Premature epiphyseal closure--a complication of etretinate therapy in children

Two children are described who developed premature epiphyseal closure while receiving etretinate for treatment of congenital hyperkeratotic disorders. The first patient was an 8 1/2-year-old boy with nonbullous ichthyosiform erythroderma who had been on treatment for 6 years, 4 months when premature fusion of the right distal tibial epiphysis was detected. Shortness of stature, thinning of long bones, and traumatic fractures were also observed in this patient. The second child was an 11-year-old girl with systematized verrucous nevi in whom symmetric fusion of both elbow epiphyses and narrowing of the femoral epiphyses bilaterally were noted following treatment with etretinate for 5 years, 5 months.     

Successful treatment of pemphigus vegetans by addition of etretinate to systemic steroids

Pemphigus vegetans is a rare variant of pemphigus vulgaris and is characterized by flaccid bullae, which become eroded and form vegetations or papillomatous proliferations, especially in the intertriginous areas. ¹ Oral administration of corticosteroids alone does not always induce disease remission in pemphigus vegetans. We report a 44-year-old Japanese man with pemphigus vegetans. Although corticosteroid therapy resulted in healing of the oral ulcers and skin bullae, verrucous vegetations continued to develop. In contrast, by combining corticosteroid with etretinate, verrucous vegetations improved. Thus we propose that the combination therapy of steroid and etretinate might be an effective adjunct in the therapy of pemphigus vegetans.     

Epidermolytic hyperkeratosis in inflammatory linear verrucous epidermal nevus

Epidermolytic hyperkeratosis presents with perinuclear vacuolization of the keratinocytes in spinous and granular layers, keratinocytes with ill-defined limits, which leads to a reticulate appearance of the epidermis, an increased number of variously shaped and sized basophilic keratohyalin granules and the same sized eosinophilic trichohyalin granules, at any level of epidermis, mainly in the stratum granulosum, and compact hyperkeratosis. This minor reactive pathologic reaction pattern of skin is found in large variety of diseases. This paper is the first case report of such pattern in inflammatory linear verrucous epidermal nevus. Our case is of a 23-year-old man with pruritic verrucous lesions of trunk and extremities initiated since 13 years ago. Physical examination revealed white linear hyperkeratotic lesions, some of them on erythematous background and also classic epidermal nevus. No skeletal, ophthalmic, and nervous system involvement was detected. Microscopic study of pruritic verrucous lesions showed psoriasiform acanthosis, mild papillomatous, hyperkeratosis, and epidermolytic hyperkeratotic changes in hair follicles and acrosyrinx accompanied with moderate perivascular inflammation.     

Elephantiasis nostras verrucosa in a patient with systemic sclerosis

Elephantiasis nostras verrucosa (ENV) is an unusual skin condition characterized by dermal fibrosis and hyperkeratotic verrucous lesions resulting from chronic nonfilarial lymphoedema. The condition is similar to ‘elephantiasis tropica’, in which elephantiasis develops secondary to filariasis. Lymphatic obstruction can be primary or due to various causes such as surgery, tumour, radiation, congestive heart failure or obesity. Recurrent attacks of cellulitis lead to further impairment of lymphatic drainage, causing permanent swelling, dermal fibrosis and epidermal thickening. We report a case of a 56‐year‐old man with systemic sclerosis (SS), who presented with painful lesions on both legs, consistent with ENV. He developed extensive, fungating, papillomatous lesions on the skin of the legs, toes and dorsa of the feet over a period of 3 years. Histology revealed dense dermal fibrosis, oedema of the papillary dermis and extensive pseudo‐epitheliomatous changes. To our knowledge, this is the first report of ENV in which SS was considered to be the primary cause for the impairment of lymphatic flow.     

Hyperkeratotic variant of porokeratosis Mibelli with dermal amyloid deposits

We report a case of hyperkeratotic variant of porokeratosis Mibelli with dermal amyloid deposits. A 66‐year‐old man presented with multiple brownish keratotic lesions on the lower extremities, a verrucous nodule on the third toe of the left foot and brownish verrucous plaques on the buttocks for several years. Histopathological examination of the hyperkeratotic plaque in the right gluteal region revealed extreme hyperkeratosis and cornoid lamella. In the papillary dermis, there were prominent eosinophilic amorphous materials which were positive to Dylon staining. Treatment with oral etretinate resulted in a remission of the skin lesions in this case.     

Etretinate in the Treatment of Disseminated Porokeratosis of Mibelli

A 30-year-old man with disseminated porokeratosis of Mibelli (DPKM) was treated with oral etretinate. The dose ranged between 75 mg/day and 50 mg/day for 21 weeks. An improvement of the lesions was observed, especially of very painful verrucous plaques of the left shin. No serious side effect was seen. The patient, who had been incapacitated, is now able to work. The benefit of long-term therapy of etretinate should be considered against its side effects.     

