The ichthyoses are a group of genetic skin disorders that cause abnormal thickening of the skin (hyperkeratosis), dry skin (xerosis), scaling, and redness (erythema). These disorders also are frequently accompanied by itching (pruritus) and painful skin fissures. In addition, all forms of ichthyosis lead to a defective epidermal barrier and trans-epidermal water loss. The disease manifestations, in particular scaling and erythema, cause life-long patient disfigurement and can lead to social ostracism.

Research has provided insights into the genetic bases of the various ichthyoses. Ichthyosis vulgaris, the most prevalent type, is associated with loss-of-function mutations of the filaggrin gene. In addition, more than twenty rare subtypes of ichthyosis have been described; all of which result from mutations of single genes affecting protein functions. The predominant subtypes of rare ichthyosis are the epidermolytic ichthyoses, caused by mutations of different genes encoding proteins called suprabasal keratins; Netherton syndrome, caused by a mutation in the gene SPINK5; and the autosomal recessive congenital ichthyoses (ARCI), caused by mutations in several genes, including ABCA12, epidermal lipoxygenases, ichthyin, and transglutaminase 1. However, gene discovery for the ichthyoses is still ongoing.

At present, therapies for most patients with ichthyosis do not address the underlying cause of the disease. Instead, they are limited to interventions to manage symptoms, such as baths, emollients, and agents that peel the thick scale, including keratolytics and retinoids. Importantly, keratolytics and retinoids can lead to unwanted side effects, such as increased skin inflammation, increased pruritus, worsening barrier defects, and other systemic side effects, such as high blood levels of triglycerides and teratogenicity. Topical steroids are used to control skin inflammation, but their side effects limit their suitability for long-term use. Innovative basic, translational, and clinical research is needed to foster the development of safer and more effective therapies.

To begin to define research directions that could improve the treatment and management of ichthyosis, the NIAMS held a roundtable discussion on gaps and unmet needs in ichthyosis research. The meeting brought together representatives from academic institutions, regulatory and funding agencies, patient organizations, and industry, and focused on the following questions:

1. What are the scientific opportunities, knowledge gaps, barriers, and unmet needs in the following areas of ichthyosis research?

  • Pathogenesis
  • Therapeutics, including drug targets and therapies to move forward
  • Clinical research
    • Natural history and co-morbidities
    • Outcome measures and biomarkers for disease severity
    • Clinical trials

2. How can we encourage new investigators to enter the field of ichthyosis research, and what are the best ways to engage individuals with ichthyosis in research and to foster collaboration among patient advocacy groups?

Course of Ichthyosis and Co-Morbidities

In severe forms of ichthyosis, manifestations of the disease are present at birth. For example, infants with certain ichthyosis subtypes are born encased in a tight shiny membrane called collodion. Although a number of clinical issues, such as fluid balance, electrolyte imbalance, risk of infection, and thermal regulation, must be addressed in these so-called collodion babies, no standard management algorithm exists. At present, there are no clinical guidelines for caring for them, and best practices with regard to even simple clinical issues are lacking. In addition, evidence regarding the potential benefits of more complex treatment options, e.g., early intervention to repair the epidermal barrier, is also lacking. To develop an evidence base to inform treatment, researchers are beginning to compare the outcomes of the various approaches currently being used to care for babies with ichthyosis.

In addition to the many pressing issues regarding care for neonates with ichthyosis, children and adults with the condition have their own distinct treatment and management needs. Additional research on the effects of the disease across the lifespan in a subtype-specific manner is critical for enhancing care for all affected individuals. Longitudinal studies of patients who are well characterized in terms of their genetic mutations and clinical disease manifestations would provide insights into the natural history of the various subtypes of ichthyosis. Resources, such as the registry and member forums supported by the Foundation for Ichthyosis and Related Skin Types (FIRST), as well as surveys distributed by FIRST and the Pediatric Dermatology Research Alliance (PeDRA), could help researchers to generate hypotheses about how best to care for patients during different stages of life. Epidemiological research on the effects of environmental factors, like climate for example, on disease course and severity would help to optimize treatment and management strategies. Finally, research to define and understand ichthyosis co-morbidities, particularly the non-cutaneous, long-term complications and psychosocial effects, could help to improve clinical outcomes and quality of life.

