Is there a genetic basis of CCCA and, if so what is it?
Clinical Applications
Dr. Schwarzenberger is the former physician editor of DermWorld. She interviews the author of a recent study each month.
By Kathryn Schwarzenberger, MD, July 1, 2019
In this month’s Clinical Applications column, Physician Editor Kathryn Schwarzenberger, MD, talks with Amy McMichael, MD, about her recent NEJM article, “Variant PADI3 in Central Centrifugal Cicatricial Alopecia.”
Dr. Schwarzenberger: In your recent study published in the New England Journal of Medicine, you and your colleagues identified a genetic mutation associated with central centrifugal cicatricial alopecia (CCCA). What inspired you to look for a genetic basis for this challenging condition?
Dr. McMichael: What inspired us to look for genetics was an interesting tale of two cities. Ncoza Dlova, MD, associate professor, chief specialist, and head of the dermatology department at the Nelson R. Mandela School of Medicine in Durban, South Africa, and I had observed that many of our patients with CCCA reported a strong family history of this form of hair loss. It seemed to be too many in one family to be related only to hair care practices. There were some patients who actually brought their family members to appointments, so we could see the hair loss for ourselves. Dr. Dlova was the first to report an autosomal dominant pattern of inheritance in CCCA, working with Drs. Ofer Sarig and Eli Sprecher in Israel.
Meanwhile, I had approached Dr. Sprecher about a more in-depth genetics study of CCCA when he visited my department. He was the one who suggested that Dr. Dlova and I work together to study the genetics in the families of affected patients as well as in unrelated patients. We had the patients and he had all the genetics expertise.
Dr. Schwarzenberger: What were your findings?
Dr. McMichael: We collected both RNA and DNA from women of African ancestry with CCCA as well as from controls of at least age 50 who did not have CCCA. Our findings identified one splice site and three heterozygous missense mutations in PADI3 in five patients (31%) in a discovery set of 16 patients. PADI3 encodes peptidyl arginine deiminase, type III (PADI3), an enzyme that post-translationally modifies other proteins that are essential to hair-shaft formation. These mutations were found to result in reduced PADI3 expression, abnormal intracellular localization of the protein, and decreased enzymatic activity — findings that support their pathogenicity. We then directly sequenced PADI3 in an additional 42 patients and observed genetic variants in nine of them. A post hoc analysis of the combined data sets showed that the prevalence of PADI3 mutation was higher among patients with CCCA than in our control cohort.
Dr. Schwarzenberger: Do you and your colleagues feel this genetic mutation is the answer to this condition? Does it adequately explain the pathogenesis of the condition, or is it possible that other factors contribute to the hair loss and scarring?
Dr. McMichael: It would appear that the PADI3 mutation is one factor in the development of CCCA, but there is likely an environmental factor as well. It is likely that the environmental factor or factors are able to start the process of loss in those who have the underlying mutation. Since we do not have a way to test for the mutation yet, we have to be diligent about prevention of the condition by counseling all our patients of African ancestry to use gentle hair care practices starting at a young age.
Dr. Schwarzenberger: Do you think we should be looking for a genetic basis of other types of hair loss?
Dr. McMichael: I think we are going to find underlying mutations in many skin diseases that have been an enigma until now. Recently, a group of researchers (Tziotzios et al, Nature Communications 2019) published a genome-wide association study in frontal fibrosing alopecia that reported associations with the HLA-B allele. As we advance our ability to perform genetics, and costs of these studies decrease, there will be more specific information published. However, the genetics will only be part of the story, as we still need treatments to slow and improve these forms of hair loss. It will be another leap to associate these genetic findings with successful treatments.
Dr. Schwarzenberger: How will this new knowledge impact the care dermatologists provide to patients with this condition? Should we start doing genetic testing on our patients with hair loss?
Dr. McMichael: It would be my dream to have genetic tests for all forms of hair loss. Even when that day comes, the answer to treating these diseases in those already affected will still be complicated. Knowing the underlying genetics of diseases will help us explain to patients that they are not to blame for their hair loss, which many of my patients report. These findings allow dermatologists to let their patients know about the underlying risk to using hair care practices that put tension on the hair or extreme heat on the scalp. The findings also allow us to educate the younger generations before there is damage to the scalp. Our patients want to know why they have CCCA, and this gives them the start to the answer.
Dr. McMichael is a professor and chair of dermatology at Wake Forest School of Medicine in Winston-Salem, North Carolina. She is a past president of the Skin of Color Society, a past vice president of the Women’s Dermatologic Society, and a past secretary-treasurer of the North American Hair Research Society. Dr. McMichael was also elected to the 2020 AAD Board of Directors. The article appeared in NEJM: doi: 10.1056/NEJMoa1816614.
