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Background Bullous congenital ichthyosiform erythroderma (BCIE) shows phenotypic variability. An epidermal nevus may represent somatic mosaicism for keratin gene mutation, which produces generalized BCIE in the next generation. This fact provides evidence that a postzygotic mutation can be passed on to the next generation in BCIE. We hypothesized that the same phenomenon occurred in a family with BCIE whose phenotypes were extremely different. Observations We studied a 19-year-old boy with severe ichthyosiform erythroderma and prominent palmoplantar hyperkeratosis with digital contracture. In contrast, the proband's mother exhibited only mild ichthyosiform skin, granular verrucous lesions, and less severe streaky palmoplantar hyperkeratosis. Mutation analysis in the proband showed a keratin K1 mutation (N187S, ie, an A-to-G transition at the second position of codon 187, resulting in an asparagine-to-serine substitution). In the mother, the same keratin gene mutation was recognized, but only faintly in the leukocyte DNA, indicating that the amount of the mutated allele in leukocyte DNA was very low compared with that from the proband. Conclusions We speculate that the mildly affected mother showed keratin 1 gene mosaicism, and that the BCIE phenotype had been transmitted in a severe form through a mechanism that passes the keratin gene mutation to the next generation. These results suggest that mild forms of BCIE may actually represent extensive epidermal nevi/keratin gene mosaicism.

It is well known that autosomal dominant skin disorders may sometimes become manifest in a mosaic form, involving the body in a linear, patchy, or otherwise circumscribed arrangement. Such cases can be explained by an early postzygotic mutation. The segmental lesions usually show the same degree of severity as that found in the corresponding nonmosaic trait. Occasionally, however, the intensity of involvement observed in the circumscribed area is far more pronounced. This phenomenon can be explained by delineating a rule of dichotomous segmental manifestations reflecting different states of zygosity. Heterozygosity for the mutation results in severity corresponding to that in the nonsegmental phenotype; loss of heterozygosity for the same allele causes markedly more severe involvement. Arch Dermatol. 1997;133:1505-1509

A 52-year-old white woman presented with a pruritic, scaly lesion on her right forearm that had been present for several months. Her medical and family histories were unremarkable. The physical examination revealed a 536-mm, wellcircumscribed, erythematous plaque on the dorsal aspect of the right forearm (Figure 1). The lesion was treated twice with cryosurgery and subsequently with diflorasone diacetate cream, but persisted despite these measures. A 4-mm punch biopsy specimen of the lesion revealed epidermal hyperplasia with compact hyperkeratosis and acanthosis. In the stratum spinosum and granulosum, there were vacuolar and granular changes with coarse, prominent keratohyaline granules. The dermis showed prominent solar elastosis (Figure 2). What is your diagnosis?

REPORT OF A CASE A 10-month-old boy was brought to our clinic by his parents for evaluation of a palmoplantar alteration that they had noticed since he was 10 weeks old. The family history was negative for similar disorders. At general physical examination, the baby was normal and healthy. Cutaneous examination ( Figure 1 and Figure 2 ) showed a yellowish keratoderma of the palms and soles. The keratoderma was surrounded by an erythematous rim that sharply demarcated the lesions from normal-appearing skin. No other cutaneous lesions were found, and the mucous membranes, nails, and teeth were all normal. A cutaneous biopsy specimen was obtained ( Figure 3 ). What is your diagnosis? A Child With Unusual Palms and Soles DIAGNOSIS: Epidermolytic palmoplantar keratoderma (PPK) of Vorner. HISTOPATHOLOGIC FINDINGS Microscopic examination showed epidermal acanthosis with an intense orthokeratotic hyperkeratosis. The granular cell layer was markedly thickened with numerous keratohyaline granules, and there was a pronounced vacuolization of the keratinocytes in the granular and spinous

