Olmsted syndrome is an uncommon inherited disorder of keratiniz-. Eduardo Fonseca1, ation that presents mutilating palmoplantar keratoderma, perioral.
Copyright C Munksgaard 2001
J Cutan Pathol 2001: 28: 271–275 Printed in Denmark ¡ All rights reserved
Journal of
Cutaneous Pathology ISSN 0303-6987
Olmsted syndrome Olmsted syndrome is an uncommon inherited disorder of keratinization that presents mutilating palmoplantar keratoderma, perioral hyperkeratosis, leukokeratosis and alopecia. We report a case of this rare syndrome diagnosed in a 48-year-old woman and confirms the existence of a generalized abnormality in keratin expression. Immunoreactivity in our case suggests an abnormal expression of keratins 5 and 14 similar to the observed in other hyperproliferative disorders. Fonseca E, Pen˜a C, del Pozo J, Almagro M, Yebra MT, Cuevas J, Contreras F. Olmsted syndrome. J Cutan Pathol 2001; 28: 271–275. C Munksgaard 2001.
Eduardo Fonseca1, Carmen Pen˜a1, Jesu´s del Pozo1, Manuel Almagro1, Ma. Teresa Yebra2, Jesu´s Cuevas3 and Fe´lix Contreras4 Departments of 1Dermatology and 2Pathology, Hospital Juan Canalejo, La Corun˜a, Spain, 3 Department of Pathology, Hospital del Insalud, Guadalajara, Spain, 4Department of Pathology, Hospital La Paz, Madrid, Spain
Eduardo Fonseca, M.D., Servicio de Dermatologı´a, Hospital Juan Canalejo, Xubias de Arriba 84, 15006 La Corun˜a, Spain e-mail: fonseca/canalejo.org Accepted November 18, 2000
Olmsted syndrome is a rare disorder of the keratinization characterized by mutilating palmoplantar keratoderma. About 20 cases of this syndrome have been previously reported.1–5 Kress et al.1 described in 1996 a case of Olmsted syndrome and demonstrated a keratin abnormality in the lesional areas. We report the case of a patient with this disease showing a similar altered pattern of keratin expression in the hyperkeratotic lesions as well as in clinically unaffected skin. Case report A 48-year-old white female presented by hyperkeratotic lesions on the acral areas of her previously amputated extremities. There was no family history of similar disorders or consanguinity. Despite the severe consequences of her cutaneous disease, the patient had no relevant antecedents of systemic or mental disturbances. The first cutaneous alterations were detected at the age of 9 months as hyperkeratotic areas on her palms, soles, and scalp. These lesions were unresponsive to treatment with topical keratolytics, and resulted in spontaneous mutilation of all fingers and toes at the age of 4 years. At this time generalized hypotrichosis was also observed. Between the 4 and 30 years of life large verrucous
masses on the hands and feet were repeatedly excised. During this period perioral hyperkeratosis, leukokeratosis, and multiple episodes of erysipela and cellulitis were noted. At the age of 30 years supra-articular amputation of both hands and feet was performed because uncontrollable keratinous mass formation and infectious complications. Verrucous masses newly formed on distal areas of the extremities after amputation required repeated surgical treatment. Histopathological studies of verrucous excised masses were reported as showing hyperkeratosis, acanthosis, and papillomatosis, without evidence of malignancy or other relevant features. A conclusive diagnosis had not been previously achieved. Physical examination revealed symmetrical hyperkeratotic plaques on the distal areas of extremities, elbows and knees (Fig. 1). Hyperkeratosis was also prominent in perioral, perianal, groin, and scalp areas. Leukokeratosis was observed in oral mucosa being more intense on the hard palate (Fig. 2). Generalized hypotrichosis, which resulted in scalp diffuse alopecia, was another remarkable feature. Analytical studies revealed normal values including hemogram, rutinary biochemical test, urinalysis, immunoglobulin quantification, and CD4 and CD8 lymphocyte counts. 271
Fonseca et al. with IgG mouse monoclonal antibody concentration of 1.7 mg/ml at an 1:50 dilution, and 34BE12 monoclonal antibody (Dako, Glostrup, Denmark) with IgG mouse concentration of 55 mg/ml at an 1:50 dilution. Fast-Red (Sigma, St. Louis, MO, USA) was used as chromogen.
Fig. 1. Hyperkeratotic plaque on the distal area of forearm.
Results In verrucous lesions AE1 immunohistochemical staining demonstrated an intense positivity of the epidermal cells with a suprabasal pattern and was negative in the basal cells (Fig. 4). Slow decrease of the immunostaining in the suprabasal epidermis was observed at the margins of the hyperkeratotic lesions (Fig. 5). In areas of skin without clinical alterations the AE1 immunostaining was negative in the basal and suprabasal epidermal cells. In both hyperkeratotic and clinically unaffected areas of skin AE1 immunostaining was positive in the single epithelium of eccrine sweat glands. A control specimen of normal
Fig. 2. Oral leukokeratosis.
