Miliary fibromas in tuberous sclerosis complex.

BACKGROUND: Tuberous sclerosis complex (TSC) is a hamartoma syndrome characterized by multiple skin lesions, such as angiofibromas, shagreen patch and miliary fibromas (MiF). OBJECTIVE: To determine the clinical and histological features of MiF. METHODS: A retrospective analysis was conducted on 133 adults with TSC. Photography was used to characterize the appearance and location of MiF. Histological features in five skin samples from four individuals were evaluated by a board-certified dermatopathologist. RESULTS: MiF were observed in 19 of 133 (14%) individuals with TSC. MiF were 1- to 3-mm skin-coloured, sessile papules scattered on the back and rarely buttocks or thighs. Most were scattered in a bilaterally symmetric distribution, but others were asymmetric or associated with a shagreen patch. Histological features of MiF included expansion of the papillary and periadnexal dermis with variable hamartomatous abnormalities involving adjacent epithelial components. CONCLUSIONS: MiF are distinct from other cutaneous lesions in TSC such as shagreen patches and angiofibromas. Recognition of this entity is important in defining the spectrum of TSC disease and reassuring individuals with TSC that these lesions are benign.

Anti-epiligrin cicatricial pemphigoid and relative risk for cancer.

It is not known whether patients with anti-epiligrin cicatricial pemphigoid (AECP) have an increased risk of malignancy. We calculated the expected numbers of cancers in a cohort of 35 such patients based on respective incidence rates for all cancers in the National Cancer Institute's Surveillance, Epidemiology, and End Results (NCI SEER) Registry. Ten patients in this cohort had solitary solid cancers; eight patients developed cancer after onset of AECP (seven within 14 months). The relative risk (RR) for cancer in this cohort was 6.8 (95% confidence intervals [CI]: 3.3-12.5). AECP seems to be associated with an increased relative risk for cancer.

Mucosal morbidity in patients with epidermolysis bullosa acquisita.

BACKGROUND: Epidermolysis bullosa acquisita is an acquired inflammatory and/or dermolytic subepidermal blistering disease characterized by IgG autoantibodies to type VII collagen. Four patients with documented epidermolysis bullosa acquisita were evaluated by a multidisciplinary team of care providers (4 dermatologists, an ophthalmologist, a radiologist, a voice and speech specialist, and an otolaryngologist) for 1 to 5 years to characterize mucosal involvement and its complications and response to treatment. Patients were evaluated clinically and by slitlamp examinations, endoscopies, computed tomographic scans, and videofluorographic swallowing studies. Spiral computed tomographic scans for virtual endoscopy were used for the nontraumatic evaluation of airways in 2 patients with respiratory tract compromise. OBSERVATIONS: Involvement of 5 or more mucosal sites--mouth, nose, conjunctiva, pharynx, and larynx--was documented in all patients. Complications included ankyloglossia, periodontal disease, scarring and crusting of nasal mucosa, symblepharon formation, obstruction of nasolacrimal ducts, deformation of the epiglottis, impaired phonation, dysphagia, esophageal strictures, and supraglottic stenosis requiring emergency tracheostomy. CONCLUSIONS: Epidermolysis bullosa acquisita may extensively (or predominantly) affect mucosal epithelia in a manner resembling cicatricial pemphigoid. Mucosal disease in these patients is often subclinical, can lead to serious complications, and is best managed using a multidisciplinary approach.

Revertant mosaicism: partial correction of a germ-line mutation in COL17A1 by a frame-restoring mutation.

Generalized atrophic benign epidermolysis bullosa is an autosomal recessive subepidermal blistering disease typified by null mutations in COL17A1. In 1 large kindred, affected individuals were homozygous for a 2-bp deletion in COL17A1, 4003delTC, which resulted in a downstream premature termination codon, nonsense-mediated mRNA decay, and abrogation of type XVII collagen synthesis. Interestingly, 1 of these patients, although phenotypically identical to her affected siblings, showed focal expression of type XVII collagen in epidermal basement membrane in a pattern suggestive of revertant mosaicism. When studies of randomly obtained epidermal, oromucosal, and peripheral blood cells failed to identify the genetic basis of this apparent mosaicism, microscopic subpopulations of potentially revertant epidermal cells (i.e., those overlying basement membrane containing type XVII collagen) were selectively isolated using laser capture microdissection. Analysis of DNA and RNA from these cells revealed a second mutation, 4080insGG, on 1 allele of COL17A1. This 2-bp insertion corrected the reading frame just proximal to the premature termination codon, countered nonsense-mediated mRNA decay, and allowed protein production by patient keratinocytes in vivo and in vitro. These studies elucidate the molecular basis of a novel form of revertant mosaicism in humans.

