Two case studies of persistent white hair regrowth after alopecia areata turning pigmented following treatment

There is a strong correlation between alopecia areata (AA) and the development of white hair. The AA presents itself in many clinical manifestations of depigmented hair as the condition advances. It is uncommon for unpigmented hair to extensively regrow for more than one hair growth cycle in AA and successful conversion to pigmented hair after treatment has not yet been reported.


| PATIENT 1
In September 2016, a 47-year-old woman visited our department (Department of Dermatology, China-Japan Friendship Hospital) for the first time due to hair loss for 1 month.The patient had adequate sleep and diet and regular menstruation and denied any significant physical trauma, stress, infection, or weight loss.She reported having good physical fitness and no family history of immunological or skin disorders.Dermatologic examination showed diffuse thinning of the black hair on the entire head, positive results on the hair pulling test, and no obvious abnormalities on the scalp.Hair microscopy showed broken hairs, exclamation mark-like hair, a yellow dot sign, and a black dot sign.
Upon receiving a diagnosis of diffuse alopecia areata (AA), she was instructed to take one 8 mg trenbolone tablet orally once daily.
After 3 months of treatment, the patient experienced a decrease in hair shedding, and an improvement in hair thickness.Subsequently, she decided to stop taking the medication without consulting a medical professional.We didn't continue to follow her up.
In August 2017, the patient again visited our department because of hair graying.She noticed that the newly grown hair after shedding was white and progressively increased in size (Figure 1).We fully informed her of the need for treatment.The patient's attitude was positive, compliance was good, and the patient self-reported that she followed the doctor's instructions for medication.
Dermatological test showed that all of her hair was white.There were no visible bald spots or receding hairlines.The pull test result was positive throughout the patient's head.Dermoscopy revealed that the majority of the hair was white.However, a few hairs had a mixed color, either with black roots and white ends, or white roots and black ends.Capillaritis, capillary dilatation, and scalp irritation were observed in newly grown white and black vellus and damaged hair.There was no evidence of exclamation point hair or black dots (Figure 2).Laboratory testing showed normal liver, kidney, and immunological function, as well as decreased levels of zinc (66.39 μmol/L, normal range 76.5-170 μmol/L) and calcium (1.45 mmol/L, normal range 1.55-2.1).
Instead of trenbolone tablets, the patient was given methylprednisolone (8 mg po qd) and compound glycyrrhizin tablets (50 mg po tid).The duration of treatment was from August 2017 to February 2019.She was also advised to eat more food containing calcium, zinc, and trace element supplements.The patient was asked to return to the doctor every 3 months, and liver and kidney functions were tested every 6 months.The need for treatment was explicitly explained to the patient.The patient was cooperative and had a positive attitude.At a follow-up appointment in November 2017, the patient's white hair gradually fell out, and most of the new hair growth was pigmented.By February 2019, the majority of her hair had turned black, with only a small area remaining white.An alopecia area measuring approximately 3 × 3 cm, with growth of black vellus hair, was observed in the parietal and posterior occipital regions (Figure 3).were no signs of black dots or exclamation mark hair (Figure 4).We made sure she understood why she needed treatment.Due to the patient's high level of satisfaction with the treatment's outcomes and lack of need for further appointments, we conducted telephone follow-ups with her every 6 months over the following 49 months (February 2019-May 2022).By May 2022, her black hair had almost completely grown out, with no significant alopecia, and she reported that her hair was generally softer than before onset.

| PATIENT 2
In July 2018, a 7-year-old boy was accompanied by his mother visited our department and reported that his hair gradually became sparse and gray with no obvious causes 6 months ago.He had no known immune or skin diseases in his family history and was generally healthy.period, the patient did not complain of discomfort, and the liver and kidney functions were rechecked every 6 months, which were normal, and no drug-induced allergies, obesity and other related potential side effects were found.

