Eli Sprecher

Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sorèze 2009

BACKGROUNDnInherited 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.nnnOBJECTIVEnWe sought to establish a consensus for the nomenclature and classification of inherited ichthyoses.nnnMETHODSnThe 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 Sorèze, France, on January 23 and 24, 2009, where subcommittees on different issues proposed terminology that was debated until consensus was reached.nnnRESULTSnIt 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.nnnLIMITATIONSnAs more becomes known about these diseases in the future, modifications will be needed.nnnCONCLUSIONnWe 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.

Desmoglein-1/Erbin interaction suppresses ERK activation to support epidermal differentiation

Genetic disorders of the Ras/MAPK pathway, termed RASopathies, produce numerous abnormalities, including cutaneous keratodermas. The desmosomal cadherin, desmoglein-1 (DSG1), promotes keratinocyte differentiation by attenuating MAPK/ERK signaling and is linked to striate palmoplantar keratoderma (SPPK). This raises the possibility that cutaneous defects associated with SPPK and RASopathies share certain molecular faults. To identify intermediates responsible for executing the inhibition of ERK by DSG1, we conducted a yeast 2-hybrid screen. The screen revealed that Erbin (also known as ERBB2IP), a known ERK regulator, binds DSG1. Erbin silencing disrupted keratinocyte differentiation in culture, mimicking aspects of DSG1 deficiency. Furthermore, ERK inhibition and the induction of differentiation markers by DSG1 required both Erbin and DSG1 domains that participate in binding Erbin. Erbin blocks ERK signaling by interacting with and disrupting Ras-Raf scaffolds mediated by SHOC2, a protein genetically linked to the RASopathy, Noonan-like syndrome with loose anagen hair (NS/LAH). DSG1 overexpression enhanced this inhibitory function, increasing Erbin-SHOC2 interactions and decreasing Ras-SHOC2 interactions. Conversely, analysis of epidermis from DSG1-deficient patients with SPPK demonstrated increased Ras-SHOC2 colocalization and decreased Erbin-SHOC2 colocalization, offering a possible explanation for the observed epidermal defects. These findings suggest a mechanism by which DSG1 and Erbin cooperate to repress MAPK signaling and promote keratinocyte differentiation.

Definitions and outcome measures for mucous membrane pemphigoid: Recommendations of an international panel of experts

Mucous membrane pemphigoid encompasses a group of autoimmune bullous diseases with a similar phenotype characterized by subepithelial blisters, erosions, and scarring of mucous membranes, skin, or both. Although knowledge about autoimmune bullous disease is increasing, there is often a lack of clear definitions of disease, outcome measures, and therapeutic end points. With clearer definitions and outcome measures, it is possible to directly compare the results and data from various studies using meta-analyses. This consensus statement provides accurate and reproducible definitions for disease extent, activity, outcome measures, end points, and therapeutic response for mucous membrane pemphigoid and proposes a disease extent score, the Mucous Membrane Pemphigoid Disease Area Index.

Severe dermatitis, multiple allergies, and metabolic wasting syndrome caused by a novel mutation in the N-terminal plakin domain of desmoplakin

Background Severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome is a recently recognized syndrome caused by mutations in the desmoglein 1 gene (DSG1). To date, only 3 families have been reported. Objective We studied a new case of SAM syndrome known to have no mutations in DSG1 to detail the clinical, histopathologic, immunofluorescent, and ultrastructural phenotype and to identify the underlying molecular mechanisms in this rare genodermatosis. Methods Histopathologic, electron microscopy, and immunofluorescent studies were performed. Whole-exome sequencing data were interrogated for mutations in desmosomal and other skin structural genes, followed by Sanger sequencing of candidate genes in the patient and his parents. Results No mutations were identified in DSG1; however, a novel de novo heterozygous missense c.1757A>C mutation in the desmoplakin gene (DSP) was identified in the patient, predicting the amino acid substitution p.His586Pro in the desmoplakin polypeptide. Conclusions SAM syndrome can be caused by mutations in both DSG1 and DSP. Knowledge of this genetic heterogeneity is important for both analysis of patients and genetic counseling of families. This condition and these observations reinforce the importance of heritable skin barrier defects, in this case desmosomal proteins, in the pathogenesis of atopic disease.

CEDNIK syndrome results from loss-of-function mutations in SNAP29.

Backgroundu2002 CEDNIK (cerebral dysgenesis, neuropathy, ichthyosis and keratoderma) syndrome is a rare genodermatosis which was shown 5u2003years ago in one family to be associated with a loss‐of‐function mutation in SNAP29, encoding a member of the SNARE family of proteins. Decrease in SNAP29 expression was found to result in abnormal lamellar granule maturation leading to aberrant epidermal differentiation and ichthyosis.