Squamous cell carcinoma arising from lesions of porokeratosis palmaris et plantaris disseminata

We report a 63-year-old Japanese man with numerous hyperkeratotic papules of porokeratosis palmaris et plantaris disseminata (PPPD) who developed multiple squamous cell carcinomas on the lesional sites of the palms and soles. The hyperkeratotic papules, which showed tightly packed columns of parakeratotic cells in the cornified layer (cornoid lamella), lost granular layer, and dyskeratotic keratinocytes in the epidermis below the cornoid lamella histologically, had been noticed on the palms and soles from the age of 28 and 43, respectively. He has no family history of such hyperkeratotic papules. Treatment with etretinate (10-50 mg/day) was given discontinuously, and the total dose of etretinate amounted to approximately 21 g over 14 years (average: 0.07 mg/kg/day). He noticed erosions on the hyperkeratotic papules on the left sole and palm more than 9 months after cessation of treatment with etretinate. Histological findings showed numerous atypical keratinocytes in the epidermis and upper dermis with mononuclear cell infiltration seen in the upper dermis. The diagnosis of squamous cell carcinoma arising from the lesions of porokeratosis palmaris et plantaris was made. Five erosions with histologically malignant changes were removed 1 cm from the margin of the erosions. These findings suggest that etretinate may have an inhibitory action on malignant changes in PPPD.     

Prolonged cutaneous herpes zoster in acquired immunodeficiency syndrome

We described the development of prolonged disseminated cutaneous herpes zoster in two patients with acquired immunodeficiency syndrome. Both patients developed hyperkeratotic, verrucous lesions that progressed despite acyclovir therapy. The biopsy specimens were typical of herpes infection. The development of acyclovir-resistant varicella-zoster virus during therapy was suspected clinically in the first patient and documented in vitro in the second patient. The inability to mount an effective cell-mediated immune response contributed to the prolonged course of cutaneous zoster in our patients. The hyperkeratotic nature of the skin lesions may reflect their chronic nature. Treatment with inadequate doses of acyclovir, allowing viral persistence and the selection of resistant strains of virus, may also be implicated. We recommend prolonged high-dose intravenous acyclovir therapy in the initial management of herpes zoster in patients with acquired immunodeficiency syndrome.     

A reactive acrosyringeal proliferation in a patient with ectodermal dysplasia: eccrine syringofibroadenoma-like lesion

A 33-year-old man with ectodermal dysplasia (ED) has suffered from keratotic, exudative, erythematous plaques on the genital area, thighs, and soles since age 17. Verrucous soft nodules in a cobblestone arrangement developed on the erythematous plaque on his left thigh when he was 31 years old. Histologic examination of the verrucous nodules demonstrated that they were composed of anastomosing thin cords of uniform, cuboidal, epithelial cells and a fibrovascular stroma. The changes are indicative of eccrine syringofibroadenoma of Mascaro (ESFA), which has been reported as a neoplasm, a hamartoma, or a nevus. With etretinate treatment, the verrucous nodules completely disappeared within two months. Similar, but much flatter, verrucous lesions recurred and disappeared twice during the subsequent two years period. These verrucous lesions were likely induced by irritation from urine, stool, and/or mechanical friction. This case of ESFA in a patient with ED clearly showed a reactive process which was successfully managed with oral etretinate.     

Etretinate in the Treatment of Disseminated Porokeratosis of Mibelli

Abstract: ABSTRACT: A 30-year-old man with disseminated porokeratosis of Mibelli (DPKM) was treated with oral etretinate. The dose ranged between 75 mg/day and 50 mg/day for 21 weeks. An improvement of the lisions was observed especially of very painful verrucous plaques of the left shin. No serious side effects was seen. The patient, who had been incapacitated, is now able to work. The benefit of long-term therapy of etretinate should ne considered against its side effects.     

Warty carcinoma of the anus: a variant of squamous cell carcinoma associated with anal intraepithelial neoplasia and human papillomavirus infection.

Warty carcinoma (WC) is a rare variant of squamous cell carcinoma primarily described in the vulva in younger women and classically associated with human papillomavirus (HPV) infection. The gross findings are similar to those of verrucous carcinoma with large, exophytic tumors with a papillomatous surface. Microscopically, the tumor is papillated and contains fibrovascular cores covered by hyperkeratotic epithelium showing presence of koilocytes. We report a case of anal squamous cell carcinoma showing similar features, occurring in a young immunosuppressed male patient with a history of multifocal anal intraepithelial neoplasia (AIN). HPV-16 has been demonstrated both in the WC and in adjacent AIN, but the HPV status appears different in the two lesions: integrated in WC and episomal in AIN lesions. We also have demonstrated by immunohistochemistry that both WC and AIN are highly proliferative entities sharing the same MIB-1 pattern, and that WAF1/CIP1 protein expression is common in the two lesions irrespective of p53 protein expression.     

