Clinical Features of Postnatal Pigmented Macular Lesions on the Pediatric Facial Region

Clinical Features of Postnatal Pigmented Macular Lesions on the Pediatric Facial Region | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Clinical Features of Postnatal Pigmented Macular Lesions on the Pediatric Facial Region Xiaoyi Chen, Jing Xiao, Yao Wu, Lian-Sheng Zhong This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8140320/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Postnatal Pigmented Macular Lesions on the pediatric facial region, also known as Acquired facial hyperpigmented macules (AFHM), which manifest as non-segmental pigmentation without apparent localized inflammation history, usually occur on children's foreheads and temples. Hyperpigmented lesions in early childhood can be the presenting sign of serious diseases or benign conditions and often cause significant parental anxiety. This report summarizes its characteristics of a cohort of pediatric outpatients at our institution to provide research ideas for the possible pathogenesis and rational treatment of facial hyperpigmentation. Methods We performed a retrospective case series of pediatric patients who visited our outpatient department from December 2019 to June 2023 at our instution. General data regarding gender, age at Onset, season when Onset occurred, and course of disease were collected. Clinical signs, laboratory test results, and prognosis were also collected. Results The clinical features, including general data regarding sex, age at Onset, season of Onset, course of disease, clinical manifestation, laboratory test features, and prognosis, were analyzed and summarized. There were 17 boys and 15 girls enrolled in the study, including one pair of twins, with no sex-related susceptibility. The manifesting rash turned red after the patient cried or was exposed to the sun, leading us to believe that exposure is not the direct trigger for AFHM onset. However, constant sun exposure may cause persistent telangiectasia, leading to a delay in pigmentation resolution. Conclusion AFHM is a benign hyperpigmentation disorder, and the pigmentation of the skin will gradually subside with the enhancement of sun protection without special treatment. Strict sun protection might be an effective treatment for AFHM. As twins tend to show the same symptoms, genetic predisposition may play an essential role in the pathogenesis of AFHM. In future studies, we need to expand the sample size to further clarify the role of genetic susceptibility in the pathogenesis of AFHM. acquired hyperpigmentation children face characteristics Figures Figure 1 Figure 2 Introduction Acquired facial hyperpigmented macules (AFHM), which manifest as non-segmental pigmentation without apparent localized inflammation history, usually occur on children's foreheads and temples. Its etiology, pathogenesis, and prognosis are still unclear. There are currently limited studies detailing the characteristics of AFHM in children. However, hyperpigmented lesions in early childhood can be the presenting sign of serious diseases or benign conditions and often cause significant parental anxiety. This report summarizes its characteristics in a cohort of pediatric outpatients at our institution to provide research ideas for the possible pathogenesis and rational treatment of AFHM. Methods We performed a retrospective case series of pediatric patients who visited our outpatient department from December 2019 to June 2023 at the Children's Hospital of Fudan University (at Xiamen). The inclusion criteria were children diagnosed with facial hyperpigmented macules Onset in infancy. They had a typical presentation(Generally multiple, with a diameter mostly less than 1 cm, located on the forehead and temporal regions). General data regarding gender, age at onset, season when onset occurred, and course of disease were collected. Clinical signs, laboratory test results, and prognosis were also collected. The study was carried out following the Declaration of Helsinki. At the time of follow-up, each patient's parent provided written informed consent to publish personal information. For infants who cannot physically return to the hospital for follow-up visits, we conduct a monthly telephone follow-up to primarily inquire about changes in pigmentation and the factors that may exacerbate or alleviate it.In the case follow-up survey, one doctor is responsible for asking questions, while another is responsible for reviewing. Statistical Analysis Quantitative data are described using the mean and standard deviation or the median and range. Qualitative data are described by frequency and percentage. All descriptions were performed with SPSS (version 23) statistical software. Results General i nformation Of the 32 screened patients, 28 successfully finished follow-up. The patients' general characteristics are outlined in Table 1. Patients' Characteristics No. (N = 32) Age at presentation, median (range), y 12.5 ± 5.7months Female 15（32） Onset age 7.0±3.9months Disease duration 5.4 ± 4.6months Onset seasons spring 2 cases, 6.3% summer 7 cases, 21.9% autumn 12 cases, 37.5% winter 11 cases, 34.3% Table 1 presents the general characteristics of our patients with AFHM. Clinical manifestation