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Background: Inherited epidermolysis bullosa (EB) comprises a highly heterogeneous group of rare diseases characterized by fragility and blistering of skin and mucous membranes. Clinical features combined with immunofluorescence antigen mapping and/or electron microscopy examination of a skin biopsy allow to define the EB type and subtype. Molecular diagnosis is nowadays feasible in all EB subtypes and required for prenatal diagnosis. The extent of skin and mucosal lesions varies greatly depending on EB subtype and patient age. In the more severe EB subtypes lifelong generalized blistering, chronic ulcerations and scarring sequelae lead to multiorgan involvement, major morbidity and life-threatening complications. In the absence of a cure, patient management remains based on preventive measures, together with symptomatic treatment of cutaneous and extracutaneous manifestations and complications. The rarity and complexity of EB challenge its appropriate care. Thus, the aim of the present study has been to generate multicentre, multidisciplinary recommendations on global skin care addressed to physicians, nurses and other health professionals dealing with EB, both in centres of expertise and primary care setting., Methods: Almost no controlled trials for EB treatment have been performed to date. For this reason, recommendations were prepared by a multidisciplinary team of experts from different European EB centres based on available literature and expert opinion. They have been subsequently revised by a panel of external experts, using an online-modified Delphi method to generate consensus., Results: Recommendations are reported according to the age of the patients. The major topics treated comprise the multidisciplinary approach to EB patients, global skin care including wound care, management of itching and pain, and early diagnosis of squamous cell carcinoma. Aspects of therapeutic patient education, care of disease burden and continuity of care are also developed., Conclusion: The recommendations are expected to be useful for daily global care of EB patients, in particular in the community setting. An optimal management of patients is also a prerequisite to allow them to benefit from the specific molecular and cell-based treatments currently under development.

Epidermal nevi are clinical manifestations of a malformation affecting the embryonic ectoderm. They appear as linear verrucous lesions and are more often located in the skin of the trunk or the extremities. Rarely, verrucous lesions affect the oral mucosa. Epidermal nevi can be a component of epidermal nevus syndrome (ENS), which is characterized by malformations involving several organs, such as the central nervous system. ENS is rarely associated with other solid tumors. We present the case of a patient affected by ENS who developed maxillary and mandibular ameloblastomas. Epidermal nevi were located in the left middle and lower third of the face and in the left cervical region, whereas the ameloblastomas arose within the left maxillary mucosa and within the left mandibular ramus. Features of the syndrome are described and the relevant literature is reviewed., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Papular epidermal nevus with "skyline" basal cell layer (PENS), a novel keratinocytic nevus, has recently been described as a mosaic condition with varying presentations. We herein describe typical PENS lesions, which usually occur sporadically, affecting two members of the same family. The concept of paradominant inheritance is proposed to explain the paradox of occasional transmission of normally sporadically occurring traits., (© 2013 Wiley Periodicals, Inc.)

The ectodermal dysplasias (EDs) are a large and complex group of inherited disorders. In various combinations, they all share anomalies in ectodermal derived structures: hair, teeth, nails and sweat gland function. Clinical overlap is present among EDs. Few causative genes have been identified, to date. Altered gene expression is not limited to the ectoderm but a concomitant effect on developing mesenchymal structures, with modification of ectodermal-mesenchymal signaling, takes place. The two major categories of ED include the hidrotic and hypohidrotic form, the latter more frequent; they differentiate each other for the presence or absence of sweat glands. We report Ear Nose Throat manifestations of ED, linked to the reduction of mucous glands in the nasal fossae with reduced ciliar function, and decrease salivary glands function. Often patients report an increased rate of infections of the upper respiratory tract and of the ear. Nasal obstruction due to the presence of nasal crusting, hearing loss and throat hoarseness are the most represented symptoms. Environmental measures, including a correct air temperature and humidification, is mandatory above all in subjects affected by hypohidrotic form., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Papular epidermal nevus with "skyline" basal cell layer (PENS), a variant of epidermal nevi, has recently been described as a small, round or polygonal papule, visible at birth or shortly thereafter, with characteristic histopathologic features. It has been considered a separate entity from keratinocytic nevi because no lesion observed thus far has followed any of the known archetypical mosaic patterns. Here we describe for the first time a PENS lesion following a linear distribution pattern along Blaschko's lines., (© 2013 Wiley Periodicals, Inc.)