Etretinate treatment in disseminated porokeratosis

A 77-year-old man with disseminated superficial porokeratosis of Mibelli (PM) over the whole body surface for 60 years was treated with oral etretinate (1 mg/kg/day) for nine months after resection of two lesions of Bowen's disease. Clinically, hyperkeratotic plaques were flattened after three months of treatment. Histological changes included disappearance of parakeratosis and residual but less stacked cornoid lamella. Etretinate may be the first choice of treatment in widespread porokeratosis.     

Erythrokeratodermia variabilis

The case of a 10 year-old Japanese boy with erythrokeratodermia variabilis is reported in addition to a review of the Japanese literature. The patient was first examined in our clinic on October 21, 1965, because of generalized hyperkeratotic lesions and erythematous lesions which had persisted since he was 3 months old. Hyperkeratotic and verrucous lesions were noted on his auricles and trunk, on which there were also sharply demarcated erythematous lesions of various sizes and shapes which were not elevated from the adjacent skin. Laboratory findings were within normal limits. Histopathological examination revealed a remarkable hyperkeratosis with a basket weave appearance, moderate acanthosis and a slightly thickened granular layer. Polyethylenglycol 400 and corticosteroid ointment were slightly beneficial to the hyperkeratotic lesions.     

The Olmsted syndrome

A 35-year-old man had a hyperkeratotic disorder of the palmoplantar skin since the age of 6 months. The palmoplantar keratoderma progressed to thick and warty hyperkeratotic plaques, which enlarged and formed verrucous lesions and deep fissures. The acral keratoderma gradually involved the dorsal surface of the hands and feet with flexion contractures of the fingers and toes (Fig. 1). Since the age of 2 years, the patient also showed universal alopecia and small sharply marginated hyperkeratotic plaques around the nose and mouth, in the groin, and in the intergluteal area (Fig. 2). All of these keratotic lesions were strikingly symmetric.
Examination of the oral mucosa revealed a white plaque over the left lateral border of the tongue; crusted white verrucous plaques were found at the labial commissures and underneath the lower lip. There was complete absence of the nails and the roentgenographic examination of the hand showed pronounced osteolysis of the distal phalanx of each of the fingers. The palmoplantar keratoderma has been complicated by the development of constricting bands of keratin around the bases of the fingers, leading to their strangulation and autoamputation (Fig. 1). The mental and physical appearance were normal. A family history of similar verrucous lesions was lacking. Histopathologic examination of the palmar skin showed massive parakeratotic hyperkeratosis and considerable acanthosis. In the thickened horny layer, many cells showed perinuclear edema. The patient was treated with topical retinoic acid cream, 0.1%, at night. This produced an improvement in the plaques around the nose and mouth.     

Hyperkeratotic and verrucous skin lesions on lower extremities of leprosy patients.

Three morphological varieties of hyperkeratotic and verrucous skin lesions on the anterior aspect of ankle joints in patients with leprosy are described: (i) verrucous lesions with thread-like horny projections similar to filiform warts; (ii) irregular compact hyperkeratotic lesions with deep fissures in between; and (iii) hyperkeratotic lesions with linear fissures corresponding to the transverse creases on the anterior aspect of the ankle. Chemical cautery was useful for the treatment of the first two varieties, and a potent topical corticosteroid with salicylic acid was useful for the third.     

Queratosis liquenoide crónica tratada con calcipotriol tópico

—Keratosis lichenoides chronica is an uncommon cutaneous disorder of unknown ethiopathogenesis. It is clinically characterized by the presence of hyperkeratotic papules spread through the trunk and extremities adopting a linear and/or reticular pattern. A facial eruption, suggestive of seborrheic eczema, is frequently associated.A 44-year-old male presented cutaneous lesions characteristics of keratosis lichenoides chronica for more than 10 years. The histological study confirmed the clinical suspiction. A treatment with calcipotriol ointment, applied twice a day, was prescribed. Eight weeks later, a partial improvement, with a thinning of the lesions and erythema remission, was observed.There is not a treatment for this disease. The best results have been obtained by PUVA and etretinate therapy. Recently, the effectiveness of the topical calcipotriol has been reported. In our case, a satisfactory improvement of the lesions, according to the patient, was obtained without complete remission. We believe that calcipotriol is a valid alternative for these patients, especially when systemic treatments involve a risk.     

