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

Abstract

Background: Severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome is a recently recognized syndrome caused by mutations in the desmoglein 1 gene (DSG1). To date, only 3 families have been reported.

Objective: We studied a new case of SAM syndrome known to have no mutations in DSG1 to detail the clinical, histopathologic, immunofluorescent, and ultrastructural phenotype and to identify the underlying molecular mechanisms in this rare genodermatosis.

Methods: Histopathologic, electron microscopy, and immunofluorescent studies were performed. Whole-exome sequencing data were interrogated for mutations in desmosomal and other skin structural genes, followed by Sanger sequencing of candidate genes in the patient and his parents.

Results: No mutations were identified in DSG1; however, a novel de novo heterozygous missense c.1757A>C mutation in the desmoplakin gene (DSP) was identified in the patient, predicting the amino acid substitution p.His586Pro in the desmoplakin polypeptide.

Conclusions: SAM syndrome can be caused by mutations in both DSG1 and DSP. Knowledge of this genetic heterogeneity is important for both analysis of patients and genetic counseling of families. This condition and these observations reinforce the importance of heritable skin barrier defects, in this case desmosomal proteins, in the pathogenesis of atopic disease.

Keywords: Atopy; atopic dermatitis; atopic sensitization; desmoplakin; desmosome; eosinophilic esophagitis; skin barrier.

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.

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.

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.

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.

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).

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.