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Multiple minute digitate hyperkeratosis
Multiple minute digitate hyperkeratosis L. Balus, M.D.,* P. Donati, M.D.,* A. Amantea, M.D.,* and A. S. Breathnach, M.D.**
Rome, ltaly, and London, England We report a case of multiple minute digitate hyperkeratosis. The patient had hundreds of keratotic lesions--some tiny and spiked, others larger, fiat papules--localized on the trunk and arms. Histologic sections showed focal areas of compact hyperorthokeratosis with few dermal changes. Ultrastructurally, keratohyalin granules were smaller than normal. The keratin pattern was one of a normal variant. Odland bodies present. Various family members of the patient, in different generations, were affected. (J AM ACAD DERMATOL 1988;18:431-6.)
First described by Goldstein ~ in 1967, multiple minute digitate hyperkeratosis is a new genetic nonfollicular disorder of keratinization. Only six reports ~6 have appeared to date in the literature, often under various names, including "disseminated spiked hyperkeratoses,'3 "hyperk6ratose piliforme diss6min6e familiale," and "minute aggregate keratoses. ''4
From the San Gallicano Dermatologie Institute,* Rome, and St. Mary's Hospital Medical School,** London. Reprint requests to: Dr. L. Balus, Instltuto Derrnatologico San Gallicano, Via S. Gallicano 25/A, Rome 00153 Italy.
We have had the opportunity to observe a familial form of multiple minute digitate hyperkeratosis and to study its clinical, histologic, and ultrastmctural features. CASE REPORT The patient is a 48-year-old woman suffering from an asymptomatic eruption on her back, which started at the age of 20 years. Progressively, the skin lesions involved the chest and upper limbs. At the age of 28 years she had surgery for fibrocystic disease of the left breast and, 10 years later, hysterectomy for a fibroid tumor. She is presently under treatment for mild hypertension. Otherwise, her general health is good.
/ Fig. 1. Pedigree of a family with multiple minute digitate hyperkeratosis, showing transmission through three generations. Affected males (solid squares), affected females (solid circles), and the proposita (arrow) are shown. 431
432
Balus et al
Journal of the American Academy of Dermatology
Fig. 2. Eruption of the back. Intermingled short spicules and larger, flat-topped keratotic papules are seen.
Fig. 3. Photomicrograph of characteristic focal digitiform hyperorthokeratosis. The epidermis between the two columns is normal. (Hematoxylin-eosin stain; × 62.) According to the patient, several members of her family were affected with a similar skin disorder. In fact, study of the pedigree revealed six affected members in different generations. We were able to examine three of them with skin eruptions similar to that of our patient (Fig. 1). Examination showed hundreds of keratotic papules over the back, shoulder, chest, arms, and thighs. Some of the lesions were short spicules with tiny, digitiform projections 1-2 mm in length; others were larger papules, 2-3 mm in diameter and height, with irregular shapes, some being flat-topped and others dome-shaped.
These two types of lesions were intermingled on the same cutaneous areas, and an almost imperceptible morphologic transition between them was seen (Fig. 2). Palpation of the pathologic skin surface produced the impression of sandpaper. The nails and hair were normal. The palms and soles were not involved, and the skin surrounding the keratotic papules was normal. Light microscopy. Several skin biopsy specimens were taken from our patient and from two relatives; all the specimens demonstrated an identical histologic appearance. On sections stained with hematoxylin and
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Multiple minute digitate hyperkeratosis 433
Fig. 4. Detail of a spiked papule seen in Fig. 3. (Heruatoxylin-eosin stain; x 125.)
Fig. 5. Larger and flattened horny projection. (Hematoxylin-eosin stain; × 125.) eosin, the keratotic skin lesions showed focal hyperorthokeratosis, with a compact, pale-staining stratum corneum. The lesions were either thin, elongated columns corresponding to two or three epidermal ridges, or larger, flattened projections occupying the space of four to six epidermal ridges. The stratum granulosum appeared normal or slightly diminished in thickness. The malpighian layer presented a mild aeanthosis and elongation of the rete ridges in the areas under the horny projections. Some enlarged capillaries were seen, but there was no significant cellular infiltrate in the papillary dermis (Figs. 3 to 5).
