Researchers identify genomic variants for rare genetic skin disorder

By Elissa Wolfson, The Science Advisory Board assistant editor

June 2, 2023 -- Researchers used genome sequencing to identify the genomic variants that cause disabling pansclerotic morphea, a rare and serious inflammatory skin disorder. The results, published Wednesday in the New England Journal of Medicine, may point the way to a treatment, the researchers said.

First described in the medical literature a century ago, only a handful of patients have since been diagnosed with disabling pansclerotic morphea, which causes severe skin lesions and poor wound healing, leading to deep scarring of all skin and muscle layers. The muscles eventually harden and break down and the joints stiffen, leading to reduced mobility. Because the disorder is so rare, there has been no standard treatment. Existing treatments designed to halt its progression often have severe side effects and are largely ineffective. People with disabling pansclerotic morphea typically live less than 10 years after diagnosis.

The disorder was originally thought to be caused by the immune system attacking the skin. Believing this to be an oversimplification, the researchers sought to learn the cause of the condition. Genome sequencing of four individuals with disabling pansclerotic morphea revealed that all four had genomic variants in the STAT4 gene, which encodes the STAT4 protein that helps turn genes on and off. The STAT4 protein also plays a role in fighting infections, and controls important aspects of wound-healing in the skin.

The scientists found that the STAT4 genomic variants resulted in an overactive STAT4 protein in the four patients, creating a harmful feedback loop of inflammation and impaired wound healing that worsened over time. To stop this feedback loop, they targeted Janus kinase (JAK), a family of enzymes in the inflammatory pathway that interact with STAT4. When treated with a JAK-inhibiting drug called ruxolitinib, the patients' rashes and ulcers improved dramatically.

The researchers concluded that ruxolitinib could be an effective treatment for patients with disabling pansclerotic morphea. "Our study provides an important new treatment option for these patients," co-first author Sarah Blackstone, a University of South Dakota medical student, said in a statement.

Other JAK inhibitors are commonly used to treat arthritis, eczema, ulcerative colitis, and other chronic inflammatory diseases. The researchers plan to continue studying other molecules in the inflammatory pathway and how they are altered in patients with disabling pansclerotic morphea and similar conditions. The team hopes to further the understanding of a broad array of more-common diseases.

"The findings of this study open doors for JAK inhibitors to be a potential treatment for other inflammatory skin disorders or disorders related to tissue scarring," senior author Dr. Dan Kastner, distinguished investigator at the National Institutes of Health and head of the National Human Genome Research Institute's Inflammatory Disease Section, said in a statement.

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