ALOX12B – Self-healing Collodion Baby

Autosomal recessive congenital ichthyosis (ARCI) encompasses a spectrum of keratinization disorders presenting at birth, including the self-healing collodion baby (SICI) subtype. ALOX12B encodes the epidermal 12R-lipoxygenase (12R-LOX), which acts in sequence with ALOXE3 to generate lipid mediators essential for epidermal barrier formation. In SICI, biallelic ALOX12B variants lead to a transient collodion membrane that resolves spontaneously within weeks, distinguishing it from more severe lifelong ichthyoses. Genetic confirmation of ALOX12B involvement in SICI supports its role in a milder ARCI phenotype.

Genetic evidence for ALOX12B in SICI comes from two key cohorts. In a Scandinavian series of 15 patients, 8 carried biallelic ALOX12B variants, segregating in unrelated families with autosomal recessive inheritance ([PMID:19890349]). A prospective ARCI cohort (n=78) identified 16 genetically confirmed SICI patients, of whom 6 harbored ALOX12B mutations ([PMID:34908195]). These 14 probands across distinct populations provide strong support for the gene-disease link.

The variant spectrum in SICI includes missense, nonsense, and splice-site changes in ALOX12B. A representative pathogenic change is c.200T>A (p.Ile67Asn), observed in multiple affected individuals ([PMID:19890349]). No recurrent founder alleles have been reported, and carrier frequencies remain low across populations. Phenotypic hallmarks—brachydactyly (HP:0001156) and ear helix kinking—are enriched in ALOX12B-mutant SICI cases.

Functional studies demonstrate that ALOX12B loss of function underlies SICI. In vitro assays of mutant 12R-LOX expressed in E. coli and mammalian cells show abrogated dioxygenase activity, halting production of 12R-HPETE and downstream hepoxilins ([PMID:15629692]). In a mouse model, an ethylnitrosourea-induced Alox12b nonsense mutation disrupts epidermal permeability barrier formation, recapitulating human ichthyosis features and supporting a haploinsufficiency mechanism ([PMID:17429434]).

No conflicting reports dispute the association of ALOX12B LoF with the self-healing phenotype; all evidence aligns on autosomal recessive inheritance and concordant functional impairment. While additional variants in ARCI genes (ALOXE3, TGM1, CYP4F22, PNPLA1) contribute to SICI, ALOX12B remains a leading cause in multiple cohorts.

Integration of genetic and experimental data confirms a strong gene-disease association. Clinical testing for ALOX12B variants in neonates with a collodion membrane can facilitate early diagnosis, genetic counseling, and tailored monitoring for transient ichthyosis features. Key Take-home: ALOX12B loss-of-function causes autosomal recessive self-healing collodion baby, guiding precision diagnostics and patient management.

References

• 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
• 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
• 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 • 2007 • A mouse mutation in the 12R-lipoxygenase, Alox12b, disrupts formation of the epidermal permeability barrier. PMID:17429434

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