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REVIEW ARTICLE

Acitretin in pediatric dermatoses


Manjyot Gautam, Harsh Tahiliani, Nitin Nadkarni, Sharmila Patil, Kiran Godse
Department of Dermatology, Dr. D Y Patil Hospital, D Y Patil University, School of Medicine, Nerul, Navi Mumbai,
Maharashtra, India

ABSTRACT

Acitretin, a synthetic retinoid and the active metabolite of etretinate has been increasingly used over the past two decades.
It has proved effective in the treatment of many conditions associated with hyperkeratosis and dyskeratosis. A Google
scholar search for the use of acitretin in pediatric dermatoses was done using the words “pediatric dermatoses,” “acitretin,”
“etretinate,” “systemic retinoids,” “psoriasis,” “pityriasis rubra pilaris,” “ichthyoses,” “disorders of keratinization,” “Darier’s
disease,” “palmoplantar keratoderma,” “verrucae,” “lichen planus,” “lupus erythematosus,” and “lichen sclerosus.” All the
articles were retrieved and classified into review articles, studies, double-blinded trials, and case reports. The final data
were then analyzed and presented in a narrative fashion. It has been found that acitretin is useful in a number of pediatric
dermatoses. It is preferred over other drugs in pustular psoriasis. Good results can be obtained in various disorders of
keratinization, and it may even prove life-saving in conditions like harlequin ichthyosis. However, long-term maintenance
therapy is required and exacerbations are known on discontinuing the drug. It can also be used as alternative therapy for many
other pediatric dermatoses where the primary treatment has failed. Acitretin should be used even in children for the proper
indications. However, proper clinical and laboratory surveillance has to be maintained in patients on long-term acitretin.

Key words: Acitretin, disorders of keratinization, oral retinoids, pediatric dermatoses

INTRODUCTION with etretinate by Bollag in 1972.[2] Etretinate was


later phased out in 1998 because of its perceived

T he term retinoids include all compounds that have


a biological activity like Vitamin A.
teratogenic effects. Acitretin is the acid metabolite
of etretinate with a shorter half-life. It was Food and
Drug Administration approved for the treatment of
Synthetic retinoids are classified into three generations psoriasis in June 1997.
based on their structure.[1]
1. First generation: Tretinoin, isotretinoin, Pharmacology
alitretinoin Pharmacokinetics
2. Second generation: Acitretin, etretinate The absorption of acitretin is poor when taken on
3. Third generation: Bexarotene, tazarotene. an empty stomach and increases on the intake with

First generation retinoids are nonaromatic, second


ADDRESS FOR CORRESPONDENCE
generation is mono-aromatic, and third generation is Dr. Manjyot Gautam,
polyaromatic compounds. Department of Dermatology, School of Medicine, Dr. D.Y. Patil Hospital,
Nerul, Navi Mumbai - 400 706, Maharashtra, India.
E-mail: manjyotgautam@gmail.com
Acitretin is a second generation retinoid with a mono-
aromatic ring structure. It was first discovered along
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DOI: How to cite this article: Gautam M, Tahiliani H, Nadkarni N, Patil S,


10.4103/2319-7250.179415 Godse K. Acitretin in pediatric dermatoses. Indian J Paediatr Dermatol
2016;17:87-94.

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Gautam, et al.: Acitretin in pediatric dermatoses

