Netherton syndrome showing a large clinical overlap with generalized inflammatory peeling skin syndrome

ARTICLE

ejd.2012.1720

Auteur(s) : Muhammad Farooq¹, Mazen Kurban^2,3,a, Ossama Abbas², Abdul-Ghani Kibbi², Atsushi Fujimoto¹, Hiroki Fujikawa¹, Yutaka Shimomura^1,a yshimo@med.niigata-u.ac.j

¹ Laboratory of Genetic Skin Diseases, Niigata University Medical School, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan

² Department of Dermatology,

³ Department of Biochemistry and molecular genetics, American University of Beirut, Beirut, Lebanon

^a These authors equally contributed to this work.

Netherton syndrome (NS; OMIM 256500) is a rare autosomal recessive disorder characterized by ichthyosiform erythroderma, atopic manifestation and the hair shaft anomaly called bamboo hair, also known as trichorrhexis invaginata. NS is caused by mutations in the SPINK5 gene located at chromosome 5q32, which encodes a serine protease inhibitor LEKTI (lymphoepithelial Kazal-type-related inhibitor) [1]. Disruption of LEKTI has been shown to result in upregulation of kallikrein-related peptidases, and excess desquamation due to premature proteolysis of several structural proteins, such as corneodesmosin (CDSN) [2]. CDSN is a major component of corneodesmosomes in the cornified layer of the epidermis, and recessively-inherited loss-of-function mutations in the CDSN gene have recently been reported to underlie generalized inflammatory peeling skin syndrome (GIPSS; OMIM 270300) [3]. In addition, heterozygous dominant-negative mutations in the CDSN gene are known to cause hypotrichosis simplex of the scalp (OMIM 146520) [4].

Here we present a 27-year old Lebanese male patient born of consanguineous healthy parents (figure 1A). Since birth, the patient has shown diffuse erythema with frequent desquamation (skin peeling) and pruritus on his whole body, without any relation to seasonal variations (figures 1B-C). He did not show increased risks of infections or nail anomalies. Although he has never suffered from allergic rhinitis, conjunctivitis or asthma, IgE and eosinophil levels were elevated, suggesting some atopic manifestations. He also showed a male pattern baldness-like hypotrichosis on the scalp, but fragility of the hair shaft was not so evident (figure 1D). In addition, premature graying of the hair was observed especially on his scalp hair and eyelashes (figures 1D-E), while none of the other family members had the symptom.

We initially diagnosed the patient as GIPSS. Under institutional approval and in adherence to the Declaration of Helsinki Principles, we isolated genomic DNA from blood samples of the family members, and performed mutation analysis of the CDSN gene. However, we did not find any mutation in the CDSN gene. Then, we considered the possibility of NS. Careful observation of the patient's hair shaft under light microscopy revealed a typical bamboo hair appearance (figure 1F). Based on this finding, we subsequently analyzed the SPINK5 gene of the patient following the method described previously [1]. Sequencing analysis identified a homozygous splice site mutation IVS23+1G>A in intron 23 of the patient‘s SPINK5 gene, whereas both parents were heterozygous for the mutation (figures 1G-I). This mutation was previously reported in families with NS, thus a recurrent mutation [5]. The mutation IVS23+1G>A has been demonstrated to result in an aberrant splicing and a premature termination codon (PTC) [5]. The aberrant transcripts with the PTC would most likely be degraded by nonsense-mediated mRNA decay, leading to no protein expression.

LEKT1 is strongly expressed in the granular layer of the epidermis, and is considered to play a crucial role in skin barrier functions through its inhibitory activities for several different proteases [2]. Furthermore, LEKTI is also expressed in the inner root sheath of the hair follicle [6] where CDSN is also predominantly expressed [4]. It is noteworthy that clinical features of our patient largely overlapped with those of GIPSS (figures 1B-C) and also partially with those of HSS (figure 1D), which further suggested the close relationship in function between LEKTI and CDSN, as well as the importance of both proteins in terminal differentiation of the epidermis and the hair follicle in humans.

Our patient showed premature graying of the hair, which is a relatively common feature among patients with NS (figures 1D-E). Our finding further supports the possibility that LEKTI may also be involved in the maintenance of melanocyte stem cells in the hair follicle.

Disclosure

Acknowledgments: We acknowledge the family members involved in this study. Financial support: This study was supported by the Special Coordination Funds for Promoting Science and Technology, the Ministry of Education, Culture, Sports, Science and Technology, Japan (to Y.S.). Conflicts of interest: none.

References

1. Chavanas S, Bodemer C, Rochat A, et al. Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome. Nat Genet 2000; 25: 141-2.

2. Yang T, Liang D, Koch PJ, et al. Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5-/- mice. Genes & Dev 2004; 18: 2354-8.

3. Oji V, Eckl KM, 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: 274-81.

4. Levy-Nissenbaum E, Betz RC, Frydman M, et al. Hypotrichosis simplex of the scalp is associated with nonsense mutations in CDSN encoding corneodesmosin. Nat Genet 2003; 34: 151-3.

5. Bitoun E, Chavanas S, Irvine AD, et al. Netherton syndrome: disease expression and spectrum of SPINK5 mutations in 21 families. J Invest Dermatol 2002; 18: 352-61.

6. Bitoun E, Micheloni A, Lamant L, et al. LEKTI proteolytic processing in human primary keratinocytes, tissue distribution and defective expression in Netherton syndrome. Hum Mol Genet 2003; 12: 2417-30.