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Laryngeal features in Lipoid proteinosis: a systematic review and meta-analysis of individual participant data

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Abstract

Purpose

Lipoid proteinosis (LP) or Urbach-Wiethe disease (OMIM 247100) is a rare syndrome characterised by early vocal folds infiltration and subsequent multi-organ involvement. LP is often unrecognised and its associated hoarseness is overlooked. The main objective of the study was to investigate hoarseness in LP and implement a diagnosis among otolaryngologists.

Methods

PubMed/MEDLINE and OMIM databases were systematically searched. Authors concentrated the search on published articles starting from the discovery of the pathogenesis of LP by Hamada et al. in 2002. Only cases in which a diagnosis was reported both clinically and through biopsy and/or genetic molecular testing were included. Characteristics of the LP cases were extracted from each included study. Results were obtained through Generalized Estimating Equations.

Results

The search strategy yielded 217 articles, of which 74 (34.1%) met the selection criteria. A total of 154 cases were included. Hoarseness was described in all LP cases and clearly stated as the onset symptom in 68.8%. The onset was on average at 19 months of age (CI: 3.00–20.00), while the mean age at diagnosis was 15 years (CI: 10.00–30.00). Therefore, the diagnostic delay amounted to 13.42 years (CI: 8.00–23.83). Hoarseness alone was responsible for an LP diagnosis in only 14.3% of cases. In 43.5% of cases, genetic analysis of the ECM1 gene was performed and exon 6 was the most frequently altered portion.

Conclusion

Analysing the largest number of published cases, the study underlined that hoarseness is the key symptom for diagnosing LP since early childhood, though frequently overlooked.

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Data availability

All data supporting the findings of this study are available within the paper and its Supplementary Information files. In particular, Online Resource 1 contains the data extracted from each LP case and included in the meta-analysis.

References

  1. Urbach E, Wiethe C (1929) Lipoidosis cutis et mucosae. Virchows Arch Für Pathol Anat Physiol Für Klin Med 273:285–319. https://doi.org/10.1007/BF02158983

    Article  Google Scholar 

  2. Hofer PA (1973) Urbach-Wiethe disease (lipoglycoproteinosis; lipoid proteinosis; hyalinosis cutis et mucosae). A review. Acta Derm Venereol Suppl (Stockh) 53:1–52

    CAS  PubMed  Google Scholar 

  3. Hamada T, McLean WHI, Ramsay M et al (2002) Lipoid proteinosis maps to 1q21 and is caused by mutations in the extracellular matrix protein 1 gene (ECM1). Hum Mol Genet 11:833–840. https://doi.org/10.1093/hmg/11.7.833

    Article  CAS  PubMed  Google Scholar 

  4. Orphanet Editorial Team (2022) Prevalence of rare diseases: Bibliographic data, Orphanet Report Series, Rare Diseases collection, Number 1: Diseases listed in alphabetical order. https://www.orpha.net/orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_alphabetical_list.pdf. Accessed August 8, 2023

  5. Hamada T (2002) Lipoid proteinosis. Clin Exp Dermatol 27:624–629. https://doi.org/10.1046/j.1365-2230.2002.01143.x

    Article  CAS  PubMed  Google Scholar 

  6. Honings J, van Rossum MM, van den Hoogen FJA (2015) Vocal fold hyalinosis in Urbach-Wiethe disease, a rare cause of hoarseness. B-ENT 11:151–155

    CAS  PubMed  Google Scholar 

  7. Gunes B, Karadag R, Uzun L et al (2019) Is it always blepharitis? Urbach-Wiethe syndrome (lipoid proteinosis). Arq Bras Oftalmol 82:242–244. https://doi.org/10.5935/0004-2749.20190051

    Article  PubMed  Google Scholar 

  8. Kabre V, Rani S, Pai KM, Kamra S (2015) Lipoid proteinosis: a review with two case reports. Contemp Clin Dent 6:233–236. https://doi.org/10.4103/0976-237X.156053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Friedman L, Mathews RD, Swanepoel PD (1984) Radiographic and computed tomographic findings in lipid proteinosis. A case report. South Afr Med J Suid-Afr Tydskr Vir Geneeskd 65:734–735

    CAS  Google Scholar 

  10. Ally M, Kinshuck AJ, Sandison A, Sandhu GS (2018) The management of laryngeal lipoid proteinosis. J Laryngol Otol 132:936–939. https://doi.org/10.1017/S0022215118001329

    Article  CAS  PubMed  Google Scholar 

  11. Di Giandomenico S, Masi R, Cassandrini D et al (2006) Lipoid proteinosis: case report and review of the literature. Acta Otorhinolaryngol Ital Organo Uff Della Soc Ital Otorinolaringol E Chir Cerv-facc 26:162–167

    Google Scholar 

  12. Vahidnezhad H, Youssefian L, Uitto J (1993) Lipoid Proteinosis. In: Adam MP, Mirzaa GM, Pagon RA, et al (eds) GeneReviews®. University of Washington, Seattle, Seattle (WA)

  13. Muda AO, Paradisi M, Angelo C et al (1995) Lipoid proteinosis: clinical, histologic, and ultrastructural investigations. Cutis 56:220–224