fatty food. The bioavailability on the oral intake of MATERIALS AND METHODS
acitretin is 60%.[3] Acitretin is metabolized in the liver
by cytochrome P450, where isomerization of acitretin A Google scholar search for the use of acitretin in
to isoacitretin takes place. It is excreted through bile pediatric dermatoses was done using the words “pediatric
as well as kidneys. It reaches maximum plasma levels dermatoses,” “acitretin,” “etretinate,” “systemic
in 2 h. retinoids,” “psoriasis,” “pityriasis rubra pilaris (PRP),”
“ichthyoses,” “disorders of keratinization,” “Darier’s
Acitretin is less lipophilic than etretinate and hence, disease,” “palmoplantar keratoderma,” “verrucae,”
it has a short elimination half-life of 50 h. This “lichen planus,” “lupus erythematosus,” and “lichen
was the main reason why it replaced etretinate. sclerosus.” All the articles were retrieved and classified
However, in the presence of alcohol, there is a reverse into review articles, studies, double-blinded trials, and
esterification of acitretin to etretinate which has a case reports. The final data were then analyzed and
much longer half-life of 80–160 days. Complete presented in a narrative fashion.
avoidance of alcohol while on acitretin therapy is
recommended.[4]
RESULTS
Preparations Psoriasis
Acitretin is commercially available as 10 and 25 mg Acitretin is not the drug of choice for the majority of
capsules. For neonates and infants requiring <10 mg the children with psoriasis who have localized disease.
dose, it is advised that the capsule should be frozen These can be managed with topical preparations alone.
and cut in the required fraction and dispensed in a
liquid (honey, milk, or infant formula). Since acitretin Only 1% children with psoriasis[9] have severe variants,
is sensitive to light, the remaining fraction should be some of which respond well to acitretin. These are:
discarded. a. Extensive plaque psoriasis with psoriasis area
severity index more than 10
Mechanism of action
b. Generalized pustular psoriasis (GPP) also called as
Acitretin is transported to its target cells by albumin
von Zumbusch disease
in the serum. Certain proteins in the cell membrane
c. Erythrodermic psoriasis
called cytosolic retinoic acid binding protein transport
d. Severe disabling palmoplantar psoriasis
acitretin intracellularly.[5] Acitretin activates the
e. Palmoplantar pustulosis.
nuclear retinoic acid receptor (RAR) without binding
to it. Certain genes containing a retinoid acid response
Acitretin is more effective for the management of GPP,
element are upregulated by these activated RARs.
erythrodermic psoriasis, palmoplantar pustulosis, and
These result in an expression of various proteins
recalcitrant plaque type psoriasis but not effective in
associated with cellular differentiation, inflammation,
psoriatic arthropathy. Guttate psoriasis in children
and apoptosis.[6-8]
is usually self-limited. However, for recalcitrant and
Indications extensive guttate lesions, acitretin has often been used
Table 1. even in children as young as 6 months. Most of the
studies of acitretin in pediatric psoriasis are based on
case reports and recommend a dose of 0.5–1 mg/kg/day.
Table 1: Indications
The response usually starts in 3 weeks, and remission
Disorders of keratinization Ichthyoses, keratodermas, pityriasis
is achieved by 3 months. It can also be used in
rubra pilaris, Darier’s disease,
porokeratosis, pachyonychia congenita the maintenance phase and in combination with
Inflammatory Psoriasis, lichen planus, lichen nitidus, narrowband ultraviolet B (NBUVB).
(papulosquamous) disorders and keratosis lichenoides chronica • Salleras et al. have reported the use of acitretin
Inflammatory Lichen sclerosus et atrophicus, lupus 10 mg/day (0.5 mg/kg/day) in a 4-year-old
(connective tissue) disorders erythematosus
girl suffering from congenital erythrodermic
Prevention of cutaneous Xeroderma pigmentosum,
psoriasis.[10] Complete remission was achieved in
malignancies and treatment epidermodysplasia verruciformis
of precancerous conditions 3 months. The maintenance dose was tapered to
Miscellaneous indications Warts, pemphigus, granuloma 30 mg/week. The patient was followed up until the
annulare, hyperkeratotic hand eczema, age of 7 years, and no adverse effect of retinoid
and langerhans cell histiocytosis
therapy was observed in this patient

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Gautam, et al.: Acitretin in pediatric dermatoses

