A molecular defect in loricrin, the major component of the cornified cell envelope, underlies Vohwinkel's syndrome.

Terminal keratinocyte differentiation involves coordinated expression of several functionally interdependent genes, many of which have been mapped to the epidermal differentiation complex (EDC) on chromosome 1q21. We have identified linkage of Vohwinkel's syndrome in an extended pedigree to markers flanking the EDC region with a maximum multipoint lod score of 14.3. Sequencing of the loricrin gene revealed an insertion that shifts the translation frame of the C-terminal Gly- and Gln/Lys-rich domains, and is likely to impair cornification. Our findings provide the first evidence for a defect in an EDC gene in human disease, and disclose novel insights into perturbations of cornified cell envelope formation.

Psoriatic sera decrease responses of stimulated granulocytes from normal and psoriatic subjects.

Previous studies have demonstrated alterations in polymorphonuclear leukocyte (PMNL) function in patients with psoriasis, but results have been variable. In this study we attempted to determine whether functional changes in PMNL from psoriatics represented an intrinsic cellular defect or a response to factors in serum. We evaluated the effect of the continuous presence of autologous and heterologous serum on lysozyme release and superoxide anion (O2-) generation by psoriatic and normal PMNL exposed to a soluble or particulate phagocytic stimulus. There were no differences in O2- generation or lysozyme release between normal and psoriatic PMNL without serum. However, in the presence of 10% autologous serum, these responses were significantly decreased for psoriatic PMNL (p less than .001). The results were not time-dependent and did not correlate with the extent of psoriatic involvement. The data support the hypothesis that serum factors exist in patients with psoriasis that may affect PMNL functions. The presence or absence of such factors could explain, in part, the differences between the various investigations of PMNL function in psoriasis.

Methoxsalen is a potent inhibitor of the metabolism of caffeine in humans.

The acute effect of a single oral dose of methoxsalen on the pharmacokinetics of caffeine was investigated in five nonsmoking volunteers with psoriasis. Caffeine, 200 mg orally, was administered to each subject at baseline before treatment with methoxsalen. One week later each subject was given a single oral dose of 1.2 mg/kg methoxsalen 1 hour before administrations of another oral dose of 200 mg caffeine. The clearance of caffeine declined markedly from 110 +/- 17 ml/min (mean +/- SE) in the control study to 34 +/- 5 ml/min after methoxsalen. During the period of maximum inhibition the mean elimination half-life of caffeine increased from 5.6 hours at baseline to 57 hours after administration of methoxsalen. The peak concentration of caffeine and the time to reach the peak concentration of caffeine were not affected by pretreatment with methoxsalen. Thus, methoxsalen, administered acutely, is a potent inhibitor of caffeine metabolism in humans with psoriasis. Results of this investigation suggest that the elimination of concurrently administered drugs may be inhibited in patients receiving methoxsalen. In comparison with other drugs, methoxsalen is the most potent inhibitor of drug metabolism in humans. Other work has shown that inhibition of drug metabolism by methoxsalen is associated with both extensive covalent binding of metabolite(s) of methoxsalen to liver microsomal protein in vitro and in vivo and inactivation of cytochrome P-450.

Selected drug complications and treatment conflicts in the presence of coexistent diseases.

The presence of different coexistent systemic diseases often times complicates the selection of the appropriate treatment of an underlying rheumatologic condition. In this article, some controversial treatment conflicts that are frequently encountered in the daily practice of rheumatology are clarified and guidelines for the best available therapeutic options are provided.

Mycosis fungoides. Small-bowel involvement complicated by perforation and peritonitis.

Mycosis fungoides (MF) is a malignant lymphoma that arises in the skin and subsequently may involve lymph nodes and viscera as part of the natural course of the disease. The disease has distinct histologic characteristics that may be recognized in extracutaneous tissues. A patient who had MF with ulcerating cutaneous nodules is presented herein. Death resulted from perforation of the small bowel involved by the disease and consequent peritonitis.

