Successful treatment of Netherton‘s syndrome with topical calcipotriol

ARTICLE

Auteur(s) : Aleksandar GODIC, Vlasta DRAGOS

Dept. of Dermatovenereology, University Clinical Centre, 2 Zaloška Street, 1525 Ljubljana, Slovenia

Article accepted on 17/11/2003

Netherton syndrome (NS) is an autosomal recessive hereditary ichthyosiform disease caused by mutations in the SPINK 5 gene, encoding the serine protease inhibitor LEKTI (lymphoepithelial Kazal-type-related inhibitor). The classical triad of clinical features includes ichthyosis, trichorrhexis invaginata, and an atopic diathesis. A generalized erythroderma is present at birth or soon afterwards. In the second year of life, skin manifestations consist of ichthyosis linearis circumflexa (ILC), or less frequently, congenital ichthyosiform erythroderma (CIE) [1]. Other manifestations of NS may include impaired cellular immunity, aminoaciduria, recurrent infections, delayed growth and development, as well as mental retardation [2]. 
Calcipotriol, a synthetic vitamin D analogue, has antiproliferative effects and promotes differentiation in some disorders of keratinization and ichthyoses [3, 4]. It also has immunomodulatory effects [5]. We reasoned that calcipotriol might be effective as a topical treatment for NS because keratinocyte proliferation is promoted and differentiation is inhibited in NS [6].

Case report

The patient was born at term following a normal pregnancy and delivery. Neither parent nor close relatives had any atopic or skin diseases. Generalized exfoliative erythroderma was noted at his birth. When he was 1 year old, hypernatremic dehydration developed as did bilateral otitis media and externa, conjunctivitis, tonsillopharyngitis, and acute enterocolitis. The boy underwent surgery with a view to repairing an incarcerated inguinal hernia when he was 4 years old. Skin biopsy was performed, revealing hyperkeratosis with areas of parakeratosis, hypergranulosis, moderate acanthosis, minimal focal spongiosis, and inflammatory infiltrate, suggestive of erythrodermic psoriasis. There were slightly elevated levels of specific IgE against egg white and cow’s milk. The skin of the patient did not improve significantly, despite treatment with several topical corticosteroids and emollients.
We examined the child for the first time at the age of 5 years. Numerous widely distributed annular lesions with double-edged scaling, suggestive of ichthyosis linearis circumflexa (ILC) were noted. Lichenification of the flexural areas was also present. Total IgE levels were elevated, as were specific IgE against house mites, grass pollen, and tree pollen.
When he was 9 years old, scalp hairs were noted to have pili torti and trichorrhexis invaginata, and the diagnosis of NS was made (Fig. 1). Treatment was initiated with topical 0.05% calcipotriol ointment bid. It was applied every fourth day on the same area, which measured in size from 18% to 27% of the total body surface area (TBSA). When the TBSA is taken into account, the amount of calcipotriol ointment used equates to less than 20 g/week/m². To avoid hypercalcemia and hypercalciuria, serum ionized calcium, serum phosphate, PTH, liver function tests, serum creatinine, and 24-hr urinary calcium levels were monitored at the baseline, week one and week three, and were within normal limits all the time during the treatment period. After 2 weeks, there was significant improvement of erythema and scaling, with nearly total remission occurring after 3 weeks, when the treatment was suspended (Fig. 2). Remission lasted 3 to 4 weeks, when a few lesions typical of ILC appeared on his trunk and limbs. The patient again responded well to topical treatment with calcipotriol. Similar intermittent remissions of the skin condition were observed during the treatment period of 9 months. No adverse effects were noted during the treatment period.

Discussion

The surprisingly good response of our patient to topical treatment with calcipotriol might just reflect a fluctuation in severity of ILC without therapy, nevertheless the apparent repeated response of background erythema/inflammation is convincing. On the other hand, Lucker et al. reported improvement of skin roughness in an 18-year-old NS girl without description of her skin manifestations, who was treated with calcipotriol ointment (50 µg/g) twice daily for 12 weeks, but the degree of erythema appeared to worsen [3]. The different clinical response to calcipotriol could be explained by differences in the epidermal cell proliferation rate, since NS shows a higher degree of hyperproliferation, or by different skin manifestations, since NS patients may suffer from ILC or CIE. Dysfunction of an epidermal serine protease inhibitor in NS [7] might trigger cytolysis or premature cornification, and activation of the stratum corneum tryptic enzymes would lead at the same time to premature degradation of corneodesmosomes, as well as premature desquamation and thinning of the stratum corneum [8].
The therapy of patients with Netherton syndrome includes emollients, topical corticosteroids, keratolytic agents, tars, PUVA, topical and oral retinoids, cyclosporine, and topical tacrolimus, all with various effects and mechanisms of action [1, 8-13]. Retinoids are widely prescribed, but their use is limited. Topically applied, they can cause skin irritation; given systemically, they are not always effective [9, 10] and may even aggravate the disease [14]. NS patients have a reduced barrier function with increased rate of transepidermal water loss. Increased skin permeability may result in intoxication by cutaneous absorption, as reported in 3 NS children treated with 0.1% tacrolimus ointment who percutaneously absorbed a significant amount of the drug, but without adverse effects. It seems reasonable to assume that patients with a barrier function defect may be at increased risk of developing significantly elevated systemic drug levels, as was previously reported for two patients with lamellar ichthyosis (LI) who developed significant drug absorption after topical treatment with salicylate and 0.1% tacrolimus ointment [15, 16].
Topical calcipotrol ointment was well-tolerated and effective in the treatment of our NS patient without an increase of calcipotriol in blood level and symptoms/signs suggestive of nephrocalcinosis and/or hypercalcemia. However, calcipotriol should be tested on a larger group of patients with NS in a bilaterally paired, double-blinded, comparative study with a close monitoring of side effects associated with systemic absorption of the drug, to evaluate its overall and long-term efficacy and safety. n

References

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