Inflammatory Peeling Skin Syndrome Caused by a Mutation in CDSN Encoding Corneodesmosin

TO THE EDITOR Peeling skin syndrome (PSS) refers to a heterogeneous group of disorders characterized by superficial detachment of the epidermal corneal layers (Hacham-Zadeh and Holubar, 1985Hacham-Zadeh S. Holubar K. Skin peeling syndrome in a Kurdish family.Arch Dermatol. 1985; 121: 545-546Crossref PubMed Scopus (21) Google Scholar). Two major forms of PSS have been recognized: acral PSS (MIM609796), caused by mutations in TGM5, encoding transglutaminase 5 (Cassidy et al., 2005Cassidy A.J. van Steensel M.A. Steijlen P.M. et al.A homozygous missense mutation in TGM5 abolishes epidermal transglutaminase 5 activity and causes acral peeling skin syndrome.Am J Hum Genet. 2005; 77: 909-917Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar; Kharfi et al., 2009Kharfi M. El Fekih N. Ammar D. et al.A missense mutation in TGM5 causes acral peeling skin syndrome in a Tunisian family.J Invest Dermatol. 2009; 129: 2512-2515Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar), and generalized PSS (MIM270300), which has been subclassified into a noninflammatory type (type A PSS), the etiology of which remains unknown, and an inflammatory type (type B), which was recently shown to be associated in a large family with a recessive mutation in CDSN, encoding corneodesmosin (Oji et al., 2010Oji V. Eckl K.M. Aufenvenne K. et al.Loss of corneodesmosin leads to severe skin barrier defect, pruritus, and atopy: unraveling the peeling skin disease.Am J Hum Genet. 2010; 87: 274-281Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar). In the present study, we report the second mutation in CDSN underlying type B PSS. A 32-year-old man was referred for investigation because of a congenital pruritic and generalized rash. The patient was of Jewish origin, and his parents were first-degree cousins. A younger sister displayed similar dermatological findings (Figure 1a). The patient said that 3 days after his birth, widespread reddish, peeling skin areas had appeared over his legs, arms, and trunk, along with redness and edema of the face. The rash has been present ever since, with rare periods of mild improvement, mainly in the spring (Figure 1b and c). From the age of 10, his nails have been thick and yellowish. Complete blood cell count and blood chemistry were within normal ranges, but IgE levels were markedly elevated (30,375IUml-1; N=0–100). Fungal cultures from nail scrapings were negative. Hair microscopy revealed normal hair shaft structures. A skin biopsy showed mild hyperkeratosis, parakeratosis, intracorneal and subcorneal separation, hypergranulosis, and acanthosis. In the dermis, a perivascular mononuclear infiltrate and scattered eosinophils were seen (Figure 1d). The patient provided written and informed consent according to a protocol approved by the local Helsinki Committee and by the Committee for Genetic Studies of the Israeli Ministry of Health. DNA was extracted from peripheral blood leukocytes using the salt/chloroform extraction method. Biological materials were unavailable from the patient's family members. Genomic DNA was PCR-amplified using primer pairs spanning the entire coding sequence as well as intron–exon boundaries of the CDSN gene as described elsewhere (Oji et al., 2010Oji V. Eckl K.M. Aufenvenne K. et al.Loss of corneodesmosin leads to severe skin barrier defect, pruritus, and atopy: unraveling the peeling skin disease.Am J Hum Genet. 2010; 87: 274-281Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar). A homozygous single-nucleotide deletion was identified in exon 2 at nucleotide position 743 (accession number NC_000000.11) (Figure 1e). The mutation, termed c.746delG, is predicted to lead to frame shift and to generate a premature stop codon 40bp downstream of the deletion (p.G249VfsX40). The mutation can be predicted to result either in the synthesis of a truncated corneodesmosin protein or in messenger RNA transcript decay. We confirmed the presence of the mutation in the patient's DNA sequence using a PCR–restriction fragment length polymorphism assay, whereby a 183-bp-long DNA fragment was amplified using mutation-specific forward primer 5′-CCCCTACATCCCCAGCTCCCACTCTGTGAC-3′ and reverse primer 5′-ACCTCGTAGCCACCATAGGA-3′ (Figure 1f). Mutation c.746delG abolishes a recognition site for DNA endonucleases AhdI. We also used this allele-specific PCR–restriction fragment length polymorphism assay to exclude the presence of the mutation in a panel of 50 population-matched control subjects. Superficial intraepidermal detachment has been described in a number of inherited disorders, including ichthyosis bullosa of Siemens (Rothnagel et al., 1994Rothnagel J.A. Traupe H. Wojcik S. et al.Mutations in the rod domain of keratin 2e in patients with ichthyosis bullosa of Siemens.Nat Genet. 1994; 7: 485-490Crossref PubMed Scopus (124) Google Scholar), epidermolysis bullosa simplex superficialis (Fine et al., 1989Fine J.D. Johnson L. Wright T. Epidermolysis bullosa simplex superficialis. A new variant of epidermolysis bullosa characterized by subcorneal skin cleavage mimicking peeling skin syndrome.Arch Dermatol. 