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Inherited epidermolysis bullosa (EB) is a clinically and genetically heterogeneous group of rare diseases characterized by skin and mucous membrane fragility. EB primarily involves the skin and, in specific subtypes, the mucous membrane, resulting in complications which can strongly affect nutritional status (e.g. gastrointestinal complications, hand deformities, pain). The aims of nutritional support mainly include improving nutritional status, alleviating the stress of oral feeding and minimizing nutritional deficiencies, thus consequently improving growth, pubertal development, bowel function, immune status and wound healing. The aim of this review is to discuss knowledge of different aspects of the disease related to nutrition and growth.

Autosomal recessive congenital ichthyosis (ARCI) belongs to a heterogeneous group of disorders of keratinization. To date, 10 genes have been identified to be causative for ARCI. NIPAL4 (Nipa‐Like Domain‐Containing 4) is the second most commonly mutated gene in ARCI. In this study, we present a large cohort of 101 families affected with ARCI carrying mutations in NIPAL4. We identified 16 novel mutations and increase the total number of pathogenic mutations in NIPAL4 to 34. Ultrastructural analysis of biopsies from six patients showed morphological abnormalities consistent with an ARCI EM type III. One patient with a homozygous splice site mutation, which leads to a loss of NIPAL4 mRNA, showed additional ultrastructural aberrations together with a more severe clinical phenotype. Our study gives insights into the frequency of mutations, a potential hot spot for mutations, and genotype–phenotype correlations.

Background/objectives Epidermolysis bullosa is a group of diseases caused by mutations in skin structural proteins. Availability of genetic sequencing makes identification of causative mutations easier, and genotype-phenotype description and correlation are important. We describe six patients with a keratin 5 mutation resulting in a glutamic acid to lysine substitution at position 477 (p.Glu477Lys) who have a distinctive, severe and sometimes fatal phenotype. We also perform in silico modeling to show protein structural changes resulting in instability. Methods In this case series, we collected clinical data from six patients with this mutation identified from their national or local epidermolysis bullosa databases. We performed in silico modeling of the keratin 5-keratin 14 coil 2B complex using CCBuilder and rendered with Pymol (Schrodinger, LLC, New York, NY). Results Features include aplasia cutis congenita, generalized blistering, palmoplantar keratoderma, onychodystrophy, airway and developmental abnormalities, and a distinctive reticulated skin pattern. Our in silico model of the keratin 5 p.Glu477Lys mutation predicts conformational change and modification of the surface charge of the keratin heterodimer, severely impairing filament stability. Conclusions Early recognition of the features of this genotype will improve care. In silico analysis of mutated keratin structures provides useful insights into structural instability.

Simple Summary Neurofibromatosis type 1 is a genetic disease that predisposes to tumors of the nervous system, primarily the neurofibroma. Plexiform neurofibromas (Pnfs) are of the greatest concern because of location, size, and frequent progression to malignancy. Although research is making great progress, the lack of in-depth understanding of the molecular mechanisms driving neoplastic progression results in the absence of prognostic indicators and therapeutic targets. We document that cell–cell cooperativity and the dynamics of the extracellular matrix play important roles in the growth and transformation of Pnf cells, directly through the cooperation of RAS and focal adhesion kinase (FAK) signaling. In turn, we found that treatment of Pnf cells with both MEK and FAK inhibitors is effective in abolishing the transforming ability of these cells. Abstract Plexiform neurofibromas (Pnfs) are benign peripheral nerve sheath tumors that are major features of the human genetic syndrome, neurofibromatosis type 1 (NF1). Pnfs are derived from Schwann cells (SCs) undergoing loss of heterozygosity (LOH) at the NF1 locus in an NF1+/− milieu and thus are variably lacking in the key Ras-controlling protein, neurofibromin (Nfn). As these SCs are embedded in a dense desmoplastic milieu of stromal cells and abnormal extracellular matrix (ECM), cell–cell cooperativity (CCC) and the molecular microenvironment play essential roles in Pnf progression towards a malignant peripheral nerve sheath tumor (MPNST). The complexity of Pnf biology makes treatment challenging. The only approved drug, the MEK inhibitor Selumetinib, displays a variable and partial therapeutic response. Here, we explored ECM contributions to the growth of cells lacking Nfn. In a 3D in vitro culture, NF1 loss sensitizes cells to signals from a Pnf-mimicking ECM through focal adhesion kinase (FAK) hyperactivation. This hyperactivation correlated with phosphorylation of the downstream effectors, Src, ERK, and AKT, and with colony formation. Expression of the GAP-related domain of Nfn only partially decreased activation of this signaling pathway and only slowed down 3D colony growth of cells lacking Nfn. However, combinatorial treatment with both the FAK inhibitor Defactinib (VS-6063) and Selumetinib (AZD6244) fully suppressed colony growth. These observations pave the way for a new combined therapeutic strategy simultaneously interfering with both intracellular signals and the interplay between the various tumor cells and the ECM.