• Ergin et al. treated a 2.5-month-old girl child suffering However, patients with the more severe variants
from infantile pustular psoriasis with acitretin 0.7 mg/ of ichthyoses like nonbullous congenital
kg/day which led to remission of the skin lesions in ichthyosiform erythroderma (NBIE), bullous
4 months. She was maintained on a dose of 0.3 mg/ congenital ichthyosiform erythroderma (BIE), and
kg/day for another 3 months. A short course of lamellar ichthyosis (LI) generally require systemic
steroids was given during the initial phase[11] therapy with synthetic retinoids,[16] where they may
• In a retrospective study of GPP in childhood, be even lifesaving.[17]
de Oliveira et al. analyzed the patient records of
7 children with GPP, who had received acitretin Retinoids do not correct the keratinization defect
at 1 time of the follow-up period with variable though they reduce the hyperkeratosis. The lesions
response. The average follow-up period was do relapse on discontinuing acitretin, and indefinite
4.6 years. It was effective in 5 patients[12] therapy is hence required.
• Chao et al. had used acitretin in a 6-week-old
infant with GPP at a dose of 1 mg/kg/day that Lamellar Ichthyosis
caused resolution of lesions in 6 weeks after There is adequate data to demonstrate the efficacy of
which acitretin was tapered to 0.4 mg/kg/day as etretinate in LI. Later acitretin replaced etretinate in
maintenance therapy for another 6 months.[13] the treatment of LI with similar efficacy.[16-19] It is used
in the dose of 0.5–1 mg/kg/day. The effect is generally
Combination Therapies seen after about 4 weeks of treatment in the form
• Kopp et al. reported a 3.5-year-old boy with GPP, who of a reduction in scales, improvement of ectropion/
was treated with methylprednisolone and acitretin eclabium, and improvement of palmoplantar
who got repeated flares on tapering the steroids. hyperkeratosis.
The patient was started on NBUVB therapy thrice
per week which allowed tapering of steroids after 10 Acitretin needs to be continued indefinitely to keep
irradiations. NBUVB was then reduced to twice per the disease under control. Fortunately, it is well-
week and acitretin dose reduced to 0.3 mg/kg/day[14] tolerated by most children.
• Acitretin has been used for the treatment of
severe or recalcitrant childhood psoriasis in Nonbullous Ichthyosiform Erythroderma
combination with NBUVB,[14] cyclosporine A,[15] The majority of patients with NBIE require indefinite
methotrexate,[12] and oral corticosteroids. treatment with acitretin.[16,18,19] The dose recommended
does not differ from that used in LI.
Although acitretin has been used a combination with
psoralen ultraviolet A (PUVA) therapy, infliximab and Bullous Ichthyosiform Erythroderma
etanercept in adults, such studies are lacking in children. The treatment of this condition with acitretin is rather
PUVA therapy is best avoided in children below challenging but a good clinical response should be
12 years of age, and a combination of methotrexate expected.[16,18] Since acitretin increases the fragility
and acitretin has a potentially cumulative hepatotoxic of the skin, increased dosage can actually worsen the
effect and should ideally be avoided. blisters of BIE. Hence, the dose has to be properly
titrated starting with a low dose and maintaining at
Disorders of Keratinization the lowest effective dose[19] with frequent monitoring.
Ichthyoses
Currently, we do not have a curative treatment for Harlequin Ichthyosis
ichthyoses. However, the advent of systemic retinoids The use of acitretin in harlequin ichthyosis is
brought a revolution in the treatment of congenital lifesaving.[19] The hyperkeratosis and fissuring
ichthyoses, especially the more severe ones. reduce within days. Ectropion and eclabium resolve
completely.[20,21] Side effects encountered are very
The most important step in the management of minor.
ichthyoses is to remove the scales and take care of the
xerosis without irritating the skin. In the majority of the Ichthyosiform Syndromes
patients, this can be achieved by judicious use of topical Acitretin is found to be effective in Sjogren–Larsson
emollients and moisturizers with or without keratolytic syndrome but ineffective in Netherton’s syndrome.[22]
agents. Most of the patients with ichthyosis vulgaris and Actually, it is contraindicated in the later because
X-linked recessive ichthyoses can be treated with topical it can cause skin irritation and precipitate a flare of
therapies alone and the need for acitretin does not arise. atopic eczema.

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Gautam, et al.: Acitretin in pediatric dermatoses

