BG12: Cicatricial junctional epidermolysis bullosa: a forgotten subtype

Extract

Manrup Hunjan,¹ Dario Balacco,² David Wen,^3,4 Ajoy Bardhan,^1,5 Natasha Harper¹ and Adrian Hegearty^1,6

¹National Adult Epidermolysis Bullosa Service, University Hospitals Birmingham NHS Trust, Birmingham, UK;  ²School of Dentistry, Institute of Clinical Science, and  ⁶Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK;  ³University of Oxford, Oxford, UK;  ⁴Royal Berkshire Hospital NHS Foundation Trust, Reading, UK; and  ⁵Dermatology Research Group, Institute of Clinical Sciences, College of Medical & Dental Sciences, University of Birmingham, Birmingham, UK

Cicatricial junctional epidermolysis bullosa (CJEB) is a rare subtype of epidermolysis bullosa (EB) first described in 1985. Patients with this subtype of EB develop blistering with scarring that can result in pseudosyndactyly and scarring alopecia. Consequently, they phenotypically resemble localized recessive dystrophic EB (RDEB) and can be misdiagnosed before a skin biopsy demonstrating a split at the level of the lamina lucida, confirming junctional EB (JEB). We report a case of a 34‐year‐old Pakistani woman who presented with blistering from birth. Initially, she was thought to have a form of RDEB; however, subsequent DNA sequencing revealed a homozygous in‐frame deletion of exons 16 and 17 in the gene encoding type XVII collagen (COL17A), confirming a diagnosis of JEB. Clinically, the patient resembled the first described cases of CJEB. Our patient had evidence of scarring, development of subsequent pseudosyndactyly and contractures of her hands and feet, as well as scarring alopecia and a history of laryngeal involvement. Features of RDEB such as pseudosyndactyly are not usually seen in JEB and therefore we employed bioinformatic approaches to investigate the difference in phenotype at a protein level. TMHMM software was used to carry out protein functional analyses and domain prediction. These revealed that our patient’s mutation resulted in a truncated type XVII collagen protein lacking the transmembrane domain. As a result, the extracellular domain (ECD) of type XVII collagen is unable to extend from the lamina lucida into the lamina densa and establish protein–protein interactions important for skin integrity. In fact, COL17–ECD interacts with integrin α6, laminin 332 and collagen IV, which connects the hemidesmosome to collagen VII. Biallelic mutations in COL7A1 give rise to RDEB. Although we discuss preliminary results from a single patient, we hypothesize that the loss of the type XVII collagen transmembrane domain dramatically attenuates (indirect) interaction with collagen VII, resulting in phenotypic manifestations typically associated with type VII collagen deficiency as seen in RDEB. The fundamental role of the transmembrane domain in ensuring skin integrity is highlighted by way of comparison to patients with JEB with differing COL17A1 mutations in which the transmembrane domain is predicted to be preserved, and in whom a partial recapitulation of the RDEB phenotype is not seen. This case brings to light a forgotten subtype of JEB and critically highlights the power of combining bioinformatic, molecular and deep phenotyping approaches for improved rare disease genotype–phenotype correlation to inform development of effective therapeutic strategies.