Follicular mucinosis represents a term for a histopathologic reaction pattern in follicular epithelium. It is a characteristic of alopecia mucinosa. However, it may also occur in a variety of unrelated conditions. Epidermal nevi are considered to be hamartomatous disorders and they can show a predominant component of non-organoid (keratinocytes) and/or organoid nevi. All the cases of epidermal nevi described with mucin deposits until now are reported as mucinous nevus or mucinous eccrine nevus; in the first type of disorder, diffuse mucin deposition is only seen in the papillary dermis, and in the second type, the mucin is found around the proliferation of eccrine structures. We believe this is the first reported case of epidermal nevus along Blaschko's lines exhibiting typical microscopic findings of mucinosis exclusively distributed inside the follicular epithelia., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

X-linked reticulate pigmentation disorder with systemic manifestations (XLPDR) is an extremely rare genodermatosis with recessive X-linked inheritance but unknown molecular basis. In males, cutaneous involvement is characterized by reticulate hyperpigmentation of the skin that is associated with a typical facies and severe systemic involvement. In the carrier females, manifestations are apparently limited to the skin with patchy linear hyperpigmentation following the lines of Blaschko that are similar to stage III incontinentia pigmenti. Thus far, only five families affected by this disorder have been described. We report on a new family with clinical features of XLPDR and compare it with those reported in the literature., (Copyright © 2013 Wiley Periodicals, Inc.)

Various combinations of limb anomalies, ectodermal dysplasias and orofacial clefts characterize heterozygous mutations in the transcription factor gene p63. The causative gene is crucial during embryonic ontogenesis, mostly in the development of limbs and other ectodermal derived tissues. The pattern of mutations in six different p63-related syndromes (EEC syndrome, AEC syndrome, ADULT syndrome, LMS syndrome, RHS syndrome, SHFM syndrome) shows genotype-phenotype correlations. The most frequent p63 mutation syndrome is the EEC syndrome, characterized by ectrodactyly, ectodermal dysplasia and cleft lip/palate. Ectodermal dysplasia is characterized by ectrodactyly often associated with syndactyly, sparse hair, dry skin, hypo-anodontia, dysplastic nails and alterations in sebaceous glands, mammary glands and nipples. The third hallmark of the EEC syndrome is orofacial clefting, in particular lip and palate. p63 mutations also cause the other five inherited syndromes: symptoms are overlapping, but each of these diseases has its own characteristic phenotypic features: for instance AEC syndrome (ankyloblepharon-ectodermal defects-cleft lip/palate) has as distinctive feature ankyloblepharon, while mammary glands and nipples hypoplasia are frequent findings in LMS syndrome and in ADULT syndrome (acro-dermato-ungual-lacrimal-tooth syndrome). The latter can be distinguished from other p63 syndromes by the absence of orofacial clefting and by prominent ectodermal signs. The narrowest genotype-phenotype correlation is in the EEC and AEC syndromes. All EEC missense mutations are clustered in the DNA binding domain and do not bind to DNA; in contrast, all missens mutations reported in AEC syndrome are localized in the α-motif domain, and it has been demonstrated that they disrupt interaction with other proteins. LMS and ADULT syndrome have their own unique mutated amino-acid residues. Only two amino-acid residues are known to be mutated amongst ADULT syndrome: asparagines 6 and arginine 298. Although R298 is in the DNA binding domain, it is functionally different from the EEC mutations, because its substitution by glutamine does not lead to a loss of DNA binding, but to a gain of transactivation activity of the ∆Np63γ isoform. In this paper we discuss the consistent phenotypic features associated with these gain of function mutations.

In the last few years the progresses in molecular analysis allow better definitions of ichthyoses and lead to the necessity of a new classification and a review of nomenclature of inherited ichthyoses. So, in 2007 the First Consensus Conference on Ichthyoses was performed. We present here a short review of the new classification of syndromic ichthyoses together with clinical and molecular features.

Porokeratotic eccrine ostial and dermal duct nevus, or porokeratotic eccrine nevus (PEN), is a hyperkeratotic epidermal nevus. Several cases of widespread involvement have been reported, including one in association with the keratitis-ichthyosis-deafness (KID) syndrome (OMIM #148210), a rare disorder caused by mutations in the GJB2 gene coding for the gap junction protein connexin26 (Cx26). The molecular cause is, as yet, unknown. We have noted that PEN histopathology is shared by KID. The clinical appearance of PEN can resemble that of KID syndrome. Furthermore, a recent report of cutaneous mosaicism for a GJB2 mutation associated with KID describes linear hyperkeratotic skin lesions that might be consistent with PEN. From this, we hypothesized that PEN might be caused by Cx26 mutations associated with KID or similar gap junction disorders. Thus, we analyzed the GJB2 gene in skin samples from two patients referred with generalized PEN. In both, we found GJB2 mutations in the PEN lesions but not in unaffected skin or peripheral blood. One mutation was already known to cause the KID syndrome, and the other had not been previously associated with skin symptoms. We provide extensive functional data to support its pathogenicity. We conclude that PEN may be caused by mosaic GJB2 mutations.

Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome, which is characterized by cleft palate and severe defects of the skin, is an autosomal dominant disorder caused by mutations in the gene encoding transcription factor p63. Here, we report the generation of a knock-in mouse model for AEC syndrome (p63(+/L514F) ) that recapitulates the human disorder. The AEC mutation exerts a selective dominant-negative function on wild-type p63 by affecting progenitor cell expansion during ectodermal development leading to a defective epidermal stem cell compartment. These phenotypes are associated with impairment of fibroblast growth factor (FGF) signalling resulting from reduced expression of Fgfr2 and Fgfr3, direct p63 target genes. In parallel, a defective stem cell compartment is observed in humans affected by AEC syndrome and in Fgfr2b(-/-) mice. Restoring Fgfr2b expression in p63(+/L514F) epithelial cells by treatment with FGF7 reactivates downstream mitogen-activated protein kinase signalling and cell proliferation. These findings establish a functional link between FGF signalling and p63 in the expansion of epithelial progenitor cells and provide mechanistic insights into the pathogenesis of AEC syndrome., (Copyright © 2012 EMBO Molecular Medicine.)

Background: The central nervous system originates ontogenetically from the ectoderm and therefore numerous neurocutaneous syndromes exist., Objective: We describe a novel neurocutaneous syndrome with characteristic epidermal papules and plaques associated with mild psychomotor retardation and epilepsy with a good prognosis., Methods: We investigated history, clinical features, laboratory parameters including karyotype, histopathological and immunohistological examination, electron microscopy, HPV infection, EEG and neurologic imaging in patients with an unusual symptom complex., Results: Six children are reported with characteristic keratotic papules and plaques of 'gem-like' appearance, randomly distributed on the trunk and the proximal part of the limbs. Four patients were unrelated and two were siblings. The cutaneous lesions appeared congenitally or developed soon after birth. The skin lesions were rounded or of an irregularly polycyclic shape, ranging from 0.5 to 1.5 cm in diameter. A few to eighteen lesions were present. The lesional surface was rough and of white or yellowish color. Histopathological examination showed acanthokeratosis, but immunostaining for keratins and melanocytes, electron microscopy and laboratory results were within normal range. During the natural course of the disease the lesions were stable and asymptomatic. All but one of our six patients developed neurologic signs and symptoms during the first year of life, in the form of epilepsy and psychomotor delay. Five children had low intellectual performance together with EEG abnormalities and some had MRI changes of the brain. One patient had marked language impairment. The central nervous system involvement had a peculiar benign and self-limiting course and total normalization occurred in one case., Limitations: We present only a small series of patients., Conclusion: Cutaneous lesions showing identical clinical and microscopical features, but without any extracutaneous abnormalities, have recently been described by Torrelo et al. [J Am Acad Dermatol 2011;64:888-892] under the designation 'papular epidermal nevus with "skyline" basal cell layer (PENS)'. An association of such nevi with neurologic abnormalities had so far only been published in the 'Atlas of Genodermatoses' edited by Caputo and Tadini. We believe that this unique and otherwise undescribed symptom complex is a new neurocutaneous phenotype that may be called PENS syndrome. Whether this new syndrome can be categorized as a distinct phenotype within the group of epidermal nevus syndromes remains speculative and has to be clarified by further investigations., (Copyright © 2012 S. Karger AG, Basel.)

The case of a male neonate of 41 weeks' gestation who developed blistering of the skin immediately after birth is described. His parents were consanguineous Tunisians. Electron microscopy of a cutaneous biopsy showed skin cleavage within the lamina lucida and immunoepitope mapping revealed a complete absence of laminin 332 expression. These findings referred to the diagnosis of junctional epidermolysis bullosa (JEB) Herlitz type. The neonate died at 3 months of age due to sepsis. Molecular analysis of laminin 332 chain genes LAMA3, LAMB3 and LAMC2 disclosed a novel homozygous nonsense mutation in LAMA3 (p.Y955X). Clinical and laboratory analyses are essential for the diagnosis of JEB subtypes, and molecular analysis screening is crucial to manage a new pregnancy in families with suspected cases of JEB., (Copyright © 2010 S. Karger AG, Basel.)

