Flexural Reticulate Hyperpigmentation Unmasking Dowling-Degos Disease: A Clinical and Histopathological Insight

Flexural Reticulate Hyperpigmentation Unmasking Dowling-Degos Disease: A Clinical and Histopathological Insight | 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 Case Report Flexural Reticulate Hyperpigmentation Unmasking Dowling-Degos Disease: A Clinical and Histopathological Insight Syrine Hamada, Kenza Benothmane, Mariame Meziane, Nadia Ismaili, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6745905/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 Dowling-Degos disease (DDD) is a rare autosomal dominant genodermatosis characterized by progressive reticulate hyperpigmentation of flexural areas. We report the case of a 40-year-old woman who presented with gradually spreading lentiginous hyperpigmented macules involving the axillae, submammary folds, neck, and genital region. Clinical examination revealed no systemic associations, and dermoscopy showed seborrheic keratosis–like features with a characteristic fine reticular pigmented network. Histopathological examination confirmed the diagnosis of DDD, revealing elongated rete ridges, basal layer hyperpigmentation, and keratin-filled horn cysts. Although genetic testing was not performed, the diagnosis was supported by clinical, dermoscopic, and histological features. This case emphasizes the importance of recognizing the hallmark patterns of DDD to distinguish it from other pigmentary disorders such as acanthosis nigricans, lentiginosis syndromes, and neurofibromatosis. Management remains symptomatic and aimed at cosmetic improvement. Topical retinoids, hydroquinon and fractional laser therapies may offer partial benefit. Early diagnosis can reduce unnecessary investigations and guide appropriate counseling. A literature review is provided to support diagnostic and therapeutic decision-making in clinical practice. Dowling-Degos disease reticulate pigmentation genodermatosis flexural hyperpigmentation dermoscopy Figures Figure 1 Figure 2 Figure 3 Introduction Dowling-Degos disease (DDD) is a rare inherited reticulate pigmentary disorder primarily involving flexural skin. First described by Wilson Jones and Grice in 1978 [ 1 ]. Linked to mutations in KRT5, POGLUT1 (protein O-glucosyltransferase 1), and POFUT1(protein O-fucosyltransferase 1), the disease affects the Notch signaling pathway, which regulates keratinocyte differentiation and epidermal architecture. The DDD’s varied phenotypes and overlap with other pigmentary disorders often delay its diagnosis. Case Report A 40-year-old woman, with no prior medical history or consanguinity, presented with lentiginous hyperpigmented macules progressively extending over two years. She had no similar clinical presentation in her family. The lesions initially appeared on the axillae and submammary folds, later involving the neck and genital area Fig. 1 ,2,3. There was no systemic symptoms nor metabolic abnormality or associated cutaneous findings such as comedones or hidradenitis suppurativa. Dermoscopy revealed fine reticulate networks and seborrheic keratosis–like appearances. Histological analysis demonstrated elongated rete ridges, hyperpigmentation of the basal layer, and multiple keratin-filled cysts. A clinical diagnosis of DDD was established. Genetic testing was unavailable. The patient wasn’t seeking for any management of her skin condition. Discussion Dowling-Degos disease (DDD) is a rare autosomal dominant disorder, classically characterized by acquired reticular hyperpigmentation in flexural sites. Onset is typically after puberty and commonly occurs in the third to fourth decade of life. DDD has no racial or gender predilection, been reported in different regions but is more common in Caucasians [ 2 ]. There have been less than 50 cases reported in the literature. Follicular DDD, a distinct type of DDD, presents uniquely with characteristics such as hyperkeratotic follicular papules resembling comedones, acne-like scars with a pitted appearance around the mouth, and perianal reticulated pigmented lesions, which can be observed during adulthood. In DDD, the hyperpigmentation progressively increases over time, interesting the intertriginous areas and is composed of lentigo-like brown macules and small brown papules with variable hyperkeratosis. The hyperpigmentation progressively increases over time, first arising in the axilla and groin and subsequently appearing in the intergluteal and inframammary folds, neck, trunk, and inner arms and thighs [ 8 ]. Occasionally, patients report associated pruritus in these areas. Dermoscopy reveals a “honeycomb” or “flower-like” pattern, and histology confirms diagnosis. Although genetic analysis provides additional confirmation, it is not mandatory in clinical practice. The mutations in the KRT5 gene , located on the long arm of chromosome 12, have been identified as a primary genetic cause of DDD, leading to altered epithelial proliferation within the pilosebaceous unit. This gene plays a key role in maintaining cell-cell adhesion and facilitating melanosome transfer. In addition to KRT5, pathogenic variants in POFUT1 (protein O-fucosyltransferase 1) and POGLUT1 (protein O-glucosyltransferase 1) have also been