Autosomal dominantly inherited generalized basaloid follicular hamartoma syndrome: report of a new disease in a North Carolina family.

BACKGROUND: An 8-year-old girl presented with hundreds of milia, measuring 1 to 2 mm; comedone-like lesions; skin-colored and hyperpigmented papules on the face, scalp, ears, neck, upper trunk, and lower arms along with diffuse scalp hypotrichosis; and pinpoint palm/sole pits. Onset was in early childhood and the disease was historically present in 6 generations. OBJECTIVE: Our objectives were to delineate the clinical and histopathologic features and mode of inheritance as a base for gene studies. METHODS: Eighteen family subjects were studied. Twenty-six skin biopsy specimens were examined. A detailed pedigree was constructed. A complete literature search was done concerning diseases with generalized basaloid follicular hamartomas. RESULTS: The lesions were basaloid follicular hamartomas and other folliculocentric abnormalities. Inheritance was autosomal dominant. Extensive literature search confirmed the finding of a unique genodermatosis. CONCLUSION: A new genodermatosis termed dominantly inherited generalized basaloid follicular hamartoma syndrome was defined by delineating its clinical and histopathologic features and mode of inheritance and by extensive literature review.

Fab fragments directed against laminin 5 induce subepidermal blisters in neonatal mice.

Patients with one form of cicatricial pemphigoid have IgG autoantibodies directed against laminin 5 (alpha3beta3gamma2), an adhesion protein in epidermal basement membrane. Anti-laminin 5 autoantibodies are not found in patients with other skin or mucosal diseases and hence serve as a specific marker for this autoimmune blistering disorder. The demonstration that experimental and patient anti-laminin 5 IgG are pathogenic in animal models indicated that such autoantibodies are central to disease pathophysiology. To investigate further the role of antibody valence and complement in triggering lesion formation in vivo, rabbit anti-laminin 5 (or normal, control) Fab fragments were passively transferred to neonatal BALB/c mice. Mice receiving anti-laminin 5 Fab fragments developed, in a dose-related fashion, circulating anti-basement membrane antibodies, deposits of immunoreactive rabbit IgG (but not murine C3) in epidermal basement membranes, and subepithelial blisters of skin and mucous membranes. Such alterations were not observed in mice treated with equivalent concentrations of normal rabbit Fab fragments. These studies demonstrated that neither complement activation nor cross-linking of laminin 5 in epidermal basement membranes was required for induction of subepidermal blister formation in this animal model of a human autoimmune bullous disease.

Hailey-Hailey disease keratinocytes: normal assembly of cell-cell junctions in vitro.

The blisters in the inherited disorder, Hailey-Hailey disease, may be caused by defective epidermal junctional complexes. We evaluated these structural complexes in vivo and in vitro. We induced a vesicular lesion in the apparently normal skin of a patient with Hailey-Hailey disease and studied a biopsy of this lesion by transmission electron microscopy. To determine whether acantholysis was related to a defect in the number or assembly of intercellular junctions, we cultured Hailey-Hailey disease keratinocytes in medium containing 0.1 mM Ca2+ and increased the [Ca2+] to 1.1 mM in order to induce assembly of cell-cell junctions. Keratinocytes were examined by double immunofluorescence with antibodies to the desmosome protein, desmoplakin, and the adherens junction protein, vinculin, at intervals after the increase in [Ca2+]. Characteristic Hailey-Hailey disease histopathology was observed by electron microscopy of the patient's skin after trauma, but we found no splitting of desmosomes. Based on the location, intensity, and rate of change of immunofluorescent staining, Hailey-Hailey and normal keratinocytes did not differ in their ability to assemble desmosomes and adherens junctions. Furthermore, we observed no significant morphologic differences between normal and Hailey-Hailey keratinocytes cultured in low and high [Ca2+]-containing media; Hailey-Hailey cells contained abundant normal-appearing desmosomes in 1.1 mM [Ca2+]. Since Hailey-Hailey disease keratinocytes can assemble normal-appearing adherens junctions and desmosomes in vitro, the functional defect may not lie in assembly of cell-cell adhering junctions, or additional perturbation may be required to expose the defect.

Passive transfer of anti-laminin 5 antibodies induces subepidermal blisters in neonatal mice.

