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