KLICK syndrome is a rare autosomal-recessive skin disorder characterized by palmoplantar keratoderma, linear hyperkeratotic papules, and ichthyosiform scaling. In order to establish the genetic cause of this disorder, we collected DNA samples from eight European probands. Using high-density genome-wide SNP analysis, we identified a 1.5 Mb homozygous candidate region on chromosome 13q. Sequence analysis of the ten annotated genes in the candidate region revealed homozygosity for a single-nucleotide deletion at position c.-95 in the proteasome maturation protein (POMP) gene, in all probands. The deletion is included in POMP transcript variants with long 5' untranslated regions (UTRs) and was associated with a marked increase of these transcript variants in keratinocytes from KLICK patients. POMP is a ubiquitously expressed protein and functions as a chaperone for proteasome maturation. Immunohistochemical analysis of skin biopsies from KLICK patients revealed an altered epidermal distribution of POMP, the proteasome subunit proteins alpha 7 and beta 5, and the ER stress marker CHOP. Our results suggest that KLICK syndrome is caused by a single-nucleotide deletion in the 5' UTR of POMP resulting in altered distribution of POMP in epidermis and a perturbed formation of the outermost layers of the skin. These findings imply that the proteasome has a prominent role in the terminal differentiation of human epidermis., ((c) 2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Focal dermal hypoplasia (FDH) is an X-linked dominant multisystem birth defect affecting tissues of ectodermal and mesodermal origin. Using a stepwise approach of (i) genetic mapping of FDH, (ii) high-resolution comparative genome hybridization to seek deletions in candidate chromosome areas and (iii) point mutation analysis in candidate genes, we identified PORCN, encoding a putative O-acyltransferase and potentially crucial for cellular export of Wnt signaling proteins, as the gene mutated in FDH. The findings implicate FDH as a developmental disorder caused by a deficiency in PORCN.

We report clinical and molecular findings in 20 patients from 11 families with autosomal recessive congenital ichthyosis (ARCI) linked to chromosome 17p13, and attributed to mutations in the ALOX gene cluster, which includes three lipoxygenase genes, ALOXE3, ALOX12B, and ALOX15B. We identified six novel missense mutations and one novel deletion leading to a premature stop codon in ALOX12B in only six out of the 11 families which led us to investigate a possible implication of ALOX15B. Mutation analysis of this gene, as well as ALOXE3, which is known to be mutated in some cases of ARCI, failed to reveal causative mutations in the five remaining ARCI families, indicating that other genes on chromosome 17p13 may be involved in this disease. However, by adding new variants to the repertoire of ALOX12B mutations in non-bullous congenital ichthyosiform erythroderma, our data contribute to an enlargement of the spectrum of mutations for the development of efficient molecular genetic tests for analysis of at risk individuals whose carrier status is unknown.

Eighteen male patients with incontinentia pigmenti (IP) showed the characteristic clinical features and, when examined, histologic skin defects observed in female patients with IP. Six of the patients had neurologic, ophthalmologic, or dental manifestations as well. Three patients showed evidence by polymerase chain reaction analysis of both the normal NEMO gene and the exon 4-10 deletion in NEMO that occurs in the majority of affected girls with IP, confirming postzygotic mosaicism for the NEMO gene.

Kindler syndrome (KS) is a rare autosomal recessive disorder characterized by skin blistering in childhood followed by photosensitivity and progressive poikiloderma. Most cases of KS result from mutations in the KIND1 gene encoding kindlin-1, a component of focal adhesions in keratinocytes. Here, we report novel and recurrent KIND1 gene mutations in nine unrelated Italian KS individuals. A novel genomic deletion of approximately 3.9 kb was identified in four patients originating from the same Italian region. This mutation deletes exons 10 and 11 from the KIND1 mRNA leading to a truncated kindlin-1. The deletion breakpoint was embedded in AluSx repeats, specifically in identical 30-bp sequences, suggesting Alu-mediated homologous recombination as the pathogenic mechanism. KIND1 haplotype analysis demonstrated that patients with this large deletion were ancestrally related. Five additional mutations were disclosed, two of which were novel. To date, four recurrent mutations have been identified in Italian patients accounting for approximately approximately 75% of KS alleles in this population. The abundance of repetitive elements in intronic regions of KIND1, together with the identification of a large deletion, suggests that genomic rearrangements could be responsible for a significant proportion of KS cases. This finding has implications for optimal KIND1 mutational screening in KS individuals.