1989; 125: 633-638Crossref PubMed Scopus (37) Google Scholar), Netherton syndrome (Geyer et al., 2005Geyer A.S. Ratajczak P. Pol-Rodriguez M. et al.Netherton syndrome with extensive skin peeling and failure to thrive due to a homozygous frameshift mutation in SPINK5.Dermatology. 2005; 210: 308-314Crossref PubMed Scopus (17) Google Scholar), and PSS. Recently, a mutation in CDSN, encoding corneodesmosin, was found to segregate with PSS type B (Oji et al., 2010Oji V. Eckl K.M. Aufenvenne K. et al.Loss of corneodesmosin leads to severe skin barrier defect, pruritus, and atopy: unraveling the peeling skin disease.Am J Hum Genet. 2010; 87: 274-281Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar) in a large Roma family. In the present study, we report the second pathogenic mutation in CDSN, thus confirming the causative role of these mutations in the pathogenesis of inflammatory PSS. CDSN codes for corneodesmosin, a secreted glycoprotein that is a component of the modified desmosomal plaques in the uppermost layers of the epidermis. Corneodesmosin molecules have been shown to interact through their glycine loop domains in a homophilic fashion to mediate adhesive interactions between corneocytes (Jonca et al., 2002Jonca N. Guerrin M. Hadjiolova K. et al.Corneodesmosin, a component of epidermal corneocyte desmosomes, displays homophilic adhesive properties.J Biol Chem. 2002; 277: 5024-5029Crossref PubMed Scopus (84) Google Scholar). Corneodesmosin has also been shown to be expressed in the inner root sheath of hair follicles (Gallinaro et al., 2004Gallinaro H. Jonca N. Langbein L. et al.A 4.2kb upstream region of the human corneodesmosin gene directs site-specific expression in hair follicles and hyperkeratotic epidermis of transgenic mice.J Invest Dermatol. 2004; 122: 730-738Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar). CDSN mutations have previously been associated with autosomal dominant hypotrichosis simplex (MIM146520) (Levy-Nissenbaum et al., 2003Levy-Nissenbaum E. Betz R.C. Frydman M. et al.Hypotrichosis simplex of the scalp is associated with nonsense mutations in CDSN encoding corneodesmosin.Nat Genet. 2003; 34: 151-153Crossref PubMed Scopus (133) Google Scholar). In this disease the mutant corneodesmosin was found to exert a toxic effect on hair follicles via the formation of amyloidosis deposits (Caubet et al., 2010Caubet C. Bousset L. Clemmensen O. et al.A new amyloidosis caused by fibrillar aggregates of mutated corneodesmosin.FASEB J. 2010; 24: 3416-3426Crossref PubMed Scopus (21) Google Scholar). Polymorphisms in the CDSN gene have also been found in association with psoriasis (Tazi Ahnini et al., 1999Tazi Ahnini R. Camp N.J. Cork M.J. et al.Novel genetic association between the corneodesmosin (MHC S) gene and susceptibility to psoriasis.Hum Mol Genet. 1999; 8: 1135-1140Crossref PubMed Scopus (116) Google Scholar). More recently, ablation of CDSN in mice was found to result in lethal epidermal permeability disruption (Matsumoto et al., 2008Matsumoto M. Zhou Y. Matsuo S. et al.Targeted deletion of the murine corneodesmosin gene delineates its essential role in skin and hair physiology.Proc Natl Acad Sci USA. 2008; 105: 6720-6724Crossref PubMed Scopus (42) Google Scholar; Leclerc et al., 2009Leclerc E.A. Huchenq A. Mattiuzzo N.R. et al.Corneodesmosin gene ablation induces lethal skin-barrier disruption and hair-follicle degeneration related to desmosome dysfunction.J Cell Sci. 2009; 122: 2699-2709Crossref PubMed Scopus (64) Google Scholar), in line with similar data obtained with ablation of another component of the epidermal barrier, filaggrin (Fallon et al., 2009Fallon P.G. Sasaki T. Sandilands A. et al.A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming.Nat Genet. 2009; 41: 602-608Crossref PubMed Scopus (350) Google Scholar). In the present study, we confirm the association between the PSS type B phenotype and deleterious mutations in CDSN. Interestingly, our patient was initially diagnosed with Netherton syndrome, a recessive disorder caused by loss-of-function mutations in SPINK5 (Chavanas et al., 2000Chavanas S. Bodemer C. Rochat A. et al.Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome.Nat Genet. 2000; 25: 141-142Crossref PubMed Scopus (657) Google Scholar). SPINK5 encodes a serine protease inhibitor, called LEKTI, in the absence of which corneodesmosin undergoes premature degradation in the upper layers of the stratum corneum (Yang et al., 2004Yang T. Liang D. Koch P.J. et al.Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5-/- mice.Genes Dev. 2004; 18: 2354-2358Crossref PubMed Scopus (88) Google Scholar). Additional elements are likely to have an important role in the interactions between structural proteins in the cornified layers of the epidermis and proteases and their inhibitors, as supported by the existence of patients displaying clinical features suggestive of PSS type B/Netherton syndrome but without mutations in CDSN or SPINK5 (our unpublished data). Altogether, these recent data seem to demarcate a group of disorders featuring excessive/aberrant desquamation due to increased proteolytic activity and/or decreased expression of adhesive proteins in the upper epidermal layers. We thank the patient for his participation in this study and Tslil Ophir for expert assistance in DNA sequencing.