There were no histologic changes of the pilar or glandular appendages. No relevant positive staining of keratinocytes or melanocytes with antibodies to epidermal cytokeratins and S-100 protein was observed. Electron microscopy. Biopsy material processed for electron microscopy showed focal hyperorthokeratosis associated with epidermal hyperplasia. In these areas, there was a slight inflammatory reaction manifested by (1) widening of intercellular spaces with exudate containing glycogen granules in basal and spinous layers, the exudate being particularly associated with melanocytes, (2) increased numbers of Langerhans cells,
434
Journal of the American Academyof Dermatology
Balus et al
Fig. 6. Stratum granulosum and lower stratum corneum in the region of a spicule. Keratohyalin granules, perhaps smaller than normal, are present. (× 4,950.) Inset: Odland bodies. ( × 30,000.)
Table I. Clinical data in cases of multiple minute digitate hyperkeratosis No. of
Age at onset
Reference
cases
Age
(yr)
Sex I (yr)
1
1
32
M
27
2
1
31
M
30
3
1
55
M
15
3
1
20
M
15
3
1
35
F
20
4
1
47
F
?
4
1
53
F
?
4
1
63
F
30
Back, shoulders Trunk
5 6
1 1
56 71
M M
30 70
Trunk Arms, legs
1
48
F
20
Trunk, arms
Our case
Site
Morphologie features
Inheritance
Chest, legs, arms Trunk
Spiked keratotic papules
No
Spiked and aggregate keratotic papules Spiked keratotic papules
Yes
Spiked keratotic papules
Yes
Spiked keratotic papules
No
Spiked and aggregate keratotic papules Spiked and aggregate keratotic papules Spiked and aggregate keratotic papules Spiked keratotic papules Spiked and large keratotic papules Spiked and large keratotic papules
No
Diffuse skin eruption Diffuse skin eruption Diffuse skin eruption Trunk
Yes
Yes Yes No No Yes
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Multiple minute digitate hyperkeratosis 435
with some in mitosis, and (3) a higher incidence than normal of Langerhans cell-lymphocyte appositions. In the granular layers, both keratohyalin granules and Odland bodies were present. Estimates of the numbers of these structures purely from examination of thin sections are hardly justified, but the impression was that both structures were of normal distribution and concentration, though most of the keratohyalin granules were smaller than normal (Fig. 6). The stratum corneum of keratotic papules had a compact arrangement of flattened cells with a considerable amount of continuous intercellular material (Fig. 7). Over its greatest extent, the keratin pattern was as seen in Fig. 7, but in some places it was less homogeneous and more fibrillar. Both types of pattern occur in normal epidermis. In the dermis, there were focal concentrations of lymphocytic cells and "cuffing" of small vessels. Therapy consisted of applications of keratolytic and vitamin A acid ointments, which resulted in transient improvement of the skin lesions. DISCUSSION Multiple minute digitate hyperkeratosis, identified by Goldstein I in 1967, is an unusual genetic disorder of keratinization (Table I). It is characterized by the following: 1. Inheritance is as an autosomal dominant trait, with onset during the second or third decade. Four cases, including our case, presented a familial incidence. 24 2. The clinical examination showed multiple asymptomatic minute keratotic papules, unrelated to the follicular orifices and located usually on the back and chest. The most distinct and constant lesion is a spiked keratotic projection, but in some cases, including our case, larger, fiat hyperkeratotic papules were observed. 2.4.6 3. Histologic study showed focal hyperorthokeratosis with a moderately acanthotic epidermis as the main features. In addition, there was some dermal cellular infiltrate. 4. Electron microscopic study showed a hypertrophied, compacted stratum corneum with a general keratin pattern of one type commonly seen in normal epidermis. Indi-
Fig. 7. Typically compact stratum comeum of a spicule. Note considerable amount of intercellular material. (x 16,900.) Inset: Keratin pattern of stratum comeum cell. ( x 100,000.)
vidual keratohyalin granules were definitely smaller than normal, and Odland bodies with a normal appearance were present. 5. No other cutaneous or visceral abnormalities have been described in multiple minute digitate hyperkeratosis except in the case reported by Ferrandiz et al, 5 in which the diagnosis was carcinoma of the larynx. An improvement of the eruption after surgical treatment of the tumor was observed, suggesting that this condition was a paraneoplastic symptom. Multiple minute digitate hyperkeratosis must be differentiated from various disseminated disorders of keratinization. Keratosis pilaris, porokeratosis, follicular lichen planus, pityriasis rubra pilaris, and Kyrle's disease can easily be distinguished by their own clinical and histologic features.