We report the identification of mutations in a non-syndromic autosomal recessive congenital ichthyosis (ARCI) in a new gene mapping within a previously identified locus on chromosome 19p12-q12, which has been defined as LI3 in the OMIM database (MIM 604777). The phenotype usually presents as lamellar ichthyosis and hyperlinearity of palms and soles. Seven homozygous mutations including five missense mutations and two deletions were identified in a new gene, FLJ39501, on chromosome 19p12 in 21 patients from 12 consanguineous families from Algeria, France, Italy and Lebanon. FLJ39501 encodes a protein which was found to be a cytochrome P450, family 4, subfamily F, polypeptide 2 homolog of the leukotriene B4-omega-hydroxylase (CYP4F2) and could catalyze the 20-hydroxylation of trioxilin A3 from the 12(R)-lipoxygenase pathway. Further oxidation of this substrate by the fatty alcohol:nicotinamide-adenine dinucleotide oxidoreductase (FAO) enzyme complex, in which one component, ALDH3A2, is known to be mutated in Sjögren-Larsson syndrome (characterized by ichthyosis and spastic paraplegia), would lead to 20-carboxy-(R)-trioxilin A3. This compound could be involved in skin hydration and would be the essential missing product in most forms of ARCI. Its chiral homolog, 20-carboxy-(S)-trioxilin A3, could be implicated in spastic paraplegia and in the maintenance of neuronal integrity.

Harlequin ichthyosis (HI) is the most severe and frequently lethal form of recessive congenital ichthyosis. Although defects in lipid transport, protein phosphatase activity, and differentiation have been described, the genetic basis underlying the clinical and cellular phenotypes of HI has yet to be determined. By use of single-nucleotide-polymorphism chip technology and homozygosity mapping, a common region of homozygosity was observed in five patients with HI in the chromosomal region 2q35. Sequencing of the ABCA12 gene, which maps within the minimal region defined by homozygosity mapping, revealed disease-associated mutations, including large intragenic deletions and frameshift deletions in 11 of the 12 screened individuals with HI. Since HI epidermis displays abnormal lamellar granule formation, ABCA12 may play a critical role in the formation of lamellar granules and the discharge of lipids into the intercellular spaces, which would explain the epidermal barrier defect seen in this disorder. This finding paves the way for early prenatal diagnosis. In addition, functional studies of ABCA12 will lead to a better understanding of epidermal differentiation and barrier formation.

Junctional epidermolysis bullosa (JEB) is a rare genodermatosis characterized by dermal-epidermal separation that is caused by mutations in the genes encoding hemidesmosomal components and laminin-5, the major epithelial adhesion ligand. Here, we report on the mutational analysis of LAMA3, LAMB3, and LAMC2 genes encoding laminin-5 chains in 19 Italian patients, 11 affected with the severe Herlitz (H JEB) and eight with the mild non-Herlitz variant of JEB (non-H JEB). Eighteen mutations, seven of which were novel, were identified and their consequences analyzed at the mRNA and protein level. Premature termination codon mutations in both alleles of LAMB3 or LAMC2 genes were found in nine of the 11 H JEB patients, with a prevalence of mutations in LAMC2. In one case, a homozygous frameshift mutation in LAMB3 was associated to illegitimate splicing leading to non-H JEB. One H JEB patient showed a large intragenic duplication within LAMC2, a genetic defect so far uncovered in laminin-5 genes. Splicing or missense mutations, were prevalent in non-H JEB patients. Collectively, five mutations appeared to be frequent in laminin-5 JEB patients: R635X, 29insC, E210K, W143X in LAMB3 and R95X in LAMC2. These recurrent mutations account for approximately 44% of laminin-5 JEB alleles in Italian patients.

Kindler syndrome is an autosomal recessive disorder characterized by neonatal blistering, sun sensitivity, atrophy, abnormal pigmentation, and fragility of the skin. Linkage and homozygosity analysis in an isolated Panamanian cohort and in additional inbred families mapped the gene to 20p12.3. Loss-of-function mutations were identified in the FLJ20116 gene (renamed "KIND1" [encoding kindlin-1]). Kindlin-1 is a human homolog of the Caenorhabditis elegans protein UNC-112, a membrane-associated structural/signaling protein that has been implicated in linking the actin cytoskeleton to the extracellular matrix (ECM). Thus, Kindler syndrome is, to our knowledge, the first skin fragility disorder caused by a defect in actin-ECM linkage, rather than keratin-ECM linkage.

Dystrophic epidermolysis bullosa (DEB) is a rare skin disorder that is clinically heterogeneous and is transmitted either in dominant (DDEB) or recessive (RDEB) mode. Nevertheless, all variants of DEB are caused by mutations in type VII collagen gene (COL7A1). We report an analysis of COL7A1 mutations in 51 Italian DEB patients, 27 affected with Hallopeau-Siemens RDEB, 19 with non Hallopeau-Siemens RDEB, two with DDEB, two with pretibial RDEB, and one with inversa RDEB. Forty-one mutations were identified, 18 of which are novel. Mutation consequences were analyzed at the mRNA and protein level and genotype-phenotype correlation was determined. Recessive inheritance of a new case of pretibial RDEB was also established. In RDEB patients, six recurrent mutations were identified: 7344G-->A, 425A-->G, 8441-14del21, 4783-1G-->A, 497insA, and G1664A, the last three being found only in Italian patients. Indeed, haplotype analysis supported propagation of ancestral mutated alleles within the Italian population for these particular mutations. Altogether recurrent mutations account for approximately 43% of RDEB alleles in Italian patients and therefore new DEB patients should first be screened for the presence of these mutations.

