fruit. As more tropical fruits are consumed in the United States, it is important to be aware that they can cause IgE-mediated adverse reactions. Angelina Crans Yoon, MD* C.K. Lin, PhDy Javed Sheikh, MD* *Department of Allergy/Clinical Immunology y Clinical Allergy/Immunology Laboratory Kaiser Permanente Los Angeles Medical Center Los Angeles, California [email protected]
References [1] Morton J. “Sapote.” Fruits of Warm Climates. Miami, FL: Julia F. Morton; 1987, pp 398e402. [2] Erwin EA, Custis NJ, Satinover SM, et al. Quantitative measurement of IgE antibodies to purified allergens using streptavidin linked to a high-capacity solid phase. J Allergy Clin Immunol. 2005;115:1029e1035. [3] Hegde VL, Ashok Kumar HG, Sreenath K, Hegde ML, Venkatesh YP. Identification and characterization of a basic thaumatin-like protein (TLP 2) as an allergen in sapodilla plum (Manilkara zapota). Mol Nutr Food Res. 2014;58:894e902. [4] Ashok Kumar HG, Venkatesh YP. In silico analyses of structural and allergenicity features of sapodilla (Manilkara zapota) acidic thaumatin-like protein in comparison with allergenic plant TLPs. Mol Immunol. 2014;57:119e128.
Expanding the spectrum: chronic urticaria and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy Chronic urticaria (CU) affects approximately 1% of the general population and occurs most frequently in adult women, usually presenting in the third to fifth decade of life.1 Current research suggests a link between CU and autoimmune disease supported in part by the detection of anti-FCεRI autoantibodies and positive autologous serum skin test reactions in many patients with CU.2e5 Despite the numerous autoimmune features of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), this rare primary immunodeficiency disorder has not been linked with CU. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy occurs as a result of a mutation in the AIRE gene that regulates central tolerance in the thymus through medullary thymic epithelial cells and thymic dendritic cells.6 Clinical manifestations identified to date include hypoparathyroidism, adrenal failure, diabetes mellitus, parietal cell atrophy, hypothyroidism, ovarian failure, testicular failure, candidiasis, alopecia, vitiligo, keratopathy, hepatitis, intestinal malabsorption, enamel hypoplasia, tympanic membrane calcification, and nail dystrophy. An acute urticarial-like rash also has been reported in 9% of patients in a Finnish cohort and appeared in association with recurrent fevers up to 4 to 5 times monthly.5,7 Given the suspected autoimmune etiology of up to 25% to 60% of patients with CU and the strong autoimmune character of APECED, a high incidence of CU in this population might be predicted.2e5 An extensive review of the literature yielded only 1 incompletely characterized case report of CU in an 18-month-old male patient with APECED in Northern Ireland.8 We present 2 cases Disclosure: Authors have nothing to disclose. Disclaimer: The views expressed are those of the authors and do not reflect the official policy of the Department of the Army, Department of the Navy, Department of Defense, or the US government.
of APECED that developed refractory CU in early adolescence and were successfully treated with omalizumab. In case 1, APECED was diagnosed when the patient was 3 years old after she presented with blepharospasm, keratoconjunctivitis, and severe hypocalcemia in the setting of intermittent chronic diarrhea. Subsequent genetic testing showed a 13-bp deletion in exon 8 of AIRE, the most common mutation among those of white British ancestry.9 Other clinical features included alopecia, vitiligo, tooth enamel hypoplasia, hypothyroidism, and premature ovarian failure. At 12 years of age, she developed CU unassociated with fever and refractory to 180 mg of fexofenadine and 10 mg cetirizine twice daily, 150 mg ranitidine twice daily, 10 mg of montelukast daily, and up to 100 mg of doxepin nightly. Serology demonstrated the presence of anti-FCεRI autoantibodies and positive histamine release assay results (Table 1). Notably, there were no flares or significant changes in the autoimmune processes previously noted and no associated fevers. Treatment with 150 mg of omalizumab administered subcutaneously every 4 weeks and later extended to every 12 weeks resulted in resolution of her symptoms. Omalizumab was discontinued; however, this resulted in a relapse that required continued treatment with omalizumab every 6 weeks to maintain control of the patient’s symptoms. In case 2, APECED was diagnosed at 9 years of age after the patient presented acutely with severe tetany and hypocalcemia in the setting of recurrent candidiasis and chronic intermittent diarrhea. Genetic testing showed that the patient was compound heterozygous with AIRE mutations R257X and c.967_979del13. Additional clinical manifestations included adrenal insufficiency, gonadal failure, vitiligo, tooth enamel hypoplasia, and dystrophic nails. At 13 years of age, she developed CU without fever that was refractory to 180 mg fexofenadine and 10 mg cetirizine twice daily, 150 mg of ranitidine twice daily, and 10 mg of montelukast daily.