- Email: [email protected]
Proteus syndrome
Volume 25 Number 2, Part 2 August 1991
2. Finan MC, Winkelmann RK. Histopathology of necrobiotic xanthogranuloma with paraproteinemia. J Cutan Pathol 1987;14:92-9. 3. Robertson DM, Winkelmann RK. Opthalmic features of necrobiotic xanthogranuloma with paraproteinemia. Am J OphthalmoI1984;97:173-83. 4. Finan MC, Winkelmann RK. Necrobiotic xanthogranuloma with paraproteinemia. Medicine 1986;65:376-88. 5. Kyle RA, Greiopp PRo Smoldering multiple myeloma. N Engl J Med 1980;302:1347-9. 6. Hashimoto K, Burk JD, Bale GF, et al. Transient bullous dermolysis of the newborn: two additional cases. 1 AM ACAD DERMATOL 1989;21:708-13. 7. Clark G. Staining procedures. 4th ed. Baltimore: Williams & Wilkins 1981:189-95.
Necrobiotic xanthogranuloma 8. Durie BGM, Salmon SE. A clinical staging system for multiple myeloma. Cancer 1975;36:842-54. 9. Alexanian R, Berlogie B, Dixon D. High-dose glucocorticoid treatment of resistant myeloma. Ann Intern Moo 1983;105:8-11. 10. Venencie PY, Puissant A, Verola 0, et al. Necrobiotic xanthogranuloma with myeloma: a case report. Cancer 1987;59:588-92. 11. Bernstein MJ. Magnetic resonance imaging. Consensus Conference. lAMA 1988;259:2132-8. 12. Daffner RH, Lupetin AR, Dash N, et al. MRI in the detection of malignant infiltration of bone marrow. Am J RoentgenoI1986;146:353-8.
Proteus syndrome Ultrastructural study of linear verrucous and depigmented nevi Vincenzo Nazzaro, MD,t Stefano Cambiaghi, MD,a Alessandro Montagnani, MD,b Alberto Brusasco, MD,a Amilcare Cerri, MD,a and Ruggero Caputo, MDa Milan, Italy Proteus syndrome is a rare hamartomatous disorder charact~erized by multifocal overgrowths that can involve any structure of the body. Clinical manifestations include macrodactyly, hemihypertrophy, subcutaneous masses, exostosis, cerebroid thickening of palms and soles, and linear skin lesions. About 50 cases have been described, but the ultrastructural features of the linear skin lesions have not been characterized. We describe the clinical, histologic, and ultrastructural findings for a 30-year-old patient who had a mild form of Proteus syndrome with linear lesions characterized by a mixed pattern of hyperkeratosis and depigmentation. Light microscopy of the linear nevus showed acanthosis and hyperorthokeratosis. Electron microscopy revealed extensive vacuolation at the interface between melanocytes and keratinocytes, with large aggregations of densely packed granules in the intercellular space. Melanocytes showed only slight degenerative changes. An immunohistochemical study of the expression of epidermal growth factor receptors revealed no significant abnormalities. (J AM ACAD DERMATOL 1991;25:377-83.) Proteus syndrome is a hamartomatous disorder characterized by multiple focal overgrowths that can involve any structure of the body. The name of the syndrome was suggested by Wiedemann et a1. 1 in 1983 from the name of the Greek god "Proteus," the polymorph, to emphasize the wide range of clio-
From the Centro Malattie Cutanee Ereditarie, Dermatology Clinie I, University of Milan,' and the Centro Auxologico Italiano.b Reprint requests: Vincenzo Nazzaro, MD, Centro Malattie Cutanee Ereditarie, Clinica Dermatologica Prima, via Pace 9, 20122 Milan, Italy. tDeceased.
16/4/23681
ical manifestations. About 50 cases have been reported; this number includes several cases described before 1983 and subsequently discovered to be Proteus syndrome. 2-8 Typical clinical features include progressive and asymmetric megalodactyly, hemihypertrophy, subcutaneous masses, localized cerebroid thickening of palms and sales, and linear skin lesions. 9- 11 It has been suggested that growth-factor abnormalities are responsible for the tissue overgrowths, but no growth-factor studies have been reported to date. Apart from four cases in adults 9, 10 aU reported cases have been in children. The long-term prognosis is not well known. Linear skin lesions, which have been observed in
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Fig. 1. Asymmetric macrodactyly of the first two fingers of the left hand.
Fig. 2. Cerebroid nodular thickening of the right heel and sole. Note scar from surgical amputation of the second and third toes. A subcutaneous mass is present on the back of the foot.
the majority of cases of Proteus syndrome, are an im]X>rtant diagnostic sign. They have been variously described as hypopigmented, hyperpigmented, or epidermal verrucous nevi. No ultrastructural study has been reported so far. We describe a mild form of the Proteus syndrome in a woman with linear, depigmented, and verrucous nevi distributed along Blaschko's lines, and we report the histologic, ultrastructural, and epidermal growth factor-binding features of her linear skin lesion.