s Rash m anifestations The patient's primary symptom was a rash that manifested as light brown macules (Figs. 1A, 1B), nearly round or irregular in shape, and ranging from millet- to peanut-sized. There were no papules, wheals, desquamations, or other skin lesions. All the patients were negative for Darier's sign. In 16 cases (50%), the rash became red after the patient cried or was exposed to the sun. The number of rashes varied from 3 to more than 10 in each patient, with symmetric or unilateral distribution and a diameter mostly less than 1 cm. Rash location The forehead region (68.8%, n=22) was the most commonly affected site in these patients, followed by the temple (9.4%, n=3), on both the forehead and temple (9.4%, n=3), on the zygoma (6.2%, n=2), on the cheek (3.0%, n=1), and on both the forehead and cheek (3.0%, n=1). Symptoms and rash development All the patients had no other symptoms. There was no significant change in the rashes in 27 patients (84.4%), while the number of rashes increased in 2 patients (6.3%), new rash sites appeared in these 2 patients (6.3%), rashes expanded in 1 patient (3.1%), and rashes darkened in 1 patient (3.1%) Laboratory e xamination In total, 22(68.8%) children underwent dermoscopy, which showed light brown pseudo-reticulomelanin with or without reticular pigments, local erythema, and linear/branching vessels (Figs. 2A, 2B). Three (9.4%) children underwent fungal tests with negative results. The ANA test for one（3.1%） patient was negative. Prognosis Of the patients, 28 (87.5%) completed telephone follow-up within a period of 6 to 42 months. Most children's rashes typically subside gradually without treatment. In 18 cases (64.3%), the rash subsided completely; in 9 cases (32.1%), the rash significantly subsided; and in 1 case (3.6%), the rash slightly subsided. Rashes generally fade in about one year. Only one child had a rash that resolved within three months. When inquiring about the medical history of the child's parents, they mentioned that they had been practicing strict sun protection after the diagnosis of AFHM. Discussion In 2014, for the first time, Hernández-Martín et al. 1 analyzed 25 children with comparable clinical findings and compiled a summary of the clinical characteristics of hyperpigmented macules. Since then, some definitions and descriptions of AFHM in books and other publications have specifically addressed this unique condition in young children. Overall, AFHM is characterized by the following clinical features: ① Onset in infancy; ② Lesions located on the forehead and temporal regions; ③ The skin lesions are generally multiple, with a diameter mostly less than 1 cm; ④Dermoscopy usually shows pseudoreticular pigmentation, with or without linear vessels; ⑤ Histopathologically, the epidermis is normal, with mild inflammatory infiltration mainly composed of lymphocytes around the dermal blood vessels, and a few melanophages scattered in the dermal papillae. Excluding other causes of increased pigmentation. Until now, the etiology is still unclear. The illness typically manifests in infancy and early childhood. It is characterized by the sudden emergence of irregularly shaped and unevenly distributed darkened patches on the forehead and temples without preceding redness, swelling, or peeling. The 32 individuals in our investigation had clinical symptoms that matched the descriptions found in the literature, as mentioned earlier. Based on past reports 1 , 2 and our investigation, hyperpigmented macules appear in any season. Locally, they are most common in the fall and rarest in the summer. As far as we know, sun exposure is the most common cause of hyperpigmentation since it dramatically increases the synthesis of melanin 3 . As pigmentation spots did not commonly occur in the summer in our study, they may not be directly related to sun exposure. However, our study found that in 16 cases (50%), the rash became red after the patient cried or was exposed to the sun; this may have been due to the temporary dilation of local capillaries due to crying or sun exposure. Constant sun exposure may cause persistent telangiectasia, leading to a delay in pigmentation resolution. One child's rash resolved within three months because of strict sun protection. Although sun exposure is not a direct cause of hyperpigmentation, sun protection positively affects the regression of pigmentation. Strict sun protection might be an effective treatment for acquired facial pigmentation. According to the histopathologic results available for some previously reported patients, hyperpigmented macules are a postinflammatory alteration, with light inflammatory lymphocytic infiltration and melanoma in the dermis. Dermal macrophages are the body's natural pigment deposition chamber, and pigment deposition occurs within the dermal macrophages 4 . No topical medications were administered in our cohort, and no prior skin lesions or irritation were noted at the rash sites. Histopathologic findings can help distinguish hyperpigmented macules from other pigmented diseases that occur on the face, such as café-au-lait spots, pigmented urticaria, tinea versicolor, and pigmented purpura (these differential diagnoses are shown in Table 2 ). It is difficult, however, for