Background and Design: Epidermolytic hyperkeratosis (EHK) is a rare autosomal dominant disorder of cornification. While different clinical presentations of EHK have been described, the distinctions have not been clear. We have examined 52 patients with EHK from 21 families in an effort to define and characterize the specific clinical features of this disorder. Results: We found that several features were useful for separating patients with EHK into clinical groups. The most distinctive characteristic was presence vs absence of severe palmoplantar hyperkeratosis. Twenty-nine patients in six families had this finding and were grouped into ''PS types'' (those with severe palm/sole hyperkeratosis). The remaining 23 patients (from 15 families) were classified as ''NPS types'' (those without severe palm/ sole hyperkeratosis). We identified three distinct PS types and three distinct NPS types. The classification was always found to be consistent in all affected family members. In those families in which mutations were defined, keratin 1 mutations were identified in the PS types and keratin 10 mutations in the NPS types. Conclusions: We were able to classify our cohort of 52 patients with EHK from 21 families into distinct types. There was a correlation between presence or absence of severe palm/sole hyperkeratosis and the specific keratin involved. (Arch Dermatol. 1994;130:1026-1035)

Ichthyosis hystrix Curth-Macklin type (CM) is a rare autosomal dominant disorder of keratinization, with wide variability of onset and clinical presentation. 1,2 Only two families and three solitary cases have been reported so far. This disease is characterized by a pathognomonic ultrastructural pattern consisting of perinuclear shells of unbroken tonofilaments in suprabasal keratinocytes. Electron microscopy is necessary to differentiate this disorder from epidermolytic hyperkeratosis (EH), which shows some clinical and histopathologic similarities. The problem of whether CM belongs to the EH group or is a distinct entity is still unsolved. Report of a Case. The patient, a 2-year-old boy, presented with wide areas of nigricans hyperkeratotic skin on the trunk and limbs without any evident desquamation. At the big folds and on the extensor surfaces of the wrists, elbows, and ankles, the hyperkeratosis was prominent and assumed a linear arrangement ( Figure 1 ). The face, scalp, and palmoplantar surfaces were unaffected.

Background: Clues from clinicopathologic studies of epidermolysis bullosa simplex (EBS) and epidermolytic hyperkeratosis (EH) have implicated abnormalities in keratin filaments as possibly underlying the pathogenesis of these diseases. Multiple avenues of study have now converged, which confirm this hypothesis. Observations: The clinical spectrum of EBS and EH is reviewed together with classic histologic, electron microscopic, and immuno—electron microscopic studies. Linkage analyses have shown in EBS and EH that the disease traits are linked to the keratin gene clusters on chromosomes 12 and 17. Transgenic mice bearing mutations or deletions in genes coding for basal cell keratin K14 express the phenotype of EBS, and transgenic mice bearing abnormal K1/K10 genes resemble EH. Increasing numbers of point mutations in the human keratin genes have been found in both sporadic and familial cases of EBS in keratins 5/14 and EH in keratins K1/10 genes, respectively, particularly in highly conserved subdomains of the keratin proteins. Conclusions: The recent and rapid progress in understanding the molecular biology of EBS and EH will also enhance knowledge about intermediate filament structure and function. Further studies of the effects of these mutations on the control of keratinocyte growth and differentiation are required. They will lead the way to rational pharmacologic or gene therapy.

Background: Transgenic animals have greatly enhanced our understanding of the contribution of various structural and regulatory components to epidermal biology. The expression of mutant versions of these components in the epidermis of transgenic mice has generated animal models of specific human skin diseases. Observations. The expression of mutant keratin genes has produced animal models of epidermolysis bullosa simplex and epidermolytic hyperkeratosis and, in doing so, has focused attention on the genetics of keratins in these and other skin disorders. Similarly, the generation of mice overexpressing growth factors and/or oncogenes, exclusively in the epidermis, has identified the role of these factors in normal skin and produced models of disease states where the regulation of these factors is perturbed. Conclusions: These models of keratin disorders and other diseases not only enable the determination of the cause of these disorders, but also allow evaluation of novel therapeutic techniques for the amelioration of these skin diseases. ( Arch Dermatol. 1993;129:1430-1436)