CASE REPORT A 30-year-old woman had partial acral giantism and linear skin lesions. She had been bom after a normal pregnancy and delivery to a healthy, 28-year-old woman
(gravida 2, para 2, abortus 0) and her 34-year-old husband. Her birth weight was 3600 gm. At 5 days ofage, she was noted to have enlargement of the first three toes of the right foot. The toes continued to enlarge, and at 3 months the second and third toes were amputated. Megalodactyly of the left index finger and thumb developed progressively during the first years of her life and continued until she reached 16 years of age. She had linear and partly raised depigmented skin lesions on her lower limbs from infancy through adulthood. During childhood and adolescence, the patient had 19 operations to reduce digit malposition and to remove overgrowing subcutaneous masses; histologic examination revealed irregular proliferation ofadipose, fibrous, lymphatic, and nervous tissues. After an uneventful pregnancy, she gave birth to a normal child who was 18 months old when we received the
Volume 25 Number 2, Part 2 August 1991
patient for treatment. Familial history did not reveal any cutaneous, skeletal, or other significant abnormalities, and there was no consanguinity. Physical examination showed a woman in good general health with normal height and weight and with no mental retardation. Macrodactyly of the left index, left thumb, and right hallux was apparent (Fig. 1). The skin of the volar aspect of the same fingers showed nodular hypertrophy and irregular thickening. There was "brainlike" hypertrophy of the right heel, and a soft mass was evident on the back of the right foot (Fig. 2). Moderate hypertrophy of the right breast was present. Linear hypopigmented skin lesions were distributed along Blaschko's lines on the left lower limb. They were flat and barely visible on the thigh and leg and had a more noticeable verrucous component on the ankle (Fig. 3). No maerocephaly, skull exostosis, or scoliosis was found. Hair, nails, and teeth were normal, and no ophthalmologic or neurologic abnormalities could be detected. X-ray examination showed bone and soft tissue hypertrophy of the first two left fingers, with irregular cortical border and exostosis of the second phalanx; skull, spine, and long bones were normal. Laboratory data, including CBC, erythrocyte sedimentation rate, protein electrophoresis, and levels of electrolytes, transaminases, urea, cholesterol, and triglycerides, were normal. Renal ultrasonography was normal. Cytogenetic studies showed normal 46,XX chromosomes.
Proteus syndrome 379
Fig. 3. Linear nevus on the lower left leg shows mixed pattern of hypopigmentation and verrucosity.
MATERIAL AND METHODS
A skin specimen was obtained from a skin lesion on the left leg. For histochemical evaluation, 4/otm frozen sections were stained with hematoxylin and eosin, periodic acid-Schiff (PAS) reaction, PAS combined with diastase, and Sudan black B fat stains. Localization of immunoreactive epidermal growth factor (EGF) receptors was performed with anti-EGF receptor monoclonal antibody (Sanbyo, Uden, The Netherlands). The sections were then processed by the alkaline-phosphotase antialkaline-phosphatase method, according to Cordell et al. 12 For electron microscopy, semithin sectionswerestained with toluidine blue and periodic acid-silver methenamine reaction, and ultrathin sections werestained with aqueous uranyl acetate and lead citrate.
RESULTS Light microscopy showed acanthosis and compact hyperorthokeratosis with augmented and irregular undulations between rete ridge and dermal papillae. In the dermis a scant, nonspecific, perivascular infiltrate consisting of lymphocytes and histiocytes was observed. PAS, aldan blue, Sudan black B fat, and periodic acid-silver methenamine stains were negative.
Electron microscopy revealed no significant abnormalities of the cellular keratinization elements. Large vesicles containing sparse, electron-dense, ribosome-like granules were frequently seen at the interface between basal keratinocytes and melanocytes (Figs. 4 and 5). Most of the vesicles were continuous, with areas of fine granularity of keratinocytes that elsewhere had a normal appearance and had the normal tonofibrils and cellular organelles. In other cases the vesicles appeared to be located in the intercellular space or within the melanocytes. Many densely packed particles similar to ,8-glycogen or ribosomes were located at the interface between melanocytes and keratinocytes (Figs. 4 and 5). Smaller amounts of the same granules were also in the intercellular space between basal keratinocytes (Fig. 6). Melanocytes were frequently. at the dermoepidermal junction and had only moderate dilation of the rough endoplasmic reticulum and swelling of mitochondria. The number of melanosomes appeared normal, and there were normally shaped melanosomes in all stages of development; no aggregations of melanosomes, macromelanosomes, autophagocy-
380 Nazzaro et ai.
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Fig. 4. Electron micrograph of skin specimen obtained from linear nevus shows marked vacuolization (v) and accumulation of granular material (asterisk) at the interface between keratinocytes (k) and melanocyte (m) (X3400). (Boxed areas refer to Figs. 5 and 6.)
tosis of melanosomes, or cytoplasmic lipid droplets were discovered. A stratum granulosum was present. Keratohyalin granules, associated with the tonofilament bundles, showed no significant abnormality. Membrane-coating granules appeared to be numerous, and lamellae derived from them were generally in their normal positions, between granular cells and corneocytes. The stratum corneum was normal. No lipidlike vacuoles or electron-lucent crystals were found in either keratinocytes or corneocytes. The EGF binding study revealed a normal distribution of EGF receptors. They were present mainly on basal keratinocytes and were less frequent in the upper epidermal layers. DISCUSSION
Proteus syndrome is characterized by multifocal overgrowths that can affect any tissue and structure of the body. I, 9-11 The abnormalities are present at birth or appear in the first years of life and usually progress up to the time of puberty. Progressive and asymmetric megalodactyly, hemihypertrophy, and multiple exostosis, involving especially the skull and the digits, are the main extracutaneous clinical manifestations. Visceral hamartomas such as pul-
monary cysts and visceral lipomatosis can also be observed. I, 13-15 Cutaneous manifestations are frequent and result from hamartomas of various components of epidermis, dermis, and/or subcutaneous tissue. Cerebriform or nodular gross thickening of palms and soles seems to be one of the most frequent and typical features of this disorder. S,11 This thickening consists of irregular proliferation of adipose and fibrous tissue with or without hyperkeratosis. 8,l1,14 Ultrastructural examination, performed in one case, showed unusually elongated cytoplasmic projections of the basal cells into the dermoepidermal junction. 8 Hamartomatous masses of subcutaneous tissue nearly always accompany Proteus syndrome; they consist of adipose tissue or a various combination of adipose, lymphatic, and hemangiomatous tissue13 , 14 and can affect any area of the body. Varicose veins,I, 3, 7,10,16 cafe-au-Iait Spots,2, 4 sebaceous nevi, 14 and decreased subcutaneous tissue10, 1\ have also been described in association with this disease. Linear epidermal nevi have been reported in more than half the cases ofProteus syndrome. Our review revealed that they frequently have a mixed pattern
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Proteus syndrome 381
Fig. 5. Higher magnification of the same specimen in Fig. 4 shows densely packed granules similar to l1-g1ycogen or ribosomes (asterisks) within intercellular space between melanocyte (m) and keratinocyte (k) (X24,500).