The IFAP syndrome is characterized by the congenital onset of ichthyosis follicularis, absence of hair, and photophobia. A limited number of patients with the disorder have been described, and X-linked recessive inheritance has been proposed. Two unrelated female patients with a complete IFAP syndrome are reported. Both patients show a diffuse distribution of the disorder without linear arrangement. Because the suggested X-linked recessive pattern of inheritance is unlikely in these patients, a different way of transmission or, alternatively, genetic heterogeneity of the disorder has to be considered.

Dystrophic epidermolysis bullosa (DEB) is a rare genetic skin disorder. In this report we have investigated an Italian child affected with recessive DEB (RDEB) and demonstrated that he was homozygous for the mutation R226X in the type VII collagen gene (COL7A1), leading to absence of type VII collagen at the dermal-epidermal junction. There was no family history of inherited skin blistering but the child's father was affected by Marfan syndrome, an autosomal dominant connective tissue disorder that results from mutations in the fibrillin-1 gene (FBN1). Analysis of this gene showed that the RDEB patient and his father were both heterozygous for a novel FBN1 mutation, C1971Y. This mutation affects one of the six obligate cysteine residues within one of the calcium-binding epidermal growth factor-like regions of the protein. At the age of 2-years the RDEB patient showed signs of early aortic dilatation, suggesting that he is likely to develop a Marfan syndrome phenotype in the future. This is a unique case of these two coexisting inherited disorders.

Smooth muscle hamartoma is a cutaneous abnormality characterized by a disorganized proliferation of normal muscle fibers of arrector pili. Usually a single congenital hypertrichotic plaque involves the trunk and the extremities. Multiple lesions have rarely been reported in the literature. We describe three members of the same family with multiple skin-colored patches on the back and legs, histologically confirmed as smooth muscle hamartomas. To our knowledge this is the first report of multiple smooth muscle hamartomas in different members of the same family and quite interestingly involving the same skin site.

Hereditary dystrophic epidermolysis bullosa (DEB) refers to a group of clinically heterogeneous skin blistering diseases due to mutations in the collagen type VII gene (COL7A1). We report two novel mutations found in a patient affected by the most severe form of DEB, the recessive Hallopeau-Siemens variant (HS-RDEB): the R1978X nonsense mutation, in exon 72, and the -96C-->T transition, in the promoter region. The allele specific analysis of the transcripts from skin fibroblasts of the patient showed that the -96C-->T mutation is associated to the absence of collagen type VII (COLVII) mRNA. This mutation, the first one ever identified in the promoter of COL7A1, falls in an Sp1 motif, localized between nucleotides -96 and -91. Gel shift analysis indicated that the -96/-91 sequence is a functional Sp1 site and that the -96C-->T transition inhibits the binding of the trascription factor. These data indicate that the -96/-91 sequence is a crucial Sp1 site whose integrity is necessary for COL7A1 expression. The compound heterozygosity for the -96C-->T null mutation and for the R1978X mutation leads to the absence of COLVII at skin level and to the severe phenotype of the HS-RDEB patient. Hum Mutat 16:275, 2000., (Copyright 2000 Wiley-Liss, Inc.)

The Hallopeau-Siemens variant of recessive dystrophic epidermolysis bullosa (HS-RDEB) is a severe inherited skin disease characterized by the absence of collagen type VII (COLVII) and anchoring fibrils (AF), caused by mutations in collagen type VII gene (COL7A1). Mutations leading to the formation of premature termination codons (PTCs) of translation are the characteristic genetic lesions in HS-RDEB patients; many PTC mutations have been found to be associated with a marked reduction or complete absence of COLVII mRNA. In this article, we report homozygosity for three different mutations in the COL7A1 of HS-RDEB patients. One mutation, the R2685X, falling in exon 109, is a novel mutation, whereas the other two, the 425A-->G falling in exon 3 and the 497insA in exon 4, have been previously identified in compound heterozygosity with different mutations in other unrelated RDEB patients. Haplotype analysis in three Italian families carrying the 497insA mutation suggested a common origin of this mutation and indicated that this is an ancestral Italian mutation. All these mutations generate PTCs and are associated with the absence of COLVII expression, as detected by immunofluorescence analysis of the patient's skin. Evaluation of the levels of the mutated COLVII mRNAs in cultured skin fibroblasts of the patients and of their parents showed that all the mutated transcripts were expressed at consistent levels. Therefore, our results indicate that a marked mRNA reduction is not a constant feature associated with PTC mutations in COL7A1.

