IRP scientists find treatment for rare genetic skin disorder

Wednesday, May 31, 2023

Genome sequencing reveals genetic basis for disabling pansclerotic morphea, a severe inflammatory disease

Researchers at the National Institutes of Health and their colleagues have identified genomic variants that cause a rare and severe inflammatory skin disorder, known as disabling pansclerotic morphea, and have found a potential treatment. Scientists discovered that people with the disorder have an overactive version of a protein called STAT4, which regulates inflammation and wound healing. The work also identified a drug that targets an important feedback loop controlled by the STAT4 protein and significantly improves symptoms in these patients. The results were published in the New England Journal of Medicine.

The study was led by researchers at the National Human Genome Research Institute (NHGRI), part of NIH, in collaboration with researchers from the University of California, San Diego (UCSD) and the University of Pittsburgh. Researchers from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute of Allergy and Infectious Diseases, both part of NIH, also participated in the study.

Only a handful of patients have been diagnosed with disabling pansclerotic morphea, a disorder first described in the medical literature around 100 years ago. The disorder causes severe skin lesions and poor wound healing, leading to deep scarring of all layers of the skin and muscles. The muscles eventually harden and break down while the joints stiffen, leading to reduced mobility. Because the disorder is so rare, its genetic cause had not been identified until now.

“Researchers previously thought that this disorder was caused by the immune system attacking the skin,” said Sarah Blackstone, a predoctoral fellow within NHGRI's Inflammatory Disease Section, a medical student at the University of South Dakota, and co-first author of the study. “However, we found that this is an oversimplification, and that both skin and the immune system play an active role in disabling pansclerotic morphea.”

fibroblast cells with nuclei shown in blue — Genomic variation in STAT4 causes disorganized fibroblasts that fail to heal wounds properly. The fibroblast's nuclei are shown in blue.