The autosomal recessive congenital ichthyoses (ARCI) are a nonsyndromic group of cornification disorders that includes lamellar ichthyosis, congenital ichthyosiform erythroderma, and harlequin ichthyosis. To date mutations in ten genes have been identified to cause ARCI: TGM1, ALOX12B, ALOXE3, NIPAL4, CYP4F22, ABCA12, PNPLA1, CERS3, SDR9C7, and SULT2B1. The main focus of this report is the mutational spectrum of the genes ALOX12B and ALOXE3, which encode the epidermal lipoxygenases arachidonate 12-lipoxygenase, i.e., 12R type (12R-LOX), and the epidermis-type lipoxygenase-3 (eLOX3), respectively. Deficiency of 12R-LOX and eLOX3 disrupts the epidermal barrier function and leads to an abnormal epidermal differentiation. The type and the position of the mutations may influence the ARCI phenotype, most patients present with a mild erythrodermic ichthyosis, and only few individuals show severe erythroderma. To date, 88 pathogenic mutations in ALOX12B and 27 pathogenic mutations in ALOXE3 have been reported in the literature. Here, we presented a large cohort of 224 genetically characterized ARCI patients who carried mutations in these genes. We added 74 novel mutations in ALOX12B and 25 novel mutations in ALOXE3. We investigated the spectrum of mutations in ALOX12B and ALOXE3 in our cohort and additionally in the published mutations, the distribution of these mutations within the gene and gene domains, and potential hotspots and recurrent mutations.

Epidermolysis Bullosa (EB) is a group of genetic conditions that cause fragile and blistering skin. Although there are different types of EB, which differ in severity, their signs and symptoms overlap. As a result of this disorder, patients face an unbearable burden in their lives, and their Quality of Life (QoL) is negatively affected at every life cycle stage. Nevertheless, the assessment of the quality of life of these patients is scanty. This project aims to develop a patient-centered questionnaire to assess the QoL of EB patients. This tool will be a valid aid for clinicians to understand patients better and identify the areas that need more attention; moreover, it will allow them to follow the patients over time and evaluate the impact of any treatments. The methodological process to develop the questionnaire consisted of two phases: firstly, a critical review of scientific literature was performed; secondly, a pseudo-Delphi study was carried out. A multidisciplinary panel (including patients, caregivers, and clinicians) actively participated in round tables to discuss the main areas of interest. Starting from this initial set of areas and through the repetition of Delphi (up to three rounds), a gradual refinement of the statements was carried out to define a list of items to be included in an easy-to-use but meaningful questionnaire. The final patient-centered questionnaire is thus able to measure the QoL beyond the physical symptoms and the clinical evolution of the disease, encompassing functional autonomy, psycho-emotional state, social relations and the working field.