Verrucous lesions on the forearms and legs were excised including perilesional clinically unaffected skin. The routine histopathological study revealed massive parakeratotic hyperkeratosis, acanthosis, and papillomatosis (Fig. 3). Mitosis were frequent at the basal layer. The upper dermis showed a moderate lymphoid infiltrate. A diagnosis of Olmsted syndrome was made. The patient refused treatment with oral retinoids and treatment with a 10% urea cream was instituted. In a 6-month follow-up an episode of genital and perigenital candidosis and a moderate improvement of the hyperkeratosis were observed. Material and methods Immunohistochemical studies from the paraffin blocks were performed using the streptavidin-biotin technique conjugated with alkaline phosphatase. Four-micron sections were stained with AE1 monoclonal antibody (Bio Genex, San Ramon, CA, USA) 272
Fig. 3. Massive hyperkeratosis, acanthosis and papillomatosis (H& E).
Fig. 4. Hyperkeratotic lesion. AE1 immunostaining showing a suprabasal pattern.
Olmsted syndrome skin showed immunostaining in the epidermal basal cells and in the single epithelium of sweat glands. Immunostaining with 34BE12 antibody showed a positive suprabasal pattern in the epidermis of verru-
Table 1. Immunostaining findings Antibodies
AE1 34BE12
Normal epidermis
Basal cell layer Full-thickness
Reported case Hyperkeratotic lesions
Unaffected skin
Suprabasal pattern Suprabasal pattern
Negative Full-thickness
cous lesions and it was negative in the basal layer (Fig. 6). In the clinically unaffected skin the immunostaining was positive in the full-thickness of the epidermis, including the basal layer (Fig. 7). In both hyperkeratotic and clinically unaffected skin the immunostaining was positive in the epithelium of eccrine sweat ducts. In the control specimen the full-thickness of the epidermis and the epithelium of eccrine sweat ducts were stained. Immunostaining findings are summarized in Table 1. Fig. 5. Margin of hyperkeratotic lesion. AE1 immunostaining shows a progressive decrease.
Fig. 6. Hyperkeratotic lesion. 34BEE12 immunostaining shows a suprabasal pattern.
Fig. 7. Clinically unaffected skin. 34BE12 immunostaining positive in the full-thickness of the epidermis.
Discussion Olmsted syndrome was described in 1927 in an Italian boy without familiar history of similar lesions.6 The about 20 cases previously reported of this syndrome include two families in which a mother and her son were involved, suggesting an autosomal dominant type of inheritance. Nevertheless, the absence of pedigrees with more than two involved relatives and the sporadic presentation in most cases also suggest a possible autosomal recessive pattern of inheritance.1,5 The clinical features are the clue for the diagnosis of Olmsted syndrome. Mutilating palmoplantar keratoderma is the more relevant manifestation. It is usually noticed during the second semester of life. Perioral keratoderma, leukokeratosis, and alopecia have been also described in most Olmsted syndrome patients. Differential diagnosis of Olmsted syndrome includes other mutilating palmoplantar keratodermas. In Vohwinkle syndrome (keratoderma hereditarium mutilans) the mutilating keratoderma is usually associated with systemic disturbances such as deafness, myopathy, and spastic paraplegia. Autoamputation of some digits may occur in other diffuse transgrediens keratodermas including pachyonychia congenita and Meleda disease.3 Acrodermatitis enteropathica is commonly considered in differential diagnosis of Olmsted syndrome based on the presence of periorificial and acral keratoderma associated with alopecia in both diseases. Nevertheless the acral mutilation observed in advanced stages of Olmsted syndrome is not a feature of acrodermatitis enteropathica. Our patient showed clinical manifestations of severe mutilating keratoderma, hyperkeratotic plaques on amputation stumps, elbows and knees, hyperkera273
Fonseca et al. tosis in periorificial areas, leukokeratosis, and alopecia, which were not associated with systemic disturbances. These features support the clinical diagnosis of Olmsted syndrome. The histopathological findings were unspecific but similar to the previously described in this syndrome. Other features commonly described in Olmsted syndrome such as nail abnormalities, flexion deformities of the fingers and joint hypermobility were not evaluable in our patient. Kress et al.1 first reported an abnormality of the keratinization in an Olmsted syndrome patient. Employing AE1 immunostaining on hyperkeratotic lesions they observed intense positive staining in the suprabal layers of the epidermis and minimal staining in the basal cell layer. This pattern of AE1 immunostaining has been referred as suprabasal pattern. AE1 was also found to be positive in the sweat ducts. Antikeratin 10 antibody showed positive staining in the germinative stratum beginning several layers of cells above the basal layer. AE1 monoclonal antibody is an antikeratin antibody that interacts with acidic keratins. In normal human