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To the Editor.— In the October 1982Archives(118:781-783) Michael presented a comprehensive commentary on the clinical, pathologic, etiologic, and therapeutic aspects of Hailey-Hailey disease, which is apparently associated with a genetic defect that was first reported by Hailey and Hailey in the April 1939Archivesunder the name "familial benign chronic pemphigus." 1 By a strange coincidence, the same condition was reported a few months later by Ayres and Anderson 2 in the September 1932Archivesunder the name "recurrent herpetiform dermatitis repens," five cases of which had been observed for more than 17 years. In 1975, Ayres and Mihan 3 reported the successful control of the conditions of three patients with Hailey-Hailey disease by the oral administration of vitamin E in the form of d-α-tocopheryl acetate in doses of 800 to 1,200 IU/day. Exacerbation occurred on several occasions when the dose was notably reduced or the treatment stopped

The clinical signs, laboratory data, and histological features of recurrent aphthous ulcers (RAU) and Behcet's syndrome suggest a viral etiology. In fact, there are reports of adenovirus isolations in herpetiform oral ulcers and on the isolation of a filterable agent in sporadic cases of Behcet's syndrome. However, isolation studies on the major and minor aphthous ulcers and more recent studies on Behcet's syndrome have been negative. A review of the literature on the role of viruses and autoimmunity in RAU and Behcet's syndrome is presented. Biopsy specimens of ulcerative lesions were grown in vitro for up to 300 days. Those cultures, along with leukocytes and body fluids, were examined by a variety of techniques for the presence of virus or viral antigens. Although a persistent or latent virus was not detected, these negative studies cannot exclude a viral etiology. In fact, the hypothesis of an infectious and viral etiology is still reasonable.

A patient with arthritis is described who developed a dermatitis herpetiformis-like rash after 8 months of D-penicillamine therapy and which cleared soon after the drug was discontinued. The histopathological findings were compatible with a diagnosis of pemphigus, showing intra-epidermal vesicles and spongiosis but no acantholysis. Intercellular antibody was detected by indirect immunofluorescence at the onset of the eruption (titre 1 in 160) and also found in serum taken prior to penicillamine treatment (titre 1 in 20). It is now well known that D-penicillamine can induce pemphigus. The findings reported here suggest the possibility that the patient was predisposed to develop the eruption before the drug was given.

Three types of ulcers are recognized: minor aphthae These are most common (CP-39). They are small painful ulcers occurring anywhere in the oral mucosa, either singly or in small crops. major aphthae These are much less common. The ulcers are usually single larger and deeper. These ulcers may heal leaving a scar. herpetiform ulcers A large number of very small ulcers occur in crops. They are very rare and the term used is descriptive rather than an indication of aetiology.

A 31-year-old homosexual man with acquired immunodeficiency syndrome (AIDS) had cutaneous herpetiform lesions that showed numerous encapsulated organisms on Tzanck preparation. Subsequent cultures of cerebrospinal fluid and skin biopsy specimens substantiated a diagnosis of disseminated cryptococcosis. Cutaneous cryptococcosis should be considered in the differential diagnosis for skin lesions in the population with AIDS.

Five patients had a form of pemphigus which in its early stages resembled dermatitis herpetiform, although the immunofluorescent findings were typical of pemphigus, Potassium iodide tests, performed for the first time In such patients, showed positive results in two patients. Follow-ups ranging from 5 to 14 years have shown a benign course with low to absent dosages of steroids