Fig. 6. Higher magnification of same specimen in Fig. 4 shows densely packed granules (asterisk) in intercellular space between adjacent keratinocytes (arrow, desmosome) (X24,500).
of verrucosity with hypopigmentation, hyperpigmentation, or both. I, 7, 9-13 Their distribution along Blaschko's lines is evident from the illustrations that accompany at least three different reports. I, 9, 17 Histologic examination, reported in a few studies, showed papillomatosis, acanthosis, and hyperkeratosis. 9,18 Our examination by light and electron microscopy of a linear, depigmented, and verrucous lesion revealed acanthosis and hyperorthokeratosis, together with large vacuoles and aggregations of ribosome-like particles at the interface between melanocytes and keratinocytes. Similar findings have been reported in the normally pigmented skin of patients with rapidly progressive or stable vitiligo. 19 Vacuoles at the interface between keratinocytes and melanocytes have also been seen in near-normal skin and in some urticarial conditions, but these vacuoles did not contain granules. 2o To our knowledge, no other condition with linear epidermal nevi manifests itself in ultrastructural features similar to those observed in our patient. 21 The whole epidermal melanin units seemed to be altered in her case. It is possible that the intercellular particles consisted of ribosomes or ,a-glycogen that had leaked through cell membranes; the larger accumulations against the melanocytes may be related to the weaker cohesion between melanocytes and keratinocytes, as compared with adjacent keratinocytes. Light-histochemical study did
not allow identification of the granular material. Marked degenerative melanocyte changes have been reported in other hypopigmentary conditions characterized by linear lesions, such as ipcontinentia pigmenti achromians (hypomelanosis of ItO)22,23 and nevus depigmentoslIs,24 but without vacuolar alteration at the interface between basal keratinocytes and melanocytes. Differential diagnosis··. of Proteus syndrome is complicated by a wide range of manifestations. Von Recklinghausen's disease may produce asymmetric growth and macrodactyly, but it may be distinguished from Proteus syndrome by the presence of axillary freckling, neurofibromas, and iris nodules. 25 Klippel-Trenaunay syndrome and congenital lymphedema may lead to hypertrophy and macrodactyly but lack exostosis and cerebroid thickening of palms and soles. Bannayan syndrome produces macrocephaly, benign mesodermal subcutaneous hamartomas, and growth retardation, but not macrodactyly and hemihypertrophy.26 Ollier's disease and Maffucci's syndrome can be differentiated from Proteus syndrome by the presence of enchondromatosis. Megalodactyly can also be observed in macrodactylia simplex congenita, but the latter is always congenital and does not increase disproportionately with growth.? Depigmented lesions that follow Blaschko's lines, as in our case, can also be seen in nevus depigmentosus 24 and incontinentia pigmenti
382 Nazzaro et al. achromians22 but without any verrucous component. Nearly all previous cases have been in children, arId the course of the syndrome over a long time is ndt well known. It has been suggested that the small number of adult cases results from a propensity for neoplastic changes, common to other hamartomatous conditions. 9 However, to our knowledge, early death from cancer has never been reported in connection with Proteus syndrome. The long-term prognosis probably depends on where a particular case falls within the broad range of phenotypes in Proteus syndrome that have been reported, and that include extremely severe forms 16 and milder ones. 9 Our 30year-old patient, who seemed to have a less severe form of the disease, demonstrated that mildly affected patients can attain adulthood without major problems and can have normal children. The causes ofthe Proteus syndrome are unknown. Alterations in growth factors or in their receptors may contribute to the development of the disease, but no data exist to support this hypothesis. In hyperproliferative skin diseases such as psoriasis, ichthyosis, and seborrheic keratosis, increased EGF receptor expression has been reported. 27, 28 In our immunohistochemical study, EGF staining was limited to basal keratinocytes, as in normal epidermis. These data, however, do not exclude a possible functional alteration of EGF or an involvement of other growth factors in the pathogenesis of the multifocal overgrowths in this syndrome. The wide range of phenotypes, the casual and irregular distribution of overgrowing tissue, the distribution of epidermal lesions along the lines of Blaschko, and the evidence that all reported cases are sporadic could be explain~d by the action of a dominant lethal gene that allows survival by mosaicism. 29 , 30 If this is the mechanism, the risk of occurrence of the syndrome in future children of an affected patient should be negligible. However, no definitive proof of this theory exists, and it is difficult to provide genetic counseling to an affected adult. REFERENCES I. Wiedemann HR, Burgio GR, Aldenhoff P, et al. The proteus syndrome. Partial gigantism ofthe hands and/or feet, nevi, hemihypertrophy, subcutaneous tumors, macrocephaly or other skull anomalies and possible accelerated growth and visceral affections. Eur 1 Pediatr 1983;140:5-12. 2. Fay IT, Schow SR. A possible case of Maffucj's syndrome. 1 Oral Surg 1968;26:739-44. 3. Horton WA. Klippel-Trenaunay syndrome. In: Bergsma D, ed. DBOAS: skin, hair and nails. Baltimore: Williams &
lourna1 of the American Academy of Dermatology
