Alternative titles; symbols
SNOMEDCT: 763401009; ORPHA: 88621; MONDO: 0012089;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 9q34.11 | Ichthyosis prematurity syndrome | 608649 | Autosomal recessive | 3 | SLC27A4 | 604194 |
A number sign (#) is used with this entry because of evidence that ichthyosis prematurity syndrome (IPS) is caused by homozygous or compound heterozygous mutation in the SLC27A4 gene (604194) on chromosome 9q34.
Ichthyosis prematurity syndrome (IPS) is a rare subtype of autosomal recessive congenital ichthyosis, a clinically and genetically heterogeneous group of inherited keratinization disorders. IPS presents with complications at midtrimester 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).
Khnykin et al. (2012) performed a detailed investigation of 23 Norwegian patients from 17 families with IPS. IPS was characterized prenatally by ultrasound findings of polyhydramnios, separation of the chorioamniotic membranes, echogenic amniotic fluid, and clear chorionic fluid. All patients were born prematurely between 29 and 35 weeks' gestation with sometimes life-threatening neonatal asphyxia requiring prolonged hospitalization in the neonatal intensive care unit. Two patients died within 24 hours of delivery. Autopsy examination of both patients revealed large keratin masses filling the bronchial tree and alveoli. The skin at birth appeared erythrodermic, swollen, and covered with a greasy, thick vernix caseosa-like scale. The skin rapidly improved to a mild, chronic pruritic ichthyosis. Skin biopsy demonstrated hyperkeratosis, acanthosis, dermal inflammation, and characteristic aggregates of curved lamellar structure in the upper epidermis. Other notable features include eosinophilia, increased serum immunoglobulin E levels, and a history of respiratory allergy and/or food allergy.
Tsuge et al. (2015) described the first Japanese patient with IPS. She was born at 32 weeks' gestation via spontaneous vaginal delivery. Apgar scores were 2 and 4 at 1 and 5 minutes, necessitating intubation and ventilation. The patient was covered in a thick layer of white, vernix caseosa-like material. The entire body, including the face, had thickening and scaling of the skin. After discharge, her skin improved into a mild flexural dermatitis with generalized ichthyosis. Subsequent evaluation at age 14 years showed skin thickening of the forehead, trunk, and limbs as well as fine desquamation and mild hyperpigmentation. She had eosinophilia (2,068 /microliter), elevated serum IgE (18,000 IU/ml), and multiple sensitivities to respiratory and food allergens.
Esperon-Moldes et al. (2019) described 2 Spanish sisters (patients 1 and 2) with IPS, born to nonconsanguineous parents at 32 and 31 weeks' gestation, respectively. The older sister, patient 1, developed bronchopneumonia and atelectasis at birth requiring mechanical ventilation. The younger sister, patient 2, presented with a dry scalp impregnated with excessive vernix caseosa and large scales on her head, eyebrows, and body. In adulthood, both were noted to have generalized mild scaly skin with follicular hyperkeratosis and skin hyperpigmentation. Patient 1 had blood eosinophilia and sweating abnormalities.
The transmission pattern of IPS in the families reported by Klar et al. (2009) was consistent with autosomal recessive inheritance.
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).
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.
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.
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.
In an affected 14-year old Japanese girl with IPS, Tsuge et al. (2015) detected compound heterozygosity for 2 novel missense mutations (C403Y, 604194.0008 and R510H, 604194.0009) in the SLC27A4 gene using next-generation sequencing analysis.
Esperon-Moldes et al. (2019) identified compound heterozygosity in 2 Spanish sisters with IPS. A frameshift mutation, c.1322dup (604194.0010), was inherited from the father, and an intronic variant, c.988-19A-G (604194.0011), predicted to alter splicing, was inherited from the mother.
Anton-Lamprecht, I. The skin. In: Papadimitriou, J. M.; Henderson, D. W.; Spagnolo, D. V. (eds.): Diagnostic Ultrastructure of Non-neoplastic Diseases. Edinburgh: Churchill Livingstone 1992. Pp. 459-550.
Brusasco, A., Gelmetti, C., Tadini, G., Caputo, R. Ichthyosis congenita type IV: a new case resembling diffuse cutaneous mastocytosis. Brit. J. Derm. 136: 377-379, 1997. [PubMed: 9115920]
Esperon-Moldes, U. S., Ginarte, M., Santamarina, M., Rodriguez-Lage, B., Rodriguez-Pazos, L., Vega, A. Novel compound heterozygous FATP4 mutations caused ichthyosis prematurity syndrome in Spanish sisters. Acta Paediat. 108: 763-765, 2019. [PubMed: 30536735] [Full Text: https://doi.org/10.1111/apa.14694]
Khnykin, D., Ronnevig, J., Johnsson, M., Sitek, J. C., Blaas, H.-G. K., Hausser, I., Johansen, F.-E., Jahnsen, F. L. Ichthyosis prematurity syndrome: clinical evaluation of 17 families with a rare disorder of lipid metabolism. J. Am. Acad. Derm. 66: 606-616, 2012. [PubMed: 21856041] [Full Text: https://doi.org/10.1016/j.jaad.2011.04.014]
Klar, J., Gedde-Dahl, Jr., T., Larsson, M., Pigg, M., Carlsson, B., Tentler, D., Vahlquist, A., Dahl, N. Assignment of the locus for ichthyosis prematurity syndrome to chromosome 9q33.3-34.13. (Letter) J. Med. Genet. 41: 208-212, 2004. [PubMed: 14985385] [Full Text: https://doi.org/10.1136/jmg.2003.012567]
Klar, J., Schweiger, M., Zimmerman, R., Zechner, R., Li, H., Torma, H., Vahlquist, A., Bouadjar, B., Dahl. N., Fischer, J. Mutations in the fatty acid transport protein 4 gene cause the ichthyosis prematurity syndrome. Am. J. Hum. Genet. 85: 248-253, 2009. [PubMed: 19631310] [Full Text: https://doi.org/10.1016/j.ajhg.2009.06.021]
Melin, M., Klar, J., Gedde-Dahl, T., Jr., Fredriksson, R., Hausser, I., Brandrup, F., Bygum, A., Vahlquist, A., Hellstrom Pigg, M., Dahl. N. a founder mutation for ichthyosis prematurity syndrome restricted to 76 kb by haplotype association. J. Hum. Genet. 51: 864-871, 2006. [PubMed: 16946994] [Full Text: https://doi.org/10.1007/s10038-006-0035-z]
Niemi, K.-M., Kuokkanen, K., Kanerva, L., Ignatius, J. Recessive ichthyosis congenita type IV. Am. J. Dermatopath. 15: 224-228, 1993. [PubMed: 7685984] [Full Text: https://doi.org/10.1097/00000372-199306000-00005]
Tsuge, I., Morishita, M., Kato, T., Tsutsumi, M., Inagaki, H., Mori, Y., Yamawaki, K., Inuo, C., Ieda, K., Ohye, T., Hayakawa, A., Kurahashi, H. Identification of novel FATP4 mutations in a Japanese patient with ichthyosis prematurity syndrome. Hum. Genome Var. 2: 15003, 2015. [PubMed: 27081519] [Full Text: https://doi.org/10.1038/hgv.2015.3]