implicated in the pathogenesis of DDD [ 3 , 7 ]. Many reports have also revealed the association of DDD with epidermal cysts, hidradenitis suppurativa, keratoacanthoma, and perianal squamous cell carcinoma [ 4 ]. Galli-Galli disease is considered a clinical variant of DDD, distinguished by the presence of non-dyskeratotic acantholysis. Comedonal Darier’s disease is characterized by distinctive nail abnormalities, palmar changes, and hyperkeratotic nodules typically located on the face, scalp, and upper trunk, with histopathologic findings of corps ronds and grains. Familial dyskeratotic comedones usually present during adolescence as numerous open comedones affecting the limbs and trunk, sparing the palms and soles, and histology reveals dyskeratosis, dermal invagination, and occasional acantholysis. Dowling-Degos disease presents variably and often overlaps with conditions such as: Acanthosis nigricans, typically thicker, hyperkeratotic, and associated with metabolic syndrome. Generalized lentiginosis or nevus spilus, usually not limited to flexural folds. Neurofibromatosis type 1 includes pigmentary changes but with hallmark features like café-au-lait macules or neurofibromas. Erythromelanosis follicularis, more common on the face and neck, often with follicular keratosis. The management of DDD remains symptomatic. Options include topical retinoids, laser therapies, fractional or pulsed dye lasers. Experimental therapies targeting Notch signaling are under investigation. The patient counseling should focus on the chronic nature of the disease and cosmetic management options [ 5 ]. Conclusion Dowling-Degos disease, though rare, has distinct clinical and histological features. Recognizing its presentation in flexural areas allows early diagnosis and reduces unnecessary testing. While no curative treatment exists, dermatologic interventions can improve the quality of life. Declarations Funding The authors did not receive support from any organization for the submitted work. Competing Interests The authors have no relevant financial or non-financial interests to disclose. Ethics Approval Not applicable – single case report. Consent to Participate Informed consent was obtained from the patient. Consent to Publish The patient has consented to the publication of anonymized clinical details and images. Data Availability Not applicable. Author Contributions All authors contributed to the design, data analysis, manuscript writing, and final approval of the submitted version. References Jones EW, Grice K: Reticulate pigmented anomaly of the flexures: Dowling Degos disease, a new genodermatosis. Arch Dermatol. 1978, 114:1150–7. 10.1001/archderm.1978.01640200004002 Kono, M.; Sawada, M.; Nakazawa, Y.; Ogi, T.; Muro, Y.; Akiyama, M. A Japanese Case of Galli-Galli Disease due to a Previously Unreported POGLUT1 Mutation. Acta Derm. Venereol. 2019, 99, 458–459. Stephan C, Kurban M, Abbas O: Dowling-Degos disease: a review. Int J Dermatol. 2021, 60:944 – 50.10.1111/ijd.15385 Supekar BB, Rambhia KD, Singh RP, Mukhi JI: Dowling-Degos disease with follicular involvement associated with hidradenitis suppurativa: a manifestation of follicular occlusion phenomenon?. Indian J Dermatol. 2020, 65:295–8. 10.4103/ijd.IJD_392_18 Mehta D, et al. Clinical and genetic insights into Dowling-Degos disease. J Dermatol. 2023. Patel G, et al. Dowling-Degos disease: A case report and review of the literature. Case Rep Dermatol Med. 2011. Betz RC, et al. The genetic basis of Dowling-Degos disease. J Am Acad Dermatol. 2007. Maruthappu T, et al. Clinical spectrum and genetic basis of Dowling-Degos disease. Int J Dermatol. 2021. Additional Declarations No competing interests reported. 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3","display":"","copyAsset":false,"role":"figure","size":377064,"visible":true,"origin":"","legend":"\u003cp\u003eAcquired symmetric and progressive reticulate, with dot-like hyperpigmentation of flexures involving the axilla, submammary folds, inguinal folds and neck\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6745905/v1/0d3fad546026355b9eedcc7e.png"},{"id":101958558,"identity":"eb2337bc-8fff-42d3-94ff-51000cdc2422","added_by":"auto","created_at":"2026-02-05 12:11:29","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1995047,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6745905/v1/5d6ba424-b2b5-4b26-969c-d97957ad099a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Flexural Reticulate Hyperpigmentation Unmasking Dowling-Degos Disease: A Clinical and Histopathological Insight","fulltext":[{"header":"Introduction","content":"\u003cp\u003eDowling-Degos disease (DDD) is a rare inherited reticulate pigmentary disorder primarily involving flexural skin. First described by Wilson Jones and Grice in 1978 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Linked to mutations in KRT5, POGLUT1 (protein O-glucosyltransferase 1), and POFUT1(protein O-fucosyltransferase 1), the disease affects the Notch signaling pathway, which regulates keratinocyte differentiation and epidermal architecture. The DDD\u0026rsquo;s varied phenotypes and overlap with other pigmentary disorders often delay its diagnosis.