Mutations in KRT1 (keratin 1) or KRT10 (keratin 10) underlie a spectrum of diseases known as keratinopathic ichthyoses. Epidermolytic ichthyosis (EI) is caused by heterozygous missense mutations in the genes KRT1 or KRT10, mutations in the gene KRT2 (keratin 2) lead to superficial epidermolytic ichthyosis, and congenital reticular ichthyosiform erythroderma is caused by frameshift mutations in the genes KRT10 or KRT1, which lead to the phenomenon of revertant mosaicism. Epidermolytic ichthyosis is also present in a mosaic pattern known as epidermolytic (acantholytic) nevus, isolated or diffuse. In the latter case, gonadic involvement is possible, leading to a rare pedigree in which a parent with diffuse epidermolytic nevus (linear EI) gives birth to a child affected by EI. We present here an update on the phenotypic presentations of keratinopathic ichthyoses and their molecular mechanisms.

IFAP syndrome is a rare genetic disorder characterized by ichthyosis follicularis, atrichia, and photophobia. Previous research found that mutations in MBTPS2, encoding site-2-protease (S2P), underlie X-linked IFAP syndrome. The present report describes the identification via whole-exome sequencing of three heterozygous mutations in SREBF1 in 11 unrelated, ethnically diverse individuals with autosomal-dominant IFAP syndrome. SREBF1 encodes sterol regulatory element-binding protein 1 (SREBP1), which promotes the transcription of lipogenes involved in the biosynthesis of fatty acids and cholesterols. This process requires cleavage of SREBP1 by site-1-protease (S1P) and S2P and subsequent translocation into the nucleus where it binds to sterol regulatory elements (SRE). The three detected SREBF1 mutations caused substitution or deletion of residues 527, 528, and 530, which are crucial for S1P cleavage. In vitro investigation of SREBP1 variants demonstrated impaired S1P cleavage, which prohibited nuclear translocation of the transcriptionally active form of SREBP1. As a result, SREBP1 variants exhibited significantly lower transcriptional activity compared to the wild-type, as demonstrated via luciferase reporter assay. RNA sequencing of the scalp skin from IFAP-affected individuals revealed a dramatic reduction in transcript levels of low-density lipoprotein receptor (LDLR) and of keratin genes known to be expressed in the outer root sheath of hair follicles. An increased rate of in situ keratinocyte apoptosis, which might contribute to skin hyperkeratosis and hypotrichosis, was also detected in scalp samples from affected individuals. Together with previous research, the present findings suggest that SREBP signaling plays an essential role in epidermal differentiation, skin barrier formation, hair growth, and eye function.

The mechanical properties of the microenvironment have been increasingly accepted as potent modulators of cell behavior and function in physiological and pathological conditions. In tumors, tissue rigidity has been recognized as a potent driver of both neoplastic initiation from healthy tissue and progression toward malignancy. Several benign or malignant tumors are fibrotic and characterized by increased deposition, turnover, and posttranslational modifications of the extracellular matrix (ECM) that progressively stiffens the stroma. Likewise, neurofibromas are complex tumors composed of transformed Schwann cells, immersed in a heterogeneous fibrotic matrix. The molecular crosstalks that govern neurofibroma onset, growth, invasiveness, and progression toward malignancy remain poorly understood. In this chapter we propose that neurofibroma development requires the integration of potent pro-tumorigenic circuitries, such as those mastered by hyperactive Ras, and altered mechanosignaling axes conveyed by a stiff ECM, and that these pathways could be orchestrated by a pro-inflammatory extracellular milieu.

Due to the fact that NF1 is one of the more frequent genetic diseases (1/2500–1/3000, see Chap. 1), in the last 20 years dedicated centers for diagnosis and follow-up of these patients have been established allowing clinicians to acquire noteworthy clinical experience. Moreover, diagnostic laboratories are now able to provide molecular analyses with a detection rate that reaches 95% of patients affected by NF1. A critical revision of the classical grid of diagnostic criteria is now mandatory in order to actualize and mix the “classical” diagnostic criteria and recent knowledge. We remind that some of the proposed new clinical signs did not reach a unanimous consensus for different reasons among the experts to be introduced as new criteria, such as anemic nevus, UBOs, elevated head circumference and neuropsychological pattern.

Cutaneous lesions of NF1, in analogy of those of tuberous sclerosis, have a specific age of onset: at birth for cafe-au-lait macules (CALMs), herald patch of plexiform tumors and anemic nevus, during childhood for CALMs at major folds (former called freckling) and choroidal hamartomas, and in late childhood and puberty for Lisch nodules and neurofibromas (see also Fig. 4.1 in Chap. 4). Definitive diagnosis may, therefore, be delayed by years.