parents to accept a facial histopathologic examination when the skin lesions of their young children have a benign appearance. Dermatoscopy is a noninvasive method to diagnose pigmented skin diseases. Recent literature 2 has demonstrated that light brown pseudoreticular pigmentation and linear/branching vessels are two major dermatoscopic features of hyperpigmented macules on the faces of young children. In our cohort, 22 (68.8%) patients underwent dermoscopy, with similar results. Table 2 Primary differential diagnoses of AHFM Entity Characteristic diagnostic features café-au-lait spot Dermatoscopy: light brown pigmentation with clear boundaries and no apparent vascular structures pigmented urticaria Positive Darier sign tinea versicolor Positive for potassium hydroxide pigmented purpura Cayenne pepper spots Post-inflammatory hyperpigmentation With a history of local inflammation, trauma, desquamation, or medication use. Riehl Melanosis primarily affects individuals with darker skin, especially elderly women. Characterized by the appearance of brown to gray, reticulate (net-like) or diffuse pigmented patches on the face, neck, and upper chest Pigmented lichen planus Common in SPTs III-V and young to middle-aged adults, Oval or irregular slate-gray to black macules and patches either on sun-exposed areas or intertriginous sites Besides sun exposure, skin injuries or inflammation, topical agent contact, and hereditary factors might also play an essential role in melanin synthesis, leading to acquired hyperpigmentation 5 . Giacaman 6 reported two instances of twin sisters, rekindling speculation about a potential shared trigger or genetic predisposition. In this study, we also report one pair of twin sisters, further suggesting the role of genetic predisposition in the Onset of acquired facial pigmentation. In future studies, we need to expand the sample size to further clarify the role of genetic susceptibility in the pathogenesis of acquired facial pigmentation. Limitations The current study has several limitations. 1. The sample size was relatively small, which might limit the generalizability of the research results. However, previous similar studies 1 , 2 with sample sizes within 30 cases still reached valuable conclusions. Therefore, this study still has certain representativeness and reference value for the specific investigated population. As this is a retrospective analysis, parents' memories may be biased; thus, we were unable to conduct longitudinal monitoring of the changes in pigmentation after reasonable sun protection. 2. Due to the Onset's age and the lesions' location in the children, none of the patients underwent histopathologic examination. Similarly, the children could not undergo a Confocal microscopy examination of the skin due to the lack of equipment. However, the dermoscopic findings of the patient's skin clinical manifestations are consistent with the AFHM manifestations reported in previous studies 1 , 2 . However, the study's dependability was as follows: First, patients at the National Children's Center, where our hospital is located, are from various parts of China. Second, the patients were included one after the other. A thorough review of every patient in our clinic is a standard procedure, and complete data are provided. In conclusion , this article summarizes the characteristics of children with AFHM, including gender, age at Onset, season when Onset occurred, and course of disease. As pigmentation spots did not commonly occur in the summer in our study, they may not be directly related to sun exposure. However, the rash turned red in half of the cases following crying or sun exposure, and we hypothesized that constant sun exposure may cause persistent telangiectasia, leading to a delay in pigmentation resolution. Therefore, strict sun protection might effectively treat acquired facial pigmentation. According to earlier research, hyperpigmented macules may result from postinflammatory inflammation, but the underlying cause remains unclear. Based on the existence of twins with concurrent disease in our study and previous literature, genetic predisposition may play an essential role in the pathogenesis of AFHM. In future studies, in addition to increasing the sample size, we can conduct genetic testing for the relevant genes (such as MC1R, OCA2, HERC2, AGR3/AHR, RAB32, TYR, etc) in these patients. We can also perform correlation analyses between the degree of ultraviolet radiation exposure and the speed and extent of pigment fading in these patients. Declarations Ethics Approval and Consent to partecipate The study was carried out following the Declaration of Helsinki and approved by the Ethics Committee of Children’s Hospital of Fudan University （at Xiamen）(No 2022-04).At the time of follow-up, each patient's parent provided written informed consent to publish personal information . Availability of data and materials The data that support the findings of this study are available from the corresponding author upon reasonable request. Competing interests The authors reports no disclosures. Funding : None. Author Contributions Xiaoyi Chen and Jing Xiao conducted the study protocol, participated in its design, and collected data. Yao Wu performed the statistical analysis and drafted the manuscript. Lian-sheng Zhong revised the manuscript. All the authors read and approved the final manuscript. Ackonwledgement We thank all parents and infants who participated in the study and all of the staff involved in the study. References Hernández-Martín A, Gilliam AE, Baselga E, et al.Hyperpigmented macules on the face of young children: a series of 25 cases. J Am Acad Dermatol. 