    CAS  PubMed  Google Scholar 

  14. Stewart LA, Clarke M, Rovers M et al (2015) Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data: the PRISMA-IPD Statement. JAMA 313:1657–1665. https://doi.org/10.1001/jama.2015.3656

    Article  PubMed  Google Scholar 

  15. Stroup DF, Berlin JA, Morton SC et al (2000) Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 283:2008–2012. https://doi.org/10.1001/jama.283.15.2008

    Article  CAS  PubMed  Google Scholar 

  16. Ganger J, Brent MR (2004) Reexamining the vocabulary spurt. Dev Psychol 40:621–632. https://doi.org/10.1037/0012-1649.40.4.621

    Article  PubMed  Google Scholar 

  17. Youssefian L, Vahidnezhad H, Daneshpazhooh M et al (2015) Lipoid proteinosis: phenotypic heterogeneity in Iranian families with c.507delT mutation in ECM1. Exp Dermatol 24:220–222. https://doi.org/10.1111/exd.12620

    Article  CAS  PubMed  Google Scholar 

  18. GBD 2015 Healthcare Access and Quality Collaborators. Electronic address: cjlm@uw.edu, GBD 2015 Healthcare Access and Quality Collaborators (2017) Healthcare Access and Quality Index based on mortality from causes amenable to personal health care in 195 countries and territories, 1990–2015: a novel analysis from the Global Burden of Disease Study 2015. Lancet Lond Engl 390:231–266. https://doi.org/10.1016/S0140-6736(17)30818-8

    Article  Google Scholar 

  19. GBD 2016 Healthcare Access and Quality Collaborators (2018) Measuring performance on the Healthcare Access and Quality Index for 195 countries and territories and selected subnational locations: a systematic analysis from the Global Burden of Disease Study 2016. Lancet Lond Engl 391:2236–2271. https://doi.org/10.1016/S0140-6736(18)30994-2

    Article  Google Scholar 

  20. Jackson D, Daly J, Saltman DC (2014) Aggregating case reports: a way for the future of evidence-based health care? Clin Case Rep 2:23–24. https://doi.org/10.1002/ccr3.58

    Article  PubMed  PubMed Central  Google Scholar 

  21. Nakamura T, Igarashi H, Ito T, Jensen RT (2014) Important of case-reports/series, in rare diseases: Using neuroendocrine tumors as an example. World J Clin Cases 2:608–613. https://doi.org/10.12998/wjcc.v2.i11.608

    Article  PubMed  PubMed Central  Google Scholar 

  22. Murad MH, Sultan S, Haffar S, Bazerbachi F (2018) Methodological quality and synthesis of case series and case reports. BMJ Evid-Based Med 23:60–63. https://doi.org/10.1136/bmjebm-2017-110853

    Article  PubMed  PubMed Central  Google Scholar 

  23. The R Foundation (2016) What is R? https://www.r-project.org/about.html. Accessed 9 Aug 2023

  24. Riley DS, Barber MS, Kienle GS et al (2017) CARE guidelines for case reports: explanation and elaboration document. J Clin Epidemiol 89:218–235. https://doi.org/10.1016/j.jclinepi.2017.04.026

    Article  PubMed  Google Scholar 

  25. Carey JC (2010) The importance of case reports in advancing scientific knowledge of rare diseases. Adv Exp Med Biol 686:77–86. https://doi.org/10.1007/978-90-481-9485-8_5

    Article  PubMed  Google Scholar 

  26. Nissen T, Wynn R (2014) The clinical case report: a review of its merits and limitations. BMC Res Notes 7:264. https://doi.org/10.1186/1756-0500-7-264

    Article  PubMed  PubMed Central  Google Scholar 

  27. Frenkel B, Vered M, Taicher S, Yarom N (2017) Lipoid proteinosis unveiled by oral mucosal lesions: a comprehensive analysis of 137 cases. Clin Oral Investig 21:2245–2251. https://doi.org/10.1007/s00784-016-2017-7

    Article  PubMed  Google Scholar 

  28. Acar A, Eryilmaz A, Gocer C et al (2004) Lipoid proteinosis of larynx: review of four cases. Int J Pediatr Otorhinolaryngol 68:1557–1561. https://doi.org/10.1016/j.ijporl.2004.07.012

    Article  PubMed  Google Scholar 

  29. Loos E, Kerkhofs L, Laureyns G (2019) Lipoid proteinosis: a rare cause of hoarseness. J Voice Off J Voice Found 33:155–158. https://doi.org/10.1016/j.jvoice.2017.05.024

    Article  Google Scholar 

  30. Uchida T, Hayashi H, Inaoki M et al (2007) A failure of mucocutaneous lymphangiogenesis may underlie the clinical features of lipoid proteinosis. Br J Dermatol 156:152–157. https://doi.org/10.1111/j.1365-2133.2006.07583.x

    Article  CAS  PubMed  Google Scholar 

  31. Oz F, Kalekoğlu N, Karakullukçu B et al (2002) Lipoid proteinosis of the larynx. J Laryngol Otol 116:736–739. https://doi.org/10.1258/002221502760238082

