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Autosomal recessive congenital ichthyosis (ARCI) is a non-syndromic congenital disorder of cornification characterized by abnormal scaling of the skin. The three major phenotypes are lamellar ichthyosis, congenital ichthyosiform erythroderma, and harlequin ichthyosis. ARCI is caused by biallelic mutations in ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, NIPAL4, PNPLA1, SDR9C7, SULT2B1, and TGM1. The most severe form of ARCI, harlequin ichthyosis, is caused by mutations in ABCA12. Mutations in this gene can also lead to congenital ichthyosiform erythroderma or lamellar ichthyosis. We present a large cohort of 64 patients affected with ARCI carrying biallelic mutations in ABCA12. Our study comprises 34 novel mutations in ABCA12, expanding the mutational spectrum of ABCA12-associated ARCI up to 217 mutations. Within these we found the possible mutational hotspots c.4541G>A, p.(Arg1514His) and c.4139A>G, p.(Asn1380Ser). A correlation of the phenotype with the effect of the genetic mutation on protein function is demonstrated. Loss-of-function mutations on both alleles generally result in harlequin ichthyosis, whereas biallelic missense mutations mainly lead to CIE or LI.

X-linked hypohidrotic ectodermal dysplasia (XLHED) is a rare genetic disorder characte-rised by abnormal development of the skin and its appendages, such as hair and sweat glands, the teeth, and mucous glands of the airways, resulting in serious, sometimes life-threatening complications like hyperthermia or recurrent respiratory infections. It is caused by pathogenic variants of the ectodysplasin A gene (EDA). Most affected males are hemizygous for EDA null mutations that lead to the absence or inactivity of the signalling protein ectodysplasin A1 (EDA1) and, thus, to the full-blown phenotype with inability to perspire and few if any teeth. There are currently no long-term treatment options for XLHED. ER004 represents a first-in-class protein replacement molecule designed for specific, high-affinity binding to the endogenous EDA1 receptor (EDAR). Its proposed mechanism of action is the replacement of missing EDA1 in yet unborn patients with XLHED. Once bound to EDAR, ER004 activates the EDA/NFκB signalling pathway, which triggers the transcription of genes involved in the normal development of multiple tissues. Following preclinical studies, named-patient use cases demonstrated significant potential of ER004 in affected males treated in utero during the late second and third trimesters of pregnancy. In order to confirm these results, we started the EDELIFE trial, a prospective, open-label, genotype-match controlled, multicentre clinical study to investigate the efficacy and safety of intra-amniotic ER004 administration as a prenatal treatment for male subjects with XLHED. This article summarises the rationale, the study protocol, ethical issues of the trial, and potential pitfalls.

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.

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.

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).

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 (

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.

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.)

Neurofibromatosis type 1 (NF1) is a genetic multisystemic disorder involving the skin, the central and peripheral nervous systems, bones, and the cardiovascular and endocrine systems. This condition is caused by inherited or de novo mutations of the NF1 gene at the 17q11.2 chromosomal region, a gene that codes for the protein neurofibromin. Neurofibromin is particularly expressed in neural cells and inhibits the RAS pathway, which regulates cellular proliferation and differentiation. The typically age-dependent emergence of diagnostic signs and the risk for severe complications in the first years of life simultaneously makes a precocious diagnosis crucial and makes the management of children with suspected NF1 challenging. Currently, no standardized specific treatments for NF1 and its complications are available. However, in recent years, increasing knowledge of the pathogenetic mechanisms has motivated the scientific search behind targeted biological agents that might change the course of the disease. Numerous clinical trials for the treatment of the most typical NF1 complications, such as plexiform neurofibromas (Ns) and NF1-related tumors, have been conducted. Consequently, encouraging in vitro and in vivo results are emerging. Insufficient efficacy and safety in in vivo data do not permit the routine use of these drugs in clinical practice. Radiotherapy appears to be indicated only for high-grade soft-tissue sarcomas, whereas surgical approaches should be considered for malignant peripheral nerve sheath tumors (MPNSTs) and Ns, optic pathway gliomas, and bone dystrophic changes because they might improve quality of life. Further prospective studies, however, are needed to confirm the efficacy, safety, and cost/benefit ratio of new therapeutic approaches and the optimal timing for their use in patients with NF1.

