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Endocrinologic disorders occasionally manifest themselves by cutaneous abnormalities. In some instances, these alterations are the most prominent complaints of the patient. It is then important that the physician is able to recognize them as the manifestation of the endocrinologic disease. In this review, we describe the main cutaneous lesions occurring in endocrinopathy, like troubles of the skin pigmentation [melasma, acanthosis nigricans, Addison's disease, Cushing's syndrome, vitiligo], generalized or pretibial myxedema, acne and androgen excess, hirsutism. Where known, we try to approach the physiopathologic mechanisms that account for cutaneous changes. Additionally, some treatments are discussed.

Activation of expression of the heme oxygenase (HO) gene appears to be involved in a cellular defense system in mammalian cells. We now demonstrate that while HO-1 mRNA levels are strongly inducible in dermal fibroblasts they are barely inducible in human epidermal keratinocytes following oxidative stress (UVA radiation and hydrogen peroxide). Paralleling this result was the observation that HO-2 mRNA levels were low in dermal fibroblasts but were high in epidermal keratinocytes. In neither case was the HO-2 gene inducible. The expression of the two HO genes led to enzymatic activity in both types of skin cells with an approximately 2.5-fold higher level of enzymatic activity present in keratinocytes compared with fibroblasts derived from the same biopsy. In addition, ferritin levels, which have been found to be augmented via the HO-dependent release of iron from endogenous heme sources, were two- to three-fold higher in keratinocytes compared with matching fibroblasts. This higher ferritin pool would result in an enhancement of cellular iron sequestering capacity that may confer increased resistance to oxidative stress. Indeed, keratinocytes showed less UVA radiation-dependent cell membrane damage than fibroblasts. These results are consistent with the hypothesis that HO expression in human epidermis and dermis is related to cellular defense mechanisms that operate in human skin.

Lamellar ichthyosis is a severe congenital skin disorder characterized by generalized large scales and variable redness. Affected individuals in three families exhibited drastically reduced keratinocyte transglutaminase (TGK) activity. In two of these families, expression of TGK transcripts was diminished or abnormal and no TGK protein was detected. Homozygous or compound heterozygous mutations of the TGK gene were identified in all families. These data suggest that defects in TGK cause lamellar ichthyosis and that intact cross-linkage of cornified cell envelopes is required for epidermal tissue homeostasis.

A 80-year-old woman presented with a spontaneously bleeding wound on her scalp. The diagnosis of angiosarcoma was made based on histopathological examination of the second biopsy 1 month later. At that time, a large hematoma was present on the scalp and forehead with two bleeding erosions and numerous small blue-black nodules as well as a right cervical lymphadenopathy. The patient was treated by wide-field electron-beam radiotherapy, which showed no effect. The particularly aggressive evolution of this angiosarcoma led to death within less than 2 months.

Objective: The authors determined the role of Candida colonization in the development of subsequent infection in critically ill patients., Design: A 6-month prospective cohort study was given to patients admitted to the surgical and neonatal intensive care units in a 1600-bed university medical center., Methods: Patients having predetermined criteria for significant Candida colonization revealed by routine microbiologic surveillance cultures at different body sites were eligible for the study. Risk factors for Candida infection were recorded. A Candida colonization index was determined daily as the ratio of the number of distinct body sites (dbs) colonized with identical strains over the total number of dbs tested; a mean of 5.3 dbs per patient was obtained. All isolates (n = 322) sequentially recovered were characterized by genotyping using contour-clamped homogeneous electrical field gel electrophoresis that allowed strain delineation among Candida species., Results: Twenty-nine patients met the criteria for inclusion; all were at high risk for Candida infection; 11 patients (38%) developed severe infections (8 candidemia); the remaining 18 patients were heavily colonized, but never required intravenous antifungal therapy. Among the potential risk factors for candida infection, three discriminated the colonized from the infected patients--i.e., length of previous antibiotic therapy (p < 0.02), severity of illness assessed by APACHE II score (p < 0.01), and the intensity of Candida spp colonization (p < 0.01). By logistic regression analysis, the latter two who were the independent factors that predicted subsequent candidal infection. Candida colonization always preceded infection with genotypically identical Candida spp strain. The proposed colonization indexes reached threshold values a mean of 6 days before Candida infection and demonstrated high positive predictive values (66 to 100%)., Conclusions: The intensity of Candida colonization assessed by systematic screening helps predicting subsequent infections with identical strains in critically ill patients. Accurately identifying high-risk patients with Candida colonization offers opportunity for intervention strategies.