Variant of keratoderma hereditaria mutilans (Vohwinkel's syndrome). Treatment with orally administered isotretinoin.

Keratoderma hereditaria mutilans (KHM), or Vohwinkel's syndrome, is a rare genodermatosis consisting of hyperkeratosis of the palms and soles with a characteristic "honeycomb" appearance, keratotic structures taking the shape of a starfish and/or knuckle pads on the dorsal surfaces of the hands, and constricting bands (pseudoainhum) encircling digits of the hands and feet. We describe three cases of a variant of KHM with an associated ichthyosiform dermatosis in a pedigree consisting of 19 affected individuals through six generations. An autosomal dominant inheritance pattern for KHM was confirmed. One of the patients was successfully treated with isotretinoin, 0.6 mg/kg/day orally. We offer five hypothetical genetic models to account for the simultaneous expression of palmar-plantar keratoderma and ichthyosiform dermatosis.

Nocardia asteroides infection with dissemination to skin and joints.

A 56-year-old diabetic woman developed multiple cutaneous lesions and septic arthritis secondary to disseminated Nocardia asteroides pulmonary infection. The diagnosis was made rapidly by Gram's and acid-fast stains of pus, sputum, and synovial fluid and later confirmed by cultures. Sulfonamides are the drugs of choice for nocardiosis, and this patient had a complete response to two weeks of intravenous trimethoprim and sulfamethoxasole followed by three months of oral therapy.

Conjunctival involvement in paraneoplastic pemphigus.

Paraneoplastic pemphigus is a recently described autoimmune inflammatory mucocutaneous disease associated with an underlying neoplasm. Although histopathologic and direct immunofluorescence findings of involved skin and mucous membranes are consistent with pemphigus vulgaris, indirect immunofluorescence and immunoprecipitation study results are unique. We treated two patients with non-Hodgkin's lymphoma and paraneoplastic pemphigus. Both patients had bilateral bulbar conjunctival hyperemia and diffuse papillary tarsal conjunctival reactions. One patient had sloughing of conjunctival epithelium and the other had tarsal conjunctival cicatrization and forniceal shortening. Histopathologic findings of conjunctivae obtained from both patients were consistent with pemphigus vulgaris. Diffuse deposition of IgG and C3 in the intercellular substance of the conjunctival epithelium was demonstrated by direct immunofluorescence. Indirect immunofluorescence testing disclosed binding of autoantibodies to rodent bladder and intestinal epithelium. Immunoprecipitation disclosed antibodies reactive to Desmoplakin I (250 kd), bullous pemphigoid (230 kd), Desmoplakin II (210 kd) and 190-kd proteins. Ophthalmologists and pathologists should be aware of the conjunctival changes in paraneoplastic pemphigus.

Cicatrizing conjunctivitis associated with paraneoplastic lichen planus.

PURPOSE: To report two cases of cicatrizing conjunctivitis associated with paraneoplastic lichen planus. METHODS: Case reports. RESULTS: Two patients were examined because of redness and discomfort in both eyes. A 63-year-old woman with follicular, small-cleaved cell lymphoma had cicatrizing conjunctivitis, stomatitis, vulvitis, and skin lesions. A 25-year-old man with malignant thymoma had cicatrizing conjunctivitis, erosive stomatitis, and penile papules. Histopathologic studies of conjunctiva and skin biopsy specimens in the first patient and labial biopsy specimens in the second revealed lichen planus. CONCLUSION: Paraneoplastic lichen planus is a possible cause of cicatrizing conjunctivitis associated with inflammatory skin and mucous membrane disease.

Immunobullous diseases with ocular involvement.

Collaborative efforts of the dermatologist and ophthalmologist and other physicians with interest and experience in the management of the autoimmune bullous diseases optimize patient care by avoiding potentially harmful delay in diagnosis or implementation of therapy. At our institution, ophthalmologic and dermatologic follow-up visits for patients with bullous disorders involving the eyes are arranged for the same day so that ophthalmic examination and monitoring and adjustment of medication by the dermatologist can be effected. During initiation of treatment, visits are monthly. Later, when patients are stabilized, intervals may be extended to 3 to 6 months. More frequent visits are arranged as needed with the ophthalmologist to manage infectious complications or problems requiring surgical management and with the dermatologist to manage extraocular disease and adverse reactions to medication and to triage concurrent illnesses.