Macroscopic, histopathologic, and immunohistochemical features of eight 1- to 7-day-old minor (Mikulicz) aphthae, one herpetiform ulcer, and one ulcer from a patient with Behcet's syndrome were studied. In addition to light and electron microscopy, methods included the peroxidase-antiperoxidase (PAP) technique to disclose binding of IgA, IgG, IgM, Clq, and C3. Observations revealed (1) the presence and distribution of extravasates of erythrocytes at and around the ulcers, (2) extravascular neutrophilic granulocytes undermining the oral epithelium of the ulcer margin, (3) the presence of numerous macrophages loaded with phagolysosomes containing debris of neutrophilic granulocytes, (4) particular pathomorphologic features of a Behcet lesion and a herpetiform lesion, and (5) the occurrence in diseased and normal oral mucosa of particular stratum spinosum cells binding nonselectively all immune components tested in this study, probably by leakage and passive diffusion of serum proteins. The observations fit the concept of immune complex vasculitis being essential in the pathogenesis of oral aphthous ulcerations.

A prospective study was carried out over a period of 4 years to determine the role of anaemia, vitamin B 12 folate or iron deficiency in the pathogenesis of minor, major and herpetiform ulcers. A series of 193 patients with recurrent oral ulceration (ROU) was examined clinically and haematologically and the results were compared with those from 80 patients with other types of oral ulcers, 204 patients with non-ulcerative oral diseases and 100 controls. A small number of patients with ROU were found to be anaemic due to iron deficiency (4·7 per cent), vitamin B 12 deficiency (0·5 per cent) or folate deficiency (2·1 per cent). The low prevalence suggests that anaemia does not play a primary aetiological role in ROU. Subnormal serum iron levels without anaemia (sideropenia) were found in 20 per cent of patients with ROU, but also in 20 per cent of those with other oral ulcers, in 13 per cent with other oral diseases and 5 per cent of the controls. The findings of an increased prevalence of sideropenia in both ROU and in patients with other oral ulcers, a correlation between severity of ulceration and sideropenia and a failure by most patients to respond clinically to iron therapy, suggest that sideropenia is secondary to the oral ulceration. Patients with minor aphthous ulcers did not show an increased prevalence of any haematological deficiency in comparison with controls. In a small number of patients ROU was associated with systemic diseases and iron deficiency or macrocytic anaemia; these ulcers could be distinguished from minor, major and herpetiform ulcers by careful clinical and haematological assessment and are termed pseudominor, pseudo-major and pseudo-herpetiform ulcers.

Biopsy specimens of 1- to 7-day-old oral ulcers from patients with minor (Mikulicz), herpetiform, and Behcet's aphthae and of nonulcerated oral mucosa of aphthous patients were subjected to a quantitative, stereologic, electron microscopic analysis of the connective tissue infiltrate residing both at the center of and lateral to the ulcers. The data representing volume fractions and the numerical density of cellular and other infiltrate components demonstrated that (1) the infiltrate under the epithelium lateral to the ulcer is different from that at the ulcer's center, (2) at both sites, composition of the gross infiltrate does not change with age of the ulcer, (3) a large population of leukocytes (about 18% in the lateral and 23% in the central region) belong to the monocyte/macrophage series, (4) blast-forming T-lymphocytes are consistently present, blast-forming B-lymphocytes and plasma cells are very rare, and (5) mast cells are several times more numerous than in normal mucosa. In a comparison of the infiltrates of Mikulicz aphthae with those of herpetiform and Behcet's ulcers, it appears that the pathogenesis of the various oral ulcerations may well be diverse.

Herpes zoster, erroneously considered a rare disease in children, is fairly common but often unrecognized because it produces little reaction in the pediatric patient. Clinical observations of seven children with this illness are presented. None of the children had been exposed to the herpes zoster virus before the onset of illness. Five had had chickenpox (immunologically related to herpes zoster) during the first year of life. The vesiculobullous lesion occurring in the children's skin had the appearance and herpetiform grouping typical of lesions in the adult. Complications of the disease were like those in the adult except that postherpetic neuralgia did not occur. Neither the illness nor its complications are usually severe in this age group. The youngster requires only supportive care and, occasionally, specific attention to the skin lesions.

