Over the past 2 decades, our understanding of the molecular basis for genetic disorders of the skin has expanded tremendously. Identifying the gene mutations that lead to phenotypic manifestations facilitates prenatal and preimplantation diagnosis using molecular techniques. For some disorders, this information has translated into early trials of gene therapy or the development of new pharmacologic therapy based on manipulation of gene product levels. Several support groups that provide education for patients and physicians are available and are listed for each subgroup of genetic disorders of skin. The National Organization for Rare Disorders (NORD; http://www.rarediseases.org) can also help families for whom there is no specific support group. More information about specific genetic disorders can be found at the National Institutes of Health Online Mendelian Inheritance in Man Web site (http://www.ncbi.nlm.nih.gov/omim) and the availability of genetic testing at GeneTests (http://www.genetests.org) or commercial sites, such as GeneDx.org and CompleteGenomics.com.
ICHTHYOSES AND ICHTHYOSIFORM DISORDERS
Named for the Greek term meaning “fish-like scales” (ichthys), this heterogeneous group of disorders is characterized by the predominant clinical feature of visible accumulation of scale. The Foundation for Ichthyosis and Related Skin Types (FIRST) is a national support group for patients with ichthyoses and other genetic disorders with skin thickening (http://www.firstskinfoundation.org/). During the past 2 decades, the underlying molecular basis for most ichthyotic disorders has been discovered. Many subtypes can be diagnosed prenatally through molecular analysis of genomic DNA obtained by chorionic villus sampling or amniocentesis. Specific diagnosis should be made as early as possible to aid in prognostication and genetic counseling. In general, therapy for these disorders is similar and focused on clearance of scale, disease severity, and tolerance of intervention rather than the specific subtype. However, the recent discovery that the orphan forms have inflammation driven by Th17/IL-23 pathway activation suggests targeted systemic anti-inflammatory therapy as a new approach. During the neonatal and early infantile period, therapy should be limited to the frequent application of bland emollients. Use of topical medications with keratolytic agents during the first 6 months of life is usually unnecessary and risks significant absorption of potentially toxic substances (eg, absorption of lactic acid or salicylic acid).
Evidence of scaling and skin thickening is often present at birth, especially in the less common genetic forms, but always manifests during infancy and occasionally childhood. Acquired ichthyosis is rare in pediatric patients, but may result from hypothyroidism, chronic renal insufficiency, malignancy (particularly lymphoma), malabsorption syndromes, essential fatty acid deficiency, sarcoidosis, and certain drugs (particularly hypocholesterolemic agents).
Ichthyosis vulgaris is by far the most common form of ichthyosis and results from mutations in FLG, the gene encoding filaggrin. Approximately 1 in 12 Northern European individuals carry an FLG mutation on at least 1 allele; homozygotes have a much more severe form. Climate plays a major role in clinical presentation, and heterozygotes may first show manifestations ...