New and emerging therapies for diseases of the oral cavity.

It is obvious from the review of the literature that most treatments for oral diseases such as lichen planus, pemphigoid, and pemphigus are based on case reports, anecdotes, and small uncontrolled studies. Efforts must be made to perform more controlled studies to evaluate the efficacy of new treatments. Small numbers of patients at each site and multiple-drug therapy make this task difficult. Dermatologists should familiarize themselves with the newer immunosuppressive agents available. Use of these drugs requires knowledge of their pharmacokinetics and potential side effects, so that they may be used effectively and safely. Relatively low doses of azathioprine, cyclophosphamide, and cyclosporine should then be added to the dermatologist's armamentarium for the treatment of severe or recalcitrant diseases. Old drugs are resurfacing with new (but often off-label) uses as the underlying mechanisms of disease become understood. Thalidomide and mycophenolate mofetil are two examples of promising drugs for the future of dermatology.

Treatment of hidradenitis suppurativa with combination hypothalamic-pituitary-ovarian and adrenal suppression. A case report.

A 33-year-old woman with severe familial hidradenitis suppurativa of the vulva and perineum was treated with a combination of dexamethasone and a new synthetic gonadotropin releasing hormone agonist, leuprolide acetate. The clinical improvement paralleled the adrenal and ovarian suppression, as demonstrated by falling blood levels of testosterone, dehydroepiandrosterone sulfate, androstenedione and estradiol.

Psoriasis: a clinical update on diagnosis and new therapies.

Psoriasis varies widely in its clinical expression, from a single fingernail pit to widespread disfiguring skin lesions and disabling arthritis. Treatments are divided into five levels, providing a framework for approaching this disease according to severity and recalcitrance to previous treatment. Powerful immunosuppressive drugs are showing some success in treating severe cases.

Fixed drug eruption from pamabrom.

A young woman presented with recurrent skin lesions that were predominantly perioral. Fixed drug reaction was diagnosed based on her history of intermittent ingestion of Pamprin, a common menstrual symptom reliever, and characteristic erythematous, pigmented, edematous patches. After oral challenge with two of the three ingredients in Pamprin, a diagnosis of fixed drug reaction to pamabrom was made. Pamabrom is a mild diuretic present in several over-the-counter and prescription menstrual symptom relievers. This is the first reported case of fixed drug reaction to pamabrom.

Treatment of psoriasis with chronic subcutaneous administration of somatostatin analog 201-995 (sandostatin). II. Effect on pancreatic and thyroid hormone.

Nine patients with psoriasis vulgaris were treated for 12 weeks with somatostatin analog, octreotide acetate (SMS 201-995) 50 or 100 micrograms by subcutaneous injection every 12 hours. The purposes of the study were to determine: (1) levels of insulin, glucose, glucagon, pancreatic polypeptide (PP), and SMS 201-995 after a subcutaneous injection of SMS 201-995 and ingestion of a standardized meal; (2) nocturnal (0200 h) thyroid stimulating hormone (TSH) levels before, during, and after treatment; and (3) the pharmacokinetics of SMS 201-995. Insulin peaks at 30 minutes were blunted from 65.8 +/- 11.0 mu U/mL without treatment to 26.7 +/- 8.6 mu U/mL and 7.7 +/- 2.0 mu U/mL after the 50- and 100-micrograms doses, respectively. Glucagon levels remained constant during the meal and were not affected by the 50-micrograms dose. Mean glucose levels were significantly elevated during insulin suppression. PP was also rapidly suppressed by SMS 201-995 and remained so for 4 hours after the injection. Nocturnal TSH was blunted after 12 weeks of treatment (P less than or equal to .05). T4 and T3 resin uptake showed no depression, and patients remained clinically euthyroid. The plasma peak of SMS 210-995 occurred 30 minutes postinjection and half-life was longer than 2 hours. After chronic administration of SMS 201-995, insulin was suppressed with resultant mild carbohydrate intolerance that persisted throughout the treatment course.

