Netherton syndrome: Successful use of topical tacrolimus ... - Colleges

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Saif and Al-Khenaizan Figure 1 Left leg of patient A showing multiple polycyclic red plaques with double-edged scales constituting ichthyosis linearis circumflexa and mucous membranes were normal. None of these patients had temperature instability, hypernatraemic dehydration nor documented secondary skin infection. Blood investigation revealed: oesinophilia with absolute oesinophil counts were 3 3 3 2.7 × 10 and 1.9 × 10 cell per mm for patients B and C, respec- 3 3 tively (normal < 0.7 × 10 cell per mm ). IgE levels were 2202 and 1522.5 IU/mL for patients B and C, respectively (normal < 400 IU/mL). Histological examination of lesional skin biopsies from the trunk of patients A, B, and C revealed parakeratotic hyperkeratosis and spongiosis compatible with ILC. Trichorrhexis invaginata was observed in light microscopy of scalp hair obtained from all three patients (Fig. 2). Other hair findings were trichorrhexis nodosa and pili torti. Based on these findings, Netherton’s syndrome was diagnosed. Patient A was treated with topical tacrolimus ointment 0.03%, which was compounded in our hospital pharmacy by mixing the content of tacrolimus (Progaf, Fujisawa, UK) capsules into petroleum jelly, and was applied twice a day on red areas with marked improvement. As the tacrolimus blood level carried out 2 weeks later was undetectable, the tacrolimus concentration was increased to 0.1%, which induced even better improvement with marked reduction in erythema and scaling. The patient was switched to Protopic oinment 0.1% once it became available in our hospital. Similarly, patients B and C were treated with topical tacrolimus 0.03% (Protopic, Fujisawa) ointment twice a day for 2 years, with no adverse effects noted. Once it became available in our hospital, and after 2 years of tacrolimus use, all three patients were switched to pimecrolimus 1% (Elidel, Novartis, Switzerland) cream twice a day with a comparable control of their skin disease. Patient D was initially treated with alclometasone dipropionate 0.05% (Perderm, Schering, Belgium) ointment twice a day with reasonable control of the Calcineurin inhibitors in Netherton syndrome Case report Figure 2 Light microscopy of scalp hair from patient A showing trichorrhexis invaginata skin eruption. At 5 months of age the patient was started on pimecrolimus 1% (Elidel, Novartis) cream twice a day with good improvement. In all four patients, the two medications were used intermittently with application on the first appearance of redness and discontinuation upon clearance. All four patients demonstrated marked reduction to nearly complete clearance of erythema, scaling and pruritus. The disease still waxes and wanes, requiring short intermittent courses of fluticasone propionate ointment 0.005% (Cutivate, Glaxo KlineSmith, UK) for few days. Trichorrhexis invaginata and hair fragility did not improve. There was no patient or parental report of burning sensation or any other local or systemic adverse effects and no cutaneous infections were observed. We noticed no significant difference in the level of control of the skin eruption between topical tacrolimus and pimecrolimus. We could not compare the response to calcineurin inhibitors and the response to Elocom because the latter was used before presentation and was stopped by the authors immediately. The parents, however, stated that the response to tacrolimus and pimcrolimus was comparable to steroids. Tacrolimus blood levels were checked initially periodically every 3–4 months and were mostly undetectable. Occasionally, it was just detectable, ranging from 1.6 ng/mL to 2.7 ng/mL, and significantly below the therapeutic range for transplants patients (5–10 ng/mL). Pimecrolimus blood level was not performed because it is not available in our hospital. Discussion Netherton’s syndrome was originally described by Netherton 1 in 1958. It is a rare disorder comprising ichthyosiform dermatitis usually in the form of ILC, trichorrhexis invaginata 1 and atopic diathesis. The degree of skin involvement is vari- 2 able. Newborns with NS may have generalized erythroderma © 2006 The International Society of Dermatology International Journal of Dermatology 2007, 46, 290–294 291
292 Case report Calcineurin inhibitors in Netherton syndrome 2 or a collodion baby phenotype with failure to thrive. Beyond infancy, skin changes evolve into ILC, which are polycyclic 2 migratory plaques with characteristic double-edged scales. The finding of trichorrhexis invaginata is pathognomic for 7 NS. Other hair shaft findings in NS include pili torti and 8 trichorrhexis nodosa. Atopy may manifest as atopic dermatitis 2 or asthma with marked elevation of IgE. Other inconsistent features include aminoaciduria, mild developmental delay, 2 and impaired cellular immunity. Netherton’s syndrome may also be complicated by temperature instability, hypernatremic 8 dehydration and frequent skin infection. There have been many reports of NS in siblings of different 9–21 sexes, mostly from consanguineous marriages, suggesting 9,10 autosomal recessive inheritance. The gene defect has been recently mapped to chromosome 5q 32, and identified as a mutation in the