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

290
Blackwell Oxford, IJD International 1365-4632 Blackwell 45 UK Publishing Journal Ltd Ltd, of Dermatology 2006
Case report
Calcineurin Saif CASE and REPORT Al-Khenaizan inhibitors in Netherton syndrome
Netherton syndrome: Successful use of topical tacrolimus and
pimecrolimus in four siblings
Ghada Bin Saif,
From the Division of Dermatology,
Department of Medicine, King Fahad National
Guard Hospital, King Abdulaziz Medical
City-Riyadh, Saudi Arabia
Correspondence
Sultan Al-Khenaizan, MBBS,
FRCPC,
DABD
Division of Dermatology, Department of
Medicine
King Fahad National Guard Hospital
PO Box 22490
Riyadh 11426
Kingdom of Saudi Arabia
E-mail: khenaizans@ngha.med.sa
Introduction
MBBS,
and Sultan Al-Khenaizan, MBBS, FRCPC, DABD
Netherton’s syndrome (NS) is a rare autosomal recessive disease
comprised of ichthyosis in the form of ichthyosis linearis
circumflexa (ILC), hair shaft defects including trichorrhexis
invaginata, trichorrhexis nodosa and pili torti and atopic
1,2
manifestations with an elevated IgE level. Tacrolimus and
3
pimecrolimus belong to the family of calcineurin inhibitors.
They bind cytoplasmic proteins and the resulting complex
binds calcineurin, inhibiting its ability to dephosphorylate the
nuclear factor of activated T cells (NF-AT), thus suppressing
3
gene transcription. There have been conflicting reports of the
usefulness of tacrolimus in NS patients, with systemic absorp-
4–6
tion being the main adverse outcome. We report four Saudi
siblings (two boys and two girls) with NS who were treated
with topical tacrolimus and pimecrolimus with good control
of their skin disease without any toxic effect.
Case Report
Patient A was a 12-year-old Saudi girl who presented with
generalized scaly skin eruption since birth. The eruption waxes
and wanes, but never completely clears. The patient used
mometasone furoate 0.1% (Elocom, Schering, Belgium)
ointments extensively for many years without medical supervision,
which temporarily helps the eruption. The parents were
first-degree cousins. The skin disease and other social reasons led
the child to quit school few years ago. Physical examination
revealed small-for-age growth parameters. Facial examination
Abstract
Netherton’s syndrome (NS) is a rare autosomal recessive disease comprised of ichthyosis in
the form of ichthyosis linearis circumflexa, hair shaft defects and atopic manifestations with an
elevated IgE level. Various therapeutic options have been used in NS with variable success.
Tacrolimus and pimecrolimus belong to the family of calcineurin inhibitors. They bind
cytoplasmic proteins and the resulting complex binds calcineurin, inhibiting its ability to
dephosphorylate the nuclear factor of activated T cells, thus suppressing gene transcription.
There have been conflicting reports of the usefulness of tacrolimus in NS patients, with systemic
absorption being the main adverse outcome. Here we report four Saudi siblings (two boys and
two girls) with NS who were treated with topical tacrolimus and pimecrolimus with good control
of their skin disease without any toxic effect. To our knowledge, this is the second report of the
use of topical pimecrolimus in NS in the English literature.
revealed small eyes, narrow palpebral fissure and frontal
bossing. Skin examination revealed generalized, polycyclic scaly
erythematous plaques with doubled-edged scaling (Fig. 1).
These were compatible with the clinical diagnosis of ichthyosis
linearis circumflexa (ILC). Scalp examination revealed diffuse
scaling with short brittle hair. There was loss of hair over the
outer third of both eyebrows. The patient’s teeth, nails, eyes and
mucous membrane were normal. Blood investigation revealed:
3
eosinophilia with absolute eosinophil count of 1.5 × 10 cell
3
3
3
per mm (normal < 0.7 × 10 cell per mm ), high IgE level of
5923.4 IU/mL (Normal < 400 IU/mL). Morning serum cortisol
level was low at 23 nmol/L (normal: 119–618 nmol/L). Adrenal
suppression was confirmed by a blunted response to a short
Synacthen stimulation test. This recovered spontaneously
after 1 year.
Patients B, C and D were a 6-year-old boy, 3-year-old girl and
40-day-old, respectively; siblings of patient A. They presented
with generalized scaly skin eruption since birth. Physical
examination revealed small-for-age growth parameters. Facial
examination revealed rosy telangiectatic cheeks, small eyes,
narrow palpebral fissures, large ears, pinched nose, frontal
bossing and prominent occiput. Skin examination of patients
B and C revealed generalized, polycyclic scaly erythematous
plaques with doubled-edged scaling at the margins. These were
compatible with the clinical diagnosis of ILC. Their scalp
examination showed diffuse scaling with short brittle hair.
They had loss of hair over the outer third of both eyebrows.
Patient D’s skin examination revealed generalized erythroderma
with extensive scalp scaling. The patient’s nails, eyes
International Journal of Dermatology 2007, 46,
290–294 © 2006 The International Society of Dermatology

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.
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International Journal of Dermatology 2007, 46, 290–294 © 2006 The International Society of Dermatology