Neurofibromatosis 1 (NF1) is a “ras-opathy” inherited in a dominant way, caused by mutations of Neurofibromin gene. Since the publication of NIH Consensus Conference results in 1988, the medical knowledge of the disease is dramatically improved, both molecularly and clinically, especially in past few years. Consequently, the increasing need for a critical review of the diagnostic approach to this neurocutaneous genetic disease is leading to a re-reading of the NIH diagnostic criteria which takes into account both the new clinical features as well as the availability of new generation molecular testing.

The past obstetrical literature indicated that women with NF1 had increased complications associated with pregnancy. However, the majority of publications were case reports involving small case series and were likely biased toward reporting on cases in which complications occurred, such as increased incidence of preeclampsia, preterm delivery, intrauterine growth restriction, pregnancy-induced hypertension, stillbirth, spontaneous abortion, or perinatal mortality. On the contrary, in 1996 a further study on 105 patients failed to confirm these data. A broad analysis (>1500 patients) carried out in 2013 identified increased risks for many complications that were unreported in previous literature and claimed for counsel in NF1 affected families planning for spontaneous or assisted conception. Finally, the association of pregnancy complications seen in NF1 women claims for adequate attention in patients who use assisted reproductive technologies because of the increased risk of multiple pregnancies.

Background Kindler Syndrome (KS) is a rare genodermatosis characterized by skin fragility, skin atrophy, premature aging and poikiloderma. It is caused by mutations in the FERMT1 gene, which encodes kindlin-1, a protein involved in integrin signalling and the formation of focal adhesions. Several reports have shown the presence of non-melanoma skin cancers in KS patients but a systematic study evaluating the risk of these tumors at different ages and their potential outcome has not yet been published. We have here addressed this condition in a retrospective study of 91 adult KS patients, characterizing frequency, metastatic potential and body distribution of squamous cell carcinoma (SCC) in these patients. SCC developed in 13 of the 91 patients. Results The youngest case arose in a 29-year-old patient; however, the cumulative risk of SCC increased to 66.7% in patients over 60 years of age. The highly aggressive nature of SCCs in KS was confirmed showing that 53.8% of the patients bearing SCCs develop metastatic disease. Our data also showed there are no specific mutations that correlate directly with the development of SCC; however, the mutational distribution along the gene appears to be different in patients bearing SCC from SCC-free patients. The body distribution of the tumor appearance was also unique and different from other bullous diseases, being concentrated in the hands and around the oral cavity, which are areas of high inflammation in this disease. Conclusions This study characterizes SCCs in the largest series of KS patients reported so far, showing the high frequency and aggressiveness of these tumors. It also describes their particular body distribution and their relationship with mutations in the FERMT-1 gene. These data reinforce the need for close monitoring of premalignant or malignant lesions in KS patients.

An international advisory group met at the National Institutes of Health in Bethesda, Maryland in 2017, to discuss a new classification system for the ectodermal dysplasias that would integrate both clinical and molecular information. We propose the following, a working definition of the ectodermal dysplasias building on previous classification systems and incorporating current approaches to diagnosis: ectodermal dysplasias are genetic conditions affecting the development and/or homeostasis of two or more ectodermal derivatives, including hair, teeth, nails, and certain glands. Genetic variations in genes known to be associated with ectodermal dysplasias that affect only one derivative of the ectoderm (attenuated phenotype) will be grouped as non-syndromic traits of the causative gene (e.g. non-syndromic hypodontia or missing teeth associated with pathogenic variants of EDA “ectodysplasin” ). Information for categorization and cataloging includes the phenotypic features, Online Mendelian Inheritance in Man number, mode of inheritance, genetic alteration, major developmental pathways involved (e.g. EDA, WNT “wingless-type”, TP63 “tumor protein p63”) or the components of complex molecular structures ( e.g. connexins, keratins, cadherins).

