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Significant Absorption of Topical Tacrolimus in 3 Patients with Netherton Syndrome

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Significant Absorption of Topical Tacrolimus in 3 Patients with Netherton Syndrome OBSERVATION Significant Absorption of Topical Tacrolimus in 3 Patients With Netherton Syndrome Angel Allen, MD; Elaine Siegfried, MD; Robert Silverman, MD; Mary L. Williams, MD; Peter M. Elias, MD; Sarolta K. Szabo, MD; Neil J. Korman, MD, PhD Background: Tacrolimus is a macrolide immunosup- limus in organ transplant recipients. None of these pressant approved in oral and intravenous formulations patients developed signs or symptoms of toxic effects of for primary immunosuppression in liver and kidney trans- tacrolimus. plantation. Topical 0.1% tacrolimus ointment has re- cently been shown to be effective in atopic dermatitis for Conclusions: Patients with Netherton syndrome have children as young as 2 years of age, with minimal sys- a skin barrier dysfunction that puts them at risk for in- temic absorption. We describe 3 patients treated with topi- creased percutaneous absorption. The Food and Drug Ad- cal 0.1% tacrolimus who developed significant systemic ministration recently approved 0.1% tacrolimus oint- absorption. ment for the treatment of atopic dermatitis. Children with Netherton syndrome may be misdiagnosed as having Observation: Three patients previously diagnosed as atopic dermatitis. These children are at risk for marked having Netherton syndrome were treated at different cen- systemic absorption and associated toxic effects. If topi- ters with 0.1% tacrolimus ointment twice daily. Two pa- cal tacrolimus is used in this setting, monitoring of se- tients showed dramatic improvement. All patients were rum tacrolimus levels is essential. found to have tacrolimus blood levels within or above the established therapeutic trough range for oral tacro- Arch Dermatol. 2001;137:747-750 ETHERTON syndrome is taneous absorption of the drug, with serum an autosomal recessive levels well above the therapeutic range. disorder characterized by congenital erythro- REPORT OF CASES derma, hair shaft de- Nfects, frequent infections, poor growth, and CASE 1 food allergies. The gene defect was re- cently localized to chromosome 5q32 and A 5-year-old boy had been born prema- identified as a mutation in the SPINK5 turely and had had congenital erythro- gene, encoding the serine protease inhibi- derma complicated by Staphylococcus au- tor LEKTI (lymphoepithelial Kazal-type reus sepsis. Continuing problems beyond related inhibitor).1 the neonatal period included erythro- From the Department of The pathognomonic cutaneous find- derma with scaling scalp, sparse hair, fre- Dermatology, Saint Louis ing in Netherton syndrome, ichthyosis lin- University Health Sciences quent otitis media, recurrent sinusitis, and Center, St Louis, Mo (Drs Allen earis circumflexa, develops in 75% of cases poor growth. Netherton syndrome was di- and Siegfried); Departments of but is not usually evident in infancy or agnosed at 9 months of age by demonstra- 2 Pediatrics and Dermatology, early childhood. A more common pre- tion of the pathognomonic hair shaft de- University of Virginia, McLean senting sign is generalized redness and fect, trichorrhexis invaginata. Initially, his (Dr Silverman); Department of scaling, which has been mistaken for atopic skin care regimen consisted of daily bath- Dermatology, University of dermatitis. The erythroderma is often ing with Cetaphil (Galderma Laborato- California–San Francisco widespread and resistant to therapy. A re- ries, LP, Paris, France) and frequent use (Drs Williams and Elias); cent report described a 20-year-old man of Aquaphor (Beiersdorf Inc, Wilton, Dermatology Service, Veterans with ichthyosis linearis circumflexa who Conn). He was unavailable for follow-up Affairs Medical Center, improved dramatically with topical tacro- care from ages 3 to 5 years. San Francisco (Dr Elias); 3 and Case Western Reserve limus treatment. We describe 3 children At age 5 years, his erythroderma was University/University Hospitals with Netherton syndrome and erythro- unresponsive to conservative topical thera- of Cleveland, Cleveland, Ohio derma treated with 0.1% tacrolimus oint- pies, including ketoconazole shampoo and (Drs Szabo and Korman). ment who experienced significant percu- 2.5% tar ointment, as well as more aggres- (REPRINTED) ARCH DERMATOL / VOL 137, JUNE 2001 WWW.ARCHDERMATOL.COM 747 ©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 sive short trials with limited applications of lactic and sali- tolerable stinging and exudative erythroderma, which sub- cylic acid lotion and 0.1% tazarotene ointment alone and sided after 1 week without the medication. Results of patch in combination with a class 1 topical corticosteroid. Ag- tests with the study drug and the extemporaneous com- gressive treatments were used on limited areas for a maxi- pound ointment were negative. Another trial of propri- mum of 1 week because of concern about percutaneous etary 0.1% tacrolimus ointment was applied to one arm absorption. We treated this patient in a double-blinded