Perivascular cells harboring multiple endocrine neoplasia type 1 alterations are neoplastic cells in angiofibromas.

Although neoplasia is caused by clonal proliferation of cells, the resulting tumors are frequently heterogeneous, being composed of both neoplastic and reactive cells. Therefore, identification of tumors as neoplastic processes is frequently obscured. We studied cutaneous angiofibroma, which is a tumor of unknown etiology. Combined analysis using immunohistochemistry, selective tissue microdissection, fluorescence in situ hybridization, sequencing analysis, and deletion analysis of the multiple endocrine neoplasia type 1 locus succeeded in the identification of a population of genetically altered, neoplastic cells in these tumors. This approach may be valuable in the future in identifying the etiology of other tumors of unknown etiology.

Clinical differentiation between Proteus syndrome and hemihyperplasia: description of a distinct form of hemihyperplasia.

Proteus syndrome is a rare and highly variable hamartomatous syndrome that can affect multiple organ systems. It is characterized by hyperplastic lesions of connective tissue, vascular malformations, linear verrucous epidermal nevi, and hyperostoses. The cause of the disorder is unknown, but the current working hypothesis is that it is caused by a mosaic alteration that leads to a highly variable phenotype, equal sex ratio, sporadic occurrence, and discordant monozygotic twins. Herein we describe our experience with 18 patients with a referring diagnosis of Proteus syndrome. It was found that imaging studies are very useful for the characterization of the syndrome. One finding was that splenic hyperplasia can be a manifestation of Proteus syndrome. Analysis of the clinical data shows that Proteus syndrome is frequently confused with "hemihyperplasia." A distinct subtype of hemihyperplasia is defined that includes static or mildly progressive hemihyperplasia and multiple lipomata.

Cutaneous tumors in patients with multiple endocrine neoplasia type 1 show allelic deletion of the MEN1 gene.

Multiple endocrine neoplasia type 1 (MEN1), the heritable tendency to develop tumors of the parathyroid, pituitary, and entero-pancreatic endocrine tissues, is the consequence of a germline mutation in the MEN1 gene. Endocrine tumors in these patients result when the mutant MEN1 allele is accompanied by loss of the normal MEN1 allele. Recently it was reported that MEN1 patients also exhibit several cutaneous tumors, including multiple angiofibromas, collagenomas, and lipomas. The purpose of this study was to examine skin lesions from patients with MEN1 for allelic loss of the MEN1 gene. Skin lesions from five patients with MEN1 were examined using fluorescence in situ hybridization. Six angiofibromas, three collagenomas, and one lipoma showed allelic deletion of the MEN1 gene. Allelic deletion was not observed in a melanocytic nevus or acrochordon from patients with MEN1. It was also not observed in an angiofibroma from a patient with tuberous sclerosis. These results suggest that loss of function of the wild-type MEN1 gene product plays a role in the development of angiofibromas, collagenomas, and lipomas in patients with MEN1.

Cycloheximide facilitates the identification of aberrant transcripts resulting from a novel splice-site mutation in COL17A1 in a patient with generalized atrophic benign epidermolysis bullosa.

Patients with generalized atrophic benign epidermolysis bullosa often show decreased expression of type XVII collagen, a transmembrane hemidesmosomal protein encoded by COL17A1. This report documents a novel splice-site mutation in COL17A1 in a patient with generalized atrophic benign epidermolysis bullosa, and applies a new methodology to define and characterize the resulting mRNA splice variants. Mutational analysis of COL17A1 identified a maternally inherited G-to-T transversion at the -1 position of exon 32. This acceptor splice-site mutation led to the formation of aberrant transcripts present at extremely low levels. Based on our recent finding that cycloheximide stabilized mutant COL17A1 transcripts in keratinocytes homozygous for a frameshift mutation, the effects of the splice-site mutation on splicing of COL17A1 transcripts were determined using reverse transcriptase polymerase chain reaction of total RNA from keratinocytes incubated for 2.5 h in the presence or absence of 10 microg cycloheximide per ml. Using this approach, an abnormally spliced transcript was identified that contains an extra 264 bases upstream from exon 32, resulting in a premature termination codon 27 bp downstream from the cryptic splice site. Three other splice variants, including one derived from the skipping of exon 32, were also identified. These results indicate the usefulness of cycloheximide treatment in evaluating the abnormal processing of mRNA due to splice-site mutations, because: (i) aberrant splicing often generates a premature termination codon, (ii) transcripts with premature termination codons can occur at low or undetectable levels due to nonsense-mediated mRNA decay, and (iii) the levels of these transcripts can be increased by cycloheximide.

A deletion mutation in COL17A1 in five Austrian families with generalized atrophic benign epidermolysis bullosa represents propagation of an ancestral allele.