SPINK5 gene, encoding a serine protease inhibitor known as lymphoepithelial kasal type related 22–27 inhibitor (LEKTI). This leads to LEKTI deficiency in the 28 epidermis and in hair roots at the protein level. Surprisingly, Rhagunath et al. found aberrant expression of other proteins, especially transglutaminases 1 and 3, which may also account 28 for the impaired epidermal barrier in NS. On reviewing photographs of NS patients previously reported in the literature, we noticed that most patients with NS have distinct dysmorphic faces. The salient features are small eyes, frontal bossing, narrow palpebral fissures and a pinched nose. We believe that this dysmorphic face is not emphasized in the literature. Various therapeutic options have been used in NS with variable success. Topical steroids are moderately effective, but the risk of systemic absorption, producing Cushing syndrome, 29,30 limits their use. Systemic and topical retinoids use is limited 9,16,31,32 by the risk of skin lesion aggravation. Other options have included topical calcipotriol, PUVA, cyclosporine and 14,33–37 ammonium lactate 12% lotion (Lac-Hydrin). Pimecrolimus and tacrolimus belong to the family of 3 calcineurin inhibitors. These macrolactam immunomodulators exert their effect by binding to cytoplasmic proteins and the resulting complex binds calcineurin, inhibiting its ability to 3 dephosphorylate NF-AT. NF-AT is a nuclear transcription factor that facilitates the transcription of several growth factor and inflammatory genes; however, it must be dephosphoryl- 38,39 ated to translocate into the nucleus. These medications inhibit T-cell proliferation and the production and release of several growth factors and pro-inflammatory cytokines, including interleukin-2 (IL-2), IL-4, interferonγ(IFNγ) and 3,39 tumor necrosis factorγ(TNFγ). Moreover, they prevent mast cell release of pro-inflammatory mediators including 39–41 histamine, cytokines, tryptase and eicosanoids. Pimecrolimus shows a selective action on T cells and mast cells as 3,39 opposed to the more pleiotropic targets of tacrolimus. In contrast to tacrolimus, pimecrolimus does not affect the differentiation, maturation and functions of dendritic cells and Saif and Al-Khenaizan 42–44 does not induce apoptosis of epidermal Langerhans’ cells. In contrast to corticosteroids, they do not affect endothelial cells and fibroblasts and therefore do not induce telangiectasia 45 and skin atrophy. The propensity of pimecrolimus to pass through the skin is approximately 90-fold lower than corti- 46 costeroids and approximately ninefold lower than tacrolimus. The differences related to skin permeation may be explained by the distinct lipophilicity/hydrophilicity distribution within 3 the molecules. The intrinsic capability of pimecrolimus and tacrolimus to cross the stratum corneum is similar, whereas 3 further penetration is impaired in the case of pimecrolimus. Tacrolimus and pimecrolimus have been approved by many 3,39 agencies for atopic dermatitis. There have been several reports of the efficacy of tacrolimus and pimecrolimus in a variety of other inflammatory dermatoses including psoriasis, 4–6,29,47,48 lamellar ichthyosis and NS. Because patients with NS may be particularly vulnerable to increased percutaneous absorption owing to a defective epidermal barrier, it is recom- 5,6,49 mended to monitor the blood drug level closely. Although systemic absorption of topical tacrolimus in NS has been reported, some patients may tolerate it without this occurrence, 6 as observed by ourselves and other authors. When switched to topical pimecrolimus, all four of our patients maintained a comparable control of their skin disease. The lesser epidermal permeation of pimecrolimus in comparison with tacrolimus may offer an added advantage in patients with NS. This, however, has to be confirmed by blood drug level studies in patients with NS. Recently, Oji et al. reported a 10-year-old boy with NS who was initially treated successfully with topical tacrolimus 0.03% ointment, which was discontinued 50 because of an increase in the blood drug level to 2.5 ng/mL. Later, this patient was switched to topical pimecrolimus 1% 50 cream with 75% reduction in the skin eruption. Interestingly, no systemic adverse effects were observed and the blood 50 pimecrolimus level remained low at < 2.4 ng/mL. The experience reported here on the use of topical tacrolimus and pimecrolimus in NS along with previous reports suggest that this mode of treatment is effective, and mostly well-tolerated. However, caution is needed when using tacrolimus and close monitoring through repeated blood drug levels is warranted to assure that no significant absorption has occurred. References 1 Netherton EW. A unique case of trichorrhexis nodosa; bamboo hairs. Arch Dermatol 1958; 78: 483–487. 2 DiGiovanna JJ. Ichthyosiform dermatoses: So many discoveries, so little progress. J Am Acad Dermatol 2004; 51: S31–S34. 3 Gisondi P, Ellis CN, Girolomoni G. Pimecrolimus in dermatology: atopic dermatitis and beyond. Int J Clin Pract 2005; 59: 969–974. 4 Allen DM, Esterly NB. Significant systemic absorption of International Journal of Dermatology 2007, 46, 290–294 © 2006 The International Society of Dermatology
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