2014;70(2):288-290. Lai S, Lu Y, Huang X, et al. Characteristic Dermatoscopic Features of Hyperpigmented Macules on the Faces of Young Children. Clin Pediatr (Phila). 2024 Feb;63(2):244-248 Silpa-Archa, N, Kohli I, Chaowattanapanit, S et al.Postinflammatory hyperpigmentation: A comprehensive overview: Epidemiology, pathogenesis, clinical presentation, and noninvasive assessment technique. J. Am. Acad. Dermatol. 2017,77 (4):591-605 Joffe RA.An assist to the next (10th) edition of Lever's Histopathology of the Skin. Am J Dermatopathol. 2009 Feb;31(1):26-30 Thawabteh AM, Jibreen A, Karaman D, et al. Skin Pigmentation Types, Causes, and Treatment—A Review. Molecules. 2023 Jun 18;28(12):4839 Giacaman A, Knöpfel N, Campos M,et al.Acquired Facial Hyperpigmented Macules in Children: 3 New Cases. Actas Dermosifiliogr. 2016 Jan-Feb;107(1):81-3 Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8140320","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":555248776,"identity":"30b7a9e7-1519-49e7-9dbf-bccdb1650a05","order_by":0,"name":"Xiaoyi Chen","email":"","orcid":"","institution":"Children‘s hospital of Fudan University at Xiamen","correspondingAuthor":false,"prefix":"","firstName":"Xiaoyi","middleName":"","lastName":"Chen","suffix":""},{"id":555248777,"identity":"829190a8-26c2-46d1-85fa-850810c397b1","order_by":1,"name":"Jing Xiao","email":"","orcid":"","institution":"Children‘s hospital of Fudan University at 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1","display":"","copyAsset":false,"role":"figure","size":6579955,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA\u003c/strong\u003e Variable number of randomly distributed hyperpigmented on the forehead of young children\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eB\u003c/strong\u003e Variable number of randomly distributed hyperpigmented on the temporal region of young children\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8140320/v1/985ed9f8143a720be553004f.png"},{"id":97897488,"identity":"2a1f87f7-1074-4176-90b1-6a30400eafbe","added_by":"auto","created_at":"2025-12-10 15:37:52","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":2412080,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA \u003c/strong\u003eLight brown pseudo-retticular under dermoscopy\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eB \u003c/strong\u003elinear vessels under dermoscopy\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8140320/v1/37af5c2a187b98bcc970dc0e.png"},{"id":102296067,"identity":"f0fd3dd5-5c11-4486-a658-20394027e1c7","added_by":"auto","created_at":"2026-02-10 10:17:05","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":10113692,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8140320/v1/a941986e-6844-4677-a3ee-f3c3efc67ba1.pdf"}],"financialInterests":"","formattedTitle":"Clinical Features of Postnatal Pigmented Macular Lesions on the Pediatric Facial Region","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAcquired facial hyperpigmented macules (AFHM), which manifest as non-segmental pigmentation without apparent localized inflammation history, usually occur on children's foreheads and temples. Its etiology, pathogenesis, and prognosis are still unclear. There are currently limited studies detailing the characteristics of AFHM in children. However, hyperpigmented lesions in early childhood can be the presenting sign of serious diseases or benign conditions and often cause significant parental anxiety. This report summarizes its characteristics in a cohort of pediatric outpatients at our institution to provide research ideas for the possible pathogenesis and rational treatment of AFHM.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eWe performed a retrospective case series of pediatric patients who visited our outpatient department from December 2019 to June 2023 at the Children's Hospital of Fudan University (at Xiamen). The inclusion criteria were children diagnosed with facial hyperpigmented macules Onset in infancy. They had a typical presentation(Generally multiple, with a diameter mostly less than 1 cm, located on the forehead and temporal regions). General data regarding gender, age at onset, season when onset occurred, and course of disease were collected. Clinical signs, laboratory test results, and prognosis were also collected. The study was carried out following the Declaration of Helsinki. At the time of follow-up, each patient's parent provided written informed consent to publish personal information. For infants who cannot physically return to the hospital for follow-up visits, we conduct a monthly telephone follow-up to primarily inquire about changes in pigmentation and the factors that may exacerbate or alleviate it.In the case follow-up survey, one doctor is responsible for asking questions, while another is responsible for reviewing.