Wilkins, 1971;7:116-8. (National Foundation-March of Dimes Series) 4. Kontras SB. Case report 19. Syndrome Identification (March of Dimes) 1974;2:1-3. 5. Cohen MM lr, Hayden PW. A newly recognized hamartomatous syndrome. In: Bergsma D, ed. DBOAS:penetrance and variability in malformation syndromes. New York: Alan R Liss, 1979;15:291-6. (National FoundationMarch of Dimes Series) 6. Pawlaczyk B, Sioda T. Hypertrophied lumbar and muscular atrophy. Synd Ident 1976;4:4. 7. Temtamy SA, Rogers YG. Macrodactyly, hemihypertrophy, and connective tissue nevi: report of a new syndrome and review of the literature. 1 Pediatr 1976;89:924-7. 8. Viljoen DL, Saxe N, Temple Camp C. Cutaneous manifestations of the Proteus syndrome. Pediatr Dermatol 1988;5:14-21. 9. Viljoen DL, Nelson MM, de long G, et al. Proteus syndrome in southern Africa: natural history and clinical manifestations in six individuals. Am 1 Med Genet 1987;27:87-97. 10. Clark RD, Donnai D, Rogers 1, et al. Proteus syndrome: an expanded phenotype. Am 1 Med Genet 1987;27:99-117. 11. Samlaska CP, Levin SW, James WD, et al. Proteus syndrome. Arch Dermatol 1989;125:1109-14. 12. Cordell lL, Falini B, Erber WN, et al. Immunoenzymatic labeling ofmonoclonal antibodies using immune complexes of alkaline phosphatase and monoclonal anti-alkaline phosphatase (APAAP complexes). 1 Histochem Cytochem 1984;32:219-29. 13. Costa T, Fitch N, Azouz EM. Proteus syndrome: report of two cases with pelvic lipomatosis. Pediatrics 1985;76: 984-9. 14. Mucke 1, Willgerodt H, Kunzel R, et aI. Variability in the Proteus syndrome: report of an affected child with progressive lipomatosis. Eur J Pediatr 1985;143:320-3. 15. Wiedemann HR, Burgio GR. Encephalocraniocutaneous lipomatosis and Proteus syndrome. Am 1 Med Genet 1986;25:403-4. 16. Mayatepek E, Kurczyndki TW, Ruppert ES, et aI. Expanding the phenotype of the Proteus syndrome: a severely affected patient with new findings. Am 1 Med Genet 1989;32:402-6. 17. Malamitsi Puchner A, Kitsiou S, Bartsocas CS. Severe proteus syndrome in an 18-month-old boy. Am 1 Med Genet 1987;27:119-25. 18. Burgio GR, Weidemann HR. Further and new details on the Proteus syndrome. Eur 1 Pediatr 1984;143:71-3. 19. Moellmann G, Klein-Angerer S, Scollay DA, et al. Extracellular granular material and degeneration of keratinocytes in the normally pigmented epidermis of patients with vitiligo. 1 Invest Dermatol 1982;79:321-30. 20. Lawlor F, Kobza Black A, Breathnach AS, et al. Vibratory angioedema: lesion induction, clinical features, laboratory and ultrastructural findings and response to therapy. Br 1 Dermatol 1989;120:93-100. 21. Obasi OE, Isitor GN. Extensive congential bilateral epidermal nevus syndrome-a case report from Nigeria with ultrastructural observations. Clin Exp Dermatol 1987; 12:132-5. 22. Morohashi M, Hashimoto K, Goodman TF lr, et aI. Ultrastructural studies ofvitiligo, Vogt-Kiyanagi syndrome, and incontinentia pigmenti achromians. Arch Dermatol 1977;113:755-66. 23. Nordlund 11, Klaus SN, Gino J. Hypomelanosis of Ito. Acta Derm Venereal (Stockh) 1977;57:261-4.
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24. Jimbow K, Fitzpatrick TB, Szabo G, et aI. Congenital circumscribed hypomelanosis; a characterization based on electron microscopic study of tuberous sclerosis, nevus depigmentosus, and piebaldism. J Invest Dermatol 1975; 64:50-62. 25. Tibbles lA, Cohen MM Jr. The Proteus syndrome: the Elephant Man diagnosed. Br Med J Clin Res 1986;293: 683-5. 26. Bialer MG, Riedy MJ, Wilson WG. Proteus syndrome versus Bannayan Zonana syndrome: a problem in differential diagnosis. Eur J Pediatr 1988;148:122-5.
Proteus syndrome 27. NanneyLB, Stoscheck CM, Magid M, et aI. Altered [l2sI] epidermal growth factor binding and receptor distribution in psoriasis. J Invest DermatolI986;86:26Q-S. 28. Rothe M, Falanga V. Growth factors. Their biology and promise in dermatologic diseases and tissue repair. Arch Dermatol1989jI25:1390-8. 29. Happle R. Lethal genes surviving by mosaicism: a possible explanation for sporadic birth defects involving the skin. J AM ACAD DERMATOL 1987;16:899-906. 30. Happle R. Cutaneous manifestation of lethal genes. Hum Genet 1986;72:280.
IgA pemphigus in a child Ruggero Caputo, MD, Grazia Pistritto, MD, Enrica Gianni, MD, Guido Canninati, MD, Anna Crupi, MD, Emilio Berti, MD, Carlo Gelmetti, MD, and Simona Croci, MD
Milan, Italy The authors describe the first case of 19A pemphigus reported in a child. (1 AM ACAD DERMATOL 1991;25:383-6.)
The term IgA pemphigus has been suggested by Beutner et al. l to designate a rare type of pemphigus characterized by a vesicular-bullous eruption that simulates subcorneal pustular dermatosis or pemphigus foliaceus, subcorneal or intraepidermal acantholysis, and intercellular IgA antibodies in the upper epidermis. Eleven cases in adults have been reported. l - ID We report the first case of IgA pemphigus in a child. CASE REPORT
An ll-year-old girl had a blistering eruption for 15 days that was initially diagnosed as streptococcal impetigo and treated unsuccessfully with erythromycin. Her eruption involved mainly the upper trunk (Fig. 1), the neck, and retroauricular areas (Fig. 2). The abdomen and buttocks were also affected. Mucous membranes, palms, and soles were spared. The eruption consisted of irregular, erythematous areas covered with small blisters, crusts, and scales, and some isolated bullae. These lesions tended to coalesce to form ringlike or serpiginous patFrom the First Department of Dermatology and Pediatric Dermatology. University of Milan. Reprint requests: Prof. Ruggero Caputo, Clinica Dermatologica r, Via Pace. 9, 20122 Milano, ITALY. 16/4/24616
Fig. 1. Vesicular, scaling lesions on trunk and arms.