Patients with generalized atrophic benign epidermolysis bullosa, a usually nonlethal form of junctional epidermolysis bullosa, have generalized blistering, nail dystrophy, patchy alopecia, and dental abnormalities. Skin fragility in most cases is due to mutations in the gene encoding type XVII collagen (COL17A1). Recently, we reported five Austrian families with generalized atrophic benign epidermolysis bullosa who share the same COL17A1 mutation. Affected individuals in three families are homozygous for 4003delTC, whereas those in two others are compound heterozygotes. To determine if the occurrence of 4003delTC in these unrelated families signifies propagation of an ancestral allele or a mutational hot spot, haplotypes were determined for polymorphisms both within and flanking COL17A1. Five intragenic polymorphisms were chosen based on their informativeness. One of these, not previously reported, was 2988 A or C that introduces a new restriction site for Eco0109 I. All the 4003delTC alleles showed the same haplotype for these five polymorphic markers. Fourteen microsatellite polymorphisms were selected based on their high heterozygosity and their location within 10q23-q25 near COL17A1. Three families shared microsatellite polymorphisms covering at most 19 cM, whereas the others shared smaller regions consistent with cross-over events during passage of this mutation through several generations. These results indicate that 4003delTC occurs on a single ancestral allele.

Multiple facial angiofibromas and collagenomas in patients with multiple endocrine neoplasia type 1.

OBJECTIVES: To evaluate patients with multiple endocrine neoplasia type 1 (MEN 1) for cutaneous manifestations. DESIGN: Survey during a 3-year period. SETTING: The National Institutes of Health, a tertiary referral research hospital in Bethesda Md. PATIENTS: A consecutive sample of 32 individuals with previously diagnosed MEN1 who were not preselected for the presence of skin lesions were examined for cutaneous abnormalities. None of the patients or family members were diagnosed as having tuberous sclerosis. INTERVENTIONS: Lesions were identified by clinical appearance, photographed, and confirmed histologically. MAIN OUTCOME MEASURE: To determine the frequency of skin lesions in patients with MEN1. RESULTS: Multiple facial angiofibromas were observed in 28 (88%) of the patients with MEN1, with 16 patients (50%) having 5 or more. Angiofibromas were clinically and histologically identical to those in individuals with tuberous sclerosis. Collagenomas were observed in 23 patients (72%). Also observed were cafe au lait macules in 12 patients (38%), lipomas in 11 patients (34%), confetti-like hypopigmented macules in 2 patients (6%), and multiple gingival papules in 2 patients (6%). CONCLUSIONS: Multiple angiofibromas, collagenomas, lipomas, confetti-like hypopigmented macules and multiple gingival papules are cutaneous manifestations of MEN1 and should be looked for in both family members of patients with MEN1 and individuals with hyperparathyroidism of other MEN1-associated tumors. Multiple angiofibromas can no longer be considered pathognomonic for tuberous sclerosis. The observation of angiofibromas in individuals without tuberous sclerosis necessitates further biochemical testing for MEN1.

Premature termination codons are present on both alleles of the bullous pemphigoid antigen 2/type XVII collagen gene in five Austrian families with generalized atrophic benign epidermolysis bullosa.

Patients with generalized atrophic benign epidermolysis bullosa (GABEB), an inherited subepidermal blistering disease, often have no immunologically detectable bullous pemphigoid antigen 2 (BPAG2) in their epidermal basement membrane. Recently, we analyzed the BPAG2 gene (GenBank no. M91669) in an Austrian family with GABEB and identified a homozygous deletion mutation, 4003delTC, that results in a downstream premature termination codon (PTC). This mutation has now been identified in additional descendants, suggesting transmission of this mutant allele through at least six generations. Screening of four other Austrian GABEB families revealed that affected members were homozygous for 4003delTC in two cases and heterozygous in two others. In the latter, mutational analysis identified two novel nonsense mutations, Q1403X and G803X, that were confirmed by restriction endonuclease digestions. Thus, PTCs on both alleles of BPAG2 are present in all of these GABEB families. Immunoprecipitation and northern blot studies of cultured keratinocytes from homozygous GABEB patients show that 4003delTC results in undetectable levels of BPAG2 protein and mRNA-findings consistent with the process of nonsense-mediated mRNA decay. Incubating keratinocytes with cycloheximide increased BPAG2 mRNA to a level detectable by northern analysis. When the latter was used in reverse transcription-PCR studies, the mutation was demonstrated, suggesting that cycloheximide may allow mutational analysis in cases where low transcript levels have previously thwarted RT-PCR studies. These findings account for the absence of BPAG2 in GABEB patients and attest to the importance of this protein in adhesion of epidermis to epidermal basement membrane.

Generalized atrophic benign epidermolysis bullosa.