Abnormal photosensitivity of skin in the photosensitivity dermatitis/actinic reticuloid syndrome (PD/AR) correlating to an abnormal photosensitivity of dermal fibroblasts from these patients has been established previously. Cultured human skin fibroblasts from normal infant and adult donors, foreskin tissue and patients with PD/AR were assayed for oxidative stress induced membrane damage following ultraviolet A (UVA) radiation (340-450 nm) and hydrogen peroxide treatment by measurement of lactate dehydrogenase release. Skin fibroblasts from PD/AR patients were, in general, 2- and 4-fold more sensitive than normal controls regarding membrane-induced damage to UVA radiation and hydrogen peroxide treatment, respectively. Cells from one patient where biopsies were taken during full disease flair and 2 years later, following disease remission by immunosuppressive therapy, showed the same cellular sensitivity. In addition, fibroblasts from foreskin tissue were resistant to UVA radiation as measured by lactate dehydrogenase release, suggesting that this frequently used source of cell culture does not provide the best control group for comparison with photosensitive disease states. All these results suggest that the target for the cellular sensitivity seen in cells from PD/AR patients is the membrane.

Epidermolytic hyperkeratosis is caused by mutations of the differentiation-specific keratins K1 and K10. These mutations produce a weakened cytoskeleton that is prone to collapse resulting in cell fragility and lysis. In this study we have analyzed cultured keratinocytes from EHK patients bearing 10R-to-H and 15L-to-S mutations within the 1A segment of the K10 rod domain. Keratinocytes were grown submerged in serum-free medium and induced to differentiate by growing to confluence and increasing the Ca++ concentration in the medium. Cultures were either harvested for mRNA sequence analysis or subjected to immunofluorescence microscopy. Differentiating keratinocytes from these patients were found to express these K10 mutations in their mRNA. Moreover, these cells could be distinguished from normal keratinocytes by their aberrant morphology. EHK keratinocytes frequently exhibited a collapsed perinuclear network of K1/K10 filaments and sometimes peripheral granules of K1 and K10 aggregates, reminiscent of the cells of the suprabasal layers in these patients. This report documents the expression of mutant keratin 10 in cultured EHK keratinocytes.

Skin fibroblasts from certain patients with the photosensitivity dermatitis/actinic reticuloid syndrome show enhanced sensitivity to ultraviolet radiation compared to normal fibroblasts. To probe further the link between oxidative damage and this disease, we have obtained a more extensive set of cell lines from patients with a severe form of the disease and examined their sensitivity towards oxidative stress by measuring cell survival following UVA radiation (330-450 nm) or hydrogen peroxide treatment (0.1-2.4 mM). The activation of the stress gene, heme oxygenase, has also been assessed by measuring the accumulation of mRNA after hydrogen peroxide treatment. Our studies have confirmed that a slight ultraviolet sensitivity is a characteristic of photosensitivity dermatitis/actinic reticuloid syndrome cell strains and we further demonstrate that these cell lines are particularly sensitive to hydrogen peroxide with up to a three- to fourfold increased sensitivity as compared to normal controls. We also show that certain ataxia telangiectasia strains that are especially sensitive to hydrogen peroxide are also slightly sensitive to ultraviolet radiation. Hydrogen peroxide induces accumulation of mRNA for the oxidant-inducible stress protein, heme oxygenase, with similar kinetics (maximum mRNA accumulation 2-4 h following treatment) and with a similar range of magnitudes in both normal (6.6-20.6 times mRNA increase over basal levels) and photosensitivity dermatitis/actinic reticuloid (2.9-12.8 times) skin cells. Because cells from photosensitivity dermatitis/actinic reticuloid patients show increased sensitivity towards oxidative stress but show no significant change in oxidant activation of the heme oxygenase gene, we propose that the defect involves a late stage of processing of oxidative damage rather than a compromised free radical scavenging system.