Palmoplantar Keratodermas different disorders. PPK - Papillon–Lefevre syndrome


Palmoplantar keratodermas (PPK) can be a severely and congenital ichthyosiform erythroderma
disabling condition adversely affecting the quality of life. responded remarkably well. No change was observed
It is in such types of PPK that acitretin is indicated. The in PPK – Unna-Thost type.[23] They also recommend
dose and tolerance of acitretin vary in different types of a careful tailoring of the dose for individual patients
PPK. Though it is not effective in the Unna-Thost type • Steijlen et al. have studied the effect of acitretin
of PPK,[23] it has been found to be useful in Papillon– in 7 patients with LI since birth. All patients were
Lefevre syndrome,[23] Vohwinkel’s disease, Conradi– treated with 35 mg acitretin daily initially for
Hunermann syndrome,[16] and KID syndrome.[19] Most 1 month. Two patients required dosage increment
cases of erythrokeratoderma variabilis can be treated and the other 5 had remission, and the maintenance
symptomatically with topical preparations. Only dose was reduced to 10–25 mg/day.[29]
severe disease requires treatment with systemic
retinoids which reduces scaling, but the erythema may Darier’s Disease
persist.[16,24,25] While there should be an initial loading Only severe cases of Darier’s disease require treatment
dose of 0.5–1 mg/kg/day, satisfactory improvement can with systemic retinoids. A good clinical response is
be maintained with a lower dose of 0.2 mg/kg/day. obtained with lower doses of acitretin as compared
to other diseases.[16,30] The patient should be started
Pityriasis Rubra Pilaris on a low dose (0.2 mg/kg/day) and the dose should
The use of acitretin should be restricted for generalized, be increased in 4 weeks if the clinical response is not
recalcitrant variants of juvenile PRP. Acitretin in a dose satisfactory. The diseases exacerbate within 3–4 weeks
of 05–1 mg/kg/day causes marked improvement in most of stopping acitretin. Hence, long-term maintenance
cases of PRP. Relapses do not occur for long periods of therapy is needed.
time after stopping therapy. Retinoids are now considered
as first-line therapy for severe variants of PRP.[26-28] Prevention of Malignancies
• Lacour et al. have retrospectively analyzed the Vitamin A and retinoids have a protective role in the
use of acitretin and etretinate in 29 children with development of skin cancers. Acitretin (1 mg/kg/day)
disorders of keratinization. Marked to moderate has been used in genodermatoses with a high risk of
improvement was noted in most patients. No malignancies. Xeroderma pigmentosum patients have
significant change in the clinical response, as well a very high risk of developing skin cancers. Treatment
as adverse effects, was noted in 22 patients who with acitretin in such patients significantly reduces
were switched from etretinate to acitretin[16] the risk of developing malignancies.[31,32] Acitretin also
• Zhang et al. investigated the efficacy of acitretin plays a very important role in chemoprophylaxis of skin
in children with severe disorders of keratinization cancers in nevoid basal cell carcinoma syndrome.[33]
and observed a clinical cure rate of 82.1% and the
effective rate was 17.9%. Two recalcitrant cases Good therapeutic response in patients with
of Darier’s disease also responded to acitretin in epidermodysplasia verruciformis has also been
6 months[18] achieved with retinoids in a dose-dependent manner
• Saracoglu et al. have reported one infant with LI and in combination with interferon alpha-2a. Acitretin
another with nonbullous congenital ichthyosiform monotherapy was ineffective. However, the lesions are
erythroderma. Both infants presented with a known to recur on stopping treatment.[34]
collodion baby appearance and were initiated on
acitretin 1 mg/kg/day. There was a satisfactory Other Indications
improvement in both cases[17] Acitretin has been used off-label for various
• Chao et al. retrospectively studied 28 cases of indications. However, only isolated case reports exist,
juvenile PRP. Five of these patients received and no controlled trials have been done.
acitretin and a moderate to excellent response
was obtained in them. They also noticed that Warts
acitretin at low doses was not effective in PRP and Solitary case reports have claimed good resolution
Griffith’s type IV responded better as compared with acitretin in patients with multiple recalcitrant
with Griffith’s type III[26] warts at doses as low as 0.5 mg/kg/day.
• Blanchet-Bardon et al. studied the effect of • Krupashankar et al. have reported the use of
acitretin in 12 children with disorders of acitretin in a patient who had multiple warts since
keratinization. The acitretin dose range was from adolescence. Resolution of warts was observed
0.42 to 1.16 mg/kg/day. The response differed in after 3 months of therapy with 0.5 mg/kg/day[35]