383
2. Finan MC, Winkelmann RK. Histopathology of necrobiotic xanthogranuloma with paraproteinemia. J Cutan Pathol 1987;14:92-9. 3. Robertson DM, Winkelmann RK. Opthalmic features of necrobiotic xanthogranuloma with paraproteinemia. Am J OphthalmoI1984;97:173-83. 4. Finan MC, Winkelmann RK. Necrobiotic xanthogranuloma with paraproteinemia. Medicine 1986;65:376-88. 5. Kyle RA, Greiopp PRo Smoldering multiple myeloma. N Engl J Med 1980;302:1347-9. 6. Hashimoto K, Burk JD, Bale GF, et al. Transient bullous dermolysis of the newborn: two additional cases. 1 AM ACAD DERMATOL 1989;21:708-13. 7. Clark G. Staining procedures. 4th ed. Baltimore: Williams & Wilkins 1981:189-95.
Necrobiotic xanthogranuloma 8. Durie BGM, Salmon SE. A clinical staging system for multiple myeloma. Cancer 1975;36:842-54. 9. Alexanian R, Berlogie B, Dixon D. High-dose glucocorticoid treatment of resistant myeloma. Ann Intern Moo 1983;105:8-11. 10. Venencie PY, Puissant A, Verola 0, et al. Necrobiotic xanthogranuloma with myeloma: a case report. Cancer 1987;59:588-92. 11. Bernstein MJ. Magnetic resonance imaging. Consensus Conference. lAMA 1988;259:2132-8. 12. Daffner RH, Lupetin AR, Dash N, et al. MRI in the detection of malignant infiltration of bone marrow. Am J RoentgenoI1986;146:353-8.
Proteus syndrome Ultrastructural study of linear verrucous and depigmented nevi Vincenzo Nazzaro, MD,t Stefano Cambiaghi, MD,a Alessandro Montagnani, MD,b Alberto Brusasco, MD,a Amilcare Cerri, MD,a and Ruggero Caputo, MDa Milan, Italy Proteus syndrome is a rare hamartomatous disorder charact~erized by multifocal overgrowths that can involve any structure of the body. Clinical manifestations include macrodactyly, hemihypertrophy, subcutaneous masses, exostosis, cerebroid thickening of palms and soles, and linear skin lesions. About 50 cases have been described, but the ultrastructural features of the linear skin lesions have not been characterized. We describe the clinical, histologic, and ultrastructural findings for a 30-year-old patient who had a mild form of Proteus syndrome with linear lesions characterized by a mixed pattern of hyperkeratosis and depigmentation. Light microscopy of the linear nevus showed acanthosis and hyperorthokeratosis. Electron microscopy revealed extensive vacuolation at the interface between melanocytes and keratinocytes, with large aggregations of densely packed granules in the intercellular space. Melanocytes showed only slight degenerative changes. An immunohistochemical study of the expression of epidermal growth factor receptors revealed no significant abnormalities. (J AM ACAD DERMATOL 1991;25:377-83.) Proteus syndrome is a hamartomatous disorder characterized by multiple focal overgrowths that can involve any structure of the body. The name of the syndrome was suggested by Wiedemann et a1. 1 in 1983 from the name of the Greek god "Proteus," the polymorph, to emphasize the wide range of clio-
From the Centro Malattie Cutanee Ereditarie, Dermatology Clinie I, University of Milan,' and the Centro Auxologico Italiano.b Reprint requests: Vincenzo Nazzaro, MD, Centro Malattie Cutanee Ereditarie, Clinica Dermatologica Prima, via Pace 9, 20122 Milan, Italy. tDeceased.
16/4/23681
ical manifestations. About 50 cases have been reported; this number includes several cases described before 1983 and subsequently discovered to be Proteus syndrome. 2-8 Typical clinical features include progressive and asymmetric megalodactyly, hemihypertrophy, subcutaneous masses, localized cerebroid thickening of palms and sales, and linear skin lesions. 9- 11 It has been suggested that growth-factor abnormalities are responsible for the tissue overgrowths, but no growth-factor studies have been reported to date. Apart from four cases in adults 9, 10 aU reported cases have been in children. The long-term prognosis is not well known. Linear skin lesions, which have been observed in
377
378
Nazzaro et al.
Journal of the American Academy of Dermatology
Fig. 1. Asymmetric macrodactyly of the first two fingers of the left hand.
Fig. 2. Cerebroid nodular thickening of the right heel and sole. Note scar from surgical amputation of the second and third toes. A subcutaneous mass is present on the back of the foot.
the majority of cases of Proteus syndrome, are an im]X>rtant diagnostic sign. They have been variously described as hypopigmented, hyperpigmented, or epidermal verrucous nevi. No ultrastructural study has been reported so far. We describe a mild form of the Proteus syndrome in a woman with linear, depigmented, and verrucous nevi distributed along Blaschko's lines, and we report the histologic, ultrastructural, and epidermal growth factor-binding features of her linear skin lesion.