Immunoglobulin estimations by an immunochemical method were performed in serum and saliva of 120 subjects; 70 patients with recurrent oral ulceration, 20 with lichen planus and 30 normal controls. Raised levels of serum IgA and IgG were found in patients with recurrent oral ulcers, as compared with normal controls, but the 5 per cent level of significance was reached only in patients, with major aphthous ulcers. In lichen planus, however, serum IgG concentration was significantly depressed, although IgA was slightly raised. Salivary IgA concentration showed little variation between the controls and patients and depressed IgA clearance was found only in herpetiform ulceration. Although IgG was not detectable by this method in parotid saliva, it was found in almost all samples of whole saliva. Serum IgM was normal in all groups of patients and IgM was not detected in any of the samples of saliva. Recurrent oral ulceration is not associated with immunoglobulin deficiency in serum or saliva. The raised serum IgG and IgA levels are consistent with those found in some autoimmune disorders. Immunoglobulin transport into saliva is discussed.

Epidermolysis bullosa simplex Dowling–Meara (MIM# 1317600) is the most severe of the three common epidermolysis bullosa simplex subtypes. In addition to the palmoplantar distribution seen in other epidermolysis bullosa simplex subtypes, extensive herpetiform blistering spontaneously develops on the trunk and limbs and may lead to scarring or milia formation. The keratin 5 and keratin 14 genes encode proteins that form the primary structural components of the basal epidermal keratinocytes, mutations in either of these genes can cause epidermolysis bullosa simplex. In this study we sequenced these genes in a family with epidermolysis bullosa simplex Dowling–Meara. We report a novel T to C transition in the helix termination peptide of KS that causes a nonconservative substitution of a highly conserved amino acid within this critical region (1466T). This mutation adds to those previously reported and provides further evidence of phenotype-genotype correlation in epidermolysis bullosa simplex.

To the Editor.— The report by Drs. DeMento and Grover in theArchives(107:883, 1973) poses a number of challenging questions, many of which remain to be answered. At this point, it appears that the best interests of the field of dermatology would be served by reporting as accurately as possible the basic findings in this (and hopefully in other comparable cases). The patient of Drs. DeMento and Grover appears to have some signs of pemphigus and some of dermatitis herpetiformis. Several possible diagnoses of the condition exist. 1. This disease may be dermatitis herpetiformis (DH) as indicated in the aforementioned report. If this is so, it should be possible to detect the junctional deposits of IgA typical of DH in the patient's skin, since such deposits have been found in virtually all cases that have been examined adequately. Examination of two biopsy specimens studied in this laboratory failed to

To the Editor.— Disseminated histoplasmosis is increasingly recognized in patients with acquired immunodeficiency syndrome (AIDS). We describe a patient with longstanding psoriasis who presented to our clinic with unusual-appearing herpetiform lesions that, after biopsy, showed cutaneous histoplasmosis. A subsequent test for the presence of AIDS proved to be positive. The patient repeatedly denied any risk factors. Report of a Case.— The patient was a 38-year-old white man with a 42-month history of widespread psoriasis and severe psoriatic arthritis. The severity of the joint involvement had resulted in the patient being confined to a wheelchair. Methotrexate had been employed by his rheumatologist (total received dose of 2205 mg). He presented to our dermatology clinic with complaints of malaise, fever, and odynophagia for 3 weeks, along with a 2-day history of a mucosal and perioral eruption. Examination revealed multiple partly grouped vesicles and pustules in the perioral area (Fig 1), along with

† B virus (Herpesvirus simiae) infections in macaque colonies are common. Herpetiform lesions as well as asymptomatic shedding of virus in bodily secretions from macaques pose a risk to animal handlers and laboratory workers. Fatal encephalitis in humans infected with B virus has occurred. Dermatologists may become involved in the initial evaluation of animal handlers exposed to this virus through bites or infectious secretions. (Arch Dermatol.1989;125:1247-1248)