Patients with a recently identified subepithelial blistering disease have IgG anti-laminin 5 autoantibodies. To determine if such antibodies can be pathogenic in vivo, we developed and characterized rabbit anti-laminin 5 IgG, and passively transferred these antibodies to neonatal mice. Immune rabbit IgG specifically bound human and murine epidermal basement membranes, immunoblotted and immunoprecipitated all laminin 5 subunits from extracts of human and murine keratinocytes, and showed no reactivity to other keratinocyte proteins or epithelial basement membranes that do not contain laminin 5. Mice (n = 29) receiving purified anti-laminin 5 IgG developed, in a dose-related fashion, circulating anti-laminin 5 antibodies, deposits of rabbit IgG and murine C3 in epidermal basement membranes, and subepidermal blisters of skin and mucous membranes. No alterations developed in controls (n = 14) receiving identical amounts of normal rabbit IgG. Passive transfer of anti-laminin 5 (but not control) IgG to neonatal C5- (n = 3) or mast cell-deficient (n = 3) mice produced subepidermal blisters with the same clinical, histologic, and immunopathologic features as those documented in BALB/c mice. These studies establish an animal model of a human blistering disease that can be used to define disease mechanisms and treatment modalities.

Passive transfer of autoantibodies from a patient with mutilating epidermolysis bullosa acquisita induces specific alterations in the skin of neonatal mice.

BACKGROUND: Epidermolysis bullosa acquisita is a subepidermal bullous disease characterized by IgG autoantibodies directed against type VII collagen in anchoring fibrils. These autoantibodies are believed to play an important role in the pathogenesis of sub-lamina densa blister formation in this disease. OBSERVATIONS: We describe a patient with epidermolysis bullosa acquisita who has developed mutilating acral involvement with early syndactyly and extensive scarring lesions of the scalp. The patient's serum contains IgG autoantibodies that bind the dermal side of 1-mol/L sodium chloride-separated human skin (at a titer up to 5120), as determined by indirect immunofluorescence microscopy, and type VII collagen, as determined by immunoblot. The severity of this patient's disease and the height of his immune response to type VII collagen prompted us to assess the pathogenicity of his autoantibodies in a murine model. Purified IgG from our patient (or that from a healthy volunteer who served as a control) was administered subcutaneously to BALB/c mice (10 mg/g of body weight) on 2 consecutive days. Light microscopy of normal-appearing skin showed pronounced dermal edema and a dense granulocyte-rich infiltrate in the superficial dermis. Deposits of human IgG, murine C3, and the membrane attack complex of complement were found in the epidermal basement membrane of all experimental mice. Immunogold electron microscopy demonstrated that deposits of human IgG in an experimental subject were localized to anchoring fibrils. Serum samples from mice receiving IgG antibodies from our patient had high titers of circulating antibodies directed against the dermal side of 1-mol/L sodium chloride-separated human skin (titer, 640 to 1280). Light, immunofluorescence, and immunogold electron microscopic studies did not detect such specific alterations in any control mice. CONCLUSIONS: Acquired autoimmunity to type VII collagen in patients with epidermolysis bullosa acquisita may result in a clinical phenotype closely resembling that observed in patients with dystrophic epidermolysis bullosa. Passive transfer of purified IgG autoantibodies from a patient with severe epidermolysis bullosa acquisita to BALB/c mice produces histologic and immunopathologic alterations consistent with those seen in patients with this disease.

Immunodominant autoepitopes of type VII collagen are short, paired peptide sequences within the fibronectin type III homology region of the noncollagenous (NC1) domain.

Autoantibodies to type VII collagen are associated with the blistering diseases epidermolysis bullosa acquisita and bullous systemic lupus erythematosus. We showed previously that these autoantibodies recognize epitopes within the noncollagenous (NC1) region of type VII collagen. That region is composed of fibronectin type III homology units that may contribute to intermolecular cross-linking and basement membrane adhesion functions of type VII collagen. In this study, we defined the specific amino acid sequences recognized by these autoantibodies. By fusion protein analysis, sera from patients with epidermolysis bullosa acquisita and bullous lupus were found to react with two regions within the fourth (E-1) and eighth (E-2) fibronectin homology repeats, each consisting of approximately 100 amino acids. Affinity purification studies showed E-1 and E-2 to be independent and non-cross-reactive epitope regions. These regions were probed further by enzyme-linked immunosorbent assay analysis of overlapping octapeptide sets derived from the amino acid sequences of E-1 and E-2. The results showed two reactive, closely associated octapeptide sequences within each region, both lying in amphipathic portions of fibronectin type III homology repeats. These studies identify short peptide sequences within the NC1 domain of type VII collagen that are targeted independently by autoantibodies. These sequences may play a direct role in determining the properties of type VII collagen that influence adhesion between this molecule and other basement membrane proteins, and their alteration by antibody binding may be the immunopathogenic event underlying epidermolysis bullosa acquisita and bullous lupus.