Measures of Severity

Clinical Outcome Measures

Currently, studies of ichthyosis pathogenesis and potential therapies are impeded by the lack of validated instruments for physician-assessed and patient-reported disease severity. A single simple outcome measure that reflects disease severity (e.g., an investigator global assessment) could be very helpful for advancing clinical studies and facilitating subsequent drug labeling. However, it is likely impossible to develop a single simple endpoint that would be broadly applicable to all of the genetic subtypes of ichthyosis. The endpoints used for drug approval must demonstrate a clinical benefit; and clinical manifestations of the subtypes vary such that an endpoint related to a clinical benefit in one form of the disease might not be relevant to another. To advance drug development, it may be necessary to develop subtype-specific severity measures.

The roundtable also focused on the need for tools to capture patient-reported outcomes (PRO), especially measures of quality of life (QoL). The group agreed that an important first step in developing meaningful QoL scales for ichthyosis will be to identify the outcomes patients care about most. The group also discussed whether the Patient Reported Outcomes Measurement Information System (PROMIS), developed by the NIH Common Fund, might be applied to ichthyosis research and clinical care. PROMIS includes several adult and pediatric PRO domains relevant to ichthyosis (e.g., pain), and researchers are developing additional tools (e.g., to assess itch) that could be applied in the disease.


The roundtable participants discussed several questions related to the development of biomarkers for ichthyoses, including whether systemic or local assays would be most useful and whether one test or a constellation of assays is needed. The group noted that the answers to these questions would vary depending on what a measure would be used for (e.g., translational research, clinical trials, drug development and approval, or clinical care). Complex and detailed composite scores would likely be required to obtain meaningful data from pathogenesis studies and clinical trials. A related issue is the need to develop non-invasive clinical measures, such as imaging modalities, which are less burdensome than assays that rely on repeat skin biopsies, which can be especially difficult for pediatric patients.

Disease Pathogenesis

A fundamental need in the field of ichthyosis research is to improve understanding of the molecular underpinnings of disease to enable the development of pathogenesis-based therapies. It will be important to clarify how genotype, the causal genetic changes in a particular individual, correlates with phenotype, the disease manifestations the person experiences. For example, researchers do not understand why, in some cases, a mutation in a single gene leads to very different phenotypes, and conversely, why mutations in a number of different genes can produce strikingly similar phenotypes. In addition, it is not clear why patients with mutations in the same gene may have very different responses to a particular therapy. Active areas of research include studies of the effects of ichthyosis mutations on epidermal lipid synthesis, and studies to understand how mutations in some cytoskeletal keratin proteins give rise to diseases, such as ichthyoses, that also affect multiple organ systems, and not just the skin. Researchers also are attempting to identify genetic and epigenetic factors that may modify the disease phenotype, including disease severity.

In many instances, it is unclear which changes in gene expression are specifically associated with a particular genetic mutation and which changes are a generalized response to a compromised skin barrier and would, therefore, be common to all ichthyoses regardless of the underlying mutation. There are a number of powerful new technologies such as tools for single cell analysis and genome editing (e.g., CRISPR/CAS9), patient-specific induced pluripotent stem cells, tools for analysis of the microbiome, metabolomic assays, and proteomic tests that could help researchers to assess the global effects of genetic mutations. Integrating the data from studies that use such technologies will likely require big data approaches; and a key goal should be to ensure that such data are widely accessible and easy to use.

Although some in vitro models of human skin are available, the development of ichthyosis models that use patient-specific cell banks from diverse populations would help to advance all aspects of research on the disease. In addition, more work is needed to determine whether suitable animal models exist or could be developed. Choosing appropriate animal or in vitro human tissue models will require scientists to characterize human clinical, genotypic, and molecular profiles to determine whether a particular model provides a useful approximation of the disease in humans. Additional work should be done to determine how best to collect and store biomaterials for ichthyosis research.


Currently, retinoids are the best available therapy for clearing scale caused by ichthyosis. However, because these drugs are not approved by the U.S. Food and Drug Administration for the treatment of ichthyosis, access to and reimbursement for retinoids can be difficult. Several barriers exist to conducting the clinical trials that would be needed to support U.S. Food and Drug Administration approval of retinoids for ichthyoses. In addition, the serious side effects caused by the most commonly prescribed retinoids also limit their use. Testing of other less common retinoids that might have better therapeutic ratios could lead to improved treatment options for patients.

While retinoids alleviate some of the effects of ichthyosis, researchers would like to develop therapies that address the underlying cause of the disease. Ichthyoses caused by defects in lipid metabolism may be particularly amenable to pathogenesis-based therapies. Researchers have recently demonstrated the feasibility of pathogenesis-based treatment for congenital hemidysplasia with ichthyosiform erythroderma and limb defects, or CHILD syndrome, a form of ichthyosis caused by a disorder of cholesterol biosynthesis. The investigators showed that CHILD syndrome could be treated using topical cholesterol to provide the missing end product of the metabolic pathway, along with a statin drug to block the accumulation of toxic metabolites that build up during impaired cholesterol biosynthesis. As more information becomes available about the pathogenesis of other forms of ichthyosis, it may be possible to develop similarly specific interventions for other subtypes.