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eQuantitative data are described using the mean and standard deviation or the median and range. Qualitative data are described by frequency and percentage. All descriptions were performed with SPSS (version 23) statistical software.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eGeneral\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003ei\u003c/strong\u003e\u003cstrong\u003enformation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOf the 32 screened patients, 28 successfully finished follow-up. The patients\u0026apos; general characteristics are outlined in Table 1.\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 284px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 284px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 284px;\"\u003e\n \u003cp\u003ePatients\u0026apos; Characteristics\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 284px;\"\u003e\n \u003cp\u003eNo. (N = 32)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 284px;\"\u003e\n \u003cp\u003eAge at\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003epresentation, median (range), y\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 284px;\"\u003e\n \u003cp\u003e12.5 \u0026plusmn; 5.7months\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 284px;\"\u003e\n \u003cp\u003eFemale\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 284px;\"\u003e\n \u003cp\u003e15（32）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 284px;\"\u003e\n \u003cp\u003eOnset age\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 284px;\"\u003e\n \u003cp\u003e7.0\u0026plusmn;3.9months\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 284px;\"\u003e\n \u003cp\u003eDisease duration\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 284px;\"\u003e\n \u003cp\u003e5.4 \u0026plusmn; 4.6months\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 284px;\"\u003e\n \u003cp\u003eOnset seasons\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 284px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 284px;\"\u003e\n \u003cp\u003espring\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 284px;\"\u003e\n \u003cp\u003e2 cases, 6.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 284px;\"\u003e\n \u003cp\u003esummer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 284px;\"\u003e\n \u003cp\u003e7 cases, 21.9%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 284px;\"\u003e\n \u003cp\u003eautumn\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 284px;\"\u003e\n \u003cp\u003e12 cases, 37.5%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 284px;\"\u003e\n \u003cp\u003ewinter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 284px;\"\u003e\n \u003cp\u003e11 cases, 34.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTable 1 presents the general characteristics of our patients with AFHM.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical manifestation\u003c/strong\u003e\u003cstrong\u003es\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRash\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003em\u003c/strong\u003e\u003cstrong\u003eanifestations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe patient\u0026apos;s primary symptom was a rash that manifested as light brown macules (Figs. 1A, 1B), nearly round or irregular in shape, and ranging from millet- to peanut-sized. There were no papules, wheals, desquamations, or other skin lesions. All the patients were negative for Darier\u0026apos;s sign. In 16 cases (50%), the rash became red after the patient cried or was exposed to the sun. The number of rashes varied from 3 to more than 10 in each patient, with symmetric or unilateral distribution and a diameter mostly less than 1 cm.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRash location\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe forehead region (68.8%, n=22) was the most commonly affected site in these patients, followed by the temple (9.4%, n=3), on both the forehead and temple (9.4%, n=3), on the zygoma (6.2%, n=2), on the cheek (3.0%, n=1), and on both the forehead and cheek (3.0%, n=1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSymptoms and rash development\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the patients had no other symptoms. There was no significant change in the rashes in 27 patients (84.4%), while the number of rashes increased in 2 patients (6.3%), new rash sites appeared in these 2 patients (6.3%), rashes expanded in 1 patient (3.1%), and rashes darkened in 1 patient (3.1%)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLaboratory\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003ee\u003c/strong\u003e\u003cstrong\u003examination\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn total, 22(68.8%) children underwent dermoscopy, which showed light brown pseudo-reticulomelanin with or without reticular pigments, local erythema, and linear/branching vessels (Figs. 2A, 2B). Three (9.4%) children underwent fungal tests with negative results.\u0026nbsp;The ANA test for one（3.1%）\u0026nbsp;patient was negative.