Calciphylaxis in three patients with end-stage renal disease.

BACKGROUND: Calciphylaxis is a rare and life-threatening condition of progressive cutaneous necrosis secondary to small- and medium-sized vessel calcification seen almost exclusively in patients with end-stage renal disease and hyperparathyroidism. Two patients had bullous lesions preceding their ulcerative lesions, an unusual presentation of this entity. One patient also had penile involvement that, to our knowledge, has not been described previously. OBSERVATIONS: Three patients, all of whom were being maintained on hemodialysis, developed painful, progressive leg ulcerations. Two patients had elevated parathormone levels, and the third patient did not. All patients had only very modest increases in their calcium x phosphate product. CONCLUSIONS: Calciphylaxis should be included in the differential diagnosis of panniculitis and vasculitis. It is important to diagnose promptly, as early treatment may prevent progression.

Peristomal pyoderma gangrenosum and inflammatory bowel disease.

Pyoderma gangrenosum (PG) is a debilitating skin disease most often associated with inflammatory bowel disease and is a reportedly rare cause of peristomal ulceration. The lesions of PG rapidly evolve from small, erythematous pustules to deep, painful, pyogenic ulcers within hours to days of onset. Although the behavior and the appearance of the lesions of peristomal PG are diagnostic, a lack of familiarity with PG often leads to misdiagnosis and inappropriate therapy. This study reports four cases of peristomal PG and discusses the 20 previously reported cases in patients with inflammatory bowel disease. Seventy-five percent of patients were female and 67% had Crohn's disease. All patients had colitis, including all of the patients with Crohn's disease, 82% of whom had additional perineal complications. The diagnosis of peristomal PG was based on clinical appearance alone in 83% of cases. The onset of peristomal PG ranged from 2 weeks to 3 years following ostomy. The response to medical therapy was variable. All cases (17 of 17) treated with high-dose corticosteroids and local wound care responded, but five cases required additional therapy. No patient was successfully treated with stoma revision. Risk factors for the development of peristomal PG include Crohn's colitis, female gender, and perineal disease. While most patients respond well to systemic steroids and local wound care, up to one third of patients require long-term medical management.

Bubble hair. Case caused by an overheating hair dryer and reproducibility in normal hair with heat.

BACKGROUND: Bubble hair is an acquired hair shaft deformity characterized by bubble-like areas in the hair shaft seen with light microscopy and corresponding cavitary defects with scanning electron microscopy. OBJECTIVE: Our purpose was to report the fourth case of bubble hair, to demonstrate a cause, and to determine whether the cavities contain gas or liquid. METHODS: Light and scanning electron microscopy were performed. The patient's hair dryer was examined. We applied heat to normal hair of the patient and that of 16 human volunteers. Approximate temperatures for bubble formation were measured. The bubble contents were investigated by applying aqueous and nonaqueous liquids to affected hairs. RESULTS: No person's hair failed to develop bubbles when subjected to sufficient heat. The cause of bubble hair in the patient was an overheating hair dryer. The cavitations contained a gas. CONCLUSION: Bubble hair is a reproducible hair shaft defect caused by heat. The use of overheating hair dryers, or any other hair care equipment that overheats, should be avoided.

Identification and partial characterization of a novel 105-kDalton lower lamina lucida autoantigen associated with a novel immune-mediated subepidermal blistering disease.