436
Balus et al
A skin eruption similar to multiple minute digitate hyperkeratosis is hyperkeratosis lenticularis perstans ( F l e g e l ' s disease), a probably autosomal dominant condition that can be excluded because o f its predominantly acral distribution o f keratotic papules, an orthokeratotic but occasionally parakeratotic epidermis, and a dermal bandlike lymphocytic infiltrate. Furthermore, an absence o f Odland bodies was described in Flegel's disease. 7 The origin o f multiple m i n u t e digitate hyperkeratosis is unknown. Since some genetic factors are clearly related to this process, they could be involved in the pathogenesis of this condition. REFERENCES
1. Goldstein N. Multiple minute digitate hyperkeratoses. Arch Dermatol 1967;96:692-3.
Journal of the American Academy of Dermatology
2. Aufgang A. Hyperk6ratose piliforme diss6min6e familiale. Ann Dermatol Syph (Paris) 1972;99:381-90. 3. Frenk E, Mevorah B, Leu Fr. Disseminated spiked hyperkeratosis. Arch Dermatol 1981;117:412-4. 4. Shutfleworth D, Graham-Brown RAC, Hutchinson PE. Minute aggregate keratoses: a report of three cases. Clin Exp Dermatol 1985;10:566-71. 5. Yoon S, Gibbs RB. Multiple minute digitate hyperkeratoses. Arch Dermatol 1975;111:1176-7. 6. Ferrandiz C, Savall R, Bauman E. Hiperqueratosis multiple minuta y digitata. Med Cutan Ibero Lat Am 1978; 5-6:279-84. 7. Frenk E, Tapernoux B. Hyperkeratosis lenticularis perstans (Hegel): a biological model for keratinization occurring in the absence of Odland bodies. Dermatologica 1976; 153:253-62.
Rome, ltaly, and London, England We report a case of multiple minute digitate hyperkeratosis. The patient had hundreds of keratotic lesions--some tiny and spiked, others larger, fiat papules--localized on the trunk and arms. Histologic sections showed focal areas of compact hyperorthokeratosis with few dermal changes. Ultrastructurally, keratohyalin granules were smaller than normal. The keratin pattern was one of a normal variant. Odland bodies present. Various family members of the patient, in different generations, were affected. (J AM ACAD DERMATOL 1988;18:431-6.)
First described by Goldstein ~ in 1967, multiple minute digitate hyperkeratosis is a new genetic nonfollicular disorder of keratinization. Only six reports ~6 have appeared to date in the literature, often under various names, including "disseminated spiked hyperkeratoses,'3 "hyperk6ratose piliforme diss6min6e familiale," and "minute aggregate keratoses. ''4
From the San Gallicano Dermatologie Institute,* Rome, and St. Mary's Hospital Medical School,** London. Reprint requests to: Dr. L. Balus, Instltuto Derrnatologico San Gallicano, Via S. Gallicano 25/A, Rome 00153 Italy.
We have had the opportunity to observe a familial form of multiple minute digitate hyperkeratosis and to study its clinical, histologic, and ultrastmctural features. CASE REPORT The patient is a 48-year-old woman suffering from an asymptomatic eruption on her back, which started at the age of 20 years. Progressively, the skin lesions involved the chest and upper limbs. At the age of 28 years she had surgery for fibrocystic disease of the left breast and, 10 years later, hysterectomy for a fibroid tumor. She is presently under treatment for mild hypertension. Otherwise, her general health is good.
/ Fig. 1. Pedigree of a family with multiple minute digitate hyperkeratosis, showing transmission through three generations. Affected males (solid squares), affected females (solid circles), and the proposita (arrow) are shown. 431
432
Balus et al
Journal of the American Academy of Dermatology
Fig. 2. Eruption of the back. Intermingled short spicules and larger, flat-topped keratotic papules are seen.
