Philip Fleckman, MD, University of Washington, Seattle, WA

Dr. Philip Fleckman

This article is a summary of a presentation that Dr. Fleckman gave at the National Family Conference in Atlanta, Georgia.

Ichthyosis is a term for a large group of different scaling skin disorders. Because the term refers to a large group, the disorders are referred as the ichthyoses. Most of the problems in the ichthyoses occur in the epidermis, the top layer of the skin that forms a barrier between our bodies and the outside world.
 
While much is going on in ichthyosis research, it will be helpful for our purposes to focus on just three topics:

• Profilaggrin mutations in ichthyosis vulgaris.
• A new name for lamellar ichthyosis/CIE and the new mutations that support the new name and suggest a common metabolic pathway underlying their cause.
• Animal models of the ichthyoses.

Before beginning, let's review a little about the epidermis:

• The epidermis forms the barrier between our bodies and the outside world.
• The epidermis can be divided into four layers based on how it appears when a biopsy of skin is viewed under the microscope. From the top (outside layer) down, these are:

1. The cornified layer
2. The granular layer
3. The spinous layer
4. The basal layers

The epidermis is attached to the middle level of the skin (the dermis) at the basal layer.

Profillaggrin mutations in ichthyosis vulgaris
Ichthyosis vulgaris (IV) gets its name from the Latin word for common (vulgar) because it occurs more often than any other form of ichthyosis. It occurs in about one in every 250 individuals in the world. Until this year, ichthyosis vulgaris was thought to be an autosomal dominant disease. All of us have 23 pairs of chromosomes, the structures that carry genetic information (genes), in every one of our cells. One of each chromosome pair comes from our mother, the other comes from our father. One of these pairs determines our sex. The other 22 pairs determine the rest of us; these 22 pairs are called autosomal chromosomes. Autosomal dominant means that a change (mutation) in a gene on one of the two chromosomes in any autosomal chromosome pair results in disease. (Autosomal recessive means that mutations in the same gene on both of the chromosomes in the pair must occur for the disease to occur.) This year Dr. Frances Smith and Dr. Irwin McLean, investigators in Dundee, Scotland, along with eighteen other investigators from across the world, showed that ichthyosis vulgaris is actually an autosomal semidominant disease. Autosomal semidominant means that a mutation in one gene of the autosomal chromosome pair results in a mild version of the disease, while mutations in the gene on both chromosomes results in the full-blown disease. It has been known for several years that different degrees of severity have been seen in ichthyosis vulgaris, but those individuals with moderate to severe disease have no visible granular layer in their epidermis. In humans, the granular layer is made up of small granules in the cells that are composed of a protein called profilaggrin. Profilaggrin gets its name because it is a precursor of filaggrin, a protein that performs at least two functions in the cornified layer. Filaggrin means filament aggregating protein, because it helps to join together structural proteins in the cornified layer to form the barrier. It is then degraded to substances that bind water in the top part of the cornified layer. Those people with ichthyosis vulgaris with no granular layer have almost no profilaggrin in their epidermis. A few years ago, Drs. John Compton and Sherri Bale, Dr. John DiGiovanna, and I showed that, in one large family, ichthyosis vulgaris with no granular layer was linked to an area of chromosome 1 where a number of genes involved in formation of the epidermis, including the gene for profilaggrin, are located. We suspected that the absence of profilaggrin reflected a mutation in the gene for profilaggrin, but we were unable to prove this. The gene for profilaggrin is quite complex and difficult to study. Drs. Smith, McLean, and coworkers worked out a way to study the gene and showed that mutations in profilaggrin underlie ichthyosis vulgaris. They found that people with mutations in the profilaggrin gene on both copies of chromosome 1 have ichthyosis vulgaris, while those with mutations in only one copy have much milder clinical findings. This means that ichthyosis vulgaris is a semidominant disease. Smith, McLean, and colleagues showed that mutations in the profilaggrin gene are very common, which explains why the disease is seen in so many people. They also showed that mutations in the profilaggrin gene are very strong predisposing factors for atopic eczema and that there is a very strong association of profilaggrin mutations with asthma occurring with atopic eczema.
 
Lamellar ichthyosis/CIE - New concepts, new mutations
This topic deals with the importance of lipids in epidermal function. Lipids are essential for all cells and for proper barrier function of the epidermis. Many members of FIRST have been diagnosed with lamellar ichthyosis or CIE. Lamellar comes from the Latin word for plate, describing the plate-like scales. CIE is short for congenital (you were born with it), ichthyosiform (ichthyosis-like), erythroderma (red skin), or the condition where one is born with red, scaling skin. The scale in lamellar tends to be large and dark, while the scale in CIE tends to be small and white. At the extreme, people with this group of diseases have the clinical findings either of lamellar or CIE. However, it has long been known that the distinction between the two is often blurred, and people can have features of both. Both are autosomal recessive diseases (the individual has a mutation in the same gene on both chromosomes) and are rare, occurring in about 1 in every 200,000 to 300,000 people. These disorders not only have varying appearances clinically, they result from mutations in a number of different genes. The first mutation identified in these disorders was in the gene for transglutaminase type 1 (TMG1). Although mutations in this gene are found in about one-third of people with lamellar ichthyosis, they can also be seen in individuals with CIE. Since the description of transglutaminase 1 mutations, investigators in France and elsewhere have identified mutations in seven other genes that result in clinical findings of lamellar ichthyosis, CIE, and overlaps between the two. Because almost all of these disorders are autosomal recessive, they are now being grouped into the large group of autosomal recessive congenital ichthyosis (ARCI). So, hello ARCI, goodbye lamellar and CIE. The French investigators speculate that all these gene codes for proteins are involved in a new, common pathway of lipid metabolism. If this turns out to be true, it might explain the common clinical presentations of what were thought to be two different disease types.
 
Animal Models of the Ichthyoses
No one argues that mice are the same as humans. However, both are mammals and have many genes in common. Many interesting tools have been developed to test on mice the effects of mutations in genes that are common to both mice and humans. One interesting model has been developed in the laboratory of Dr. Dennis Roop, a member of the Medical and Scientific Advisory Board of FIRST In this model, investigators are able to induce the findings of epidermolytic ichthyosis (formerly called EHK). They are now using these mouse models to test therapeutic drugs to treat this disease. In summary, ichthyosis vulgaris is an autosomal semidominant disease resulting from mutations in the profilaggrin gene. Lamellar ichthyosis and CIE are now being grouped into autosomal recessive congenital ichthyosis (ARCI) and result from mutations in what might be a common metabolic pathway. And, animal models of ichthyosis are useful tools for understanding what causes and how to treat these disorders.