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrognosis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOf the patients, 28 (87.5%) completed telephone follow-up within a period of 6 to 42 months. Most children\u0026apos;s rashes typically subside gradually without treatment. In 18 cases (64.3%), the rash subsided completely; in 9 cases (32.1%), the rash significantly subsided; and in 1 case (3.6%), the rash slightly subsided. Rashes generally fade in about one year. Only one child had a rash that resolved within three months. When inquiring about the medical history of the child\u0026apos;s parents, they mentioned that they had been practicing strict sun protection after the diagnosis of AFHM.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn 2014, for the first time, Hern\u0026aacute;ndez-Mart\u0026iacute;n et al. \u003csup\u003e1\u003c/sup\u003e analyzed 25 children with comparable clinical findings and compiled a summary of the clinical characteristics of hyperpigmented macules. Since then, some definitions and descriptions of AFHM in books and other publications have specifically addressed this unique condition in young children. Overall, AFHM is characterized by the following clinical features: ① Onset in infancy; ② Lesions located on the forehead and temporal regions; ③ The skin lesions are generally multiple, with a diameter mostly less than 1 cm; ④Dermoscopy usually shows pseudoreticular pigmentation, with or without linear vessels; ⑤ Histopathologically, the epidermis is normal, with mild inflammatory infiltration mainly composed of lymphocytes around the dermal blood vessels, and a few melanophages scattered in the dermal papillae. Excluding other causes of increased pigmentation. Until now, the etiology is still unclear. The illness typically manifests in infancy and early childhood. It is characterized by the sudden emergence of irregularly shaped and unevenly distributed darkened patches on the forehead and temples without preceding redness, swelling, or peeling. The 32 individuals in our investigation had clinical symptoms that matched the descriptions found in the literature, as mentioned earlier. Based on past reports\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e and our investigation, hyperpigmented macules appear in any season. Locally, they are most common in the fall and rarest in the summer. As far as we know, sun exposure is the most common cause of hyperpigmentation since it dramatically increases the synthesis of melanin\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. As pigmentation spots did not commonly occur in the summer in our study, they may not be directly related to sun exposure.\u003c/p\u003e\u003cp\u003eHowever, our study found that in 16 cases (50%), the rash became red after the patient cried or was exposed to the sun; this may have been due to the temporary dilation of local capillaries due to crying or sun exposure. Constant sun exposure may cause persistent telangiectasia, leading to a delay in pigmentation resolution. One child's rash resolved within three months because of strict sun protection. Although sun exposure is not a direct cause of hyperpigmentation, sun protection positively affects the regression of pigmentation. Strict sun protection might be an effective treatment for acquired facial pigmentation. According to the histopathologic results available for some previously reported patients, hyperpigmented macules are a postinflammatory alteration, with light inflammatory lymphocytic infiltration and melanoma in the dermis. Dermal macrophages are the body's natural pigment deposition chamber, and pigment deposition occurs within the dermal macrophages\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. No topical medications were administered in our cohort, and no prior skin lesions or irritation were noted at the rash sites. Histopathologic findings can help distinguish hyperpigmented macules from other pigmented diseases that occur on the face, such as caf\u0026eacute;-au-lait spots, pigmented urticaria, tinea versicolor, and pigmented purpura (these differential diagnoses are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). It is difficult, however, for parents to accept a facial histopathologic examination when the skin lesions of their young children have a benign appearance. Dermatoscopy is a noninvasive method to diagnose pigmented skin diseases. Recent literature\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e has demonstrated that light brown pseudoreticular pigmentation and linear/branching vessels are two major dermatoscopic features of hyperpigmented macules on the faces of young children. In our cohort, 22 (68.8%) patients underwent dermoscopy, with similar results.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePrimary differential diagnoses of AHFM\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEntity\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCharacteristic diagnostic features\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ecaf\u0026eacute;-au-lait spot\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDermatoscopy:\u003c/p\u003e\u003cp\u003elight brown pigmentation with clear boundaries and no apparent vascular structures\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003epigmented urticaria\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePositive Darier sign\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003etinea versicolor\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePositive for potassium hydroxide\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003epigmented purpura\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCayenne pepper spots\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePost-inflammatory hyperpigmentation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eWith a history of local inflammation, trauma, desquamation, or medication use.