Fig. 3. Photomicrograph of characteristic focal digitiform hyperorthokeratosis. The epidermis between the two columns is normal. (Hematoxylin-eosin stain; × 62.) According to the patient, several members of her family were affected with a similar skin disorder. In fact, study of the pedigree revealed six affected members in different generations. We were able to examine three of them with skin eruptions similar to that of our patient (Fig. 1). Examination showed hundreds of keratotic papules over the back, shoulder, chest, arms, and thighs. Some of the lesions were short spicules with tiny, digitiform projections 1-2 mm in length; others were larger papules, 2-3 mm in diameter and height, with irregular shapes, some being flat-topped and others dome-shaped.
These two types of lesions were intermingled on the same cutaneous areas, and an almost imperceptible morphologic transition between them was seen (Fig. 2). Palpation of the pathologic skin surface produced the impression of sandpaper. The nails and hair were normal. The palms and soles were not involved, and the skin surrounding the keratotic papules was normal. Light microscopy. Several skin biopsy specimens were taken from our patient and from two relatives; all the specimens demonstrated an identical histologic appearance. On sections stained with hematoxylin and
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Multiple minute digitate hyperkeratosis 433
Fig. 4. Detail of a spiked papule seen in Fig. 3. (Heruatoxylin-eosin stain; x 125.)
Fig. 5. Larger and flattened horny projection. (Hematoxylin-eosin stain; × 125.) eosin, the keratotic skin lesions showed focal hyperorthokeratosis, with a compact, pale-staining stratum corneum. The lesions were either thin, elongated columns corresponding to two or three epidermal ridges, or larger, flattened projections occupying the space of four to six epidermal ridges. The stratum granulosum appeared normal or slightly diminished in thickness. The malpighian layer presented a mild aeanthosis and elongation of the rete ridges in the areas under the horny projections. Some enlarged capillaries were seen, but there was no significant cellular infiltrate in the papillary dermis (Figs. 3 to 5).
There were no histologic changes of the pilar or glandular appendages. No relevant positive staining of keratinocytes or melanocytes with antibodies to epidermal cytokeratins and S-100 protein was observed. Electron microscopy. Biopsy material processed for electron microscopy showed focal hyperorthokeratosis associated with epidermal hyperplasia. In these areas, there was a slight inflammatory reaction manifested by (1) widening of intercellular spaces with exudate containing glycogen granules in basal and spinous layers, the exudate being particularly associated with melanocytes, (2) increased numbers of Langerhans cells,
434
Journal of the American Academyof Dermatology
Balus et al
Fig. 6. Stratum granulosum and lower stratum corneum in the region of a spicule. Keratohyalin granules, perhaps smaller than normal, are present. (× 4,950.) Inset: Odland bodies. ( × 30,000.)
Table I. Clinical data in cases of multiple minute digitate hyperkeratosis No. of
Age at onset
Reference
cases
Age
(yr)
Sex I (yr)
1
1
32
M
27
2
1
31
M
30
3
1
55
M
15
3
1
20
M
15
3
1
35
F
20
4
1
47
F
?
4
1
53
F
?
