Dermatology: Practical and Conceptual Research Letter | Dermatol Pract Concept. 2025;15(3):5331 1 Three Novel Mutations in ALOX12B Gene in Patients with Autosomal Recessive Congenital Ichthyosis from Turkey Özge Zorlu1, Semih Aşıkovalı2 1 Tekirdağ Namık Kemal University Medical Faculty, Dermatology and Venereology Department, Tekirdağ, Turkey 2 Tekirdağ Namık Kemal University Medical Faculty, Department of Medical Genetics, Tekirdağ, Turkey Key words: ALOX12B mutations, Autosomal recessive ichthyosis, Turkey, collodion ichthyosis, ALOX12B gene Citation: Zorlu Ö, Aşıkovalı S. Three Novel Mutations in ALOX12B Gene in Patients with Autosomal Recessive Congenital Ichthyosis from Turkey. Dermatol Pract Concept. 2025;15(3):5331. DOI: https://doi.org/10.5826/dpc.1503a5331 Accepted: March 21, 2025; Published: July 2025 Copyright: ©2025 Zorlu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: None. Authorship: All authors have contributed significantly to this publication. Corresponding Author: Özge Zorlu, MD, Tekirdağ Namık Kemal University, Medical Faculty, Dermatology Department Tekirdağ, Turkey. ORCID ID: 0000-0001-5555-130X. E-mail: zorluzg@gmail.com Introduction ALOX12B mutations are usually associated with milder phenotypes of autosomal recessive congenital ichthyosis (ARCI), including minimal erythema, fine scaling, or self- improving collodion ichthyosis (SICI) [1-3]. We report three novel ALOX12B mutations in unrelated patients with ARCI. The genetic analysis was performed using the NextSeq500 (Illumina Inc., San Diego, CA, USA) instrument. All vari- ants identified in index cases were confirmed by Sanger sequencing. Case Presentation Patient 1, a 1-day-old girl from a nonconsanguineous family, had collodion membrane (CM), ectropion, and eclabium at birth. No systemic or organ abnormality was revealed, except low-set ears and conductive hearing loss (CHL) on the left side. Her family history was unremarkable. An ALOX12B mutation (c.1533-2A>G) was revealed (Table 1). After three months, the CM completely regressed, exposing xerotic skin. After three years, the child has xerotic skin, slight erythema, and scaling on her scalp without developmental delay. She is using only emollients. Patient 2, a 40-year-old female from a consanguine- ous family, had had diffuse dusky erythema and ichthyotic scaling throughout the entire body since birth, without any seasonal change, ectropion, eclabium, palmoplantar kerato- derma, or alopecia (Figures 1A and 1B). The history of CM is unknown. Bilateral minimal CHL was present. She was oth- erwise healthy. No family history of ichthyosis was present. Genetic tests revealed an ALOX12B mutation (c.1808C>T) (Table 1). She has been continuing acitretin treatment, with a good response. Patient 3, a 1-day-old boy from first-degree consanguine- ous parents, had intrauterine growth retardation, CM, ectro- pion, eclabium, bilateral anteriorly overfolded ears, bilateral CHL, and left renal ectasia at birth (Figures 1C and 1D). 2 Research Letter | Dermatol Pract Concept. 2025;15(3):5331 Figure 1. (A, B) Clinical features of Patient 2. Diffuse, dusky erythema and ichthyotic scaling on the back and face. (C) Clinical features of Patient 3. Collodion membrane, ectropion, and eclabium at birth. (D) Anteriorly overfolded right ear at birth. Table 1. Mutations Identified in ALOX12B. Patient no Mutation Zygosity Consequence on Protein Site Domain ACMG [6] 1 c.1533-2A>G - Homozygous Splicing Intron 11 LPG Likely pathogenic 2 c.1808C>T p.Pro603Leu Homozygous Missense Exon 14 LPG Likely pathogenic 3 c.695C>T p.Ser232Leu Homozygous Missense Exon 6 LPG Variant of uncertain significance Abbreviations: LPG: lipoxygenase domain; ACMG: American College of Medical Genetics and Genomics. Research Letter | Dermatol Pract Concept. 2025;15(3):5331 3 He was otherwise healthy. His family history was unre- markable. An ALOX12B mutation (c.695C>T) was present (Table 1). After four weeks, the CM completely regressed, exposing xerotic skin. After almost three years, the child has xerotic skin, fine scaling with focal accentuation around the flexural regions, feet and ankles, neck, and armpits, slight palmar erythema, palmar hyperlinearity, Dennie-Morgan lines, attention deficit hyperreactivity disorder, and speech delay (Figure 2). He is otherwise healthy and continues to use emollients. ALOX12B mutations often lead to milder phenotypes of ARCI, yet variabilities in severity can occur [1,4]. Patients 1 and 3 have milder phenotypes compatible with SICI. How- ever, patient 2 still has more severe ichthyosiform lesions on the entire body, compatible with congenital ichthyosiform erythroderma, and needs systemic treatment. In patients with SICI, the skin is near normal follow- ing the shedding of the CM. Mild signs of ichthyosis, such as xerosis and fine scaling with focal accentuations, can be present in older ages [1,2,4]. As possible explana- tions for improvement of keratinization after birth, high intrauterine hydrostatic pressure, variants of mutations, epigenetic, and environmental factors were suggested [1,4,5]. Figure 2. Clinical features of Patient 3. Resolution of skin lesions at three years of age. (A) Den- nie-Morgan lines, fine scaling, and minimal erythema on the axillas. (B) Slight erythema with fine scaling around inguinal regions. (C) Fine scaling inside the ear and around the neck. Partially im- proved right ear that was anteriorly overfolded at birth. (D) Palmar hyperlinearity. An anteriorly overfolded ear was reported as associated with ALOX12B mutation and might be used as a clinical diagnostic marker [4]. We observed bilateral anteriorly over- folded ears in only Patient 3. Conclusion Due to the rarity of the disease and genetic heterogeneity, a detailed description of each case is crucial to establish an exact genotype-phenotype correlation. 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