The exact locus that causes Harlequin Icthyosis is disputed. The vast majority of individuals born with the disorder show a mutation on Chromosome 2 between positions 34 and 35, from base pair 215,621,772 to base pair 215,828,656 (1,2).
Characteristics of the Disease
Harlequin Ichthyosis is a rare autosomal recessive genetic disease that affects the skin. Most infants born with HI are born premature or with low birth weight. The disease affects an important structural component of the skin, a protein called Keratin. Keratin is a structural protein found in the hair, claws, skin, horns, and nails of mammals. In normal individuals keratin has an alpha-protein structure, called alpha-keratin. However, in those afflicted by HI, the structure of the keratin in the skin is a cross-beta- protein structure. This makes it more similar to the beta-keratin found in the shells, scales, feathers, beaks, and shells of birds and reptiles. As a result the skin of infants with HI is thick, hard, and waxy. The skin is tight, and so it splits, creating diamond shaped plaques that resemble the pattern of a Harlequin clowns garments. The plaques are separated by deep fissures. Also the ears tend to be underdeveloped, and the eyelids and lips show ectropion and eclabium or are severely turned out. The nose is also deformed, showing a flattened structure and reduced nostrils. The limps have restricted movement, as does the chest which can affect breathing. In addition to abnormalities in the structure of keratin, some studies have shown that individuals with HI overproduce Lamellar Granules, which aid in the formation of a water proof barrier in the skin. This creates an abnormal epidermal barrier, that prevents water from entering or leaving the skin as it should. Thus adding to the dryness and cracking of the skin.
Harlequin Ichthyosis is usually fatal, but a few individuals have survived to adolescence and adulthood. Those that survive struggle with protein malnutrition and maintaining moist flexible skin.
Treatment or Management of the Condition
In the first days of life the priority of treatment is respiration, which is usually assisted, and infection, which sets in do to the open fissures in the skin. After this nutrition must be handled. A large increase in normal protein intake can combat the malnutrition issue, and prevent retarded growth. If the infant survives, treatment then shifts to managing the skin condition directly. This entails long soaks in a bath with oils, and almost continuous application of moisturizing lotions with high lipid content.
The majority of studies have shown that HI is a product of a deletion or missense mutation of the ABCA12 gene. Some found both intragenetic deletions and frameshift deletions. The exact affect of these mutations is unclear. Testing has shown that lamellar granules, which aid in formation of the water proof barrier in the skin, may be overproduced. However, most cases of Harlequin Ichthyosis show a defect in keratin structure, so it may be possible that multiple mutations are responsible or the ABCA12 affects a wide range of epidermal characteristics.
There is currently no genetic test involved in diagnosis. Since characteristics are so obvious at birth. Most diagnosis both before and after birth, consists of skin biopsies.
Other relevant information
Survival rates in infants presenting with Harleqin Ichthyosis have only recently increased. The last 20 years have seen the first generation of HI sufferers to live past infancy, the oldest of which is 18. This is due to advances in neonatal care and the introduction of newborn intensive care units, which are vital to helping HI babies survive.
Harlequin Icthyosis is extremely rare, there are currently only 10 people living with it in the Untied States. It is estimated to occur in 1 out every 300,000 births.
Much of the research being done on Harlequin Ichthyosis, being so rare, is done on mice. The harlequin ichtyosis mutation in mice occured spontaneously in a colony at Jackson Laboratory, Bar Harbor, Maine in 1989.
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