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

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Severe dermatitis, multiple allergies, and metabolic wasting syndrome caused by a novel mutation in the N-terminal plakin domain of desmoplakin Maeve A. McAleer, MB, MRCP, Elizabeth Pohler, PhD, Frances J.D. Smith, PhD, Neil J. Wilson, MSc, Christian Cole, PhD, Stuart MacGowan, PhD, Jennifer L. Koetsier, BS, Lisa M. Godsel, PhD, Robert M. Harmon, PhD, Robert Gruber, MD, Debra Crumrine, BS, Peter M. Elias, MD, Michael McDermott, FRCPath, Karina Butler, FRCPI, Annemarie Broderick, MRCPI, Ofer Sarig, PhD, Eli Sprecher, MD, PhD, Kathleen J. Green, PhD, W.H. Irwin McLean, PhD, DSc, FRS, FRSE, FMedSci, Alan D. Irvine, MD Journal of Allergy and Clinical Immunology Volume 136, Issue 5, Pages 1268-1276 (November 2015) DOI: 10.1016/j.jaci.2015.05.002 Copyright © 2015 The Authors Terms and Conditions

Fig 1 Clinical phenotype. A, Generalized erythroderma and ichthyosis when the patient was 6 months of age. Hypotrichosis and macrocephaly are also evident. B, Improvement in erythrodermic ichthyosis after treatment with acitretin. C, Plantar keratoderma. D, Erythema, scaling, and diffuse hypotrichosis of the scalp. E, Pustulosis on the abdomen during an episode of systemic sepsis. Journal of Allergy and Clinical Immunology 2015 136, 1268-1276DOI: (10.1016/j.jaci.2015.05.002) Copyright © 2015 The Authors Terms and Conditions

Fig 2 Histopathology. A, Skin showing irregular psoriasiform hyperplasia, hyperkeratosis and parakeratosis, and a mild superficial dermal inflammatory infiltrate. B, Skin showing a florid subcorneal pustular dermatosis superimposed on background changes similar to those in Fig 2, A, with irregular hyperplasia and marked hyperkeratosis and parakeratosis. C, Esophageal squamous mucosa showing separation and detachment of superficial squamous epithelial cells in the absence of any mucosal inflammatory process. Journal of Allergy and Clinical Immunology 2015 136, 1268-1276DOI: (10.1016/j.jaci.2015.05.002) Copyright © 2015 The Authors Terms and Conditions

Fig 3 Molecular genetics. A, Pedigree of the family in this study. The arrow indicates the proband. B, Sequence of the DSP exon 14 spanning codons 584 to 588. Both parents are wild-type for this region, and the proband has the heterozygous missense mutation c.1757A>C (indicated by the arrow), predicting the amino acid substitution p.His586Pro at the protein level. C, Primary structure of desmoplakin. Amino acid boundaries of the 3 major domains of the protein are indicated. The p.His586Pro mutation lies within the plakin domain in the N-terminal head of desmoplakin. Journal of Allergy and Clinical Immunology 2015 136, 1268-1276DOI: (10.1016/j.jaci.2015.05.002) Copyright © 2015 The Authors Terms and Conditions

Fig 4 Ultrastructural abnormalities. A, Abundant keratin filaments (asterisks) anchored to desmosomes (arrows) in the cytoplasm of a spinous cell in normal human epidermis. B, Note the scarcity of keratin filaments at the same level in the proband. C, Common desmosomal structure with normal inner dense plaque (arrowheads) in a human control sample. D, In contrast, a poorly formed inner dense plaque lacking evidence of keratin filament attachment was observed in the proband. Journal of Allergy and Clinical Immunology 2015 136, 1268-1276DOI: (10.1016/j.jaci.2015.05.002) Copyright © 2015 The Authors Terms and Conditions

Fig 5 Stratum corneum (SC) ultrastructural abnormalities. A, Mature lamellar bilayers (arrows) and normal postsecretory lipid processing in the upper portion of the stratum granulosum (SG)–SC interface in normal human skin. B and C, In addition to areas of processed lamellar bilayer arrays (arrows), the patient sample shows abnormal lamellar bilayer organization with disruption by nonlamellar domains (Fig 5, B, asterisks), delayed lipid processing, and incompletely processed lamellar material (Fig 5, C, arrows and asterisks, respectively). D, Normal lamellar body secretion with homogenous extracellular bilayers in a healthy human. E and F, Inhomogenous lamellar body secretion with foci of vesicular contents at the SG-SC interface and premature secretion in the stratum spinosum (SS) in the patient. G, Predominantly abnormal, ellipsis-shaped lamellar bodies with aberrant internal structures in the patient. H-J, Non–membrane-bound droplets throughout the SC, containing electron-dense material, possibly lipids (Fig 5, H). In contrast to the normal regular cornified envelope (double arrows) and corneocyte lipid envelope (Fig 5, I, arrowhead), note the thinning of the cornified envelope (double arrows) and absence of the corneocyte lipid envelop in the patient (Fig 5, J). Journal of Allergy and Clinical Immunology 2015 136, 1268-1276DOI: (10.1016/j.jaci.2015.05.002) Copyright © 2015 The Authors Terms and Conditions

Fig 6 Immunostaining. Paraffin-embedded sections of control biopsy material from patients and control subjects were stained for key desmosome components and interacting epidermal proteins (control epidermis: A, C, E, and G, left panels; proband: B, D, F, and H, right panels). Fig 6, A and B, Staining for desmoplakin (DSP; green). Note the reduction in staining in the proband's skin plus the accumulation of desmoplakin in the cytoplasm. Fig 6, C and D, Plakoglobin staining (PG; red) is weaker in the patient's skin and appears less intense at the cell borders. Fig 6, E and F, Desmoglein 1 expression (DSG1; green) is drastically reduced in the patient's epidermis. Fig 6, G and H, Staining for keratin 10 (K10), a major component of the intermediate filament cytoskeleton in suprabasal keratinocytes, which was greatly reduced in the proband. Nuclei were visualized with 4′,6-diamidino-2-phenylindole. The dashed line in each image indicates the location of the dermal-epidermal junction. Calibration bar = 20 μm. Journal of Allergy and Clinical Immunology 2015 136, 1268-1276DOI: (10.1016/j.jaci.2015.05.002) Copyright © 2015 The Authors Terms and Conditions