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532 SHORT COMMUNICATION Congenital Ichthyosis and Recurrent Eczema Associated with a Novel ALOXE3 Mutation Takuya TAKEICHI 1 , Yusuke OKUNO 2,3 , Chiyo SAITO 4 , Daiei KOJIMA 3 , Michihiro KONO 1 , Akimichi MORITA 4 , Kazumitsu SUGIURA 5 and Masashi AKIYAMA 1 * Departments of 1 Dermatology and 3 Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, 2 Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Departments of Dermatology, 4 Nagoya City University, Nagoya, and 5 Fujita Health University School of Medicine, Toyoake, Japan. *E-mail: [email protected] Accepted Oct 12, 2016; Epub ahead of print Oct 14, 2016 The arachidonate lipoxygenase 3 (ALOXE3) gene is a causative gene of lamellar ichthyosis, congenital ichthyo- siform erythroderma (CIE) and pleomorphic ichthyosis (PI, also called self-healing/self-improving collodion baby) (1, 2). Oxygenation of the linoleate moiety of ceramides catalysed by ALOXE3 constitutes an indis- pensable step in the covalent linkage of ω-hydroxyl ceramides to proteins of the cornified cell envelope and, subsequently, for the formation of the corneocyte lipid envelope. To date, 18 pathogenic mutations in ALOXE3 have been reported in autosomal recessive congenital ichthyoses (ARCI) (www.hgmd.cf.ac.uk, as of Human Gene Mutation Database professional 2016.6.27). They comprise 5 missense, 5 nonsense, 4 splice-site, 3 small deletion and 1 gross deletion mutations (Table SI 1 ) (1, 3–11). Recently, Hellström Pigg et al. (11) reported that 9 out of 132 (6.8%) ARCI patients in Scandinavia had causative mutations in ALOXE3. All forms of ARCI are associated with significantly im- paired skin barrier function, mostly due to the inability of mutated keratinocytes to produce and/or secrete the lipids required for formation of the corneocyte lipid envelope and the extracellular lipid layers in the stratum corneum. Impaired function of ALOXE3 can cause significantly defective skin barrier formation. Clinically, Wang et al. (9) reported that decreased skin barrier function in CIE caused by ALOXE3 mutation leads to cutaneous fungal in- fections. We describe here a previously unreported muta- https://www.medicaljournals.se/acta/content/abstract/10.2340/00015555-2549 1 tion in A LOXE3, p.Leu436Pro, in a Japanese female with CIE complicated with recurrent eczema and depression. CASE REPORT The proband is a 38-year-old Japanese woman, the first child born to first-cousin parents. She presented with generalized ery­ thema and ichthyosis from one week after birth. She often showed round, scaly, itchy erythema on the trunk and extremities. Physical examination revealed multiple erythemas with fine whitish scales on the extremities (Fig. 1 a and b). Recurrent fungal infections accompanied by slight pain were seen in her skin and nails. She had been diagnosed with depression and had been treated with oral duloxetine hydrochloride, etizolam and lithium carbonate. A skin biopsy specimen from the right forearm revealed mild acanthosis, mild hyperkeratosis and slight spongiosis in the epidermis (Fig. 1c). Mild lymphocytic infiltration was seen around the vessels in the upper dermis, suggesting overlapping of mild ichthyosis and chronic eczema. She was treated with a heparinoid-containing moisturizer and an oral anti-histamine, and the eruptions impro- ved gradually. Ethical approval was obtained and all research was performed in accordance with the principles of the Declaration of Helsinki. Genomic DNA from the patient’s peripheral blood leukocytes was used for whole-exome sequencing analysis, as described previously (12). Analysis of whole-exome sequencing data re- vealed the previously unreported homozygous missense mutation c.1307T>C (p.Leu436Pro) in ALOXE3, which was confirmed by Sanger sequencing (Fig. 1d). Her mother was shown to be a heterozygous carrier of this mutation (Fig. 1d). Paternal DNA was not available for analysis because the father had already died. The mutation has not been described in the Human Genetic Variation Database, which includes 1,208 exome-sequencing data sets of healthy Japanese controls, nor in the ExAC database, which includes 60,706 exome data (http://exac.broadinstitute.org/ as of 29/11/2015). T at nucleotide position 1,307 is the second Fig. 1. Clinical and histo­pathological features of the proband with congenital ichthyosiform erythroderma. (a, b) Multiple round erythemas with slight pigmentation and fine whitish scaling are seen on (a) the legs and (b) the right ankle. (c) Haematoxylin-eosin staining shows partial parakeratosis, moderate hyper­keratosis and mild spongiosis in the epidermis. Dermal lymphocytic infiltration is observed. Scale bar: 100 μm (original magnification × 200). (d) Sanger sequencing reveals a homozygous mutation of ALOXE3, c.1307T>C (p.Leu436Pro), GenBank NM_021628.2, in the affected patient, and a heterozygous change in her mother. doi: 10.2340/00015555-2549 Acta Derm Venereol 2017; 97: 532–533 This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2017 Acta Dermato-Venereologica.