We report phakomatosis pigmentovascularis detected in a Caucasian child characterized by the presence of a nevus flammeus and nevus anemicus on the face, a telangiectatic linear nevus of the right leg, and a very extensive blue spot covering 60% of the body surface, with ocular melanosis. Multiple angiomatous lesions of the kidney are associated without alterations of the central nervous system (CNS). This association has not been reported before; it could be a further expression of the complex of developmental defects. Our case corresponds exactly to type IIb in the classification of phakomatosis pigmentovascularis proposed by Hasegawa. As this classification seems very extensive, the higher incidence of cases corresponding to the second subtype suggests that we should identify it by the term phakomatosis pigmentovascularis, while the others could be considered as only very uncommon variants.

We present an unusual new clinical feature which developed in a patient with congenital reticular ichthyosiform erythroderma. This rare ichthyotic disorder is characterized by erythematous ichthyotic skin surrounding slowly enlarging areas of normal skin, and by a pathognomonic ultrastructural pattern, namely perinuclear deposits of a filamentous material in vacuolized keratinocytes. At the age of 18 years, a 23-year-old woman developed several irregular hyperpigmented macules on her limbs, which were almost black in colour. These lesions have not been observed in the other patients affected by the disease nor, to our knowledge, in other ichthyotic disorders. Electron microscopy and immunohistochemistry demonstrated that the lesions were strictly related to the ichthyotic skin and that their dark colour was especially due to melanosome accumulation in activated dendritic melanocytes. An unusual postinflammatory hyperpigmentation, in which the lack of pigment deposition in the keratinocytes is due to a transfer defect in pathological cells, is hypothesized. A characteristic hyperplastic stimulation of the epidermis is also taken into consideration to explain the lack of a similar picture in other erythrodermic ichthyotic disorders with a continuous inflammatory process.

We report a young woman in whom the history, clinical features, histopathological and ultrastructural findings led to a diagnosis of peeling skin syndrome (PSS). PSS is a rare and not well classified genodermatosis, mainly characterized by the spontaneous separation of the stratum corneum from the stratum granulosum. The unusual feature in our patient was the strict localization to the palm. PSS has been described as a more generalized disease frequently sparing palms and soles. We propose the diagnosis label of 'localized PSS' for this previously undescribed variant of a rare keratinization defect.

We report a case of myiasis caused by larvae of Dermatobia hominis in a 12-year-old boy. The infestation was acquired in Uruguay and was characterized by a single, large, inflammatory, nodular lesion located on the scalp. The lesion was accompanied by local pruritus and pain as well as diffuse headache and regional lymphadenopathy. From the lesion a single larva in stage III, of noteworthy size, was removed. Very few pediatric cases of myiasis due to D. hominis have been reported in the literature. Furthermore, as far as we know, just one adult case of myiasis caused by D. hominis acquired in Uruguay has been published.

Background: The epidermal nevus syndromes include different diseases that have the common feature of mosaicism. One of these has been recently identified and named phacomatosis pigmentokeratotica, in analogy to phacomatosis pigmentovascularis. It is characterized by an organoid nevus with sebaceous differentiation, a speckled-lentiginous nevus, and other associated anomalies. It has been hypothesized that this syndrome is caused by a particular genetic mechanism known as the twin-spot phenomenon., Observations: We describe 3 patients manifesting an association of organoid nevus showing sebaceous differentiation and speckled-lentiginous nevus with associated anomalies and update the neurologic findings of a previously described patient. Hemiatrophy seems to be a common finding in all cases; hyperpathia, dysesthesia, and hyperhidrosis, as well as other neurologic defects, may be present., Conclusions: The findings in these patients allowed us to better delineate this syndrome. Further studies are needed to elucidate the underlying genetic defect. At present, however, the hypothesis that best explains this phenotype is twin spotting. Clinical recognition of this syndrome can contribute to the classification of the epidermal nevus syndromes and give insight into unusual genetic mechanisms occurring in humans.

"Pure" ectodermal dysplasias are developmental disorders affecting only tissues of ectodermal origin. Two different pure ectodermal dysplasias involving only hair and nails have been described to date. Here we describe congenital nail dystrophy and hypotrichosis associated with folliculitis decalvans in a family suggesting autosomal-dominant transmission. This report documents peculiar clinical and ultrastructural hair findings that fit poorly into previously described conditions. Thus the reported patients could represent a new type of pure ectodermal dysplasia.