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.

A novel INDEL mutation in theEDA gene resulting in a distinctX- linked hypohidroticectoder mal dysplasia phenotypein an Italian familyEditorX-Linked Hypohidrotic Ectodermal Dysplasia (XL-HED; MIM305100) is characterized by hypodontia, misshaped teeth, hypo-hidrosis, sparse hair, peculiar facial features,1,2and occurs in lessthan 1 in every 100.000 individuals.1XL-HED is caused bymutations in the Ectodysplasin-A (EDA) gene located at Xq12-q13 with more than 100 causative mutations reported todate.1,3,4The identification of disease-causing mutations con-firms the diagnosis, however, does not automatically imply agenotype–phenotype correlation.

Identification of a novelframeshift mutation in theEDAR gene causing autosomaldominant hypohidroticectoder mal dysplasiaEditorThe ectodermal dysplasias (EDs) are a group of inherited disor-ders affecting ectodermal-derived tissues, including the hair,nails, teeth, skin and sweat glands.1,2Hypohidrotic ectodermaldysplasia (HED) represents one of the major types of ED andresults from mutations in the EDA (MIM *300451), EDAR(MIM *604095) EDARADD (MIM *606603) and TRAF6 (MIM*602355) genes. The inheritance of HED can be X-linked(XLHED; MIM#305100) or autosomal either dominant(MIM#129490) or recessive (MIM#305100).3,4No definitegenotype–phenotype correlations have been established to date.However, recently identified EDAR mutations demonstrate thatpathogenic variants result in variable phenotypes with mild-to-severe clinical manifestations.5We report a novel mutation in the EDAR gene in an Italianfamily with autosomal dominant HED that supports emergingevidence for a genoytype–phenotype correlation.5The clinical,genetic and functional studies were conducted according to theHelsinki declaration and written informed consent was obtainedfrom all participating family members; including consent topublish data and clinical images. Three members of the familywere available for detailed clinical investigation (V:5; IV:7; IV:5),and four underwent molecular genetic analysis (V:5; IV:7; IV:5;III:2)

Neurofibromatosis 1 is a complex inherited neurocutaneous disease that is often difficult to diagnose early because of its age-dependent presentation. The diagnosis is also extremely difficult to communicate to patients and their parents because of the disease's clinical variability, unpredictable evolution, and uncertain prognosis. Since 1988, the year of publication of the last Consensus Conference statement concerning the diagnosis of neurofibromatosis 1, our understanding of the disease has naturally increased and, in addition to the availability of increasingly precise molecular analyses, some new clinical signs have been reported such as anaemic nevi, unidentified bright objects, choroidal hamartomas, and a typical neuropsychological phenotype. We critically review the current diagnostic criteria, and suggest the addition of new signs on the basis of published findings and our own clinical experience. This proposal aims to improve diagnostic power in paediatric age, securing a better and more reliable healthcare transition toward adult age. We finally recommend a new Consensus Conference in order to revise the diagnostic criteria, possibly differentiated by age of presentation.

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.

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.

ejd.2013.1968 Auteur(s) : Angelo V. Marzano1 angelovalerio.marzano@policlinico.mi.it, Silvia Alberti-Violetti1, Rolando Crippa2, Francesca Angiero3, Gianluca Tadini1, Carlo Crosti1 1 U.O. Dermatologia, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Via Pace 9, 20122 Milan, Italy; 2 U.O. Patologia Orale e Laserterapia, Istituto Stomatologico Italiano, Milan, Italy; 3 Department of Surgical Sciences and Integrated Diagnostic, University of Genoa, Genoa, Italy Pyoderma gangrenosum [...]