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• Proietti et al. have reported the use of acitretin Table 2: Adverse effects
in a patient with numerous warts. Resolution of System Side effects
lesions was obtained after 8 weeks of therapy, and Minor Major
it was discontinued in another 4 weeks.[36] Teratogenicity Retinoic acid embryopathy
Cutaneous Xerosis, retinoid
Lichen Planus dermatitis, pyogenic
granulomas,
Although acitretin is the drug of choice for the
photosensitivity,
treatment of acute generalized lichen planus as well telogen effluvium,
as unresponsive oral lichen planus in adults, there are proneness to
no data supporting its use in the pediatric population. infections, abnormal
hair texture, nail
softening, and
Brockow et al. successfully treated a 9-year-old boy paronychia
with acute extensive eruptive lichen planus with oral Mucosal Dry eyes,
acitretin (0.5 mg/kg/day). The extent and severity photophobia,
of lichen planus reduced markedly after 4 weeks of reduced night vision,
cheilitis, dry mouth,
therapy and remission was obtained after 8 weeks. epistaxis, and nasal
The therapy was discontinued after 12 weeks.[37] mucosa dryness
Hepatic Elevation of liver Toxic hepatitis
Lupus Erythematosus enzymes
Although acitretin (1 mg/kg/day) has been reported Lipids Hypertriglyceridemia,
hypercholesterolemia
to be effective in cutaneous lupus erythematosus Gastrointestinal Nausea, diarrhea, Flare up of inflammatory
including the hypertrophic variant in adults,[38,39] such and abdominal pain bowel disease, pancreatitis
studies are lacking in the pediatric age group. Musculoskeletal Fatigue, tendinitis, Myopathies, myopathies,
arthralgia, and premature epiphyseal closure,
myalgia osteophyte formation, diffuse
Lichen Sclerosus
skeletal hyperostosis
Bousema et al. in their randomized controlled trial Neurologic Headache Depression, psuedotumor
observed that severe vulvar lichen sclerosus et cerebri
atrophicus responded well to acitretin; however, there Hematologic Leukopenia, agranulocytosis
Others Hypoglycemia,
was a huge dropout rate in that study.[40]
hypothyroidism

Miscellaneous
There exist anecdotal case reports about the use Teratogenicity
of acitretin in extensive and palmoplantar lichen Acitretin causes retinoid embryopathy[44] if taken during
nitidus,[41] porokeratosis,[42] granuloma annulare, pregnancy and, therefore, it has to be used with caution
keratosis lichenoides chronic, hyperkeratotic hand in teenage girls who have achieved menarche. Retinoid
eczema, and pemphigus.[43] embryopathy leads to craniofacial dysmorphias,
appendageal abnormalities, hip malformations,
Contraindications meningoencephalocele, and multiple synostoses.[45]
The absolute contraindication to oral retinoids viz., There have been a few case reports of embryopathy
pregnancy is unlikely to be applicable in children. with acitretin since it has been commercially marketed,
However, this contraindication should be kept in but etretinate has been associated multiple times with
mind while prescribing acitretin to adolescent females. severe embryopathy.[46] Therefore, strict contraception
should be advised 1 month prior to starting therapy and
The relative contraindications include patients with should be followed for 3 years after stopping treatment.
hepatic, renal, or lipid derangements.[43] Oral retinoids Abstinence from alcohol is also important in women
are also relatively contraindicated in neonates and of childbearing age on acitretin therapy. It is advisable
children; however, they should be considered when the to use two simultaneous methods of contraception.
benefits outweigh the risks, and regular monitoring of Acitretin reduces the efficacy of progesterone only
treatment should be done. mini pill; hence, this method of contraception is best
avoided. There are no reproductive risks due to semen
Side Effects of men taking acitretin according to the available data.
Minor side effects are common in most patients
receiving long-term acitretin therapy. All adverse Mucocutaneous
effects except teratogenicity are dose dependent and Mucocutaneous side effects are the most frequently
disappear on stopping therapy [Table 2]. encountered side effects. These include dryness of

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Gautam, et al.: Acitretin in pediatric dermatoses

