Beyond the Skin: Immunological Profiles and Infectious Complications in ALOX12B-associated Autosomal Recessive Congenital Ichthyosis

Asena Pinar Sefer¹Isa An²Necmiye Keser Ozturk³Leyla Baykal Selcuk⁴Oguz Salih Dincer⁵Mehdi Benamar⁶Feven Getachew⁶Klaus Schmitz-Abe⁶Pankaj B Agrawal⁷Feyza Bayram Catak³Baran Erman⁸Sevgi Bilgic Eltan³Elif Karakoc Aydiner³Ahmet Ozen³Talal A Chatila⁶Safa Baris^3*

• ¹Recep Tayyip Erdoğan University, Rize, Türkiye
• ²TC Saglik Bakanligi Sanliurfa Egitim ve Arastirma Hastanesi, Şanlıurfa, Türkiye
• ³Marmara Universitesi Tip Fakultesi, Istanbul, Türkiye
• ⁴Karadeniz Teknik Universitesi Tip Fakultesi, Trabzon, Türkiye
• ⁵Recep Tayyip Erdogan Universitesi Tip Fakultesi, Rize, Türkiye
• ⁶Harvard Medical School, Boston, United States
• ⁷University of Miami, Coral Gables, United States
• ⁸Hacettepe Universitesi Tip Fakultesi, Ankara, Türkiye

Abstract Background: Pathogenic variants in ALOX12B, a crucial enzyme involved in epidermal lipid processing, are among the most common causes of autosomal recessive congenital ichthyosis (ARCI). Although traditionally considered a cutaneous disorder, the systemic immunological implications of ALOX12B deficiency remain poorly understood. Objectives: We aimed to broaden the dermatologic and immunologic spectrum of ALOX12B-associated ARCI by characterizing the clinical, immunologic, and genetic features of six patients from three consanguineous families. Methods: This prospective study included six patients with ALOX12B-associated ARCI identified through whole-exome sequencing. Detailed dermatological evaluations, infection histories, immunoglobulin profiles, lymphocyte subset analyses, and vaccine response assessments were performed. Results: All patients exhibited early-onset generalized ichthyosis, ranging from delayed-onset lamellar ichthyosis to collodion membrane presentations accompanied by nonbullous erythroderma. Two distinct biallelic ALOX12B variants were identified: a novel p.Thr383Lys and the known p.Cys544Arg. Several patients demonstrated recurrent bacterial or fungal infections (n = 5), markedly elevated serum IgE levels (n = 4), and isolated abnormalities in vaccine responsiveness (n = 2). Lymphocyte counts and other immunoglobulin classes were generally preserved; however, decreased IgG levels were observed in one patient (P3.1). Intravenous immunoglobulin replacement therapy reduced the frequency of infections in patients (P1.1 vs P1.2). Conclusions: Our findings suggest that ALOX12B-related ARCI may involve secondary immune dysregulation, driven by chronic compromise of the epidermal barrier. An immunologic evaluation is warranted in selected cases, particularly those with a history of susceptibility to infections. Multidisciplinary care, encompassing dermatology, immunology, and genetics, is crucial for achieving optimal outcomes in ARCI.