Acta Dermato-Venereologica 99-9CompleteContent | Page 12

CLINICAL REPORT 789 Novel DSP Spectrin 6 Region Variant Causes Neonatal Erythroderma, Failure to Thrive, Severe Herpes Simplex Infections and Brain Lesions Svetlana VAKKILAINEN 1# , Laura PUHAKKA 1# , Paula KLEMETTI 1 , Kaarina HEISKANEN 1 , Mikko SEPPÄNEN 2 , Mikko MUONA 3,4 , Celine POSSEME 5 , Darragh DUFFY 5 , Timo VÄISÄNEN 6,7 , Outi ELOMAA 8 , Maarit PALOMÄKI 9 , Harri SAXÉN 1 , Annamari RANKI 10 and Katariina HANNULA-JOUPPI 8,10 New Children’s Hospital, University of Helsinki and Helsinki University Hospital, 2 Rare Disease Center, New Children’s Hospital, University of Helsinki and Helsinki University Hospital, 3 Blueprint Genetics, 4 Folkhälsan Research Center, Helsinki, Finland, 5 Immunobiology of Dendritic Cells, Inserm U1223, Institut Pasteur, Paris, France, 6 Department of Pathology, Cancer and Translational Medicine Research Unit, University of Oulu, 7 Department of Pathology, Oulu University Hospital, Oulu, 8 Stem Cells and Metabolism Research Program, University of Helsinki and Folkhälsan Research Center, 9 Department of Radiology, Helsinki Medical Imaging Center, Helsinki University Hospital, and 10 Department of Dermatology and Allergology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland # These authors contributed equally and should be considered as first authors. 1 Desmoplakin (DSP) and Desmoglein 1 (DSG1) variants result in skin barrier defects leading to erythroderma, palmoplantar keratoderma and variable other features. Some DSG1 variant carriers present with SAM syndro- me (Severe dermatitis, multiple Allergies, Metabolic wasting) and a SAM-like phenotype has been reported in 4 subjects with different heterozygous DSP variants. We report here a patient with a novel DSP spectrin re- gion (SR) 6 variant c.1756C>T, p.(His586Tyr), novel features of brain lesions and severe recurrent muco- cutaneous herpes simplex virus infections, with a fa- vourable response to ustekinumab. Through a review of reported cases of heterozygous variants in DSP SR6 (n  = 15) and homozygous or compound heterozygous variants in DSG1 (n  = 12) and SAM-like phenotype, we highlight phenotypic variability. Woolly hair, nail ab- normalities and cardiomyopathy characterize patients with DSP variants, while elevated immunoglobulin E and food allergies are frequent in patients with DSG1 variants. Clinicians should be aware of the diverse ma- nifestations of desmosomopathies. Key words: desmoglein; desmoplakin; metabolic wasting; SAM syndrome; severe dermatitis. Accepted Apr 29, 2019; E-published Apr 29, 2019 Acta Derm Venereol 2019; 99: 789–796. Corr: Svetlana Vakkilainen, New Children’s Hospital, University of Helsinki and Helsinki University Hospital, Stenbäckinkatu 9, FIN-00290 Helsinki, Finland. E-mail: [email protected] D esmoplakin and desmogleins form the integral parts of desmosomes, which are adhesive intercellular junctions crucial in tissues prone to mechanical stress (e.g. skin, heart, gastrointestinal mucosa) (1). Desmo­ somal proteins play a role in cell signalling and skin barrier function. Desmoglein 1 (DSG1) and Desmoplakin (DSP) encode critical components of desmosomes, and pathogenic variants in both genes have been implicated in inflam­ matory skin disorders. DSG1 variants have been reported recently in patients with designated SAM syndrome SIGNIFICANCE Desmoplakin (DSP) and Desmoglein 1 (DSG1) gene chan- ges result in skin barrier defects leading to widespread red scaly rash, skin thickening on the palms and soles and va- riable other features. We report here a patient with a no- vel DSP gene change, novel features of brain lesions and severe viral infections, and a favourable response to treat- ment with ustekinumab. Woolly hair, nail abnormalities and heart problems characterize patients with DSP gene chan- ges, while elevated serum IgE levels and food allergies are frequent in patients with DSG1 gene changes. Clinicians should be aware of the diverse consequences of DSP and DSG1 gene abnormalities. (Severe dermatitis, multiple Allergies and Metabolic wasting) with an extremely variable phenotype consis­ ting of severe erythrodermic dermatitis, failure to thrive (FTT), recurrent infections, metabolic wasting, multiple allergies, increased immunoglobulin (Ig) E levels and eosinophilia (2–7). Two patients with different heterozygous DSP vari­ ants were reported to have a SAM-like phenotype (8, 9). Autosomal dominant DSP variants within the same spectrin 6 (SR6) region also cause erythrokeratoderma and cardiomyopathy (10), and palmoplantar keratoderma (PPK) with woolly hair, cardiomyopathy and arrhythmias (11). Recently, 2 additional patients with heterozygous DSP SR6 variants have been reported to display SAM syndrome, together with ectodermal dysplasia and car­ diomyopathy (coined SAMEC syndrome) (12). The lack of epithelial barrier proteins commonly seems to lead to immunological dysregulation. Impaired epit­ helial barrier function enhances Th2 responses and leads to chronic activation of the immune system (13). DSG1 deficiency results in increased expression of various genes encoding cytokines involved in allergic manifes­ tations, such as IL5 and TNF (2). In SAMEC, DSG1 was linked to an inability to retain ERBB2-interacting protein (ERBIN) at the cell membrane, probably hampe­ ring NF-κB pathway inhibition and promoting epithelial This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2019 Acta Dermato-Venereologica. doi: 10.2340/00015555-3203 Acta Derm Venereol 2019; 99: 789–796