Four patients with systemic lupus erythematosus (SLE) had a vesicobullous eruption that histologically resembled dermatitis herpetiformis. Immunofluorescence microscopy patterns in the skin studied in three patients, however, were characteristic of SLE. Treatment of the underlying collagen-vascular disease improved the eruption, while recurrence coincided with exacerbation of the systemic disease. This distinctive lesion is an important parameter of SLE activity. ( Arch Dermatol 115:1427-1428, 1979)

In Reply.— Nishikawa and his associates point to their finding that six of 51 serum samples taken from patients with untreated pemphigus with IC antibodies had CF IC antibodies in titers of 1:20 or more and that one of these six serum samples (from a patient with herpetiform pemphigus) had a titer of CF antibodies comparable to that of the indirect immunofluorescence (IF) titer. In effect, 45 of 51 of their patients had either no detectable titers of CF antibodies or titers of less than 1:20. These findings are comparable to our own, with serum samples of patients with both pemphigus and pemphigoid. Specifically, the serum samples from four of ten patients with pemphigoid Differences Between PAs and PLAs* Characteristics Observed PAs PLAs Coexistence of PAs and PLAs In vivo binding associated with acantholytic lesions Present in some, but not all, areas of normal skin and mucosa Not present if they exist

To the Editor.— According to the recent report by Kumar et al in the July 1980Archives(116:812-814), complementfixing (CF) intercellular (IC) antibodies in titers comparable to those seen by the ordinary indirect IgG test are a characteristic of pemphigus-like antibodies. Recently, 51 serum samples from untreated patients with pemphigus (clinically, histologically, and immunopathologically confirmed) were tested in our laboratory for the presence of CF IC antibodies. Six serum samples were found to have positive CF IC antibodies in titers greater than 1:20. In one case diagnosed as herpetiform pemphigus, the titer of CF IC antibodies (1:20) did not differ substantially from the titer of ordinary IgG antibodies (1:40). In addition, we could demonstrate IgG deposition in the IC spaces of organ-cultured human skin using pemphigus serum samples including CF IC antibodies; no C3 deposition was found. These bound IC antibodies were able to fix complement. We believe that the

To the Editor.— I found the report of Drs. Demento and Grover in theArchives(107:883, 1973) very interesting. Isolated reports in which features of pemhigus and dermatitis herpetiformis have overlapped have appeared from time to time. The confusion engendered by these reports gave rise to the myth that dermatitis herpetiformis could sometimes transform into pemphigus. Rook and Whimster 1 stated that until a case could be produced that at one stage showed the unequivocal histologic changes of dermatitis herpetiformis and at a later stage those of pemphigus, it could not be held that dermatitis herpetiformis transformed to pemphigus. The real cause for this confusion was inadequate information, a point emphasized by Pierard 2 in discussing such a case, which he considered had been pemphigus from the onset. One of the sources of inadequate information is the bad habit of recording the histological findings as `typical of' or `consistent with'

• We encountered eight patients with epidermolysis bullosa (EB) simplex of the Dowling-Meara type, who presented in infancy with severe blistering and were originally clinically thought to have recessive dystrophic EB. One infant died in the neonatal period, and the others have had reduced blistering with advancing age. However, in two of the three older patients, the development of severe disabling hyperkeratosis of the palms and soles has been a prominent feature. The correct diagnosis of EB simplex was initially not made in five patients, because, on routine histologic examination, the blister was apparently subepidermal. Electron microscopy confirmed the correct diagnosis of EB simplex by demonstration of basal cell cytolysis. There was clumping of tonofilaments in seven patients. Immunofluorescence demonstrated a cleft above the basal layer in three cases. The findings of severe extensive blistering at birth that improves with age, milia formation, acral distribution with herpetiform groups of blisters in older children, intraoral lesions, absence of scarring, and intraepidermal clefting due to basal cell cytolysis and clumping of tonofilaments within these basal cells as seen on electron microscopic examination present a subtype of EB simplex similar to that described by Dowling and Meara. This has been recognized in the European but not in the American literature and is probably more frequent than has been previously reported. ( Arch Dermatol 1986;122:190-198)