\u003c/p\u003e"},{"header":"Case Report","content":"\u003cp\u003eA 40-year-old woman, with no prior medical history or consanguinity, presented with lentiginous hyperpigmented macules progressively extending over two years. She had no similar clinical presentation in her family. The lesions initially appeared on the axillae and submammary folds, later involving the neck and genital area Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e,2,3. There was no systemic symptoms nor metabolic abnormality or associated cutaneous findings such as comedones or hidradenitis suppurativa. Dermoscopy revealed fine reticulate networks and seborrheic keratosis\u0026ndash;like appearances. Histological analysis demonstrated elongated rete ridges, hyperpigmentation of the basal layer, and multiple keratin-filled cysts. A clinical diagnosis of DDD was established. Genetic testing was unavailable. The patient wasn\u0026rsquo;t seeking for any management of her skin condition.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eDowling-Degos disease (DDD) is a rare autosomal dominant disorder, classically characterized by acquired reticular hyperpigmentation in flexural sites. Onset is typically after puberty and commonly occurs in the third to fourth decade of life. DDD has no racial or gender predilection, been reported in different regions but is more common in Caucasians [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. There have been less than 50 cases reported in the literature. Follicular DDD, a distinct type of DDD, presents uniquely with characteristics such as hyperkeratotic follicular papules resembling comedones, acne-like scars with a pitted appearance around the mouth, and perianal reticulated pigmented lesions, which can be observed during adulthood. In DDD, the hyperpigmentation progressively increases over time, interesting the intertriginous areas and is composed of lentigo-like brown macules and small brown papules with variable hyperkeratosis. The hyperpigmentation progressively increases over time, first arising in the axilla and groin and subsequently appearing in the intergluteal and inframammary folds, neck, trunk, and inner arms and thighs [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Occasionally, patients report associated pruritus in these areas. Dermoscopy reveals a \u0026ldquo;honeycomb\u0026rdquo; or \u0026ldquo;flower-like\u0026rdquo; pattern, and histology confirms diagnosis. Although genetic analysis provides additional confirmation, it is not mandatory in clinical practice. The mutations in the \u003cb\u003eKRT5 gene\u003c/b\u003e, located on the long arm of chromosome 12, have been identified as a primary genetic cause of DDD, leading to altered epithelial proliferation within the pilosebaceous unit. This gene plays a key role in maintaining cell-cell adhesion and facilitating melanosome transfer. In addition to KRT5, pathogenic variants in \u003cb\u003ePOFUT1\u003c/b\u003e (protein O-fucosyltransferase 1) and \u003cb\u003ePOGLUT1\u003c/b\u003e (protein O-glucosyltransferase 1) have also been implicated in the pathogenesis of DDD [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Many reports have also revealed the association of DDD with epidermal cysts, hidradenitis suppurativa, keratoacanthoma, and perianal squamous cell carcinoma [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Galli-Galli disease is considered a clinical variant of DDD, distinguished by the presence of non-dyskeratotic acantholysis. Comedonal Darier\u0026rsquo;s disease is characterized by distinctive nail abnormalities, palmar changes, and hyperkeratotic nodules typically located on the face, scalp, and upper trunk, with histopathologic findings of corps ronds and grains. Familial dyskeratotic comedones usually present during adolescence as numerous open comedones affecting the limbs and trunk, sparing the palms and soles, and histology reveals dyskeratosis, dermal invagination, and occasional acantholysis.\u003c/p\u003e \u003cp\u003eDowling-Degos disease presents variably and often overlaps with conditions such as:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eAcanthosis nigricans, typically thicker, hyperkeratotic, and associated with metabolic syndrome.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eGeneralized lentiginosis or nevus spilus, usually not limited to flexural folds.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eNeurofibromatosis type 1 includes pigmentary changes but with hallmark features like caf\u0026eacute;-au-lait macules or neurofibromas.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eErythromelanosis follicularis, more common on the face and neck, often with follicular keratosis.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eThe management of DDD remains symptomatic. Options include topical retinoids, laser therapies, fractional or pulsed dye lasers. Experimental therapies targeting Notch signaling are under investigation. The patient counseling should focus on the chronic nature of the disease and cosmetic management options [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eDowling-Degos disease, though rare, has distinct clinical and histological features. Recognizing its presentation in flexural areas allows early diagnosis and reduces unnecessary testing. While no curative treatment exists, dermatologic interventions can improve the quality of life.