Aberrant nucleic acids generated during viral replication are the main trigger for antiviral immunity, and mutations that disrupt nucleic acid metabolism can lead to autoinflammatory disorders. Here we investigated the etiology of X-linked reticulate pigmentary disorder (XLPDR), a primary immunodeficiency with autoinflammatory features. We discovered that XLPDR is caused by an intronic mutation that disrupts the expression of POLA1, which encodes the catalytic subunit of DNA polymerase-α. Unexpectedly, POLA1 deficiency resulted in increased production of type I interferons. This enzyme is necessary for the synthesis of RNA:DNA primers during DNA replication and, strikingly, we found that POLA1 is also required for the synthesis of cytosolic RNA:DNA, which directly modulates interferon activation. Together this work identifies POLA1 as a critical regulator of the type I interferon response.

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.

Tinea imbricata is a chronic superficial mycosis caused by Trichophyton concentricum. It is characterized by widespread, annular, concentric, squamous lesions. Tinea imbricata is endemic in three geographical areas: Southwest Pacific, Southeast Asia, and Central and South America. Tinea imbricata in travelers returning from endemic areas is exceptionally rare. We report a case of tinea imbricata in an Italian child who acquired the infection during a trip to Solomon Islands. Three cultures were positive for T. concentricum. The patient was successfully treated with griseofulvin and terbinafine cream.

Ectodermal dysplasias are a group of genetic disorders defined by ectodermal derivative impairment (EDI). To test the impact of the Wnt/beta-catenin pathway in the genetic screening of EDI, we performed a molecular gene study of WNT10A in 60 subjects from a population of 133 young Italian patients referred for the impairment of at least one major ectodermal-derived structure and who had a previous negative molecular screen for ectodysplasin signaling pathway genes ED1, EDAR, and EDARADD. Fourteen WNT10A mutations were identified in 33 subjects (24.8%), 11 of which were novel variants. The phenotype was evaluated through a detailed clinical examination of the major and minor ectodermal-derived structures. This study is the first to show that, after ED1, WNT10A is the second molecular candidate for EDI in a large Italian Caucasian population. The study confirmed that Phe228Ile is the most frequent WNT10A variant in Caucasian populations, and that WNT10A mutations are associated with large variability in EDI.

Hypohidrotic ectodermal dysplasia (HED) is a rare disease characterized by deficiency in development of structure derived from the ectoderm and is caused by mutations in the genes EDA, EDAR, or EDARADD. Phenotypes caused by mutations in these three may exhibit similar clinical features, explained by a common signaling pathway. Mutations in EDA gene cause X linked HED, which is the most common form. Mutations in EDAR and EDARADD genes cause autosomal dominant and recessive form of HED. The most striking clinical findings in HED are hypodontia, hypotrichosis and hypohidrosis that can lead to episodes of hyperthermia. We report on clinical findings in a child with HED with autosomal dominant inheritance pattern with a heterozygous mutation c.1072C>T (p.Arg358X) in the EDAR gene. A review of the literature with regard to other cases presenting the same mutation has been carried out and discussed.

Bone status impairment represents a complication of generalized forms of epidermolysis bullosa (EB); however, the prevalence and the main determinants of this event in localized forms remain poorly defined. Birmingham epidermolysis bullosa severity (BEBS) score and 25-hydroxyvitamin D levels are strongly associated with low bone mass, suggesting that vitamin D may play a potential beneficial role in bone health. Further longitudinal studies are needed in order to confirm this hypothesis. Bone status impairment represents a complication of generalized forms of EB; thus, we aimed to estimate the prevalence of low bone mass, to examine mineralization differences in various EB subtypes and to identify the most important determinants of bone impairment in children with either generalized or localized EB. An observational study of 20 children (11 males; mean age ± standard deviation, 11.7 ± 3.9 years) with EB was performed. Clinical history, physical examination, laboratory studies, X-ray of the left hand and wrist for bone age, and dual energy X-ray absorptiometry scans of the lumbar spine were obtained. Areal bone mineral density (aBMD Z-scores) and bone mineral apparent density were related to the BEBS score. Areal BMD Z-score (mean −1.82 ± 2.33, range, −7.6-1.7) was reduced (