We report a missplicing event affecting the expression of bullous pemphigoid antigen BP180 (type XVII collagen) in a patient with generalized atrophic benign epidermolysis bullosa (GABEB). The segregation of the mutated allele in the family is consistent with the pathogenic role of the mutation. The homozygous mutation 2441-2A --> G disrupts a splice-site sequence in gene (BPAG2) for BP180 and results in an in-frame exon skipping within the collagenous ectodomain of the protein. The consequent deletion of 9 amino acids in the mutant BP180 is predicted to alter the structure of the homotrimer and is expected to exert a deleterious effect on stability of the protein that would account for the complete absence of immunoreactivity of the proband's skin to antibodies directed against BP180. These findings underscore the importance of structural integrity of the extracellular domain of BP180 for the stability of the protein.

The wide phenotypical heterogeneity within the ichthyosis congenita group of diseases is well known. We report a case of a very rare and unusual autosomal recessive ichthyosis congenita, type IV, according to the ultrastructural classification. Our case presented the triad clue for the diagnosis, characterized by follicular hyperkeratosis, prematurity and perinatal complications, but the clinical diagnosis was further complicated by hypereosinophilia and a strongly positive Darier's sign suggesting diffuse cutaneous mastocytosis. The diagnosis was provided only by electron microscopy, which showed the pathognomonic markers of ichthyosis congenita type IV, namely a large number of membrane structures in the stratum corneum and stratum granulosum. As a consequence, correct genetic counselling for the parents was carried out, and they were informed about the benign course of the disease after the complications of the perinatal period. This case is a further example of the reliability of ultrastructural markers in the diagnosis of inherited keratinization disorders, especially those with an unusual clinical appearance.

Epidermolysis bullosa (EB) pruriginosa is a rare clinical subset of dystrophic EB, characterized by marked itching and presence of prurigo-like or lichenoid features. In order to further delineate the phenotype and understand the pathogenesis of this disorder, the clinical, histological and ultrastructural findings of a 19-year-old patient presenting a typical form of EB pruriginosa are described. The prevalence of papular itchy lichenoid lesions, signs of scratching and paucity of blisters at the time of clinical examination may result in incorrect diagnosis and treatment. Microscopic studies of the lesions show the typical findings of dystrophic EB associated with an unusually high density of collagen bundles and absence of elastic fibres in the upper dermis. Itching lichenoid lesions of EB pruriginosa could represent an abnormal dermal reactivity of some patients to their inherited bullous disorder.

Junctional epidermolysis bullosa (JEB) is a heterogeneous group of rare inherited skin disorders in which defects in cell adhesion components cause incomplete formation of hemidesmosomes. We have immunohistochemically examined the skin from ten JEB patients (JEB gravis, n = 4; JEB mitis, n = 3; JEB plus pyloric atresia [JEB/PA], n = 3) using monoclonal antibodies specific for the integrin adhesion receptors alpha 3 beta 1 and alpha 6 beta 4, and for the alpha 3, beta 3, and gamma 2 subunits of the basement membrane ligand, laminin 5. Consistent with our previous reports, only the JEB gravis patients without associated pyloric atresia expressed reduced or absent epitopes for laminin-5 subunits in their epidermal basement membrane. In contrast, all three JEB/PA cases showed abnormalities in integrin alpha 6 beta 4, but not in laminin 5, expression in their basal epidermal cells. Integrin beta 4 subunit was undetectable in the biopsied epidermis of these JEB/PA individuals using five different monoclonal antibodies that recognize both intra- and extracellular epitopes. The absence of the beta 4 subunit in the epidermis of JEB/PA specimens was confirmed by Western blot analysis of tissue extracts. Epidermal expression of the integrin alpha 6 subunit was variable in the JEB/PA patients. Abnormal integrin alpha 6 beta 4 expression may define the subset of JEB cases with pyloric atresia. These results strongly implicate a functional role for alpha 6 beta 4 in the formation of complete hemidesmosomes and in stable adhesion of basal keratinocytes to the basement membrane in vivo.

We report on a 25-year-old woman with typical manifestations of the cardio-facio-cutaneous (CFC) syndrome, but without mental retardation. She had valvular and infundibular pulmonic stenosis, brittle and woolly hair with patchy alopecia, scant body hair, dry and hypohydrotic skin, and characteristic facial traits. To our knowledge, this is the first case of CFC syndrome without mental retardation but typical cutaneous findings.