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThe authors did not receive support from any organization for the submitted work.\u003c/p\u003e\n\u003cp\u003eCompeting Interests\u003c/p\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003eEthics Approval\u003c/p\u003e\n\u003cp\u003eNot applicable \u0026ndash; single case report.\u003c/p\u003e\n\u003cp\u003eConsent to Participate\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from the patient.\u003c/p\u003e\n\u003cp\u003eConsent to Publish\u003c/p\u003e\n\u003cp\u003eThe patient has consented to the publication of anonymized clinical details and images.\u003c/p\u003e\n\u003cp\u003eData Availability\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003eAuthor Contributions\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the design, data analysis, manuscript writing, and final approval of the submitted version.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eJones EW, Grice K: Reticulate pigmented anomaly of the flexures: Dowling Degos disease, a new genodermatosis. Arch Dermatol. 1978, 114:1150\u0026ndash;7. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1001/archderm.1978.01640200004002\u003c/span\u003e\u003cspan address=\"10.1001/archderm.1978.01640200004002\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKono, M.; Sawada, M.; Nakazawa, Y.; Ogi, T.; Muro, Y.; Akiyama, M. A Japanese Case of Galli-Galli Disease due to a Previously Unreported POGLUT1 Mutation. Acta Derm. Venereol. 2019, 99, 458\u0026ndash;459.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStephan C, Kurban M, Abbas O: Dowling-Degos disease: a review. Int J Dermatol. 2021, 60:944\u0026thinsp;\u0026ndash;\u0026thinsp;50.10.1111/ijd.15385\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSupekar BB, Rambhia KD, Singh RP, Mukhi JI: Dowling-Degos disease with follicular involvement associated with hidradenitis suppurativa: a manifestation of follicular occlusion phenomenon?. Indian J Dermatol. 2020, 65:295\u0026ndash;8. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.4103/ijd.IJD_392_18\u003c/span\u003e\u003cspan address=\"10.4103/ijd.IJD_392_18\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMehta D, et al. Clinical and genetic insights into Dowling-Degos disease. J Dermatol. 2023.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePatel G, et al. Dowling-Degos disease: A case report and review of the literature. Case Rep Dermatol Med. 2011.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBetz RC, et al. The genetic basis of Dowling-Degos disease. J Am Acad Dermatol. 2007.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaruthappu T, et al. Clinical spectrum and genetic basis of Dowling-Degos disease. Int J Dermatol. 2021.\u003c/span\u003e\u003c/li\u003e\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":false,"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":"Dowling-Degos disease, reticulate pigmentation, genodermatosis, flexural hyperpigmentation, dermoscopy","lastPublishedDoi":"10.21203/rs.3.rs-6745905/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6745905/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eDowling-Degos disease (DDD) is a rare autosomal dominant genodermatosis characterized by progressive reticulate hyperpigmentation of flexural areas. We report the case of a 40-year-old woman who presented with gradually spreading lentiginous hyperpigmented macules involving the axillae, submammary folds, neck, and genital region. Clinical examination revealed no systemic associations, and dermoscopy showed seborrheic keratosis\u0026ndash;like features with a characteristic fine reticular pigmented network. Histopathological examination confirmed the diagnosis of DDD, revealing elongated rete ridges, basal layer hyperpigmentation, and keratin-filled horn cysts. Although genetic testing was not performed, the diagnosis was supported by clinical, dermoscopic, and histological features. This case emphasizes the importance of recognizing the hallmark patterns of DDD to distinguish it from other pigmentary disorders such as acanthosis nigricans, lentiginosis syndromes, and neurofibromatosis. Management remains symptomatic and aimed at cosmetic improvement. Topical retinoids, hydroquinon and fractional laser therapies may offer partial benefit. Early diagnosis can reduce unnecessary investigations and guide appropriate counseling. A literature review is provided to support diagnostic and therapeutic decision-making in clinical practice.\u003c/p\u003e","manuscriptTitle":"Flexural Reticulate Hyperpigmentation Unmasking Dowling-Degos Disease: A Clinical and Histopathological Insight","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-03 07:49:31","doi":"10.21203/rs.3.rs-6745905/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":"95a37a9a-46f4-4c03-9772-85cedd64db96","owner":[],"postedDate":"June 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-05T12:09:16+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-03 07:49:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6745905","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6745905","identity":"rs-6745905","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}