Certain skin basement membrane components, such as bullous pemphigoid antigens and epidermolysis bullosa acquisita antigen, were discovered as a result of an autoimmune reaction. In this report, we describe a unique lamina lucida determinant associated with a novel immune-mediated subepidermal bullous dermatosis. This unique bullous dermatosis resembled severe toxic epidermal necrolysis clinically. The histologic findings resemble dermatitis herpetiformis. Direct immunofluorescence microscopy detected linear immunoglobulin G (IgG) and C3 deposition at the cutaneous basement membrane zone of lesional and perilesional skin. Direct and indirect immunoelectron microscopy localized the IgG deposits to the lowest portion of the lamina lucida. The patient's autoantibodies, belonging to the IgG1 subclass, labeled basement membrane zone of normal intact human skin, oral mucosa, and conjunctiva, and localized to the dermal side of salt-split normal adult and neonatal human skin, but failed to react with human fetal skin up to 142 gestational days. The patient's autoantibodies failed to react with bullous pemphigoid antigens or epidermolysis bullosa acquisita antigen (type VII collagen) by immunoblotting. Instead, the patient's autoantibodies unequivocally labeled a 105-kilodalton (kD) protein in cellular extracts and conditioned media of human cultured keratinocytes and dermal fibroblasts. The titer of the patient's antibody against the cutaneous basement membrane zone and the intensity of the antibody reactivity against the 105-kD protein paralleled the patient's disease activity. Thus, this 105-kD lower lamina lucida protein represents a novel autoantigen and this patient's disease represents a novel autoantigen and this patient's disease represents a deep lamina lucida pemphigoid, distinguishable from all other known autoimmune bullous dermatoses.

Neonatal pemphigus vulgaris in a child born to a woman in remission.

We describe the tenth reported case of neonatal pemphigus that mimicked Bart's syndrome and review previously published cases. Unlike previous cases, the child was born with significant blistering to a mother who was in complete remission throughout the pregnancy. High antepartum maternal titers of anti-intercellular space antibodies, increased maternal disease activity, and maternal disease that requires high doses of corticosteroids or use of combined therapy correlate with poor fetal outcome, including intrauterine death.

Intracytoplasmic retention of type VII collagen and dominant dystrophic epidermolysis bullosa: reversal of defect following cessation of or marked improvement in disease activity.

It has been recently shown that the presence of perinuclear "stellate bodies" within the epidermis in patients with a form of dominant dystrophic epidermolysis bullosa named "transient bullous dermolysis of the newborn" corresponds to collections of type VII collagen. To determine the temporal relationship of this unique immunohistochemical defect with course of clinical disease activity, we have longitudinally studied the expression of two epitopes of type VII collagen (LH 7:2; L3d) in nine patients in four such kindreds by immunofluorescence and immunoelectron microscopic technique. In every infant so studied at the time of active blistering, type VII collagen was detectable primarily within basilar and, to a lesser extent, suprabasilar keratinocytes. In contrast, type VII collagen was detectable solely in linear array along the dermoepidermal junction in skin from each patient following complete cessation or at least marked diminution of visible clinical disease activity. These findings support the hypothesis that the temporary mechanical fragility and blistering of the skin in infants with this rare subset of dominant dystrophic epidermolysis bullosa reflect the presence of reduced amounts of type VII collagen along the dermoepidermal junction, and that this diminution may be the result of either a delay in transport and integration of type VII collagen from basilar keratinocytes into the skin basement membrane or excessive phagocytosis of type VII collagen.

Epidermolysis bullosa acquisita and bullous systemic lupus erythematosus. Diseases of autoimmunity to type VII collagen.

Autoimmunity to C7 is a genetically predisposed condition that results in the production of predominantly IgG class basement membrane autoantibodies that may cause basement membrane damage and subepidermal blisters by at least two pathogenic mechanisms. Autoimmunity to C7 cuts across traditional disease classifications (EBA versus bullous SLE), presents with heterogeneous clinical and pathologic features, mimics other diseases, and may be difficult to diagnose and treat. Autoimmunity to C7 is associated with susceptibility to SLE and perhaps inflammatory bowel disease.

Autoantibodies to type VII collagen recognize epitopes in a fibronectin-like region of the noncollagenous (NC1) domain.

Autoantibodies to type VII collagen are characteristic of the blistering diseases epidermolysis bullosa acquisita and bullous systemic lupus erythematosus (SLE). Blisters in those diseases are due to defective adhesion of the lamina densa subregion of the epithelial basement membrane to the underlying dermis. Previous studies indicating that type VII collagen contributes to lamina densa-dermal adhesion by cross-linking lamina densa and dermal matrix proteins suggests that autoantibodies may contribute to blisters by interfering with type VII collagen function. That hypothesis is supported by previous studies showing autoantibodies from a small number of epidermolysis bullosa acquisita patients recognize proteolytic fragments containing the 145-kD noncollagenous domain of type VII collagen. In this study, we examined reactivity of autoantibodies from a large number of epidermolysis bullosa acquisita and bullous SLE patients with fusion proteins representing most of the noncollagenous domain of type VII collagen and that those regions are homologous to type III repeats of fibronectin. These results suggest autoantibodies binding to fibronectin homology regions within the 145-kD noncollagenous domain may interfere with the adhesion function of type VII collagen and contribute to lamina densa-dermal dysadhesion in epidermolysis bullous acquisita and bullous SLE.