Defective Lamellar Granule Secretion in Arthrogryposis, Renal Dysfunction, and Cholestasis Syndrome Caused by a Mutation in VPS33B

BACKGROUNDnArthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome is a rare and usually fatal metabolic autosomal recessive disorder, which has recently been shown to result from mutations in VPS33B located on chromosome 15q26.1. Neurological signs and ichthyosis almost invariably accompany the disease.nnnOBSERVATIONSnWe assessed a consanguineous family with 2 identical twins affected with ARC syndrome. Complete sequencing of the VPS33B gene revealed a homozygous missense mutation (D234H), which segregated with the disease in the affected family. The mutation causes aberrant splicing, resulting in the skipping of exon 9 or exons 9 and 10. VPS33B encodes a homologue of the class C yeast vacuolar protein-sorting molecule, Vps33, which regulates soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein-mediated vesicle-to-target fusion, necessary for secretion to occur. Lamellar granules, forming a specialized vesicular system in the epidermal upper layers, are usually secreted at the boundary between granular and lower cornified cell layers. However, ultrastructural examination of the skin in ARC syndrome revealed many entombed lamellar granules in the cornified cells.nnnCONCLUSIONSnThe present observations indicate that VPS33B deficiency results in abnormal secretion of lamellar granules, which underlies ichthyosis in ARC syndrome. These data underscore the importance of SNARE-mediated vesicle fusion during normal epidermal differentiation.

Epidermolysis Bullosa Simplex

The prevalence of epidermolysis bullosa simplex (EBS) is estimated to be approximately 6 to 30 per 1 million live births. The disease is usually caused by missense mutations in KRT5 and KRT14, encoding keratins mostly expressed in the epidermal basal layer. Major advances in understanding of the molecular basis of EBS and other keratin disorders have led to the development of DNA-based prenatal testing.

In Vitro Analysis of LIPH Mutations Causing Hypotrichosis Simplex: Evidence Confirming the Role of Lipase H and Lysophosphatidic Acid in Hair Growth

Hypotrichosis simplex (HS) is a group of isolated alopecias that can be inherited as an autosomal-dominant or an autosomal-recessive trait. Hair loss usually begins in early childhood, and is diffuse and progressive. Mutations in LIPH, which encodes lipase member H, have recently been shown to cause an autosomal-recessive form of HS. Here we describe an Austrian HS patient who was found to be carrying compound heterozygous mutations in the LIPH gene: a 7-bp frameshift duplication (c.403_409dup; p.Gln137HisfsX1) and a recently reported 30-amino acid in-frame duplication (c.280_369dup; p.Gly94_Lys123dup). To examine the impact of LIPH mutations on lipid metabolism, we established an in vitro assay to measure the action of this phospholipase in a cell-based system. Both the 7-bp duplication frameshift mutation and all known in-frame mutations were observed to reduce the in vitro activity of the lipase in response to the addition of phosphatidic acid, the substrate of lipase H. The reduced production of lysophosphatidic acid (LPA) led to a reduced response of cells expressing the human G-protein-coupled receptor p2y5 (p2y5) receptor. Our study increases the spectrum of known LIPH mutations and provides biochemical evidence for the important role of lipase H and its product LPA in human hair growth.

Molecular basis of hypotrichosis with juvenile macular dystrophy in two siblings

Backgroundu2002 Hypotrichosis with juvenile macular dystrophy (HJMD) is a rare autosomal recessive disorder characterized by sparse and short scalp hair from birth, followed within a few years by progressive macular degeneration leading to blindness. HJMD was shown to result from mutations in CDH3 encoding P‐cadherin.

Disadhesion of epidermal keratinocytes: A histologic clue to palmoplantar keratodermas caused by DSG1 mutations

BACKGROUNDnRecent developments in molecular genetics may lead to re-examination of the histopathology of inherited palmoplantar keratodermas (PPKs) based on more precise groupings of the various entities and syndromes.nnnOBJECTIVEnWe sought to characterize the histopathological findings in PPKs associated with mutations in DSG1, which encodes desmoglein 1.nnnMETHODSnWe studied the histopathology of 3 cases of keratosis palmoplantaris striata type I and one case of diffuse PPK, all associated with autosomal-dominant mutations in DSG1. Our cases for comparison included 4 cases with Mal de Meleda PPK associated with autosomal-recessive SLURP1 mutations, one case with pachyonychia congenita type II PPK associated with an autosomal-dominant KRT17 mutation, and one case with focal PPK associated with an autosomal-dominant KRT16 mutation.nnnRESULTSnThe distinguishing histopathological features of the 3 keratosis palmoplantaris striata type I cases and the diffuse PPK case associated with DSG1 mutation were: varying degrees of widening of the intercellular spaces and partial disadhesion of keratinocytes in the mid and upper epidermal spinous cell layers, often extending to the granular cell layer. These findings, which are associated with haploinsufficiency of desmoglein 1, were not observed in any of the other 6 PPK cases. Mild perinuclear eosinophilic condensations and cytoplasmic vacuolizations were observed in the spinous cell layer keratinocytes of the pachyonychia congenita type II PPK and the nonspecified focal PPK cases.nnnLIMITATIONSnThere were a limited number of patients and control patients with hereditary PPKs.nnnCONCLUSIONnWidening of the intercellular spaces and disadhesion of epidermal keratinocytes may serve as a histologic clue to PPKs caused by DSG1 mutations.