An unusual ocular manifestation of discoid lupus erythematosus.

BACKGROUND: Discoid lupus erythematosus is a chronic skin disease characterized by well-demarcated papules and plaques. Mucous membrane changes are common; however, conjunctival involvement is unusual. We report a case of unilateral, chronic, isolated discoid lupus erythematosus of the conjunctiva. OBSERVATIONS: A 32-year-old man presented for evaluation of chronic conjunctivitis of the right eye that had persisted for 9 years. A biopsy of the bulbar conjunctiva revealed a mixed mononuclear cellular infiltrate distributed along the epithelial basement membrane zone and around the stromal blood vessels. Immunohistopathologic examination revealed a diffuse, granular pattern of fluorescence corresponding to immunoglobulins and complement components along the epithelial basement membrane zone and in the walls of the stromal blood vessels. Electron microscopy demonstrated changes in the epithelial basal lamina consistent with discoid lupus erythematosus, including areas that were multilayered. Immunoelectron microscopy identified sub-basal lamina deposits of immunoglobulin G. CONCLUSIONS: Discoid lupus erythematosus should be a suspected cause of chronic conjunctival inflammation; the diagnosis is substantiated by immunopathologic and ultrastructural studies.

Treatment of psoriasis with chronic subcutaneous administration of somatostatin analog 201-995 (sandostatin). I. An open-label pilot study.

Increased levels of human growth hormone (HGH) may correlate with the severity of psoriasis and native somatostatin (SRIF) may improve it by inhibiting HGH release. The synthetic SRIF analog, SMS 201-995, is a potent and long-lasting HGH inhibitor. Nine patients with chronic plaque psoriasis completed 12 weeks of open treatment with SMS 201-995. Overall improvement was minimal to marked in six patients and unchanged in three; none worsened. Means of 24-hour pooled HGH (1.7 +/- 0.7 micrograms/L) and fasting plasma somatomedin-C (SM-C) (0.45 +/- 0.22 U/mL) were normal at baseline and were not significantly altered by treatment. A high frequency of gastrointestinal side effects occurred, but no patient discontinued treatment because of them. SMS 201-995 may be a useful therapy for psoriasis, but its mechanism of action is unknown. Double-blind placebo-controlled trials are currently in progress to confirm the efficacy of SMS 201-995 in psoriasis.

Squamous cell carcinoma arising in acne conglobata.

A squamous cell carcinoma was found on the back of a man who had had acne conglobata for more than forty years. Squamous cell carcinomas called Marjolin's ulcers may arise in the sites of chronic inflammation and scarring such as thermal burn scars, discoid lupus erythematosus, leg ulcerations, and foci of osteomyelitis. Squamous cell carcinoma has also been reported in all three diseases included in the so-called "follicular occlusion triad": acne conglobata, dissecting cellulitis of the scalp, and hidradenitis suppurativa.

Treatment of primary cutaneous B cell lymphoma with local radiotherapy.

A patient with primary cutaneous B cell lymphoma that presented as a solitary nodule on the abdomen was successfully treated with local radiotherapy. A brief review of special studies used to diagnose this tumor as well as clinical characteristics of the tumor is presented.

Paraneoplastic acrokeratosis: Bazex syndrome.

Paraneoplastic acrokeratosis, or Bazex syndrome, is a rare, distinct dermatosis characterized by psoriasiform acral hyperkeratosis. In most cases, it is a specific cutaneous sign of an occult squamous cell carcinoma of the upper aerodigestive tract that has metastasized to cervical lymph nodes. We report the fifth American case of paraneoplastic acrokeratosis. The patient's skin disease was more remarkable for its hyperpigmentation than its hyperkeratosis. Nearly all of the hyperpigmentation resolved, but the nail dystrophy persisted seven months after the tumor had been treated using surgery and radiation.