Junctional EB was once considered a uniformly fetal autosomal recessive skin disease. One of the first and best characterized forms of generalized JEB that has a more favorable prognosis was GABEB. Since its initial description in 1976, many additional cases have been compiled, all sharing the features of chronic blistering from birth, nail dystrophy, hair loss, and abnormal teeth. In addition, some patients have large melanocytic nevi that form at sites of prior blisters. The first clues as to the protein defective in these patients was provided by immunofluorescence microscopy studies, which showed absent or decreased expression of type XVII collagen in these patient's epidermal BM. This protein was a promising candidate because it is located in the ultrastructural plane where blisters from in patients with GABEB. It is also the same hemidesmosomal protein against which antibodies are directed in patients with autoimmune blistering diseases: bullous, gestational, and cicatricial pemphigoid. The demonstration of decreased expression of type XVII collagen in patients with GABEB pointed the way to a crucial distinction that could not be based on clinical and histologic findings--that of discriminating infants with GABEB from those with the lethal Herlitz variant of JEB. These two diseases may be differentiated because decreased expression of type XVII collagen is found exclusively in GABEB, whereas decreased expression of laminin 5 is most likely associated with Herlitz JEB. The molecular basis of GABEB has been determined. The immunofluorescence microscopy studies mentioned above directed mutation studies to the COL17A1 gene. Several mutations in COL17A1 have been described in patients with GABEB, almost all of which result in a PTC. As a consequence of the PTC, mutant COL17A1 transcripts are rapidly degraded by nonsense-mediated mRNA decay, blocking production of type XVII collagen from the mutant allele. Heterozygous carriers of the mutation are thus rendered untouched by the mutation. In the homozygous state, however, this results in the absence of this vital adhesion protein, leading to chronic blistering and skin fragility observed in these patients. These studies also significantly increase our knowledge about the normal functions of type XVII collagen. The fact that patients deficient in type XVII collagen have fragile skin attests to the role of this protein in the adhesion of basal keratinocytes to epidermal BM. The severity of GABEB, however, is much less than that observed in patients with a complete deficiency of laminin 5, suggesting that type XVII collagen functions cooperatively with other hemidesmosomal proteins in promoting adhesion. Studies using GABEB keratinocytes will help characterize these kinds of interactions. The ultimate prospect of mutation analysis in these patients is the hope of correcting their genetic defect and curing their disease. Until then, the physician plays an important role in making the diagnosis, providing general supportive skin care, advising avoidance of trauma, treating infections, and supporting the patient's psychosocial development. Further studies of patients with GABEB will lead to new therapeutic approaches, as well as reveal additional complex functions of type XVII collagen not only in skin, but also in hair, teeth, and nails.

A child with antibodies targeting both linear IgA bullous dermatosis and bullous pemphigoid antigens.

BACKGROUND: Some patients with subepidermal blistering diseases show clinical, histologic, and immunopathologic features of both linear IgA bullous dermatosis and bullous pemphigoid. Such patients can be further characterized by defining the target of their circulating autoantibodies. We present the first case report of a child with linear deposits of IgA and IgG with circulating autoantibodies characteristic of both linear IgA bullous dermatosis and bullous pemphigoid. OBSERVATIONS: Widely distributed subepidermal vesicles showing neutrophils in the dermal papillae developed in a 3-year-old boy. Direct immunofluorescence microscopy of perilesional skin revealed linear deposits of IgA, IgG, and C3 in the epidermal basement membrane. The patient responded to therapy with dapsone, and after 6 months, it was possible to discontinue treatment. Circulating IgA antibodies from this child bound the epidermal side of 1-mol/L saline-split skin and immunoblotted the 97-kd linear IgA bullous dermatosis antigen. Circulating IgG antibodies bound the epidermal and, at low titer, dermal sides of split skin. These IgG antibodies immunoblotted and immunoprecipitated bullous pemphigoid antigens 1 and 2. CONCLUSIONS: Linear deposits of IgA and IgG in the epidermal basement membrane of patients with subepidermal bullous lesions may signify the coexistence of circulating autoantibodies directed against linear IgA bullous dermatosis and bullous pemphigoid antigens.

Treatment of Mycobacterium haemophilum infection with an antibiotic regimen including clarithromycin.

A patient with rheumatoid arthritis developed ulcerated nodules predominantly on his legs. Skin biopsy and culture demonstrated rheumatoid vasculitis and infection with Mycobacterium haemophilum. Improvement was not seen until clarithromycin was added to his treatment regimen.

Acquired cutaneous smooth muscle hamartoma.

A 35-year-old white man had an indurated, indistinct plaque on the anterior aspect of the neck for 10 years. Results of biopsy specimens showed an excess of smooth muscle bundles scattered throughout the dermis. Unlike previously reported cases of acquired smooth muscle hamartomas, it did not occur in association with a Becker nevus.