FATP4 – Ichthyosis Prematurity Syndrome

Ichthyosis prematurity syndrome (IPS) is an autosomal recessive disorder marked by premature birth, neonatal asphyxia, and a thick, vernix caseosa–like scaling that evolves into non-scaly ichthyosis with atopic features. Affected infants often present between 30 and 34 weeks of gestation with respiratory distress necessitating mechanical support. Lifelong dermatologic manifestations include hyperkeratosis, pruritus, and atopic diathesis, reflecting a primary defect in epidermal barrier formation.

The disease gene was first identified in 2009 when biallelic mutations in SLC27A4 (encoding FATP4) were found in multiple IPS probands; patient fibroblasts exhibited reduced very long-chain fatty acid (VLCFA)–CoA synthetase activity and impaired VLCFA incorporation into lipids (PMID:19631310). In a Norwegian cohort, 23 patients from 17 families demonstrated consistent prenatal polyhydramnios and neonatal asphyxia, with ultrastructural skin abnormalities confirming the diagnosis (PMID:21856041).

Subsequent reports have expanded the mutational spectrum: a recurrent homozygous c.1430T>A (p.Val477Asp) founder mutation was identified in siblings from distinct populations (PMID:24889544), and novel compound heterozygous missense alleles (c.1208G>A (p.Cys403Tyr) and c.1529G>A (p.Arg510His)) were reported in a Japanese patient (PMID:27081519).

Across published cohorts, at least 16 distinct pathogenic alleles—including missense, splice-site, frameshift, and nonsense variants—have been identified in over 30 mutant alleles, underscoring allelic heterogeneity. The recurrent p.Val477Asp substitution and population-specific splice variants support targeted molecular diagnostics. Representative variant: c.1430T>A (p.Val477Asp).

Functional studies corroborate a loss-of-function mechanism: patient fibroblasts show markedly reduced VLCFA-CoA synthetase activity and lipid incorporation, and Fatp4 knockout mice recapitulate skin barrier defects and perinatal lethality (PMID:19631310). Protein–protein interaction assays reveal that FATP4 cooperates with ichthyin (NIPAL4) in epidermal lipid processing, and loss of FATP4 disrupts this complex (PMID:23290633).

No conflicting reports have disputed the SLC27A4–IPS association. The breadth of genetic and experimental evidence over 15 years, including multiple unrelated families, functional concordance, and animal models, fulfills criteria for a definitive gene–disease relationship.

Key Take-home: Autosomal recessive FATP4 deficiency causes IPS via impaired VLCFA metabolism and disrupted epidermal barrier function, supporting targeted genetic testing to guide perinatal management and long-term dermatologic care.

References

• American journal of human genetics • 2009 • Mutations in the fatty acid transport protein 4 gene cause the ichthyosis prematurity syndrome. PMID:19631310
• Journal of the American Academy of Dermatology • 2012 • Ichthyosis prematurity syndrome: clinical evaluation of 17 families with a rare disorder of lipid metabolism. PMID:21856041
• Pediatric dermatology • 2014 • Ichthyosis prematurity syndrome: a case report and review of known mutations. PMID:24889544
• Human genome variation • 2015 • Identification of novel FATP4 mutations in a Japanese patient with ichthyosis prematurity syndrome. PMID:27081519
• BMC research notes • 2011 • FATP4 missense and nonsense mutations cause similar features in Ichthyosis Prematurity Syndrome. PMID:21450060
• Journal of dermatological science • 2013 • Interactions between FATP4 and ichthyin in epidermal lipid processing may provide clues to the pathogenesis of autosomal recessive congenital ichthyosis. PMID:23290633

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