The generalized or atypical granuloma annulare represents 8.5-15 p. 100 of all cases of granuloma annulare (GA). It differs from the localized GA variant by its morphology, its localization, a later age of onset, its protracted course, a poor response to therapy and its facultative association to diabetes mellitus. We present a typical case of generalized GA associated with eczematous dermatitis.

Background: Loricrin and involucrin are major precursor proteins to the cornified cell envelope expressed late in epidermal differentiation. Involucrin expression starts in the upper spinous layers in normal human epidermis and precedes loricrin expression, which is restricted to the granular layer. Subsequently, both proteins become cross-linked by the activity of transglutaminases TGK/E as major components of the cornified cell envelope by N epsilon-(gamma-glutamyl)lysine isopeptide bonds. In this study, three cases of lamellar ichthyosis were analyzed by immunohistologic study with antibodies to loricrin, involucrin, filaggrin, and transglutaminase TGK., Observations: A high expression of loricrin and involucrin with a peculiar and abnormal cytoplasmic staining concurred with a diminished cytoplasmic staining of transglutaminase TGK as assessed by antibodies B.C.1 and K.D.3. This pattern was absent in a collodion baby at birth but present 2 weeks later before a phenotype of lamellar ichthyosis appeared clinically., Conclusions: The results suggest that in our cases of lamellar ichthyosis, (1) disturbed membrane anchorage of transglutaminase TGK could alter loricrin and involucrin cross-linkage and the formation of the cornified cell envelope and that (2) immunohistologic study might serve as an early diagnostic and prognostic tool in the treatment of collodion babies.

Eccrine syringofibroadenoma is a rare benign neoplasm with differentiation towards eccrine ducts. Its recognition depends on the histopathological examination; it is to be differentiated mainly from fibroepithelial basal cell carcinoma. Two new cases which occurred in a 70-year-old woman and a 39-year-old woman are presented. Clinically the two neoplasms were each a solitary hyperkeratotic, partially oozing nodule. On microscopic examination they both showed proliferation of small neoplastic cells in a reticular pattern; immature or mature eccrine ductal structures were seen within them. The neoplastic cells in the two cases differed in their content of PAS-positive glycogen.

Epidermolytic hyperkeratosis is a hereditary skin disorder characterized by blistering and a marked thickening of the stratum corneum. In one family, affected individuals exhibited a mutation in the highly conserved carboxyl terminal of the rod domain of keratin 1. In two other families, affected individuals had mutations in the highly conserved amino terminal of the rod domain of keratin 10. Structural analysis of these mutations predicts that heterodimer formation would be unaffected, although filament assembly and elongation would be severely compromised. These data imply that an intact keratin intermediate filament network is required for the maintenance of both cellular and tissue integrity.

Five spontaneously healing collodion babies were recorded in a large Swiss kindred. They all had consanguineous parents. Their distribution in the family indicates autosomal recessive inheritance. At birth they had the typical features of collodion babies. The collodion-like membrane was shed within the first month, leaving a slightly scaly skin for a few weeks. Thereafter the skin remained normal without any evidence of a disorder of cornification.

We report on a patient with AIDS who developed erythema nodosum, an association that has not previously been reported. Extensive clinical and laboratory investigations disclosed no obvious origin of erythema nodosum apart from HIV infection with disseminated Kaposi sarcoma.

A 43-year-old fish fancier with fish tank granuloma presented with a sporotrichoid-like skin infection of the right arm with multiple papulo-nodular lesions along the lymphatic drainage. Acid fast bacilli were found in skin biopsy specimens and Mycobacterium marinum grew in cultures. The clinical and histopathological findings in M. marinum infection are reviewed and the differential diagnosis, laboratory findings with this atypical mycobacterium, and therapeutic modalities are discussed. Finally, the importance of an adequate and pertinent patient's history for a correct and timely diagnosis is stressed.