| DISCUSS ION
There is a close relationship between AA and white hair formation.
AA manifests as different clinical forms of white hair as the disease progresses.During onset, gray/white hair is typically unaffected because AA specifically targets pigmented hair, which is common in patients with a mix of black and gray/white hair. 1 Tan et al. 2 reported a case of AA in which the lesions did not involve white hairs.The patient was a 47-year-old male who lost only black hair in the flaky alopecia spots on the top of his head while retaining white hair.Jia et al. 3 reported four similar cases.None of these patients had any abnormalities in their remaining white hair, which had a similar diameter and length to the unaffected hair.
The mechanism behind the selective retention of white hair in AA can be observed in the overnight graying phenomenon during the acute onset of diffuse AA.This phenomenon refers to the rapid F I G U R E 5 Hair condition and digital dermoscopy images of Patient 2. Before treatment (July 2018), the patient had sparse white hair over the whole head (A-C).After 12 months of treatment (July 2019), patient's gray hair fell out, and newborn cuirasses were black (D-F).After 39 months of treatment (October 2021), the patient's hair was entirely transformed into thick black hair (G-I).
whitening of hair over a short period. 4,5One of the most famous records of this phenomenon is the case of the French Queen Marie Antoinette, who turned gray overnight at age 38, right before she was beheaded. 6Therefore, this phenomenon is also known as Marie Antoinette syndrome. 7Apart from historical anecdotes, this phenomenon has also been reported in the scientific literature.Tan et al. 6,8 reported the case of an 82-year-old female patient whose hair suddenly turned white within a few days and who was diagnosed with diffuse AA.She tried topical betamethasone valerate for 6 weeks, but there was no improvement or deterioration.Eventually, she was prescribed a wig.
Hypopigmented hair can not only be spared during the onset of AA but can also be preferentially regenerated during the recovery period.In the recovery process of most AA patients, many patches of thin and fragile white vellus hair will temporarily regenerate, usually not lasting longer than the first cycle of hair regeneration.
Eventually, the hair will gradually regain its length, diameter, and pigment, finally becoming healthy pigmented hair. 9Persistent regenerative hypopigmented hair, as observed in this patient, is rare.There was a reported case of a 62-year-old woman with diffuse AA who experienced a six-month regrowth of white hair after 2 months of oral prednisolone, but it was not mentioned whether her pigment subsequently recovered. 10Wade et al. 11 reported a 17-year-old female patient with AA who had persistent regrowth of white hair at an occipital patch for 7 years.There is also a case report of a 57-year-old man with a history of AA who relapsed with permanent regrowth of white hair in the previous alopecia area. 12There is no report of pigment conversion after treatment.
We believe that nonpigmented hair can be present throughout the entire process.Pigmented hair is susceptible to targeted attacks during the active stage, leading to overnight graying.White/gray hair first grows during the stable stage and achieves complete repigmentation in the recovery stage, with only a few patients experiencing permanent white hair regrowth.This report discusses two rare cases of persistent regrowth of unpigmented hair following AA.
The patient developed complete white hair after AA, which was retained for one and a half years.A small section of white hair on the posterior occipital region has been retained for 5 years and has not regained pigment to date.
Given the relationship between AA and gray hair, it is likely that hair follicle melanocytes are involved in the pathogenesis of AA. 13 Nagai H et al. 14 found AA could be induced by inducing CD8 (+) T cell-mediated immunity to hair follicle melanocytes lesions.This provides evidence for the hypothesis that hair follicle melanocytes are one of the targets of AA.Bertolini et al. 15 reported a study on AA follicles, in which immunostaining showed that CD8+ T cells recognized and attacked the self-antigen presented by melanocytes, providing direct support for the theory of immune attack against melanocytes.Therefore, melanocytes and melanocyte proteins have been investigated as potential autoantigens.[18] However, the specific autoantigen responsible for AA has not yet been identified.
According to our clinical experience, we believe that patients should be given methylprednisolone to inhibit the damage to follicles caused by effector T lymphocytes and prevent the progression of the disease. 19Glycyrrhizin, the main component of compound glycyrrhizin tablets, has effects similar to those of steroid hormones but without hormone-related adverse reactions. 20These two drugs can regulate immunity, reduce inflammation-induced damage to the hair follicle growth cycle, restore the normal growth cycle of hair follicles, and promote hair growth.This helps to control the disease, restore hair growth and pigmentation, and prevent further recurrence.
These cases had a satisfactory clinical outcome after treatment.
The patient's light-colored and mixed-pigment hair can most likely be attributed to immune competition caused by either the body itself or the drug.We speculate that the above drugs may affect melanocytes or melanin-associated antigens while regulating immunity, but the specific mechanism needs further verification at the histopathological and molecular levels.

| LIMITATI ON AND FUTURE PROS PEC TS
The current study design is confined to just two case studies.
Although these provide useful insights, the results may not be generalizable.To obtain a more comprehensive understanding of the impact of the suggested treatment plan on hair repigmentation after AA, it is necessary to conduct future studies with a larger group of patients, perhaps as part of randomized controlled trials.Therefore, enrolling more patients is imperative to obtain more substantial findings from this analysis.The absence of a control group or compari-

FU N D I N G I N FO R M ATI O N
The work is funded by nervo-endocrine-immune mechanism of Shaoyao-Gancao decoction for the treatment of liver stagnation and spleen deficiency type alopecia areata by regulating the HPA axis, 81973691.
Dermoscopy revealed predominantly pure black hair with a few pure white strands, rare mixed-color hair, and new black vellus hair.There F I G U R E 1 The patient's hair condition photographed from different views in August 2017.All of the hair on her head was white.F I G U R E 2 Digital dermoscopy images of the patient in the (A) parietal and (B) posterior occipital regions obtained in August 2017.
Dermatological examination showed sparse white hair throughout his entire head, with strongly positive hair pulling test results.Microscopic examination showed broken hair, exclamation point hair, and scalp telangiectasia.He was diagnosed with diffuse AA.Since July 2018, he was prescribed methylprednisolone tablets (4 mg, orally once daily) and compound glycyrrhizin tablets (50 mg, once daily).His hair gradually increased in size and regained color.The duration of treatment was from July 2018 to October 2021.During the 39 months of treatment, the patient was compliant, self-reported that he took the medication on time, and repeated the consultation every 3 months, totaling 14 faceto-face consultations.After 12 months of adherence to the medication (July 2019), the patient's gray hair began to fall out, and the newborn cuirasses were black, and at the 39th month (October 2021), the hair had completely turned into thick black hair, and then treatment was discontinued.Hair microscopy showed strong black hair shafts with a small amount of gray-white vellus hair (Figure 5).During the treatment F I G U R E 3 Hair conditions during the treatment.The photography dates were (A) December 2017, (B) March 2018, and (C) February 2019.F I G U R E 4 Digital dermoscopy images of the patient in the (A) parietal and (B) posterior occipital regions obtained in February 2019.
son to other treatments hinders our understanding of the efficacy of the treatment regimens employed.Including comparison data could strengthen the outcomes in future studies.The long-term implications of the therapy are not discussed.Including follow-up data or long-term monitoring plans could shed light on the treatment's longterm efficacy.The impact of the patient's lifestyle, food, or other external factors on treatment success is not addressed.Including these considerations in future studies could result in a more comprehensive view.AUTH O R CO NTR I B UTI O N S Conceived the concept of this work and designed the study: Yuanzi Tian, Qingwu Liu.Involved in the conduct of the study and contributed to data collection, Contributed to data analysis and/or interpretation of the results, Approved the final version of the article: Ying Wang, Dingquan Yang.