Ectodermal dysplasias (EDs) are a group of genetic disorders characterized by the abnormal development of the ectodermal-derived structures. X-linked hypohidrotic ectodermal dysplasia, resulting from mutations in ED1 gene, is the most common form. The main purpose of this study was to characterize the phenotype spectrum in 45 males harboring ED1 mutations. The study showed that in addition to the involvement of the major ectodermal tissues, the majority of patients also have alterations of several minor ectodermal-derived structures. Characterizing the clinical spectrum resulting from ED1 gene mutations improves diagnosis and can direct clinical care.

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.

In order to evaluate the serum anti-skin autoantibodies and cytokine concentrations in patients with different epidermolysis bullosa (EB) types and severity, 42 EB patients and 38 controls were enrolled. Serum anti-skin antibodies were significantly higher in the patients than in the controls (p = 0.008, p < 0.001, p < 0.001, p < 0.001 and p < 0.001 for desmoglein 1 (DSG1) desmoglein 3 (DSG3), bullous pemphigoid 180 (BP180), BP230 and type VII collagen (COL7), respectively). The same trend was observed for interleukin (IL)-1β, IL-2, IL-6, IL-10, tumor necrosis factor-β, and interferon-γ (p < 0.001, p < 0.001, p < 0.001, p = 0.008, p < 0.001 and p = 0.002, respectively). Increases in anti-skin antibodies and cytokine concentrations were higher in patients with recessive dystrophic EB than in those with different types of EB, in generalized cases than in localized ones, and in patients with higher Birmingham Epidermolysis Bullosa Severity (BEBS) scores than in those with a lower score. The BEBS score was directly correlated with BP180, BP230, COL7 (p = 0.015, p = 0.008 and p < 0.001, respectively) and IL-6 (p = 0.03), whereas IL-6 appeared significantly associated with DSG1, DSG3, BP180, BP230 and COL7 (p = 0.015, p = 0.023, p = 0.023, p = 0.015 and p = 0.005, respectively). This study showed that autoimmunity and inflammatory responses are frequently activated in EB, mainly in severe forms, suggesting the use of immunosuppressive drugs or biologicals that are active against pro-inflammatory cytokines to reduce clinical signs and symptoms of disease.

Hypohidrotic ectodermal dysplasia (HED) is a rare disease characterized by deficiency in development of structure derived from the ectoderm and is caused by mutations in the genes EDA, EDAR, or EDARADD. Phenotypes caused by mutations in these three may exhibit similar clinical features, explained by a common signaling pathway. Mutations in EDA gene cause X linked HED, which is the most common form. Mutations in EDAR and EDARADD genes cause autosomal dominant and recessive form of HED. The most striking clinical findings in HED are hypodontia, hypotrichosis and hypohidrosis that can lead to episodes of hyperthermia. We report on clinical findings in a child with HED with autosomal dominant inheritance pattern with a heterozygous mutation c.1072CT (p.Arg358X) in the EDAR gene. A review of the literature with regard to other cases presenting the same mutation has been carried out and discussed.La displasia ectodérmica hipohidrótica (DEH) es una entidad infrecuente caracterizada por deficiencia en el desarrollo de estructuras derivadas del ectodermo y es causada por mutaciones en los genes EDA, EDAR o EDARADD, que pueden exhibir hallazgos clínicos similares, debido a una vía de señalización común. Las mutaciones en el gen EDA causan la DEH ligada al X, que es la forma más frecuente. Por su parte, las mutaciones en los genes EDAR y EDARADD causan la DEH con patrón de herencia autosómica dominante y recesiva. Los hallazgos clínicos más resaltantes son hipodoncia, hipotricosis e hipohidrosis, que pueden llevar a episodios de hipertermia. Se presentan los hallazgos clínicos en un niño con DEH con patrón de herencia autosómica dominante, cuyo análisis molecular demostró mutación heterocigótica c.1072CT(p.Arg358X) en el gen EDAR, y se discuten los diferentes aspectos clínicos encontrados en esta mutación en los casos descritos en la literatura.