CASE REPORT A 30-year-old woman had partial acral giantism and linear skin lesions. She had been bom after a normal pregnancy and delivery to a healthy, 28-year-old woman
(gravida 2, para 2, abortus 0) and her 34-year-old husband. Her birth weight was 3600 gm. At 5 days ofage, she was noted to have enlargement of the first three toes of the right foot. The toes continued to enlarge, and at 3 months the second and third toes were amputated. Megalodactyly of the left index finger and thumb developed progressively during the first years of her life and continued until she reached 16 years of age. She had linear and partly raised depigmented skin lesions on her lower limbs from infancy through adulthood. During childhood and adolescence, the patient had 19 operations to reduce digit malposition and to remove overgrowing subcutaneous masses; histologic examination revealed irregular proliferation ofadipose, fibrous, lymphatic, and nervous tissues. After an uneventful pregnancy, she gave birth to a normal child who was 18 months old when we received the
Volume 25 Number 2, Part 2 August 1991
patient for treatment. Familial history did not reveal any cutaneous, skeletal, or other significant abnormalities, and there was no consanguinity. Physical examination showed a woman in good general health with normal height and weight and with no mental retardation. Macrodactyly of the left index, left thumb, and right hallux was apparent (Fig. 1). The skin of the volar aspect of the same fingers showed nodular hypertrophy and irregular thickening. There was "brainlike" hypertrophy of the right heel, and a soft mass was evident on the back of the right foot (Fig. 2). Moderate hypertrophy of the right breast was present. Linear hypopigmented skin lesions were distributed along Blaschko's lines on the left lower limb. They were flat and barely visible on the thigh and leg and had a more noticeable verrucous component on the ankle (Fig. 3). No maerocephaly, skull exostosis, or scoliosis was found. Hair, nails, and teeth were normal, and no ophthalmologic or neurologic abnormalities could be detected. X-ray examination showed bone and soft tissue hypertrophy of the first two left fingers, with irregular cortical border and exostosis of the second phalanx; skull, spine, and long bones were normal. Laboratory data, including CBC, erythrocyte sedimentation rate, protein electrophoresis, and levels of electrolytes, transaminases, urea, cholesterol, and triglycerides, were normal. Renal ultrasonography was normal. Cytogenetic studies showed normal 46,XX chromosomes.
Proteus syndrome 379
Fig. 3. Linear nevus on the lower left leg shows mixed pattern of hypopigmentation and verrucosity.
MATERIAL AND METHODS
A skin specimen was obtained from a skin lesion on the left leg. For histochemical evaluation, 4/otm frozen sections were stained with hematoxylin and eosin, periodic acid-Schiff (PAS) reaction, PAS combined with diastase, and Sudan black B fat stains. Localization of immunoreactive epidermal growth factor (EGF) receptors was performed with anti-EGF receptor monoclonal antibody (Sanbyo, Uden, The Netherlands). The sections were then processed by the alkaline-phosphotase antialkaline-phosphatase method, according to Cordell et al. 12 For electron microscopy, semithin sectionswerestained with toluidine blue and periodic acid-silver methenamine reaction, and ultrathin sections werestained with aqueous uranyl acetate and lead citrate.
RESULTS Light microscopy showed acanthosis and compact hyperorthokeratosis with augmented and irregular undulations between rete ridge and dermal papillae. In the dermis a scant, nonspecific, perivascular infiltrate consisting of lymphocytes and histiocytes was observed. PAS, aldan blue, Sudan black B fat, and periodic acid-silver methenamine stains were negative.
Electron microscopy revealed no significant abnormalities of the cellular keratinization elements. Large vesicles containing sparse, electron-dense, ribosome-like granules were frequently seen at the interface between basal keratinocytes and melanocytes (Figs. 4 and 5). Most of the vesicles were continuous, with areas of fine granularity of keratinocytes that elsewhere had a normal appearance and had the normal tonofibrils and cellular organelles. In other cases the vesicles appeared to be located in the intercellular space or within the melanocytes. Many densely packed particles similar to ,8-glycogen or ribosomes were located at the interface between melanocytes and keratinocytes (Figs. 4 and 5). Smaller amounts of the same granules were also in the intercellular space between basal keratinocytes (Fig. 6). Melanocytes were frequently. at the dermoepidermal junction and had only moderate dilation of the rough endoplasmic reticulum and swelling of mitochondria. The number of melanosomes appeared normal, and there were normally shaped melanosomes in all stages of development; no aggregations of melanosomes, macromelanosomes, autophagocy-
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Fig. 4. Electron micrograph of skin specimen obtained from linear nevus shows marked vacuolization (v) and accumulation of granular material (asterisk) at the interface between keratinocytes (k) and melanocyte (m) (X3400). (Boxed areas refer to Figs. 5 and 6.)
tosis of melanosomes, or cytoplasmic lipid droplets were discovered. A stratum granulosum was present. Keratohyalin granules, associated with the tonofilament bundles, showed no significant abnormality. Membrane-coating granules appeared to be numerous, and lamellae derived from them were generally in their normal positions, between granular cells and corneocytes. The stratum corneum was normal. No lipidlike vacuoles or electron-lucent crystals were found in either keratinocytes or corneocytes. The EGF binding study revealed a normal distribution of EGF receptors. They were present mainly on basal keratinocytes and were less frequent in the upper epidermal layers. DISCUSSION
Proteus syndrome is characterized by multifocal overgrowths that can affect any tissue and structure of the body. I, 9-11 The abnormalities are present at birth or appear in the first years of life and usually progress up to the time of puberty. Progressive and asymmetric megalodactyly, hemihypertrophy, and multiple exostosis, involving especially the skull and the digits, are the main extracutaneous clinical manifestations. Visceral hamartomas such as pul-
monary cysts and visceral lipomatosis can also be observed. I, 13-15 Cutaneous manifestations are frequent and result from hamartomas of various components of epidermis, dermis, and/or subcutaneous tissue. Cerebriform or nodular gross thickening of palms and soles seems to be one of the most frequent and typical features of this disorder. S,11 This thickening consists of irregular proliferation of adipose and fibrous tissue with or without hyperkeratosis. 8,l1,14 Ultrastructural examination, performed in one case, showed unusually elongated cytoplasmic projections of the basal cells into the dermoepidermal junction. 8 Hamartomatous masses of subcutaneous tissue nearly always accompany Proteus syndrome; they consist of adipose tissue or a various combination of adipose, lymphatic, and hemangiomatous tissue13 , 14 and can affect any area of the body. Varicose veins,I, 3, 7,10,16 cafe-au-Iait Spots,2, 4 sebaceous nevi, 14 and decreased subcutaneous tissue10, 1\ have also been described in association with this disease. Linear epidermal nevi have been reported in more than half the cases ofProteus syndrome. Our review revealed that they frequently have a mixed pattern
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Proteus syndrome 381
Fig. 5. Higher magnification of the same specimen in Fig. 4 shows densely packed granules similar to l1-g1ycogen or ribosomes (asterisks) within intercellular space between melanocyte (m) and keratinocyte (k) (X24,500).