Inherited deficiencies of classical pathway complement components are rare and associated with autoimmune diseases and with increased susceptibility to bacterial infections. We report the clinical evolution and studies of the complement system in a 17-year-old female patient of Swiss origin presenting with systemic lupus erythematosus (malar rash, photosensitivity, leukopenia and antinuclear antibodies), in whom the hemolytically active second complement component (C2) was less than 10% of the normal value and antigenic C2 was not detectable. Linkage studies showed that the patient is HLA-A25, B18 positive and has the slow factor B allotype BfS. Further immunological assessment revealed low IgG4 concentrations in the patient, who had the G2M(23) allotype. The asymptomatic first degree family members had half-normal C2 levels compatible with a heterozygous state of C2 deficiency. Therapy with hydroxychloroquine for 17 months and topical sunscreen preparations produced marked clinical improvement. During the 4 years of follow-up, the patient has been well and shown only an abnormal titer of antinuclear antibodies. No infections were observed. To the best of our knowledge, 99 cases of homozygous C2 deficiency have been described so far and are discussed here.

Normal epidermal melanocytes are stimulated in vitro by fibroblast- and keratinocyte-derived growth factors. In this work, the paracrine responsiveness of human melanoma cells was investigated by cocultivation with growth-inhibited 3T3 fibroblasts. In short-term assays (3-4 days), melanoma cell growth was found to be improved if the cells were plated onto half-confluent 3T3 cell monolayers. In contrast, long-term cocultivation (greater than 7 days) resulted in significant growth inhibition of melanoma cells. These phenomena were not observed when melanoma cells were grown in 3T3 cell supernatants, which suggests a possible mediation by extracellular matrix components and/or by heterologous junctional communications.

A 22-month-old boy had xanthomatous skin lesions, neurofibromatosis, and chronic granulocytic leukemia. Histologic examination of the xanthomatous skin lesions disclosed juvenile xanthogranulomas. Twenty-three previously published cases of this association are reviewed.

Nucleolar organizer regions (NORs) are loops of DNA which are present within the nucleoli of cells that possess ribosomal RNA (rRNA) genes. NORs are associated with proteins which can be visualized by a simple silver staining technique. As the number of NORs appears to reflect cell and nuclear activity its determination in benign, intermediate and malignant conditions could be of help in their differential diagnosis. In this study, we investigated 35 fibrohistiocytic tumors of the skin of benign, intermediate and malignant potential from 32 patients: 15 fibrous histiocytomas (FH), 5 FH with atypia (AFH), 7 atypical fibroxanthomas (AFX), 5 dermatofibrosarcoma protuberans (DFSP) and 3 malignant FH (MFH). A one-step silver technique was used on formalin or Bouin fixed specimens. Ag-NOR counts from benign conditions (FH, AFH) significantly differed from that of their intermediate-risk (AFX, DFSP) and malignant (MFH) counterparts. Furthermore, in 2 cases (one AFX; one MFH) which twice recurred, Ag-NOR counts steadily increased with time. However, a distinction could not be achieved between AFX and MFH. Although Ag-NOR is a simple and valuable technique, it does not allow a definite distinction between malignant and intermediate processes, at least as far as fibrohistiocytic tumors of the skin are concerned.

3 patients with lamellar ichthyosis have been treated orally with the aromatic retinoid Ro 10-9359 for periods of more than 2 years. This treatment resulted in a satisfactory improvement in the skin condition without any major side-effects. A light- and electron-microscopic study showed a marked decrease in the thickness of the lamellar stratum corneum without giving any clues concerning the mechanism of the therapeutic effect of this drug.

Report of a patient presenting circumscribed, inflammatory verrucous skin lesions. These lesions appeared in the course of a long lasting lithium therapy and regressed after cessation of this treatment.

