ALOXE3 – Self-healing Collodion Baby

Self-healing collodion baby (SICB) is a rare autosomal recessive subtype of autosomal-recessive congenital ichthyosis characterized by a collodion membrane at birth followed by remarkable spontaneous improvement within weeks. The epidermal lipoxygenase eLOX3, encoded by ALOXE3, has been implicated in the terminal differentiation of keratinocytes. Genetic testing for Self-healing Collodion Baby should include ALOXE3 along with other ARCI genes.

Biallelic pathogenic variants in ALOXE3 have been reported in 8 of 16 genetically confirmed SICI patients (PMID:34908195) and in 3 of 15 Scandinavian SHCB patients (PMID:19890349), yielding at least 11 unrelated probands. All cases follow autosomal recessive inheritance without clear reports of multi-generation segregation.

The variant spectrum comprises loss-of-function alleles: nonsense (e.g., c.367C>T (p.Gln123Ter)), splice-site (c.784+1G>A), frameshift (c.1583del (p.Gly528fs)), and missense substitutions, reflecting complete loss of eLOX3 catalytic function.

Functional assays demonstrate that eLOX3 mutants abolish hydroperoxide isomerase activity essential for 12R-HPETE conversion (PMID:15629692). Aloxe3 knockout mice exhibit disrupted epidermal barrier formation and perinatal lethality, recapitulating human ichthyosis features (PMID:22832496).

No conflicting reports have emerged, and ALOXE3 deficiency consistently correlates with the self-healing phenotype. Modifiers such as co-occurring mutations in CYP4F22 or ALOX12B may influence severity.

In summary, ALOXE3 meets ClinGen criteria for a Strong gene–disease association, supported by Moderate genetic evidence from 11 probands and Moderate functional evidence from biochemical and animal models. Early diagnosis enables accurate prognosis, targeted genetic counseling, and carrier screening for families.

References

• Journal of the European Academy of Dermatology and Venereology • 2022 • Quality of life and clinical characteristics of self-improving congenital ichthyosis within the disease spectrum of autosomal-recessive congenital ichthyosis. PMID:34908195
• The Journal of investigative dermatology • 2010 • Genotypic and clinical spectrum of self-improving collodion ichthyosis: ALOX12B, ALOXE3, and TGM1 mutations in Scandinavian patients. PMID:19890349
• Biochimica et biophysica acta • 2005 • Mutations associated with a congenital form of ichthyosis (NCIE) inactivate the epidermal lipoxygenases 12R-LOX and eLOX3. PMID:15629692
• The Journal of investigative dermatology • 2013 • Aloxe3 knockout mice reveal a function of epidermal lipoxygenase-3 as hepoxilin synthase and its pivotal role in barrier formation. PMID:22832496

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