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Brief Report |

Association of Epidermolysis Bullosa Simplex With Mottled Pigmentation and EXPH5 Mutations ONLINE FIRST

Iana Turcan, MD1; Anna M. G. Pasmooij, PhD1; Peter C. Van den Akker, MD, PhD1,2; Henny Lemmink, PhD2; Richard J. Sinke, PhD2; Marcel F. Jonkman, MD, PhD1
[+] Author Affiliations
1Center for Blistering Diseases, Department of Dermatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
2Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
JAMA Dermatol. Published online July 06, 2016. doi:10.1001/jamadermatol.2016.2268
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Importance  Epidermolysis bullosa simplex (EBS) is a group of clinically and genetically diverse mechanobullous genodermatoses characterized by the fragility of skin and mucous membranes. Recently, mutations in EXPH5 encoding exophilin-5 (also known as Slac2-b, an effector protein involved in intracellular vesicle trafficking and exosome secretion) have been implicated in the pathophysiology of EBS. Herein, we report a novel homozygous nonsense mutation in EXPH5 responsible for an EBS subtype with mottled pigmentation.

Objective  To identify the gene mutation(s) accountable for the mottled pigmentation phenotype in a patient with suspected inherited skin fragility disorder.

Design, Setting, and Participant  Data for this case report were acquired in an outpatient clinic and concern a referral from the primary care physician to the national Center for Blistering Diseases in The Netherlands. Data were acquired and analyzed from 2014 to 2016.

Main Outcomes and Measures  Clinical examination and investigation were performed of the molecular basis of patient’s skin fragility and mottled pigmentation phenotype. Electron microscopy studies described the underlying abnormalities on an ultrastructural level.

Results  The clinical phenotype is characterized by mild generalized skin fragility, trauma-induced skin blistering since infancy, and development of remarkable diffuse mottled pigmentation on the trunk and proximal extremities. Sequencing the complete set of genes associated with epidermolysis bullosa revealed a homozygous nonsense mutation in exon 6 of EXPH5: c.3917C>G, p.Ser1306*. Electron microscopy revealed disruption of keratin filament cytoskeleton and accumulation of melanosomes in a disordered distribution in the keratinocytes.

Conclusions and Relevance  To our knowledge, the current study illustrates the first clinically well-documented, mottled pigmentation phenotype related to a novel EXPH5 mutation. In addition, by means of electron microscopy image analysis, it proposes a hypothesis for the pigmentary changes in this rare autosomal recessive EBS subtype. These findings expand the genetic and phenotypic spectrum of human inherited skin fragility disorders, and we propose the addition of EBS resulting from EXPH5 mutations to the EBS-mottled pigmentation subtype.

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Figure 1.
Mutation Analysis and Family Pedigree of a Patient With Epidermolysis Bullosa Simplex–Auto-recessive (EBS-AR) Resulting From EXPH5 Mutations

A, Schematic illustration of exophilin-5 protein and location of all EXPH5 mutations disclosed to date (dark blue) and mutation reported in current study (red). Homozygous mutations are depicted in large arrowheads, whereas the compound heterozygous are shown in small arrowheads (modified from McGrath et al2). B, Clinical pedigree of the index patient. DNA analysis was performed in individuals lll:6, lll:7, and IV:3; m/wt, mutation/wild-type, or wt/wt, wild-type/wild-type, respectively, underlines the genotype of the particular individual. C, Sequencing of genomic DNA from individual IV:3 identified a homozygous mutation in EXPH5 in exon 6. A cytosine at position 3917 is substituted by a guanine (c.3917C>G). This substitution leads to a nonsense mutation (p.Ser1306*). D, Immunofluorescence study with monoclonal antibody LL001 reveals keratin 14 in a blister (asterisk) in a lesional skin biopsy.

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Figure 2.
Clinical Features

A and B, Mottled pigmentation on the trunk and axillary area, respectively. C, Trauma-induced hemorrhagic scale-crusts on the ankle (white arrowhead). D, Dermatoscopy of positive ballpoint rub test reveals skin fragility on application of mechanical stress. Ruler is in millimeters.

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Figure 3.
Transmission Electron Microscopy Studies

A, Electron microscopy at low magnification shows basal keratinocytes that exhibit a “clear” aspect with an obvious deficiency in keratin filaments or aggregation of keratin filaments (black arrowhead). Some suprabasal keratinocytes show retraction of keratin filaments from the nuclear envelope creating a “perinuclear halo” (white arrowhead). B, Higher magnification depicts loss of desmosomes and cellular architecture of basal keratinocytes; note intracellular vesicles (white arrowhead). C, Striking pliability of the cell membrane containing an aggregation of desmosomes. D, Melanosomes (blue arrowhead) and mitochondria (black arrowhead) accumulate in a basal cell with clumping of keratin (green arrowhead); note the extracellular vesicle (red arrowhead).

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