Ichthyosis Prematurity Syndrome

A number sign (#) is used with this entry because ichthyosis prematurity syndrome (IPS) is caused by mutation in the FATP4 (SLC27A4; 604194) gene.

Clinical Features

Autosomal recessive congenital ichthyosis is a clinically and genetically heterogeneous group of inherited keratinization disorders. The rare subtype ichthyosis prematurity syndrome presents with complications at mid-trimester of pregnancy leading to prematurity, a thick caseous and desquamating skin, respiratory complications, and persistent eosinophilia. Skin features evolve into a flat follicular hyperkeratosis with atopy (Klar et al., 2004).

Population Genetics

IPS has a high prevalence in a small geographic region in middle Norway and adjacent Sweden (see Anton-Lamprecht, 1992 and Klar et al., 2004). Cases have been reported in other ethnic groups (see, e.g., Niemi et al., 1993 and Brusasco et al., 1997).

Mapping

Klar et al. (2004) performed genomewide linkage analysis in 16 families with ichthyosis prematurity syndrome from Norway and Sweden. Thirteen families had 1 or 2 affected members or had pairs of sibs with at least 1 affected; 3 families had 1 affected single child. A maximum multipoint lod score of 3.73 at theta = 0.0 was obtained with the short tandem repeat D9S778. A 12-cM region was defined by haplotype analysis and recombinant events at D9S250 and D9S63. This region was further refined by allelic association to a 1-Mb region at chromosome 9q33.3-q34.13 with no indication of genetic heterogeneity. Haplotype analysis suggested the presence of 2 founder mutations.

In 28 affected and 22 healthy sibs from 22 unrelated Norwegian and Swedish families with ichthyosis prematurity syndrome, 13 of which had been previously studied by Klar et al. (2004), Melin et al. (2006) confirmed linkage to chromosome 9q33.3-q34.13 and refined the IPS haplotype to a 76-kb core region. Sequencing of DNA from 3 patients revealed no alterations in the exons or flanking intronic sequences of 4 candidate genes, TBC1D13 (616218), ENDOG (600440), C9ORF114, and CCBL1 (600547), and there were no significant differences in transcript levels between patients and controls for those genes. Based on the average length of the haplotype in IPS patients, the age of a founder mutation was calculated to be approximately 1,900 years.

Klar et al. (2009) performed a homozygosity scan on a consanguineous family of North African origin in which several individuals had ichthyosis prematurity syndrome. Affected family members were found to be homozygous for a 76-kb genomic region on chromosome 9p that coincided with the IPS locus in the Scandinavian families.

Pathogenesis

Klar et al. (2009) observed abnormal distribution of lipids between epidermal layers in ichthyosis prematurity syndrome that is consistent with the expression pattern of FATP4 in normal epidermis, and suggested a defect in lipid homeostasis and skin barrier formation in IPS. Klar et al. (2009) also demonstrated that FATP4 deficiency in human fibroblasts is associated with reduced VLCFA-CoA synthetase activity and a reduced incorporation of VLCFA into neutral and polar lipids.

Molecular Genetics

Klar et al. (2009) performed sequence analysis of the FATP4 gene in a North African family, a Middle Eastern family, and 18 families of Scandinavian origin segregating IPS. They identified 7 different mutations. All affected members of the Scandinavian families were homozygous or compound heterozygous for a nonsense mutation (C168X; 604194.0001), indicating a founder effect. A splice site mutation (604194.0002) and a missense mutation (604194.0007) were identified in homozygosity in affected members of the North African and the Middle Eastern families, respectively. None of the mutations were found in 120 healthy control individuals.