Fig. 6. Higher magnification of same specimen in Fig. 4 shows densely packed granules (asterisk) in intercellular space between adjacent keratinocytes (arrow, desmosome) (X24,500).
of verrucosity with hypopigmentation, hyperpigmentation, or both. I, 7, 9-13 Their distribution along Blaschko's lines is evident from the illustrations that accompany at least three different reports. I, 9, 17 Histologic examination, reported in a few studies, showed papillomatosis, acanthosis, and hyperkeratosis. 9,18 Our examination by light and electron microscopy of a linear, depigmented, and verrucous lesion revealed acanthosis and hyperorthokeratosis, together with large vacuoles and aggregations of ribosome-like particles at the interface between melanocytes and keratinocytes. Similar findings have been reported in the normally pigmented skin of patients with rapidly progressive or stable vitiligo. 19 Vacuoles at the interface between keratinocytes and melanocytes have also been seen in near-normal skin and in some urticarial conditions, but these vacuoles did not contain granules. 2o To our knowledge, no other condition with linear epidermal nevi manifests itself in ultrastructural features similar to those observed in our patient. 21 The whole epidermal melanin units seemed to be altered in her case. It is possible that the intercellular particles consisted of ribosomes or ,a-glycogen that had leaked through cell membranes; the larger accumulations against the melanocytes may be related to the weaker cohesion between melanocytes and keratinocytes, as compared with adjacent keratinocytes. Light-histochemical study did
not allow identification of the granular material. Marked degenerative melanocyte changes have been reported in other hypopigmentary conditions characterized by linear lesions, such as ipcontinentia pigmenti achromians (hypomelanosis of ItO)22,23 and nevus depigmentoslIs,24 but without vacuolar alteration at the interface between basal keratinocytes and melanocytes. Differential diagnosis··. of Proteus syndrome is complicated by a wide range of manifestations. Von Recklinghausen's disease may produce asymmetric growth and macrodactyly, but it may be distinguished from Proteus syndrome by the presence of axillary freckling, neurofibromas, and iris nodules. 25 Klippel-Trenaunay syndrome and congenital lymphedema may lead to hypertrophy and macrodactyly but lack exostosis and cerebroid thickening of palms and soles. Bannayan syndrome produces macrocephaly, benign mesodermal subcutaneous hamartomas, and growth retardation, but not macrodactyly and hemihypertrophy.26 Ollier's disease and Maffucci's syndrome can be differentiated from Proteus syndrome by the presence of enchondromatosis. Megalodactyly can also be observed in macrodactylia simplex congenita, but the latter is always congenital and does not increase disproportionately with growth.? Depigmented lesions that follow Blaschko's lines, as in our case, can also be seen in nevus depigmentosus 24 and incontinentia pigmenti
382 Nazzaro et al. achromians22 but without any verrucous component. Nearly all previous cases have been in children, arId the course of the syndrome over a long time is ndt well known. It has been suggested that the small number of adult cases results from a propensity for neoplastic changes, common to other hamartomatous conditions. 9 However, to our knowledge, early death from cancer has never been reported in connection with Proteus syndrome. The long-term prognosis probably depends on where a particular case falls within the broad range of phenotypes in Proteus syndrome that have been reported, and that include extremely severe forms 16 and milder ones. 9 Our 30year-old patient, who seemed to have a less severe form of the disease, demonstrated that mildly affected patients can attain adulthood without major problems and can have normal children. The causes ofthe Proteus syndrome are unknown. Alterations in growth factors or in their receptors may contribute to the development of the disease, but no data exist to support this hypothesis. In hyperproliferative skin diseases such as psoriasis, ichthyosis, and seborrheic keratosis, increased EGF receptor expression has been reported. 27, 28 In our immunohistochemical study, EGF staining was limited to basal keratinocytes, as in normal epidermis. These data, however, do not exclude a possible functional alteration of EGF or an involvement of other growth factors in the pathogenesis of the multifocal overgrowths in this syndrome. The wide range of phenotypes, the casual and irregular distribution of overgrowing tissue, the distribution of epidermal lesions along the lines of Blaschko, and the evidence that all reported cases are sporadic could be explain~d by the action of a dominant lethal gene that allows survival by mosaicism. 29 , 30 If this is the mechanism, the risk of occurrence of the syndrome in future children of an affected patient should be negligible. However, no definitive proof of this theory exists, and it is difficult to provide genetic counseling to an affected adult. REFERENCES I. Wiedemann HR, Burgio GR, Aldenhoff P, et al. The proteus syndrome. Partial gigantism ofthe hands and/or feet, nevi, hemihypertrophy, subcutaneous tumors, macrocephaly or other skull anomalies and possible accelerated growth and visceral affections. Eur 1 Pediatr 1983;140:5-12. 2. Fay IT, Schow SR. A possible case of Maffucj's syndrome. 1 Oral Surg 1968;26:739-44. 3. Horton WA. Klippel-Trenaunay syndrome. In: Bergsma D, ed. DBOAS: skin, hair and nails. Baltimore: Williams &
lourna1 of the American Academy of Dermatology