Labeling of fractured human skin with antibodies to BM 600/nicein, epiligrin, kalinin and other matrix components.

A variety of methods were used to fracture the dermal-epidermal junction (DEJ) of human skin. These included warm and hot phosphate buffered saline, trypsin, cold 1 M salt, potassium bromide and proteolytic digestion with dispase. The localization and sensitivity of basement membrane components (bullous pemphigoid antigen, BM 600/nicein, epiligrin, kalinin, laminin, collagens IV and VII (EBA antigen) and linkin) were determined after the DEJ was fractured by each method. We found that the basement membrane zone proteins, BM 600/nicein, epiligrin and kalinin remained with the dermal side of the DEJ fractured through the lamina lucida by cold salt, phosphate buffered saline and potassium bromide. BM 600/nicein, epiligrin and kalinin were not detected after treatment with trypsin. In contrast, laminin, another glycoprotein in the lamina lucida, was insensitive to all of the procedures, but co-localized to the dermal side of DEJ-fractured skin. We also found that separation of the DEJ with brief exposure of skin to 56 degrees C provided a useful substrate for testing the autoantibodies in the sera of patients with epidermolysis bullosa acquisita (EBA). Heat-separated skin can be prepared in a significantly shorter period of time than salt-separated skin.

Adherens junctions: demonstration in human epidermis.

Adherens junctions are intercellular and cell-matrix junctions that, like desmosomes and hemidesmosomes, mediate adhesion of cells to each other or to matrix structures. These junctions have been detected recently in cultured human keratinocytes, indicating that they may be of importance in epidermis. To investigate the localization of adherens junctions in normal epidermis, we examined human epidermis, human oral mucosa, and monkey esophagus for the presence of vinculin, a major protein of the intracellular plaques of adherens junctions that is thought to be present in all adherens junctions. Western blot analysis demonstrated vinculin in extracts of epidermis. Immunohistochemistry of vinculin in these tissues displayed two distinct locations for adherens junctions: i) at the dermal-epidermal junction, and ii) in the region of cell-cell contacts in all layers of the epidermis. The location of vinculin in the region of the epidermal-dermal junction is reminiscent of the distribution of vinculin-containing focal contacts in cultured keratinocytes, and the intercellular staining of vinculin in epidermis is consistent with the presence of vinculin in adherens junctions in cultured keratinocytes at sites of cell-cell contact. These results demonstrate that adherens junctions are present in human epidermis, oral mucosa, and monkey esophagus. Vinculin-containing junctions in epidermis may be important in the pathogenesis of skin diseases involving alterations in intercellular integrity.

Bullous SLE: a phenotypically distinctive but immunologically heterogeneous bullous disorder.

Bullous systemic lupus erythematosus (SLE) is a rare blistering disease with a distinctive combination of clinical, histologic and immunopathologic features that together constitute a unique bullous disease phenotype. There appear to be at least two immunologically distinct subtypes of bullous SLE characterized by the presence or absence of circulating and/or tissue-bound basement membrane zone autoantibodies that recognize type VII collagen. The two subtypes are not clearly distinguishable except by indirect immunofluorescence and/or direct immunoelectron microscopy. In patients without circulating antibodies, immunoelectron microscopy is required to distinguish between the two subtypes. Patients with autoantibodies to type VII collagen are similar but not identical to patients with epidermolysis bullosa acquisita--another bullous disease associated with autoantibodies to type VII collagen. Autoantibodies to type VII collagen in patients with bullous SLE is only one of several lines of evidence that indicate autoimmunity to that protein and susceptibility to SLE are associated phenomena. In addition, there is emerging evidence for an association between epidermolysis bullous acquisita and SLE. There is also evidence that autoantibodies to type VII collagen are pathogenic in bullous SLE (and epidermolysis bullosa acquisita) and that their production is regulated by the class II major histocompatibility complex DR beta 1 allele, 1501 and possibly other DR beta 1 alleles that share a similar sequence of amino acids in the second hyper-variable region.