twice a day for 7 days, with the same adverse reaction. A fashion with extemporaneously formulated 0.1% tacro- tacrolimus level determined within 48 hours of the last limus in white petrolatum twice daily on one side of the application was 23 ng/mL. Complete blood cell count, scalp and face and white petrolatum on the other side. renal function, and hepatic function were normal. The He had a marked decrease in crusting, scale, and ery- patient did not tolerate retreatment with extemporane- thema on both sides, but the tacrolimus-treated side was ously compounded 0.03% tacrolimus ointment. A 24- noted at 3-week and 8-week follow-up visits to have near- hour postapplication drug level was 8.3 ng/mL. She elected complete clearing. A total of 15 g of tacrolimus oint- to discontinue treatment with tacrolimus ointment. ment was then applied sparingly to his trunk, shoul- ders, scalp, and face twice daily. On day 5, whole-blood CASE 3 tacrolimus level was 37.2 ng/mL 2 hours after treatment (therapeutic trough range in organ transplant recipi- A 3-year-old boy had been born with facial erythema and ents, 5-20 ng/mL). Care was taken to draw the blood from a scaly patch on his left wrist. During the first week of a site that had not been treated for 2 days before the phle- life, he had developed more widespread erythematous, botomy. One week later, a second 2-hour postdose drug polycyclic, and serpiginous plaques with migratory, hy- level was 19 ng/mL with the patient receiving the same perkeratotic, double-edged peripheral scaling. At birth, dose of medication. Despite these levels, his blood pres- he had had long dark hair, which fell out after a few weeks sure, serum electrolyte levels, glucose level, complete and was replaced by sparse, brittle hair. Infancy and child- blood cell count, serum urea nitrogen level, and serum hood had been complicated by frequent otitis media and creatinine level remained within normal limits. Subse- externa; allergies to spinach, peanuts, milk, and eggs; and quently, the drug was applied twice a week, only to the erythroderma. The patient was only minimally respon- most severely involved areas, the scalp and face. On this sive to numerous topical corticosteroid preparations and regimen, postapplication blood levels monitored at 2-day antihistamines. The diagnosis of Netherton syndrome had trough times were less than 1.5 ng/mL (lower limit of been confirmed at age 2 years, when trichorrhexis in- quantitation for the assay). vaginata was found on light microscopic examination of the patient’s hair. CASE 2 At age 3 years, the patient was deemed eligible for inclusion in a clinical trial of 0.1% tacrolimus ointment A 14-year-old girl presented with trichorrhexis invagi- twice daily for the treatment of atopic dermatitis (Fu- nata, short stature, patches of ichthyosis linearis circum- jisawa Healthcare, Inc, protocol 99-0-054). The proto- flexa, and widespread congenital erythroderma associ- col not did include monitoring of laboratory measures. ated with severe pruritus and elevated IgE level. Her An average of 3 g was spread over the body and scalp with dermatitis and pruritus had been treated long-term with each application. Baseline and follow-up blood pres- applications of 0.1% triamcinolone acetonide ointment sures remained within normal limits (measured with an since early infancy. During the preceding 5 years, her age-appropriate cuff, 80/50 mm Hg at baseline and 90/55 course had been complicated by recurrent staphylococ- mm Hg at his 6-month visit). The patient experienced cal and streptococcal skin infections, flares of her eryth- rapid improvement in his skin along with decreased pru- roderma, and poor growth, falling below the fifth per- ritus and slow regrowth of his hair. After 8 months of centile for age. At chronologic age 10 years 5 months, intermittent therapy (interrupted by two 2-week courses her bone age was 6 years 10 months, which was delayed of systemic corticosteroids), a blood level was obtained 2 SDs below the mean. Adrenocortical suppression was to monitor for systemic absorption. The level, 10.2 ng/ documented, with a low morning cortisol level of 13.8 mL, was determined 30 hours after the last application nmol/L (reference range, .118.6 nmol/L). She was sub- of medication from a site that had not been treated for sequently given a lower-potency topical corticosteroid 2 days before phlebotomy. Complete blood cell count, (fluocinolone oil [Derma-smoothe FS; Hill Dermaceuti- renal function, and hepatic function were normal. The cals, Inc, Sanford, Fla]) and growth hormone replace- patient’s parents elected to discontinue use. ment, resulting in a 6-cm growth spurt during 9 months. At age 12 years, she was treated with extemporane- COMMENT ously compounded 0.1% tacrolimus ointment applied to one leg twice a day for 1 month, resulting in marked im- Despite dramatic clinical improvement with topical ta- provement. For the next 6 months, she applied the com- crolimus in these 3 cases, the risk of systemic exposure pounded ointment to a larger area, with excellent re- from percutaneous absorption is a serious concern in sponse.
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