Cutaneous depigmentation due to adhesive plaster was observed in four patients. It occurred after an eczematous reaction, was irreversible and strictly limited to the contact area. There is evidence that the depigmentation was induced, at least in two patients, by the polyvinyl/rubber-plastic sheet of the adhesive plaster. Patch tests and animal experiments did not permit to identify the depigmenting component or contaminant of the plastic sheet. Light- and electron microscopy showed a complete disappearance of the epidermal melanocytes in the depigmented skin. During the first year after damage, they were mostly replaced by indeterminate cells. Later on the predominant basal non-keratinocytes of the epidermis were Langerhans cells.

The diagnostic significance of 8 previously proposed minor features of atopic dermatitis (AD) was evaluated. The minor features studied were: nipple eczema, cheilitis, Dennie-Morgan infraorbital fold, pityriasis alba, anterior neck folds, wool intolerance, white dermographism and infraauricular fissuring. The incidence of these features was appreciated in 105 patients with typical AD (median age 8.5 years) and compared to that in 113 control subjects (median age 16 years). The ages of all studied individuals ranged from 7 months to 24 years. Two of these signs, anterior neck folds and the Dennie-Morgan infraorbital fold as defined by us, were shown to be of no diagnostic significance. The other 6 features were confirmed to be valuable diagnostic clues in AD.

The treatment of vitiligo is still unsatisfactory in many patients. The only two methods that have been evaluated in numerous patients are classic psoralen-light therapy and local treatment with potent fluorinated corticosteroids. These two methods in addition to some more recent therapies that have still been insufficiently investigated are reviewed in light of the data in the newer literature.

A family in which the mother and six of her sons present an ichthyosis of the vulgaris type has been analysed clinically, histologically and electron microscopically. Phenotypically the ichthyosis in the mother is purely of the dominant type, while that in all the affected sons shows, to varying degrees, features of both the dominant and X-linked recessive variants. The findings are interpreted as reasonably good evidence that the mother has transmitted to all her affected sons both the autosomal dominant and the X-linked recessive genes for ichthyosis. Although genetically this is a most unusual situation, it corresponds best to our findings.

Direct identification of Chlamydia trachomatis with fluorescent monoclonal antibodies in smears was recently introduced for a rapid diagnosis of lower urogenital tract infections. In the present study the performance of this method was compared with that of the classical cell culture procedure with McCoy cells and iodine staining on 880 clinical specimens (table I). One hundred and twenty specimens in which one of the two methods failed for technical reasons are therefore not available for comparison. Among the remaining 760 specimens there was agreement between the two methods in 724 (95 p. 100). The sensitivity of direct identification was 85 p. 100, its specificity 97 p. 100 (table II). Our results are comparable to those reported in the literature and confirm that direct identification of Chlamydia trachomatis with fluorescent monoclonal antibodies is a useful, reasonably sensitive method for rapid diagnosis of this infection. Failures, which are relatively frequent (8 p. 100 in our series), are mostly due to inadequate specimen collection, the smears containing no epithelial cell.

The albinotic skin and hair of 2 patients with Hermansky-Pudlak syndrome were investigated by light and electron microscopy. Incubation of hairbulbs and epidermis in 1-dopa revealed a weak tyrosinase activity. The epidermal melanocyte population was of normal density. The most striking feature was the presence of numerous giant melanosomes resembling those mainly reported in various hyperpigmented skin lesions. The association of this melanosomal disorder with the platelet dysfunction and ceroid storage typical of the autosomal recessive Hermansky-Pudlak syndrome might provide new insights into the mechanism leading to formation of giant melanosomes.

Four members of a Swiss family were affected with oculo-cutaneous hypopigmentation of dominant transmission which differed from the previously described cases of dominant oculo-cutaneous albinism by its ultrastructure. The hypopigmentation described here is characterized by the formation of numerous, but very small, melanosomes. Melanocytic tyrosinase activity was normal in light microscopy. However, on electron microscopy, tyrosinase activity was strong in premelanosomes of stage I only, and decreased rapidly in the later stages. One of the affected members also presented a Prader-Willi syndrome and a chromosomal anomaly, both being probably unrelated to the pigmentary disorder.