Wilkins, 1971;7:116-8. (National Foundation-March of Dimes Series) 4. Kontras SB. Case report 19. Syndrome Identification (March of Dimes) 1974;2:1-3. 5. Cohen MM lr, Hayden PW. A newly recognized hamartomatous syndrome. In: Bergsma D, ed. DBOAS:penetrance and variability in malformation syndromes. New York: Alan R Liss, 1979;15:291-6. (National FoundationMarch of Dimes Series) 6. Pawlaczyk B, Sioda T. Hypertrophied lumbar and muscular atrophy. Synd Ident 1976;4:4. 7. Temtamy SA, Rogers YG. Macrodactyly, hemihypertrophy, and connective tissue nevi: report of a new syndrome and review of the literature. 1 Pediatr 1976;89:924-7. 8. Viljoen DL, Saxe N, Temple Camp C. Cutaneous manifestations of the Proteus syndrome. Pediatr Dermatol 1988;5:14-21. 9. Viljoen DL, Nelson MM, de long G, et al. Proteus syndrome in southern Africa: natural history and clinical manifestations in six individuals. Am 1 Med Genet 1987;27:87-97. 10. Clark RD, Donnai D, Rogers 1, et al. Proteus syndrome: an expanded phenotype. Am 1 Med Genet 1987;27:99-117. 11. Samlaska CP, Levin SW, James WD, et al. Proteus syndrome. Arch Dermatol 1989;125:1109-14. 12. Cordell lL, Falini B, Erber WN, et al. Immunoenzymatic labeling ofmonoclonal antibodies using immune complexes of alkaline phosphatase and monoclonal anti-alkaline phosphatase (APAAP complexes). 1 Histochem Cytochem 1984;32:219-29. 13. Costa T, Fitch N, Azouz EM. Proteus syndrome: report of two cases with pelvic lipomatosis. Pediatrics 1985;76: 984-9. 14. Mucke 1, Willgerodt H, Kunzel R, et aI. Variability in the Proteus syndrome: report of an affected child with progressive lipomatosis. Eur J Pediatr 1985;143:320-3. 15. Wiedemann HR, Burgio GR. Encephalocraniocutaneous lipomatosis and Proteus syndrome. Am 1 Med Genet 1986;25:403-4. 16. Mayatepek E, Kurczyndki TW, Ruppert ES, et aI. Expanding the phenotype of the Proteus syndrome: a severely affected patient with new findings. Am 1 Med Genet 1989;32:402-6. 17. Malamitsi Puchner A, Kitsiou S, Bartsocas CS. Severe proteus syndrome in an 18-month-old boy. Am 1 Med Genet 1987;27:119-25. 18. Burgio GR, Weidemann HR. Further and new details on the Proteus syndrome. Eur 1 Pediatr 1984;143:71-3. 19. Moellmann G, Klein-Angerer S, Scollay DA, et al. Extracellular granular material and degeneration of keratinocytes in the normally pigmented epidermis of patients with vitiligo. 1 Invest Dermatol 1982;79:321-30. 20. Lawlor F, Kobza Black A, Breathnach AS, et al. Vibratory angioedema: lesion induction, clinical features, laboratory and ultrastructural findings and response to therapy. Br 1 Dermatol 1989;120:93-100. 21. Obasi OE, Isitor GN. Extensive congential bilateral epidermal nevus syndrome-a case report from Nigeria with ultrastructural observations. Clin Exp Dermatol 1987; 12:132-5. 22. Morohashi M, Hashimoto K, Goodman TF lr, et aI. Ultrastructural studies ofvitiligo, Vogt-Kiyanagi syndrome, and incontinentia pigmenti achromians. Arch Dermatol 1977;113:755-66. 23. Nordlund 11, Klaus SN, Gino J. Hypomelanosis of Ito. Acta Derm Venereal (Stockh) 1977;57:261-4.
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24. Jimbow K, Fitzpatrick TB, Szabo G, et aI. Congenital circumscribed hypomelanosis; a characterization based on electron microscopic study of tuberous sclerosis, nevus depigmentosus, and piebaldism. J Invest Dermatol 1975; 64:50-62. 25. Tibbles lA, Cohen MM Jr. The Proteus syndrome: the Elephant Man diagnosed. Br Med J Clin Res 1986;293: 683-5. 26. Bialer MG, Riedy MJ, Wilson WG. Proteus syndrome versus Bannayan Zonana syndrome: a problem in differential diagnosis. Eur J Pediatr 1988;148:122-5.
Proteus syndrome 27. NanneyLB, Stoscheck CM, Magid M, et aI. Altered [l2sI] epidermal growth factor binding and receptor distribution in psoriasis. J Invest DermatolI986;86:26Q-S. 28. Rothe M, Falanga V. Growth factors. Their biology and promise in dermatologic diseases and tissue repair. Arch Dermatol1989jI25:1390-8. 29. Happle R. Lethal genes surviving by mosaicism: a possible explanation for sporadic birth defects involving the skin. J AM ACAD DERMATOL 1987;16:899-906. 30. Happle R. Cutaneous manifestation of lethal genes. Hum Genet 1986;72:280.
IgA pemphigus in a child Ruggero Caputo, MD, Grazia Pistritto, MD, Enrica Gianni, MD, Guido Canninati, MD, Anna Crupi, MD, Emilio Berti, MD, Carlo Gelmetti, MD, and Simona Croci, MD
Milan, Italy The authors describe the first case of 19A pemphigus reported in a child. (1 AM ACAD DERMATOL 1991;25:383-6.)
The term IgA pemphigus has been suggested by Beutner et al. l to designate a rare type of pemphigus characterized by a vesicular-bullous eruption that simulates subcorneal pustular dermatosis or pemphigus foliaceus, subcorneal or intraepidermal acantholysis, and intercellular IgA antibodies in the upper epidermis. Eleven cases in adults have been reported. l - ID We report the first case of IgA pemphigus in a child. CASE REPORT
An ll-year-old girl had a blistering eruption for 15 days that was initially diagnosed as streptococcal impetigo and treated unsuccessfully with erythromycin. Her eruption involved mainly the upper trunk (Fig. 1), the neck, and retroauricular areas (Fig. 2). The abdomen and buttocks were also affected. Mucous membranes, palms, and soles were spared. The eruption consisted of irregular, erythematous areas covered with small blisters, crusts, and scales, and some isolated bullae. These lesions tended to coalesce to form ringlike or serpiginous patFrom the First Department of Dermatology and Pediatric Dermatology. University of Milan. Reprint requests: Prof. Ruggero Caputo, Clinica Dermatologica r, Via Pace. 9, 20122 Milano, ITALY. 16/4/24616
Fig. 1. Vesicular, scaling lesions on trunk and arms.
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