lips, cheilitis, and dryness with inflammation of like features have also been reported with use of
mucous membranes and transitional epithelia.[47,48] retinoids; such involvement is, however, independent
Epistaxis, rhinitis, photophobia, xerophthalmia, of dose and duration of therapy. Recent studies on the
conjunctivitis, and taste disturbances have also effect of acitretin in adults have failed to demonstrate
been reported occasionally. Thinning, redness, and any skeletal side effects, but the drug should be used
scaling of the skin particularly over the palms and with caution in children. Very few case reports of
soles can also occur. Retinoid dermatitis is associated other rheumatological manifestations like arthralgias,
with high dose acitretin therapy. Acitretin therapy myalgias, arthritis, osteopenia, and vasculitis have
can also cause increased hair loss, nail fragility, and been reported.
paronychia. Long-term retinoid therapy may cause
periungual pyogenic granuloma. Photosensitivity Other Side Effects
may also occur rarely, but it is advisable to counsel Pseudotumor cerebri when retinoids are used
children about photoprotection since they are likely concomitantly with tetracyclines and minocyclince.[55]
to indulge in outdoor activities. A higher incidence of There are occasional reports of blurring of vision with
mucocutaneous side effects is seen at higher doses.[49] reduced night vision. Oral retinoids also increase the
insulin sensitivity which may lead to hypoglycemia and
Hepatotoxicity should be used with caution in diabetic children.[47]
The most common hepatic side effect of acitretin Capillary glucose levels should be monitored more
therapy is the transient elevation of liver enzymes frequently than usual in such patients.
which returns to normal on discontinuing the drug.[50]
This is less common in children since cofactors like Overdose Side Effects
alcoholism, diabetes, and obesity are less likely to exist These side effects are similar to Vitamin A toxicity
in them. Patients on simultaneous treatment with other and include headache, nausea, vomiting, drowsiness,
hepatotoxic drugs have a higher risk of developing vertigo, and visual disturbances.[47]. Acitretin should
hepatic side effects while on acitretin therapy. There be immediately stopped when patients experience any
are a few case reports[51] of severe hepatic reactions like of these symptoms.
cholestatic hepatitis and cirrhosis, but their incidence
is very low (0.26%). Drug Interactions
Refer Table 3.
Hyperlipidemia
Acitretin also interferes with the lipid metabolism Monitoring guidelines
and alters the serum lipid profile. Hyperlipidemia is After a careful history and physical examination, a
dose-dependent and returns to normal within 8 weeks baseline complete blood count, liver enzymes, fasting
of stopping therapy. Increased triglyceride is the most cholesterol with triglycerides, and blood sugars in
commonly encountered lipid profile disorder.[48] A case diabetics should be done. These investigations should
of pancreatitis developing due to increased triglycerides be repeated every month for the first 2 months and
has also been reported.[51] Hypercholesterolemia due every 3 monthly thereafter.[43] Weekly tests should
to increased very low-density lipoproteins and low- be performed if the liver function tests are abnormal,
density lipoproteins is also encountered frequently. and treatment with acitretin should be terminated if
High-density lipoproteins can also be decreased in transaminases are 3 times the normal value. Values
patients on acitretin therapy.[50] Therefore, dietary lower than 3 times should be managed with the help
restrictions like avoidance of alcohol and a high fish
oil diet play an important role in patients on acitretin Table 3: Drug interactions
therapy. Drugs that can cause toxicity or Vitamin A, tetracycline,
increase serum levels of acitretin doxycycline, minocycline,
Skeletal Abnormalities when prescribed concomitantly macrolides, and azoles
There are occasional reports of bone changes in Drugs that can reduce the serum Rifampin, rifabutin,
levels of acitretin and thereby its phenytoin, carbamazepine,
children in the form of premature epiphyseal
efficacy (CYP3A4 inducers) and phenobarbital
closure, skeletal hyperostosis, and extraosseous
Acitretin can increase the serum Cyclosporine
calcification.[52-54] Periosteal thickening and decreased levels and potential toxicity of
cortical bone thickness have been associated with long- Acitretin can reduce the serum Progestin‑only contraceptives
term etretinate therapy. Long-term retinoid therapy is levels and efficacy of (minipill)
also associated with extraspinal tendon and ligament Other important interactions Alcohol (reverse esterification
to etretinate)
calcification. Diffuse idiopathic skeletal hyperostosis

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Gautam, et al.: Acitretin in pediatric dermatoses

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unnecessary radiation. They recommend targeted erythrodermic psoriasis: Case report and literature review.
X-rays for atypical musculoskeletal pains. Other Pediatr Dermatol 1995;12:231-4.
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12. de Oliveira ST, Maragno L, Arnone M, Fonseca Takahashi MD,
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14. Kopp T, Karlhofer F, Szépfalusi Z, Schneeberger A,
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with narrowband ultraviolet B phototherapy in a child with
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