With the advent of new technologies such as induced pluripotent stem cells and gene editing tools, it may be possible to correct the causal genetic defects in ichthyoses. Alternatively, the effects of genetic mutations could be alleviated by using small interfering RNAs to downregulate expression of genes that contribute to disease pathogenesis. Furthermore, despite the heterogeneity of genetic mutations that cause ichthyoses, some evidence suggests that different forms of the disease share molecular signatures that could provide new targets for therapy. For example, scientists have recently observed high expression of cytokines in the Th17/IL-23 pathway across several rare forms of ichthyosis, and the upregulation of these cytokines correlates with increased disease severity (specifically the degree of inflammation and erythema). These reports suggest that targeted anti-Th17/IL-23 therapies may benefit ichthyosis patients across a range of different subtypes.

The roundtable participants also discussed other innovative opportunities for new therapies such as the creation of "second skins"—engineered removable material that would compensate for the loss of epidermal barrier function. The group also noted that improvements in methods to deliver molecules through the skin could enhance topical therapies. Finally, they talked about challenges associated with conducting clinical trials in children—a major barrier to creating new therapies for this important patient population, and the NIH-supported Best Pharmaceuticals for Children Act programs, which provide resources for addressing some barriers to pediatric clinical studies.

Engagement of Patients, Patient Advocates, New Investigators, and Industry

Patient advocacy organizations such as FIRST play an important role in helping to engage patients in research and clinical trials, providing seed funding for research, and sponsoring meetings that facilitate the open exchange of ideas and information. Partnerships between researchers and patient groups help patients to learn about relevant clinical trials and advances, and provide scientists with opportunities to gain a broader perspective on clinical issues and patients’ experiences. Structured collaborations, such as those fostered by PeDRA, a network of clinician researchers, are also critical since many ichthyosis subtypes are very rare and assembling enough patients to conduct patient-oriented research, including clinical trials, often requires concerted multi-site efforts. Ichthyosis researchers can help to attract investigators into the field through networking within organizations focused on dermatology research. For established researchers with expertise focused on particular technologies (e.g., ‘omics, imaging, and informatics), the opportunity to apply the technologies in a new disease area could draw them to ichthyosis research. Sponsored multi- and interdisciplinary ichthyosis forums that encourage attendance by trainees could bring new researchers into the field. For early-stage investigators and mentors, the NIH supports a number of career development awards. To encourage more interest from industry, scientists could highlight the fact that disease manifestations such as hyperkeratosis are shared between patients with ichthyosis and those with more common skin conditions that affect larger numbers of individuals.

Participants (* indicates current K awardee)

BELKIN, Alexey M., Ph.D., Center for Scientific Review, National Institutes of Health
BRASH, Alan, Ph.D., Vanderbilt University School of Medicine
CHOATE, Keith A., M.D., Ph.D., Yale University School of Medicine (co-chair)
COULOMBE, Pierre A., Ph.D., Johns Hopkins Bloomberg School of Public Health
DIGIOVANNA, John J., M.D., National Cancer Institute, National Institutes of Health
ELIAS, Peter, M.D., University of California, San Francisco Medical Center
FLECKMAN, Philip, M.D., University of Washington School of Medicine
GUTTMAN, Emma, M.D., Ph.D., Icahn School of Medicine at Mount Sinai
DE GUZMAN STRONG, Cristina, Ph.D., Washington University in St. Louis
KASPAR L., Roger, Ph.D., TransDerm, Inc.
LERNER, Ethan, M.D., Ph.D., Harvard Medical School and Massachusetts General Hospital
LINDSTROM, Jill, M.D., U.S. Food and Drug Administration
PALLER, Amy, M.D., Northwestern University Feinberg School of Medicine (co-chair)
PICKFORD, Jean, Foundation for Ichthyosis Related Skin Types
TENG, Joyce, M.D., Ph.D., Stanford University School of Medicine
ZAJICEK, Anne, M.D., Pharm.D., Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health


BAKER, Carl, M.D., Ph.D.
BURROWS, Stephanie, Ph.D.
CARTER, Robert H., M.D.
CIBOTTI, Ricardo, Ph.D.
KATZ, Stephen I., M.D., Ph.D. (co-chair)
KESTER, Mary Beth, M.S.
LINDE, Anita M., M.P.P.
MOEN, Laura K., Ph.D.
REUSS, Reaya, M.S.