To the Editor.— We recently reported that five of 15 patients with various disorders of keratinization had secondary hyperparathyroidism. 1 We now confirm and extend those observations to a larger, totally separate group of patients. Patients and Methods.— Families with epidermolytic hyperkeratosis, lamellar ichthyosis, congenital nonbullous ichthyosiform erythroderma, ichthyosis vulgaris, and Darier's disease answered an advertisement to participate in studies on the genetic basis of their disease(s). Diagnoses were established by clinical findings, inheritance pattern, and skin biopsy specimens of at least one member of each family. Coded serum and plasma samples were immediately frozen and shipped to New Haven, Conn, for analysis of parathyroid hormone (PTH), creatinine, calcium, 25(OH) vitamin D, and 1,25 (OH) 2 vitamin D as previously described. 1 Results.— Samples from 65 patients were analyzed. The patients fell into two distinct groups: those with normal serum PTH values and those with PTH levels at least 1.8

Comedo-like follicular papules of hair-follicles, confined to the left side of the upper part of the body, were found in a 22-year-old woman. Histological features were of epidermolytic hyperkeratosis with involvement of the follicular epithelium and the sebaceous duct with compact hyperkeratosis, but almost no interfollicular epidermal alterations were found. Because of the nevoid distribution, the prominent follicular plugging, and epidermolytic hyperkeratosis, we describe this condition as nevoid follicular epidermolytic hyperkeratosis.

• Two cases of epidermolytic hereditary palmoplantar keratoderma were studied by histologic, ultrastructural, protein-chemical, and genetic methods. Histologically, epidermolytic hyperkeratosis was seen at the spinous and granular layers. Electron microscopy showed the aggregation of tonofibrils and an early appearance of keratohyaline granules as well as vacuolar formation in the epidermal cells. Some of these morphologic abnormalities were detected even in the basal cells. The decrease of 67-kilodalton (kd) keratin and the appearance of 48-kd keratin were noted by using sodium dodecyl sulfate polyacrylamide gel electrophoresis. Genetic analysis of the keratin gene family using 67-kd keratin complementary DNA by Southern blot analysis revealed the conserved gene organization of the 67-kd keratin gene. These findings suggest that undetermined regulatory abnormalities of keratinization, but not the gene structure itself, may be causative factors of this rare disease. ( Arch Dermatol 1988;124:555-559)

Three members of a family with severe epidermolytic hyperkeratosis were successfully treated with topical tretinoin therapy. During hospitalization a controlled paired-comparison study was performed treating one half of each patient with retinoic acid and the other half with the appropriate placebo. The retinoic acid was evaluated at concentrations 0.05% and 0.1% and in both an alcohol-polyethylene glycol solution as well as in a cream base. Special studies, using the scanning electron microscope, revealed basic alterations in the ultrastructure of diseased skin which help to explain the repeated pyodermas, persistent malodor, and lack, of a physiologically effective stratum corneum with the disorder. While the ineffective barrier function permitted systemic effects from topical corticosteroid applications in one patient, no adverse reactions were seen with prolonged, full-body tretinoin therapy over a period of eight months. Significant therapeutic results were recorded photographically.

Two unrelated families are presented in which only one monozygotic twin demonstrated ichthyosis hystrix, while a nontwin sibling showed ichthyosis vulgaris. Zygosity in the twins was determined by using physical traits, placental characteristics, blood typing, dermatoglyphics, and skin grafting.

Seven cases of a solitary tumor, with the histopathologic feature of granular degeneration, were identified as isolated epidermolytic acanthoma. Clinically the lesion is not diagnostic, but resembles a wart. It is apparently not heritable, although it shows the same microscopic features as the dominantly inherited dermatoses recently termed epidermolytic hyperkeratosis.

Two cases of localized epidermolytic hyperkeratosis, investigated by electron microscopy, show the dermis and basal cell region to be normal. The "halos" in routine paraffin sections proved to be large areas of perinuclear endoplasmic recticulum which with other morphologic evidence represent signs of increased metabolic activity. The cause of hyperkeratosis in epidermolytic hyperkeratosis is increased epidermal cell turnover and increased speed of migration of epidermal cells towards the horny layer. A concept as to the role of the keratinosome in the formation of the horny layer is presented.

