Gianluca Tadini

Mutations in ABCA12 underlie the severe congenital skin disease harlequin ichthyosis

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.

Genetic and Clinical Mosaicism in a Type of Epidermal Nevus

BACKGROUND Many skin disorders are characterized by a mosaic pattern, often with alternating stripes of affected and unaffected skin that follow the lines of Blaschko. These nonrandom patterns may be caused by a postzygotic mutation during embryogenesis. We studied the genetic basis of one such disorder, epidermal nevus of the epidermolytic hyperkeratotic type. Epidermolytic hyperkeratosis is an autosomal dominant blistering skin disease arising from mutations in the genes for keratin (K) 1 and 10. The offspring of patients with epidermal nevi may have generalized epidermolytic hyperkeratosis. METHODS We studied the K1 and K10 genes in blood and in the keratinocytes and fibroblasts of lesional and nonlesional skin from three patients with epidermal nevi and four of their offspring with epidermolytic hyperkeratosis. RESULTS In the patients with epidermal nevi, point mutations in 50 percent of the K10 alleles of epidermal cells were found in keratinocytes from lesional skin; no mutations were detected in normal skin. This mutation was absent or underrepresented in blood and skin fibroblasts. In the offspring with epidermolytic hyperkeratosis, the same mutations as those in the parents were found in 50 percent of the K10 alleles from all cell types examined. CONCLUSIONS Epidermal nevus of the epidermolytic hyperkeratotic type is a mosaic genetic disorder of suprabasal keratin. The correlation of mutations in the K10 gene with lesional skin and the correlation of the normal gene with normal skin provide evidence that genetic mosaicism can cause clinical mosaicism.

Deficiency of PORCN, a regulator of Wnt signaling, is associated with focal dermal hypoplasia

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.

Mutant p63 causes defective expansion of ectodermal progenitor cells and impaired FGF signalling in AEC syndrome.

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.

Encephalocraniocutaneous lipomatosis. Case report and review of the literature

Abstract: Encephalocraniocutaneous Hpomatosis is a congenital disorder characterized by unilateral cerebral malformations and ipsilateral scalp, face, and eye lesions. Distinguishing histopathologic features are dysgenesis and neoplasia of the adipose tissue. A Caucasian boy had soft tumors and elastic papules on his head since birth, associated with atrophic areas, and a bllobed lesion on the upper right eyelid. On the bulbar conjunctiva of the right eye, an oval 6‐mm lesion was present. Ultrasonogram, computerized tomographic scan, and magnetic resonance imaging revealed a dilation of the right lateral ventriculus, a mass on the pontocerebellar angle, agenesia of the corpus callosum, an arachnoldal cyst on the right hemisphere, microcalcifications, and pachygyria. The histology of a soft cutaneous tumor was consistent with a fibrollpoma, and dispersed extracellular lipid globules in the upper dermis were found on electron microscopy. The diagnosis suggested by these findings was encephalocraniocutaneous lipomatosis. Even in view of the rarity of the syndrome (11 cases described in the literature), this patient seems unusual because of the bilateral distribution of the cutaneous lesions and because of the agenesia of the corpus callosum. The peculiar ultrastructural findings require further confirmation.

Rapp-Hodgkin syndrome and AEC syndrome: are they the same entity?

Summary Rapp‐Hodgkin syndrome and AEC syndrome are two disorders in which ectodermal dysplasia and clefting are associated. Rapp‐Hodgkin syndrome is an autosomal dominant condition characterized by cleft lip and palate, peculiar craniofacial features, and ectodermal dysplasia, consisting of abnormalities of teeth, hair, nails and sweating. AEC syndrome manifests the same defects plus ankyloblepharon and a higher frequency of scalp dermatitis. A child affected by ectodermal dysplasia associated with clefting, ankyloblepharon, severe scalp dermatitis, and the characteristic Rapp– Hodgkin fades is reported. The overlap between Rapp–Hodgkin syndrome and AEC syndrome is discussed. Critical review of both disorders suggests that AEC syndrome and Rapp–Hodgkin syndrome represent the same entity.

Porokeratotic eccrine nevus may be caused by somatic connexin26 mutations.

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.

Is it time to change the neurofibromatosis 1 diagnostic criteria

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 diseases 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.

Multicentre consensus recommendations for skin care in inherited epidermolysis bullosa

BackgroundInherited 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.MethodsAlmost 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.ResultsRecommendations 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.ConclusionThe 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.

PITYRIASIS ROTUNDA : REPORT OF A FAMILIAL OCCURRENCE AND REVIEW OF THE LITERATURE

Pityriasis rotunda is an uncommon dermatosis characterized by multiple, widely distributed, strikingly circular hypopigmented or hyperpigmented patches that are slightly scaly. It has been described in Oriental and black patients, usually in association with certain infective or malignant systemic diseases. Pityriasis rotunda is rare in white patients and does not act as a marker of malignancy. Our ultrastructural and histologic findings demonstrated that pityriasis rotunda is more closely related to congenital ichthyoses than ichthyosis vulgaris, contrary to previous reports. On the basis of our studies and a review of the literature, it seems that two types of pityriasis rotunda exist with significant prognostic differences.