Background Ichthyoses are genetic disorders of keratinization which are uncomfortable due to their conspicuous scaling, itching and cosmetic problems. Ichthyoses can lead to social discrimination and psychological problems. Ichthyosis vulgaris (IV) is the most common form of these geno-dermatoses. IV is a chronic disorder that often requires continuous therapy. Emollient and keratolytic products are the mainstay treatments of IV. It is important that efficient, safe and well tolerated therapies should be available. Direct comparative data regarding efficacy of different emollient products in IV patients are very few. Objective The aim of the study was to investigate the keratolytic and moisturizing properties as well as the tolerance of a new urea topical formulation (Ureadin Rx10) when applied to hyperkeratotic and dry skin in patients with (IV) in comparison with a standard emollient cream. Methods The study was conducted as a two-center, randomized, controlled, single-blind, intra-patient (right-vs.-left) trial design. A total of 30 patients with IV between 8 and 65 (mean age: 25 years) treated with a 10% urea-based lotion, Ureadin Rx 10 * *Ureadin RX 10 is a registered trade name of ISDIN, Spain. (URx), for 4 weeks or a glycerol-based emollient cream, Dexeryl † †Dexeryl is a registered trade name of Pierre Fabre Dermatologie. (DC), in a right-vs.-left study design. Primary outcome was a 5-point SRRC Index score (evaluating scaling roughness, redness and cracks) evaluated at baseline and after 2 and 4 weeks of treatment. As secondary endpoints patients evaluated also the global efficacy (GE) and global tolerability (GT) scores with the help of a 10 cm visual analogue scale (0 = no efficacy at all/very bad tolerability; 10: excellent efficacy/excellent tolerability). Results At baseline the mean (SD) SRRC score was 9.5 (1.9) in the URx treated sites and 9.5 (1.9) in the DC treated sites. A total of 27 patients (90%) concluded the study period. Three patients were withdrawn prematurely because of itching and burning sensation after DC application (1 patient) or URx application (2 patients). At week 4, in comparison with baseline values, both treatments were shown to be clinically effective: SRRC significantly (p = 0.0001) decreased to 3.3 (1.8) after URx (a 65% relative reduction) and to 5.7 (2.5) after DC (a 40% relative reduction). SRRC was significantly lower in URx treated regions in comparison with DC both after 2 and 4 weeks of treatment (p = 0.0005). Mean GE score in areas treated with URx was significantly (p = 0.0001) higher than in the areas treated with the DC (8.9 vs.7.3). Both treatments were in general well tolerated. GT score was 8.1 (range 10 to 3) with URx and 8.4 (range 10 to 3) with DC application (p = ns). The two main limitations of this trial are the study design (single blind), and the small sample size which is not adequate for an evaluation of safety. Conclusion Ureadin Rx 10 lotion has shown a greater efficacy on ichthyosis vulgaris in term of reduction of scaling, roughness, redness and cracking in comparison with a glycerol-based emollient cream. Tolerability of the two topical treatments was comparable. Further studies with larger sample sizes are needed for the evaluation of safety and tolerability of urea 10% lotion in this clinical setting.

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 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.

Ectodermal dysplasias (ED) are a group of clinically and genetically heterogeneous conditions commonly characterized by abnormal development of at least two structures derived from the embryonal ectoderm (hair, teeth, nails, and sweat glands). X-linked hypohidrotic ED, which is caused by mutations in the gene EDA (MIM 305100), is the most frequent form. In this study, we investigated the phenotype of 40 male patients, aged 2 to 20 years, who all showed developmental defects of ectodermal derivatives and a mutation in EDA. Specialist assessments of the involved organ systems were performed. 95% of these patients presented with impairment of sweating, which was only moderate in 35%, while two subjects did not show any alteration of sweat gland function. Severe oligodontia was found in 80% of the subjects, 10% had hypodontia. 90% of the patients showed abnormal crown morphology of the teeth. Severe involvement of the scalp hair was observed in 22% of the patients, moderate involvement in 72%, and no relevant alterations of hair morphology, quantity or growth in 2 patients. Onychodystrophy was seen in 67% of our patients. Concerning minor alterations of ectodermal tissues, we found dry eye signs in 92% of the subjects investigated, recurrent respiratory infections in 82%, hearing loss in 10%, atopic dermatitis in 35%, and a neuropsychological disorder in 10%. Our study shows that an EDA mutation can be present in males also in the context of only one of the major clinical signs of X-linked ED, but associated with minor alterations. Therefore we suggest that EDA gene analysis should be considered also for males with a mild ED phenotype.

X-linked reticulate pigmentary disorder (XLPDR) is a rare, multi-systemic disease with only a limited number of families described in the literature. XLPDR has a genetic origin and the gene has been mapped to Zp22p21. Dental features resemble those of hypohidrotic ectodermal dysplasia. A case of a 3-years-old boy is described.

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.