Transepidermal water loss (TWL) measurements in subjects having one of four distinct forms of ichthyosis were determined hygrometrically. The observed TWL was highest in epidermolytic hyperkeratosis but was significantly elevated above normal in all forms. The increased TWL rates through greatly thickened horny layers as compared to normal layers imply inefficient water barrier function of the stratum corneum in these disorders.

• Four patients with nevus comedonicus (NC) and the histological changes of epidermolytic hyperkeratosis (EH) are described. The relationship between NC and other epidermal nevi in which EH may occur is further emphasized by this finding. ( Arch Dermatol 117:86-88, 1981)

† We describe herein a patient in whose family 11 of 20 members have a palmoplantar keratoderma. The pathologic findings in the proband were those of epidermolytic hyperkeratosis. As in the other families described, the disease was found to be inherited as an autosomal dominant trait. All involved family members had hyperkeratosis of the palms and soles as infants. Light microscopy showed hyperkeratosis, hypergranulosis with large irregular keratohyalin granules, and large clear spaces in the cells of the granular and upper spinous layers. Our electron microscopic findings showed that the clear spaces were areas of cytoplasm filled with a fibrillar material and cellular organelles; abnormal clumps of tonofilaments and keratohyalin were also present. We consider this disorder to be a form of keratoderma rather than a localized ichthyosis. ( Arch Dermatol 1981;117:229-231)

To the Editor.— Epidermolytic hyperkeratosis is a nonspecific dermal process with a distinctive histopathologic picture described as (1) an isolated and/or incidental finding associated with acquired solitary skin lesions,1-3(2) occurring as the main histologic pattern of bullous congenital ichthyosiform erythroderma,2,4and (3) appearing in congenital epidermal nevi (disseminated, linear, and circumscribed Fig 1.—Photomicrograph of superficial basal cell carcinoma. To right, focus of epidermolytic hyperkeratosis is observed (hematoxylin-eosin, ×80). types).2,3,5I saw an unusual case of epidermolytic hyperkeratosis associated with basal cell carcinoma. Report of a Case.— A 65-year-old woman was seen with a lesion of several months' duration on the anterior part of the right leg. On examination, it was an erythematous scaly patch, 3 × 1 cm in diameter. Findings from a general physical examination and results of routine laboratory studies were otherwise normal. The clinical diagnosis was basal cell carcinoma. Histopathologic examination of the

To the Editor.— We report a unique, readily diagnosable dermatosis of children and young adults that we have recognized for the past ten to 12 years. Although generally considered a nuisance cosmetic condition, it has occasionally confounded dermatologists and triggered expensive endocrinologic evaluations. The initial cases were of young children who were brought in by distraught mothers with the vexing problem of "I can't wash the dirt off!" Examination revealed what, indeed, appeared to be dirty-appearing skin, usually around the neck, but sometimes on the arms or trunk. The children woefully recounted their discomfort due to their mother's efforts to scrub their necks clean. The clinical differential diagnoses include pityriasis (tinea) versicolor, Gougerot and Carteaud's reticular and confluent papillomatosis, acanthosis nigricans, pseudoacanthosis nigricans, epidermolytic hyperkeratosis, hyperkera-tosis of the nipple and areola,1and idiopathic deciduous skin.2 The diagnosis is made with a single wipe of the affected area using an alcohol-soaked cotton ball. The "dirt" wipes away, revealing sparkling clean skin beneath, to the chagrin of any (especially maternal) observers.