Oral retinoid therapy for disorders of keratinization: single-centre retrospective 25 years' experience on 23 patients

BACKGROUND: Over the last three decades, the oral retinoids etretinate and acitretin have revolutionized the treatment of disorders of keratinization (DOK). Many patients with DOK require life-long treatment with oral retinoids. However, the longest follow-up data of patients with DOK on oral retinoid therapy is 10 years for adults and up to 11 years for children. OBJECTIVES: The aim of our study was to collect long-term retrospective data including disease response, side-effects and pregnancy outcome in a cohort of patients with DOK who were among the first in the world to commence oral retinoids 25 years ago. METHODS: Between 1979 and 1981, 30 patients with DOK were commenced on oral etretinate in our department. Case notes of these patients were reviewed retrospectively, and patients interviewed where possible to obtain the following information: diagnosis, age when treatment commenced, duration of treatment, reason for discontinuation of therapy, side-effects, abnormal investigation results and pregnancy outcomes. RESULTS: Case notes of 23 of the 30 patients were available for review; of these, two patients were deceased and 14 were interviewed. In the 23 patients, the mean age of commencing treatment was 33.5 years (range 4.2-61) and the mean duration of etretinate therapy was 5.2 years (range 1 month to 14 years). Reasons for discontinuing treatment were an overall improvement in the skin disease (six of 23), no benefit +/- side-effects (11 of 23) and noncompliance (one of 23). Two patients died of causes unrelated to their skin disease or treatment, 12 and 4 years after stopping etretinate. Five patients (one female, four males) subsequently changed to acitretin and are currently continuing therapy. The mean total duration of retinoid therapy (etretinate and acitretin) for the four males was 23.7 years (range 20.6-25.1). The female patient continued intermittent courses (due to planned pregnancies) of oral retinoids for a total of 10.1 years over the last 25 years. Abnormal investigation results included elevated serum triglycerides and cholesterol (two of 23), isolated high triglycerides (three of 23), isolated high cholesterol (three of 23), worsening of liver enzymes in a patient with alcohol dependence, and elevated serum alkaline phosphatase (ALP) in healthy adults (three of 23). In two children, the elevated pretreatment ALP levels increased further after commencing etretinate but returned to normal in adulthood while treatment continued. One patient developed diffuse idiopathic skeletal hyperostosis after 21 years of retinoid therapy. One female patient had two early spontaneous abortions 2.75 and 3.2 years after discontinuing etretinate; she subsequently had two normal children. Two other females had normal children 1, 3 and 5 years after stopping etretinate. Two male patients fathered a total of three healthy children while on etretinate. CONCLUSIONS: This study provides the longest available follow-up data of children and adults with DOK on oral retinoid therapy. Such information is essential for clinicians and their patients with DOK embarking on life-long treatment with retinoids.     

Combined treatment of epidermodysplasia verruciformis with etretinate and α-interferon*

Epidermodysplasia verruciformis (EV) is an uncommon cutaneous disease in which a focal and genetically determined immunological impairment is associated with chronic human papilloma virus (HPV) infection. In sun-exposed areas, when an oncogenic HPV type is the agent, skin cancer may occur. The treatment of EV is difficult and often unsatisfactory; etretinate has been reported in some instances as effective in improving lesions. We report a typical case of EV with pityriasis versicolor-like lesions on the trunk and many flat, erythematous wart-like lesions on the face, dorsal areas of the hands and legs. We performed a treatment with etretinate (1 mg/kg/day for 6 weeks) and subsequently with etretinate and α₂r-interferon (3 MU, 3 times per week for 2 weeks, then 6 MU, as above, for 4 weeks). After 4 weeks of therapy with etretinate we observed moderate improvement; we did not observe any further clinical improvement in the final 2 weeks. The subsequent combined treatment with etretinate and a-interferon achieved further improvement. We conclude that the association of etretinate and a-interferon may represent an efficacious treatment of EV.     

Clinical evaluation of etretinate for the treatment of canine solar-induced squamous cell carcinoma and preneoplastic lesions.

BACKGROUND: Tumors of the skin and subcutaneous tissue account for 30% of all canine neoplasms. Canine solar-induced squamous cell carcinoma (SCC) is the most frequently reported canine cutaneous neoplasm. OBJECTIVE: The purpose of this study was to provide preliminary observations on the safety and efficacy of etretinate for the treatment of solar-induced SCC and associated preneoplastic lesions in dogs. METHODS: Etretinate was administered to 10 dogs at 1 mg/kg twice daily for a minimum of 90 days. RESULTS: Clinically, two dogs showed complete resolution of their preneoplastic lesions, three dogs had partial responses, two dogs maintained stable disease, and three dogs showed progression of lesions after 90 days of etretinate administration. Three dogs showed histologic improvement, four dogs showed no changes, and three dogs showed evidence of progressing SCC. Treatment-related biochemical abnormalities included reversible hypertriglyceridemia and transient serum liver enzyme elevations in three dogs. CONCLUSION: These preliminary findings suggest that etretinate, at the dosage administered, may provide therapeutic efficacy for solar-induced preneoplastic lesions in the dog, particularly for those multifocal lesions not easily managed by local methods of therapy.