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRiehl Melanosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eprimarily affects individuals with darker skin, especially elderly women. Characterized by the appearance of brown to gray, reticulate (net-like) or diffuse pigmented patches on the face, neck, and upper chest\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePigmented lichen planus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCommon in SPTs III-V and young to middle-aged adults, Oval or irregular slate-gray to black macules and\u003c/p\u003e\u003cp\u003epatches either on sun-exposed areas or\u003c/p\u003e\u003cp\u003eintertriginous sites\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eBesides sun exposure, skin injuries or inflammation, topical agent contact, and hereditary factors might also play an essential role in melanin synthesis, leading to acquired hyperpigmentation\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Giacaman\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e reported two instances of twin sisters, rekindling speculation about a potential shared trigger or genetic predisposition. In this study, we also report one pair of twin sisters, further suggesting the role of genetic predisposition in the Onset of acquired facial pigmentation. In future studies, we need to expand the sample size to further clarify the role of genetic susceptibility in the pathogenesis of acquired facial pigmentation.\u003c/p\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eLimitations\u003c/h2\u003e\u003cp\u003eThe current study has several limitations. 1. The sample size was relatively small, which might limit the generalizability of the research results. However, previous similar studies \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e with sample sizes within 30 cases still reached valuable conclusions. Therefore, this study still has certain representativeness and reference value for the specific investigated population. As this is a retrospective analysis, parents' memories may be biased; thus, we were unable to conduct longitudinal monitoring of the changes in pigmentation after reasonable sun protection. 2. Due to the Onset's age and the lesions' location in the children, none of the patients underwent histopathologic examination. Similarly, the children could not undergo a Confocal microscopy examination of the skin due to the lack of equipment. However, the dermoscopic findings of the patient's skin clinical manifestations are consistent with the AFHM manifestations reported in previous studies\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. However, the study's dependability was as follows: First, patients at the National Children's Center, where our hospital is located, are from various parts of China. Second, the patients were included one after the other. A thorough review of every patient in our clinic is a standard procedure, and complete data are provided.\u003c/p\u003e\u003cp\u003e\u003cb\u003eIn conclusion\u003c/b\u003e, this article summarizes the characteristics of children with AFHM, including gender, age at Onset, season when Onset occurred, and course of disease. As pigmentation spots did not commonly occur in the summer in our study, they may not be directly related to sun exposure. However, the rash turned red in half of the cases following crying or sun exposure, and we hypothesized that constant sun exposure may cause persistent telangiectasia, leading to a delay in pigmentation resolution. Therefore, strict sun protection might effectively treat acquired facial pigmentation. According to earlier research, hyperpigmented macules may result from postinflammatory inflammation, but the underlying cause remains unclear. Based on the existence of twins with concurrent disease in our study and previous literature, genetic predisposition may play an essential role in the pathogenesis of AFHM. In future studies, in addition to increasing the sample size, we can conduct genetic testing for the relevant genes (such as MC1R, OCA2, HERC2, AGR3/AHR, RAB32, TYR, etc) in these patients. We can also perform correlation analyses between the degree of ultraviolet radiation exposure and the speed and extent of pigment fading in these patients.\u003c/p\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics Approval and \u0026nbsp;Consent to partecipate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was carried out following the Declaration of Helsinki and approved by the Ethics Committee of Children\u0026rsquo;s Hospital of Fudan University\u0026nbsp;（at Xiamen）(No 2022-04).At the time of follow-up, each patient\u0026apos;s parent provided written informed consent to publish personal information\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003cp skip=\"true\"\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp skip=\"true\"\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors reports no disclosures.