The Spitz nevus (large spindle and/or epithelioid cell nevus) is a benign acquired melanocytic tumour found predominantly in children and adolescents. Depending on the architecture (junctional, compound, dermal) and cytology (predominance of spindle or epithelioid cells, or presence of both cell types) several variants have been distinguished. A histological feature occasionally leading to diagnostic difficulties is the involvement of the suprabasal epidermis. The present study details the occurrence of intraepidermal involvement (pagetoid spread, nesting of cells, trans-epidermal elimination) according to the age of the patients. 89 cases of Spitz nevus were reviewed. There were 19 compound Spitz nevi with evidence of epidermal involvement, 56 cases of compound Spitz nevi without evidence of epidermal involvement and 14 cases of dermal Spitz nevi. The epidermal involvement mainly consisted of nesting of nevus cells above the basal cell layer, 9 cases clearly showing evidence of transepidermal elimination of cell nests. Upward spread of single melanocytes (pagetoid spread) was minimal and always associated with nesting or trans-epidermal elimination. The mean age of patients was significantly lower in the group of compound nevi with intraepidermal involvement (7.16 +/- 4.52 years), than in the group of compound nevi without epidermal involvement (13.18 +/- 8.88 years). The age of the latter group was significantly lower than the group of pure intradermal nevi (30.14 +/- 11.25 years). Thus, involvement of the suprabasal epidermis is not a feature of Spitz nevi in adults; in such a case the diagnosis of malignant melanoma should be considered.

A 77-year-old patient with diabetes and progressive renal failure suffered from severe pruritus accompanied by umbilicated, keratotic papules corresponding clinically and histologically to reactive perforating collagenosis. UV-B light therapy considerably improved the pruritus and the skin lesions.

With the diaminobenzidine method, endogenous peroxidase activity was demonstrated in the nuclear envelope and in the endoplasmic reticulum of non-keratinized keratinocytes and Langerhans cells of the epidermis of the newborn mouse, adult guinea pig and man. In the guinea pig all non-keratinized layers of keratinocytes showed this enzyme activity, whereas in the two other species examined peroxidase activity was limited to the suprabasal layers. The most pronounced activity was found in the Langerhans cells. The melanocytes were negative. With the same method, cytochrome c/cytochrome oxidase activity could be localized in the mitochondria of all epidermal cells of mouse and man, but not in the guinea pig.

A generalized ichthyosis with an associated spastic syndrome of the lower extremities, clinically suggestive of Sjögren-Larsson syndrome, was observed in a Tunisian boy. The fatty acid analysis of the serum phospholipids revealed significant abnormalities in the fatty acid pattern of phospholipids. However, the alterations observed were different from those reported in Sjögren-Larsson syndrome. We report light and electron microscopic changes in the ichthyotic skin of this patient, which have not been previously reported in lamellar ichthyosis and in Sjögren-Larsson syndrome. The epidermis was moderately hyperplastic and covered with a thick, compact, orthokeratotic stratum corneum. The stratum spinosum was strikingly altered in some areas. Varying numbers of keratinocytes contained big vacuoles, measuring often up to the size of the nuclei; the vacuoles, were well limited but only partially lined by a membrane, they were empty or contained small amounts of a flaky material. Attempts to stain the vacuoles with PAS, Alcian blue and Fettrot were negative. Etretinate treatment produced a marked shedding of the horny layer without significant improvement of the clinical appearance. The described microscopical alterations of the epidermis remained mostly unchanged during treatment, but, in addition, a marked oedema and vacuolisation of the upper stratum granulosum was observed.

This review considers the following melanocytic and nevocytic nevi: nevus spilus, cellular blue nevus, benign juvenile melanoma, mongolian spot and nevus of Ota. Clinical aspects, histopathology and prognosis are outlined, based on data from the recent literature.