epidermis AE1 only stains the basal cell layer, a pattern that has been designated as basal pattern. Antikeratin 10 antibody in the normal human epidermis stains the full-thickness of the epidermis except the basal cells. Kress et al. interpreted their results as caused by retardation in the maturation of keratinocytes, manifested by persistence in the germinative stratum of keratins 5 and 14, which are normally present at the basal layer and decrease with the maturation of keratinocytes. The decrease of keratin 5 and 14 expression is correlated in normal skin by an increase of expression of keratins 1 and 10. Kress et al. also considered consistent with retardation in the maturation of keratinocytes the beginning of antikeratin 10 stain several layers of cells above the basal cell layer, instead in the first suprabasal layer. A suprabasal pattern of AE1 immunostain had been previously reported in psoriasis and other benign hyperproliferative disorders of the epidermis.7 Raskin and Tu8 commented the article of Kress et al. and considered that reported keratin abnormal expression might to be caused by the long-term treatment with oral retinoids administered to the patient. This objection was based on the well-known activity of retinoids on the expression of keratinocyte genes, including keratin genes.9 These authors also pointed out that although keratin 14 in normal skin is paired with the basic keratin 5, AE1 antibody has no direct interaction with keratin 5. As consequence, in pathological situations the changes in AE1 immunostaining are not directly related with abnormal keratin 5 expression, as suggested by Kress et al. We have observed a suprabasal pattern of AE1 immunostaining in hyperkeratotic lesions of Olmsted syndrome, similar to the described by Kress et al. Our 274
patient received no systemic or topical treatment when biopsies were performed excluding the possible pharmacological origin of the keratin abnormality. In addition we have also observed an abnormal stain with AE1 in clinically unaffected skin at the margins the lesions which showed a negative stain instead a basal pattern. Using another antikeratin antibody, the 34BE12 monoclonal antibody, which reacts with basic keratins, we have observed an abnormal immunostaining in hyperkeratotic lesions of Olmsted syndrome. In normal skin 34BE12 antibody stains the full-thickness of the epidermis,10 but we have found a suprabasal pattern of immunostaining in hyperkeratotic lesions. This abnormality was limited to the hyperkeratotic areas since the clinically unaffected skin at the margins of the lesions showed a normal immunostaining pattern. We think that our data confirm the existence of an abnormality of keratinization directly related to the disease in Olmsted syndrome. This abnormality seems to be generalised in clinically affected and unaffected skin, which is concordant with the widespread distribution of the cutaneous and mucous lesions. The location of hyperkeratotic lesions is probably related to external factors like trauma. The combination of our results using AE1 and 34BE12 suggests that both keratin 5 and keratin 14 expression are abnormal and are compatible with the features observed in other hyperproliferative disorders. In all our specimens immunostained with AE1 and 34BE12 as well as in the immunostained with AE1 by Kress et al. the epidermal cells of eccrine sweat ducts showed a normal immunostaining both in clinically hyperkeratotic and clinically normal skin. These findings suggest that the abnormal keratinization is restricted to the epidermis.1
References 1. Kress DW, Seraly MP, Falo L, Kim B, Jegasothy BV, Cohen B. Olmsted syndrome. Case report and identification of a keratin abnormality. Arch Dermatol 1996; 132: 797. 2. Ueda M, Nakagawa K, Hayashi K, Shimizu R, Ichihashi M. Partial improvement of Olmsted syndrome with etretinate. Pediatr Dermatol 1993; 10: 376. 3. Santos OLR, Amorim JH, Voloch K, Goes MC, Silva MR, Pereira AC Jr. The Olmsted syndrome. Int J Dermatol 1997; 36: 359. 4. Frı´as-Iniesta J, Sa´nchez-Pedren˜o P, Martı´nez-Escribano JA, Jime´nez-Martı´nez A. Olmsted syndrome: report of a new case. Br J Dermatol 1997; 136: 935. 5. Armstrong AP, Percival N. Olmsted’s syndrome. J R Soc Med 1997; 90: 81. 6. Olmsted H. Keratodermia palmaris et plantaris congenitalis: report of a case showing associated lesions of unusual location. Am J Dis Child 1927; 33: 757.
Olmsted syndrome 7. Weiss RA, Guillet GYA, Freedberg IM, et al. The use of monoclonal antibody to keratin in human epidermal disease: alterations in immunohistochemical staining pattern. J Invest Dermatol 1983; 81: 224. 8. Raskin CA, Tu JH. Keratin expression in Olmsted syndrome. Arch Dermatol 1997; 133: 389.
9. Smack DP, Korge BP, James WD. Keratin and keratinization. J Am Acad Dermatol 1994; 30: 85. 10. Gown AM, Vogel AM. Monoclonal antibodies to human intermediate filament proteins. II. Distribution of filament proteins in normal human tissues. Am J Pathol 1984; 114: 309.
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