As the clinical concept and histologic specificity of familial benign chronic pemphigus have gradually become widely accepted, this disease entity has been recognized with increased frequency. Over 110 confirmed cases have appeared in the literature since the original description by Hailey and Hailey in 1939. 1 Our interest in writing this report was stimulated by the recent finding of six atypical cases of familial benign chronic pemphigus. It is our purpose to call attention to the unusual features of these cases. During the process of academic recognition and acceptance, familial benign chronic pemphigus has received a variety of descriptive names, such as chronic recurrent acantholysis (Pinkus and Epstein), 2 vesicular Darier's disease (Ellis), 3 recurrent herpetiform dermatitis repens (Ayears and Anderson), 4 dyskeratosis bullosa hereditaria (Becker and Obermayer), 5 and dyskeratoid dermatosis (Frank and Rein). 6 There is agreement, however

There have been reports in the past year or so of several cases of a dermatosis of the vesiculobullous type with features which would indicate that if it is not new, it is at least an unusual variation of a known cutaneous condition. Careful comparison of the histologic features and etiologic factors (or their consistent absence) seems to point to a single disease entity, although the disease has been variously diagnosed as keratosis follicularis (Darier) with vesiculation, familial benign chronic pemphigus and recurrent herpetiform dermatitis repens. In view of the relative infrequency of occurrence and in order to establish additional diagnostic criteria, 2 cases are here reported in which the condition is similar to that in the aforementioned reports. REPORT OF CASES Case 1.— P. S., an unmarried American bank clerk aged 35, was seen in April 1936. He sought treatment for a recurring eruption of the neck, first noticed

In theArchives of Dermatology and Syphilologyof March 1939 we 1 described, under the designation of keratosis follicularis (Darier) with vesiculation, an unusual clinical picture of a patient. One month later in the same journal Hailey and Hailey 2 reported 4 cases, those of two pairs of brothers, of an eruption which corresponded suggestively to the condition in our case. They viewed the disease as a hitherto undescribed one and designated it familial benign chronic pemphigus. In September 1939 Ayres and Anderson 3 reported under the title "Recurrent Herpetiform Dermatitis Repens" 5 cases of a vesicular and bullous eruption which they admitted was identical with that in the cases described by Hailey and Hailey. Since that time Hailey and Hailey 4 have published another series of familial cases of the disease and again expressed the opinion that the dermatosis represents a form of pemphigus and a new dermatologic entity.

The infectious (virus) nature of many herpetiform eruptions has been established by the production in animals and in human beings of comparable reactions in skin or mucous membrane from inoculation with material from spontaneously evoked lesions. Concerning herpes febralis and herpes progenitalis, similar studies have led to the conclusion that their respective viruses are immunologically distinct, a distinction corroborated by the epidemiologic features of both. 1 Long before a virus became suspected, nineteenth century clinicians of wide experience were sufficiently impressed with the persistent history of venereal disease in patients presenting genital herpes to surmise a venereal origin for the latter. Yet no single, unequivocal case history is recorded that establishes this clinical picture as a venereal contagion in its own right. For this reason the following short reports of 2 cases are recorded. The absolute reliability of the pertinent facts cogently argues acceptance of the theory of a venereal

SINCE Pels and Goodman 1 described their case of a bullous type of Darier's disease, many similar reports have appeared, but under different titles. "Familial benign chronic pemphigus" was recorded by Hailey and Hailey 2 ; Ayres and Anderson 3 called the disease "recurrent herpetiform dermatitis repens"; the term "dyskeratoid dermatosis" was used by Frank and Rein, 4 and Franks and Traub 5 suggested the term "familial benign chronic bullous dermatosis." Many cases are recorded in recent American literature. 6 The aforementioned cases are similar as regards histories, clinical pictures and microscopic data, and most observers agree that they are instances of the same disease. The profusion of names indicates that the exact nature of the disease is not agreed on. This is largely due to different interpretations of the histologic observations. We do not propose to contribute a new legend, but we shall attempt to show that the disease is