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: None.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eXiaoyi Chen and Jing Xiao conducted the study protocol, participated in its design, and collected data. Yao Wu performed the statistical analysis and drafted the manuscript. Lian-sheng Zhong revised the manuscript. All the authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAckonwledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;We thank all parents and infants who participated in the study and all of the staff involved in the study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eHern\u0026aacute;ndez-Mart\u0026iacute;n A, Gilliam AE, Baselga E, et al.Hyperpigmented macules on the face of young children: a series of 25 cases. J Am Acad Dermatol. 2014;70(2):288-290.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eLai S, Lu Y, Huang X, et al.\u0026nbsp;Characteristic Dermatoscopic Features of Hyperpigmented Macules on the Faces of Young Children.\u0026nbsp;Clin Pediatr (Phila). 2024 Feb;63(2):244-248\u003c/li\u003e\n \u003cli\u003eSilpa-Archa, N, Kohli I, Chaowattanapanit, S et al.Postinflammatory hyperpigmentation: A comprehensive overview: Epidemiology, pathogenesis, clinical presentation, and noninvasive assessment technique. J. Am. Acad. Dermatol. 2017,77 (4):591-605\u003c/li\u003e\n \u003cli\u003eJoffe RA.An assist to the next (10th) edition of Lever\u0026apos;s Histopathology of the Skin.\u0026nbsp;Am J Dermatopathol. 2009 Feb;31(1):26-30\u003c/li\u003e\n \u003cli\u003eThawabteh AM, Jibreen A, Karaman D, et al.\u0026nbsp;Skin Pigmentation Types, Causes, and Treatment\u0026mdash;A Review.\u0026nbsp;Molecules. 2023 Jun 18;28(12):4839\u003c/li\u003e\n \u003cli\u003eGiacaman A, Kn\u0026ouml;pfel N, Campos M,et al.Acquired Facial Hyperpigmented Macules in Children: 3 New Cases. Actas Dermosifiliogr. 2016 Jan-Feb;107(1):81-3\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"acquired hyperpigmentation, children, face, characteristics","lastPublishedDoi":"10.21203/rs.3.rs-8140320/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8140320/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003ePostnatal Pigmented Macular Lesions on the pediatric facial region, also known as Acquired facial hyperpigmented macules (AFHM), which manifest as non-segmental pigmentation without apparent localized inflammation history, usually occur on children's foreheads and temples. Hyperpigmented lesions in early childhood can be the presenting sign of serious diseases or benign conditions and often cause significant parental anxiety. This report summarizes its characteristics of a cohort of pediatric outpatients at our institution to provide research ideas for the possible pathogenesis and rational treatment of facial hyperpigmentation.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe performed a retrospective case series of pediatric patients who visited our outpatient department from December 2019 to June 2023 at our instution. General data regarding gender, age at Onset, season when Onset occurred, and course of disease were collected. Clinical signs, laboratory test results, and prognosis were also collected.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eThe clinical features, including general data regarding sex, age at Onset, season of Onset, course of disease, clinical manifestation, laboratory test features, and prognosis, were analyzed and summarized. There were 17 boys and 15 girls enrolled in the study, including one pair of twins, with no sex-related susceptibility. The manifesting rash turned red after the patient cried or was exposed to the sun, leading us to believe that exposure is not the direct trigger for AFHM onset. However, constant sun exposure may cause persistent telangiectasia, leading to a delay in pigmentation resolution.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eAFHM is a benign hyperpigmentation disorder, and the pigmentation of the skin will gradually subside with the enhancement of sun protection without special treatment. Strict sun protection might be an effective treatment for AFHM. As twins tend to show the same symptoms, genetic predisposition may play an essential role in the pathogenesis of AFHM. In future studies, we need to expand the sample size to further clarify the role of genetic susceptibility in the pathogenesis of AFHM.\u003c/p\u003e","manuscriptTitle":"Clinical Features of Postnatal Pigmented Macular Lesions on the Pediatric Facial Region","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-09 04:47:59","doi":"10.21203/rs.3.rs-8140320/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"82d9ddc4-b597-410d-ac3f-275c0fb15e13","owner":[],"postedDate":"December 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-07T06:40:19+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-09 04:47:59","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8140320","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8140320","identity":"rs-8140320","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}