To the Editor.— In the February 1981Archives(117:86-88), Barsky et al reported four cases of nevus comedonicus (NC) in which the histologic changes of epidermolytic hyperkeratosis were seen in the wall of the comedones. The article states that "various authors have reported on the association of NC with several other histological phenomena but these did not occur in the individual comedo." I would like to call attention to the report of Bleiberg and Brodkin 1 describing the microscopic findings of buds of proliferating basal cell epithelioma projecting into the dermis from the cyst wall of a comedo (epidermoid cyst) in a patient with linear basal cell nevus and comedones. It is evident that the histologic variants seen in NC parallel those seen in epidermal nevi (epithelial nevi). Barsky et al concur with the opinion of Degos et al 2 that all epidermal nevi are basically alike. This point is

Nine patients with a familial type of diffuse hyperkeratosis of the palms and soles are reported. Skin biopsies (and, in one case, epidermal kinetic studies) showed the changes of epidermolytic hyperkeratosis. It is suggested that the category of epidermolytic hyperkeratosis be expanded to include this variety of keratoderma palmaris et plantaris.

In contrast to recently reported successful methotrexate therapy of congenital bullous ichthyosiform erythroderma (CBIE), two cases failed to respond to the dosages of methotrexate normally used in psoriasis. Thiamiprine was also without effect. This was despite the demonstration of markedly increased epidermal turnover in these patients using tritiated thymidine autoradiography. We suspect the failure to respond is because the increased epidermal cell turnover in this disease is a secondary phenomenon involving mechanisms not responsive to antimetabolites.

The location of the proliferative pool of cells in normal epidermis, ichthyosis vulgaris, lamellar ichthyosis, X-linked ichthyosis, epidermolytic hyperkeratosis, and psoriasis was examined using autoradiographic and projection techniques. A significant number of thymidine-labeled cells (deoxyribonucleic acid-synthesizing cells) were found above the basal cell layer in all conditions examined. Cell proliferation in the epidermis is not limited to the basal layer but also occurs in more superficial cells.

The blending together of epidermolytic hyperkeratosis and focal acantholytic dyskeratosis in the same biopsy specimens exemplifies the lability and variability of epidermal metabolism. A clue to the pathogenesis of these distinctive changes may be contained in this unusual histologic collision.

Epidermolytic hyperkeratosis (EH) is a distinctive histologic expression of an epithelial pathologic process. The characteristic histopathologic features appear in a variety of acquired and congenital skin lesions. They range from focal EH confined to a single rete ridge, that is clinically unapparent, to widespread EH that is manifested clinically as bullous congenital ichthyosiform erythroderma. Microscopic examination enables detection of EH beneath an array of clinical masquerades.

On the basis of clinical, histological, and cellular kinetic observations, a separation of the major ichthyosiform dermatoses into four groups is proposed. Ichthyosis vulgaris patients have dry skin and fine scales on their trunk and extremities, but gross changes in the skin of their legs may be more severe. A granular layer is histologically absent. Lamellar ichthyosis patients have large, coarse scales. The granular layer is prominent in this condition. Epidermolytic hyperkeratosis consists of a clinical spectrum of disorders; generalized forms may be bullous, and localized forms may resemble linear nevi. Intracellular and intercellular edema gives the epidermis a characteristic reticular pattern in histological sections. Psoriasiform erythroderma is clinically and histologically indistinguishable from universal psoriasis. Increased mitotic activity and consequent increased scale formation appear to be important pathogenetic features in these disorders, except for ichthyosis vulgaris in which mitotic counts were actually lower than in the control specimens.

Epidermolytic hyperkeratosis (EH) is a descriptive term for histopathologic changes that have been observed in various related and unrelated benign conditions. In two lesions on chronically sundamaged skin, EH occurred in association with nuclear atypia. This phenomenon represents an epidermolytic variant of solar keratosis.

The histologic features traditionally associated with Darier's disease were found in a variety of other conditions. These histologic changes occurred in (1) single lesions that were ( a ) clinically inapparent, ( b ) papular, or ( c ) nodular, and in (2) multiple lesions that were ( a ) persistent or ( b ) evanescent. The term "focal acantholytic dyskeratosis" describes the dominant histologic features and, like the designation "epidermolytic hyperkeratosis," denotes a distinctive histologic pattern with numerous clinical expressions.