THE LITERATURE on this comparatively new entity, first described by Ayres and Anderson under this name, 1 has been summarized recently by Sachs, Hyman and Gray. 2 Although Pels and Goodman 3 were probably the first to describe this condition, they regarded it only as a variant of Darier's disease (keratosis follicularis). Priority has been accorded to Hailey and Hailey, 4 who were the first to consider this disease as a dermatologic entity. There is, however, no agreement on the classification of the disease, and thus a considerable number of names have been suggested. While observers agree on the identity of the clinical course and picture of this disease, the interpretation of the peculiar histologic features is still under discussion. This situation seems to warrant the publication of a case which I had the opportunity to observe. REPORT OF CASE M. G., a married white woman aged 31, was first

A series of 5 cases observed during seventeen years is presented here for the purpose of studying a clinical picture which to us is unfamiliar and which does not appear to have been described in dermatologic literature.1 The history and appearance of the cutaneous lesions in all 5 cases were strikingly similar. Briefly, the principal features may be summarized as follows: Age and sex: Two patients were women, a mother aged 70 and a daughter aged about 45. The other 3 were men, with ages ranging from about 25 to 49. The 2 women were in exceptionally good financial circumstances and the 3 men in moderately good circumstances. Course: Attacks recurred over a period ranging from several years to as many as twenty. Individual attacks: The attacks lasted from four to six weeks in case 5, clearing spontaneously, and as long as several months in each

A Case for Diagnosis. Presented by Dr. H. G. Miskjian, Cleveland. J. K., a man aged 40, is well developed and well nourished and in apparently good health. He has been suffering from his present slightly pruriginous cutaneous disease for about twenty years. The onset apparently was gradual, and the eruption has never entirely disappeared. It does not appear to be subject to any seasonal variation or other influence. There has been no ingestion of drugs. Scattered over the body, including the palms and the soles and excepting the face, there is a nodular eruption of rather remarkable symmetry. The total number of lesions approximates a hundred. In some places there is definite herpetiform grouping, and the lesions are in various stages of development. The lesions begin as small sharply defined red areas, gradually become raised above the level of the skin, and develop into rather hemispherical nodules whose

In spite of significant advances of the past two decades in the differentiation of bullous disorders, particularly from the standpoint of histopathology, certain blistering eruptions of the skin still defy accurate classification. This is true of the cases presented herein, which seem to represent an entity, puzzling to us and equally so to dermatologic colleagues elsewhere who have been privileged to observe it. Seven patients, all men but one, all middle-aged or older, have been observed over a period of several years with a persistent eruption of identical pattern which consists of grouped, pruritic vesicles confined to one or more circumscribed plaques about the head or neck, extending through a succession of annoying flares and leading eventually to scarring of the affected sites. In two instances, brief episodes of vesicular exanthems have occurred. In one case, lesions of the mouth and pharynx appeared and

A patient had an unusual blistering disease combining the features of both dermatitis herpetiformis and pemphigus vulgaris. The clinical features resembled dermatitis herpetiformis, and the disease was responsive to dapsone. Repeated biopsies, however, showed a mixture of features suggestive of both dermatitis herpetiformis and pemphigus vulgaris. Electron microscopic studies suggested pemphigus vulgaris. Her serum showed the serologic stigmata of pemphigus vulgaris, and intercellular IgG was demonstrated by direct immunofluorescence. Since this type of atypical blistering disease defies classification under the present criteria for diagnosis, and may prove to be a unique disease, it is suggested that patients whose disease resembles dermatitis herpetiformis with pronounced acantholysis be tentatively set aside under the category of ``acantholytic herpetiform dermatitis."