title: Homozygous ALOXE3 Nonsense Variant Identified in a Patient with Non-Bullous Congenital Ichthyosiform Erythroderma Complicated by Superimposed Bullous Majocchi's Granuloma: The Consequences of Skin Barrier Dysfunction.
abstract: Non-bullous congenital ichthyosiform erythroderma (NBCIE) is a hereditary disorder of keratinization caused by pathogenic variants in genes encoding enzymes important to lipid processing and terminal keratinocyte differentiation. Impaired function of these enzymes can cause pathologic epidermal scaling, significantly reduced skin barrier function. In this study, we have performed a focused, genetic analysis of a probrand affected by NBCIE and extended this to his consanguineous parents. Targeted capture and next-generation sequencing was performed on NBCIE associated genes in the proband and his unaffected consanguineous parents. We identified a homozygous nonsense variant c.814C>T (p.Arg272*) in ALOXE3 (NM_001165960.1) in the proband and discovered that his parents are both heterozygous carriers of the variant. The clinical manifestations of the proband's skin were consistent with NBCIE, and detailed histopathological assessment revealed epidermal bulla formation and Majocchi's granuloma. Infection with Trichophyton rubrum was confirmed by culture. The patient responded to oral terbinafine antifungal treatment. Decreased skin barrier function, such as that caused by hereditary disorders of keratinization, can increase the risk of severe cutaneous fungal infections and the formation of Majocchi's granuloma and associated alopecia. Patients with NBCIE should be alerted to the possible predisposition for developing dermatophytoses and warrant close clinical follow-up.
authors.affiliation: Department of Dermatology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100730, China. tombearwt@126.com.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Dermatology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100730, China. xuchenchen86@163.com.
authors.forename: Chenchen
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Dermatology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100730, China. xiping_zhou@126.com.
authors.forename: Xiping
authors.initials: X
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China. jiajialiapple66@163.com.
authors.forename: Chunjia
authors.initials: C
authors.lastname: Li
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China. hbzhang@ibms.pumc.edu.cn.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Medicine, University of Massachusetts, Worcester, MA 01655, USA. Bill.lian@umassmemorial.org.
authors.forename: Bill Q
authors.initials: BQ
authors.lastname: Lian
authors.affiliation: Department of Pathology, Brigham & Women's Hospital, Harvard Medical School, 221 Longwood Ave. EBRC 401, Boston, MA 02115, USA. jonathan_lee@hms.harvard.edu.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Department of Pathology, Brigham & Women's Hospital, Harvard Medical School, 221 Longwood Ave. EBRC 401, Boston, MA 02115, USA. Jshen5@partners.org.
authors.forename: Jun
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Dermatology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100730, China. yuehualiu@263.net.
authors.forename: Yuehua
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pathology, Brigham & Women's Hospital, Harvard Medical School, 221 Longwood Ave. EBRC 401, Boston, MA 02115, USA. cglian@bwh.harvard.edu.
authors.forename: Christine Guo
authors.initials: CG
authors.lastname: Lian
mesh_terms: D001706:Biopsy; D002648:Child; D018389:Codon, Nonsense; D003241:Consanguinity; D004252:DNA Mutational Analysis; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D017490:Ichthyosis, Lamellar / Q000150:complications / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics*; D008084:Lipoxygenase / Q000235:genetics*; D008297:Male; D009281:Naphthalenes / Q000008:administration & dosage / Q000627:therapeutic use; D010375:Pedigree; D010641:Phenotype; D012867:Skin / Q000378:metabolism / Q000473:pathology; D000077291:Terbinafine; D016896:Treatment Outcome
chemical_list: D018389:Codon, Nonsense; D009281:Naphthalenes; C511051:ALOXE3 protein, human; D008084:Lipoxygenase; D000077291:Terbinafine
keywords: Whole Exon Sequencing (WES); arachidonatelipoxygenase 3 (ALOXE3); autosomal recessive congenital ichthyosis (ARCI); non-bullous  congenital ichthyosiformerythroderma (NBCIE); peroxisome proliferator-activated receptor α (PPARα)