|Dr. Jouni Uitto|
Harlequin ichthyosis is a devastating congenital skin condition, which often leads to death of the newborn shortly after birth. Harlequin ichthyosis is also known as "harlequin fetus" because the affected children, in most cases, are born prematurely. The infants are encased in a thick skin described as a "coat of armor," that severely restricts their movement. As this thick skin dries out, it forms hard diamond-shaped plaques, which severely affect the facial features, distorting the lips, eyelids, and ears. In general, newborns with Harlequin ichthyosis die within a few days of birth because of respiratory distress, bacterial infections, and feeding difficulties. However, as a result of improved neonatal intensive care, some of the affected individuals survive and the skin comes to resemble severe non-bullous congenital ichthyosiform erythroderma, i.e., red and scaly skin without blisters.
The molecular basis of Harlequin ichthyosis was not known until very recently. Two groups have now been able to demonstrate mutations in the ABCA12 gene in patients with this disorder. First, a group of scientists at the Centre for Cutaneous Research in London set out to identify and map minute variations in the DNA sequences in families with affected and unaffected children with Harlequin ichthyosis. Evaluation of these families placed the probable site of the gene to the long arm of chromosome 2. Microsatellite markers narrowed the focus to the location of 6 identifiable genes. Within this relatively small region on the chromosome, the gene ABCA12 was considered as a candidate gene, for the following reasons. First, a characteristic feature of the cells of the epidermis in Harlequin ichthyosis is abnormality in the way that lipids are transported and discharged into the top layers of the skin, together with abnormal lamellar granules.
Definitions of terms, in order of appearance
Plaques - patches or flat areas.
Respiratory distress - trouble breathing.
Molecular basis - genetic defect.
DNA sequences - the order of nucleotides, the building blocks of DNA, in a gene.
Microsatellite - a segment of DNA with variable sequence that can be sequenced to follow the inheritance of a copy of a gene.
Epidermis - the outermost layer of skin.
Transmembrane transporter - a protein that carries substances across cell membranes.
Expression - the outward appearance of a person's disease as a result of a genetic defect.
Sequencing - reading the order of nucleotides in DNA.
Allele - a copy of the gene, one inherited from the mother and the other one from the father.
Keratinization - the normal conversion of keratin, the protein that makes up hair, skin, and nails to resilient layers.
Chorionic villus sampling - a doctor obtains a piece of the placenta, which contains the same genetic materials as the baby, for testing of mutations.
Preimplantation genetic diagnosis - embryos are created outside the body by in vitro fertilization and genetic testing is performed on the embryos. Only the embryos that did not inherit the mutation are transferred to the woman's womb to create a pregnancy.
What are the translational consequences of finding the gene harboring mutations in Harlequin ichthyosis? In other words, is there something that benefits the patients and their families? An immediate benefit is the possibility of DNA-based prenatal diagnosis, which has not been possible without the knowledge of the mutated gene. Considering the severity of Harlequin ichthyosis, which frequently has a lethal outcome during the early newborn period, there has been a demand for prenatal testing in families at risk for recurrence of the disease. In the past, prenatal diagnosis has relied on fetal skin biopsy that is performed late during the second trimester of pregnancy. It is predictable that in Harlequin ichthyosis, as has been the case in many other severe skin diseases, DNA-based prenatal testing will replace the fetal skin biopsy in short order. Such testing can be performed as early as the tenth week of gestation by chorionic villus sampling, or perhaps even earlier by non-invasive analysis of the fetal cells and DNA in maternal circulation. Finally, knowledge of precise mutations in these devastating diseases forms the basis for the application of preimplantation genetic diagnosis.
Dr. Uitto is the Chair of the Department of Dermatology and Cutaneous Biology and the Director of the Jefferson Institute of Molecular Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA.
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