Genetic mosaicism is thought to be a common phenomenon in inherited skin disorders. It is the leading molecular mechanism explaining cutaneous hamartomas and nevoid disorders, skin manifestations of most X-linked genodermatoses and specific forms of clinical variability and topographic distribution in autosomal skin disorders. The developmental (in utero) origin and timing dependence are two major attributes for the current definition of cutaneous mosaicism. Chromosomal mosaicism, lyonization in X-linked genodermatoses, and various types of mosaicism (i.e. type 1, type 2 and revertant mosaicism) in autosomal skin disorders are mechanisms well defined at the molecular level. All these concepts have been fully included in the current medical terminology in dermatology and genetics. Mitotic crossing-over, paradominant inheritance, monoallelic expression of autosomal traits and mosaicism in acquired skin disorders remain without a formal molecular proof and still represent sources of debate in the scientific community. This review summarizes current concepts, discoveries and controversies in the field of cutaneous mosaicism for practitioners and clinical researchers to enhance their understanding of such a underestimated clinical phenomenon and its biological basis.

An uncommon type of epidermal nevus characterized by hyperpigmented hyperkeratotic bands following a Blaschko-linear pattern and generalized follicular hyperkeratosis were observed in a 17-year-old male patient who additionally showed tufted hair folliculitis on the scalp and clinodactyly of the fifth finger of both hands. The combination of epidermal nevus with skeletal abnormalities was first described by Gobello et al. [Dermatology 2000;201:51-55] as a new epidermal nevus syndrome that was named after the first author of this work. Our case shows identical clinical and histopathological features and represents the second case of this rare syndrome reported in the literature.

Background: Inherited ichthyoses belong to a large, clinically and etiologically heterogeneous group of mendelian disorders of cornification; typically involving the entire integument. Over the recent years, much progress has been made defining their molecular causes. However, there is no internationally accepted classification and terminology. Objective: We sought to establish a consensus for the nomenclature and classification of inherited ichthyoses. Methods: The classification project started at the First World Conference on Ichthyosis in 2007. A large international network of expert clinicians, skin pathologists, and geneticists entertained an interactive dialogue over 2 years, eventually leading to the First Ichthyosis Consensus Conference held in Soreze, France, on January 23 and 24, 2009, where subcommittees on different issues proposed terminology that was debated until consensus was reached. Results: It was agreed that currently the nosology should remain clinically based. "Syndromic" versus "nonsyndromic" forms provide a useful major subdivision. Several clinical terms and controversial disease names have been redefined: eg, the group caused by keratin mutations is referred to by the umbrella term, "keratinopathic ichthyosis"-under which are included epidermolytic ichthyosis, superficial epidermolytic ichthyosis, and ichthyosis Curth-Macklin. "Autosomal recessive congenital ichthyosis" is proposed as an umbrella term for the harlequin ichthyosis, lamellar ichthyosis, and the congenital ichthyosiform erythroderma group. Limitations: As more becomes known about these diseases in the future, modifications will be needed. Conclusion: We have achieved an international consensus for the classification of inherited ichthyosis that should be useful for all clinicians and can serve as reference point for future research. (I Am Acad Dermatol 2010;63:607-41.)

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.

Summary Background Basal epidermolysis bullosa simplex (EBS) is a hereditary skin blistering disorder resulting in most cases from missense mutations in the keratin 5 (KRT5) or keratin 14 (KRT14) genes. Objectives To identify the underlying mutations in different EBS subtypes and correlate genotype and phenotype. Methods Mutation analysis was performed in 53 patients with EBS and their families by direct sequencing of the KRT5 and KRT14 genes. Results We identified 39 different mutations, of which 15 have not been published previously. Three novel deletion/insertion mutations, among them one in-frame duplication, were associated with the rare phenotype of EBS with mottled pigmentation. We identified for the first time a patient with compound heterozygosity for KRT5 mutations causing Dowling–Degos disease and EBS. Conclusions Identification of novel mutations and genotype–phenotype correlations in EBS allow improved understanding of disease pathogenesis as well as better patient management.