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Acitretin-Induced Acral Hemorrhagic Lesions in Darier-White Disease

Cutis. 2014 December;94(6):E1-E5
December 5, 2014|Dermatology
Elisa Zavattaro, MD, PhD;Melissa Celasco, MD;Giorgio Delrosso, MD
Author and Disclosure Information

 

Elisa Zavattaro, MD, PhD; Melissa Celasco, MD; Giorgio Delrosso, MD; Simona Ferri, MD; Carlo Bornacina, MD; Guido Valente, MD; Federica Veronese, MD; Nicola Fusco, MD; Marisa Gariglio, MD, PhD; Enrico Colombo, MD

From the Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy. Drs. Zavattaro, Celasco, Delrosso, Ferri, Bornacina, Veronese, and Colombo are from the Dermatology Unit; Drs. Valente and Fusco are from the Pathology Unit; and Dr. Gariglio is from the Virology Unit.

The authors report no conflict of interest. Dr. Zavattaro received a research grant from Regione Piemonte (LR 4/2006 for brain drain containment, DR 225/2009).

Correspondence: Enrico Colombo, MD, Dermatology Unit, Department of Translational Medicine, University of Piemonte Orientale Amedeo Avogadro, Via Solaroli 17, 28110 Novara, Italy (enrico.colombo@med.unipmn.it).

Darier-White disease (DD) is an autosomal-dominant inherited disease characterized by keratotic papules that are usually located in seborrheic areas. Systemic retinoids generally are first-line treatment in cases of diffuse DD. We report the case of an 84-year-old woman with a hypertrophic variant of DD with acral lesions. Oral retinoids (acitretin) were administered as a first treatment of DD, with good clinical results. After a few months, hemorrhagic vesicles developed on palmoplantar surfaces. Suspension of the therapy led to the disappearance of the cutaneous manifestations.

     Practice Points

 

  • ­The first-line treatment of Darier-White disease (DD) is oral retinoids.
  • ­Numerous side effects of retinoids have been described. Clinicians should take these cutaneous manifestations into consideration in patients affected by DD.

  


Figure 2. Palmoplantar hemorrhagic vesicles and macules with diffuse xerosis and scaling were present 7 months after beginning acitretin therapy (A and B). Within 2 weeks of discontinuing acitretin, the hemorrhagic lesions spontaneously regressed (C and D).

Figure 3. Histopathologic analysis of a skin biopsy specimen obtained from a hemorrhagic lesion during treatment with acitretin revealed hyperkeratosis, acanthosis, papillomatosis, hypergranulosis, and subcorneal hemorrhagic vesicles (H&E, original magnification ×45).

Comment

We report the case of an 84-year-old woman who developed hemorrhagic lesions on the palmoplantar surfaces and dorsal aspect of the feet as a side effect of oral retinoids for treatment of DD. The first reported case of acral hemorrhagic lesions associated with DD was described 50 years ago in 4 patients with manifestations located mainly on the palms, soles, and dorsal fingers. Local trauma was identified as a triggering factor in the development of the vesicles; however, data regarding the temporal relationship between keratotic papules and hemorrhagic elements and treatment were not specified.5 Twenty-five years later, Coulson and Misch6 described a case of DD in which the hemorrhagic lesions were the first sign of the disease, but correlation with therapy was not reported. A case of retinoid-induced hemorrhagic DD was reported in a female who was treated with etretinate for approximately 10 years after the diagnosis of DD with good clinical response. After 10 years of therapy, she developed hemorrhagic bullae solely on the dorsal aspect of the hands without any direct association with local trauma, along with a small number of nonhemorrhagic bullae.17

In our patient, the onset of hemorrhagic vesicles and red maculae occurred primarily on the palmoplantar surfaces. The lesions were smaller than bullae and contained hemorrhagic elements. Of note, the skin lesions appeared as early as 7 months after the patient started acitretin therapy.

The development of hemorrhagic lesions on different body sites as a consequence of oral retinoid administration also has been reported in patients with psoriasis.15 Emerging evidence indicates that retinoic acid activates vascular endothelial growth factor gene transcription,18 and vascular endothelial growth factor can modify permeability of the endothelial cells. Based on these observations, we propose that DD is characterized by loss of adhesion between epidermal cells (acantholysis) and abnormal keratinization. This defect favors the formation of empty intraepidermal lacunae. An increase in endothelial permeability due to oral retinoid administration promotes the gathering of serum and red blood cells into the lacunae, leading to the onset of hemorrhagic blisters. Moreover, continued microtrauma to the palmoplantar surfaces may account for the peculiar localization of the hemorrhagic lesions described in our patient.

Our unique report of hemorrhagic lesions (vesicles and maculae) presenting in a DD patient treated with acitretin is rare. The first histologic specimen taken from a palmar pit revealed the characteristic histopathologic findings of DD and did not support the diagnosis of the hemorrhagic variant of DD. In the second biopsy, the absence of acantholysis and the poor content of dyskeratotic cells were evident, together with superficial hemorrhagic vesicles. Additionally, the appearance and the disappearance of the cutaneous manifestations were closely correlated with the beginning and suspension of the acitretin therapy, together with an improvement of typical lesions of DD during acitretin treatment. These occurrences indicated a strict causal relationship between treatment with the retinoid and the appearance of hemorrhagic lesions.

Conclusion

We report a rare case of palmoplantar hemorrhagic lesions induced by acitretin for treatment of DD. In our patient, the lesions could have been triggered by a combination of noxious effects of the drug and alterations in keratinocyte physiology due to DD. There is a need for clinicians to be aware of the possible side effects of acitretin and to inform their patients, particularly those presenting with DD, about the possibility of developing hemorrhagic lesions. The latter should be added to the list of potential dermatologic adverse effects of acitretin.

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