4
1
63
F
30
Back, shoulders Trunk
5 6
1 1
56 71
M M
30 70
Trunk Arms, legs
1
48
F
20
Trunk, arms
Our case
Site
Morphologie features
Inheritance
Chest, legs, arms Trunk
Spiked keratotic papules
No
Spiked and aggregate keratotic papules Spiked keratotic papules
Yes
Spiked keratotic papules
Yes
Spiked keratotic papules
No
Spiked and aggregate keratotic papules Spiked and aggregate keratotic papules Spiked and aggregate keratotic papules Spiked keratotic papules Spiked and large keratotic papules Spiked and large keratotic papules
No
Diffuse skin eruption Diffuse skin eruption Diffuse skin eruption Trunk
Yes
Yes Yes No No Yes
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Multiple minute digitate hyperkeratosis 435
with some in mitosis, and (3) a higher incidence than normal of Langerhans cell-lymphocyte appositions. In the granular layers, both keratohyalin granules and Odland bodies were present. Estimates of the numbers of these structures purely from examination of thin sections are hardly justified, but the impression was that both structures were of normal distribution and concentration, though most of the keratohyalin granules were smaller than normal (Fig. 6). The stratum corneum of keratotic papules had a compact arrangement of flattened cells with a considerable amount of continuous intercellular material (Fig. 7). Over its greatest extent, the keratin pattern was as seen in Fig. 7, but in some places it was less homogeneous and more fibrillar. Both types of pattern occur in normal epidermis. In the dermis, there were focal concentrations of lymphocytic cells and "cuffing" of small vessels. Therapy consisted of applications of keratolytic and vitamin A acid ointments, which resulted in transient improvement of the skin lesions. DISCUSSION Multiple minute digitate hyperkeratosis, identified by Goldstein I in 1967, is an unusual genetic disorder of keratinization (Table I). It is characterized by the following: 1. Inheritance is as an autosomal dominant trait, with onset during the second or third decade. Four cases, including our case, presented a familial incidence. 24 2. The clinical examination showed multiple asymptomatic minute keratotic papules, unrelated to the follicular orifices and located usually on the back and chest. The most distinct and constant lesion is a spiked keratotic projection, but in some cases, including our case, larger, fiat hyperkeratotic papules were observed. 2.4.6 3. Histologic study showed focal hyperorthokeratosis with a moderately acanthotic epidermis as the main features. In addition, there was some dermal cellular infiltrate. 4. Electron microscopic study showed a hypertrophied, compacted stratum corneum with a general keratin pattern of one type commonly seen in normal epidermis. Indi-
Fig. 7. Typically compact stratum comeum of a spicule. Note considerable amount of intercellular material. (x 16,900.) Inset: Keratin pattern of stratum comeum cell. ( x 100,000.)
vidual keratohyalin granules were definitely smaller than normal, and Odland bodies with a normal appearance were present. 5. No other cutaneous or visceral abnormalities have been described in multiple minute digitate hyperkeratosis except in the case reported by Ferrandiz et al, 5 in which the diagnosis was carcinoma of the larynx. An improvement of the eruption after surgical treatment of the tumor was observed, suggesting that this condition was a paraneoplastic symptom. Multiple minute digitate hyperkeratosis must be differentiated from various disseminated disorders of keratinization. Keratosis pilaris, porokeratosis, follicular lichen planus, pityriasis rubra pilaris, and Kyrle's disease can easily be distinguished by their own clinical and histologic features.
436
Balus et al
A skin eruption similar to multiple minute digitate hyperkeratosis is hyperkeratosis lenticularis perstans ( F l e g e l ' s disease), a probably autosomal dominant condition that can be excluded because o f its predominantly acral distribution o f keratotic papules, an orthokeratotic but occasionally parakeratotic epidermis, and a dermal bandlike lymphocytic infiltrate. Furthermore, an absence o f Odland bodies was described in Flegel's disease. 7 The origin o f multiple m i n u t e digitate hyperkeratosis is unknown. Since some genetic factors are clearly related to this process, they could be involved in the pathogenesis of this condition. REFERENCES
1. Goldstein N. Multiple minute digitate hyperkeratoses. Arch Dermatol 1967;96:692-3.
Journal of the American Academy of Dermatology
2. Aufgang A. Hyperk6ratose piliforme diss6min6e familiale. Ann Dermatol Syph (Paris) 1972;99:381-90. 3. Frenk E, Mevorah B, Leu Fr. Disseminated spiked hyperkeratosis. Arch Dermatol 1981;117:412-4. 4. Shutfleworth D, Graham-Brown RAC, Hutchinson PE. Minute aggregate keratoses: a report of three cases. Clin Exp Dermatol 1985;10:566-71. 5. Yoon S, Gibbs RB. Multiple minute digitate hyperkeratoses. Arch Dermatol 1975;111:1176-7. 6. Ferrandiz C, Savall R, Bauman E. Hiperqueratosis multiple minuta y digitata. Med Cutan Ibero Lat Am 1978; 5-6:279-84. 7. Frenk E, Tapernoux B. Hyperkeratosis lenticularis perstans (Hegel): a biological model for keratinization occurring in the absence of Odland bodies. Dermatologica 1976; 153:253-62.