    Article  PubMed  Google Scholar 

  32. Xu W, Wang L, Zhang L et al (2010) Otolaryngological manifestations and genetic characteristics of lipoid proteinosis. Ann Otol Rhinol Laryngol 119:767–771

    PubMed  Google Scholar 

  33. Kartal D, Çınar SL, Kartal L et al (2016) Lipoid proteinosis. Acta Dermatovenerol Alp Pannonica Adriat 25:19–21. https://doi.org/10.15570/actaapa.2016.5

    Article  PubMed  Google Scholar 

  34. Meletti S, Cantalupo G, Santoro F et al (2014) Temporal lobe epilepsy and emotion recognition without amygdala: a case study of Urbach-Wiethe disease and review of the literature. Epileptic Disord Int Epilepsy J Videotape 16:518–527. https://doi.org/10.1684/epd.2014.0696

    Article  Google Scholar 

  35. Siebert M, Markowitsch HJ, Bartel P (2003) Amygdala, affect and cognition: evidence from 10 patients with Urbach-Wiethe disease. Brain J Neurol 126:2627–2637. https://doi.org/10.1093/brain/awg271

    Article  Google Scholar 

  36. Claeys KG, Claes LRF, Van Goethem JWM et al (2007) Epilepsy and migraine in a patient with Urbach-Wiethe disease. Seizure 16:465–468. https://doi.org/10.1016/j.seizure.2007.02.014

    Article  PubMed  Google Scholar 

  37. Rickert SM, O’Cathain E (2022) Pediatric voice. Pediatr Clin North Am 69:329–347. https://doi.org/10.1016/j.pcl.2022.01.003

    Article  PubMed  Google Scholar 

  38. Sood S, Street I, Donne A (2017) Hoarseness in children. Br J Hosp Med Lond Engl 78:678–683. https://doi.org/10.12968/hmed.2017.78.12.678

    Article  Google Scholar 

  39. Savage MM, Crockett DM, McCabe BF (1988) Lipoid proteinosis of the larynx: a cause of voice change in the infant and young child. Int J Pediatr Otorhinolaryngol 15:33–38. https://doi.org/10.1016/0165-5876(88)90048-1

    Article  CAS  PubMed  Google Scholar 

  40. Dogramaci AC, Celik MM, Celik E, Bayarogullari H (2012) Lipoid proteinosis in the eastern Mediterranean region of Turkey. Indian J Dermatol Venereol Leprol 78:318–322. https://doi.org/10.4103/0378-6323.95447

    Article  PubMed  Google Scholar 

  41. Heyl T (1970) Genealogical study of lipoid proteinosis in South Africa. Br J Dermatol 83:338–340. https://doi.org/10.1111/j.1365-2133.1970.tb15712.x

    Article  CAS  PubMed  Google Scholar 

  42. Gordon H, Gordon W, Botha V (1969) Lipoid proteinosis in an inbred Namaqualand community. Lancet Lond Engl 1:1032–1035. https://doi.org/10.1016/s0140-6736(69)91827-3

    Article  CAS  Google Scholar 

  43. Van Hougenhouck-Tulleken W, Chan I, Hamada T et al (2004) Clinical and molecular characterization of lipoid proteinosis in Namaqualand, South Africa. Br J Dermatol 151:413–423. https://doi.org/10.1111/j.1365-2133.2004.06076.x

    Article  CAS  PubMed  Google Scholar 

  44. Iyandemye J, Thomas MP (2019) Low income countries have the highest percentages of open access publication: a systematic computational analysis of the biomedical literature. PLoS ONE 14:e0220229. https://doi.org/10.1371/journal.pone.0220229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hamada T, Wessagowit V, South AP et al (2003) Extracellular matrix protein 1 gene (ECM1) mutations in lipoid proteinosis and genotype-phenotype correlation. J Invest Dermatol 120:345–350. https://doi.org/10.1046/j.1523-1747.2003.12073.x

    Article  CAS  PubMed  Google Scholar 

  46. Horev L, Wollina DU, Potikha T et al (2009) Lipoid proteinosis: identification of two novel mutations in the human ECM-1 gene and lack of genotype-phenotype correlation. Acta Derm Venereol 89:528–529. https://doi.org/10.2340/00015555-0673

    Article  CAS  PubMed  Google Scholar 

  47. Rey LK, Kohlhase J, Möllenhoff K et al (2016) A novel ECM1 splice site mutation in lipoid proteinosis: case report plus review of the literature. Mol Syndromol 7:26–31. https://doi.org/10.1159/000444615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Chen Z, Calawerts W, Zhang Y et al (2017) A case report: hybrid treatment approach to lipoid proteinosis of the larynx. J Voice Off J Voice Found. https://doi.org/10.1016/j.jvoice.2015.12.007

    Article  Google Scholar 

  49. Epple A, Hoxha E, Schneiderbauer R et al (2018) Hyalinosis cutis et mucosae: a clinical investigation with special regard to mucosal changes. J Dtsch Dermatol Ges J Ger Soc Dermatol JDDG 16:211–213. https://doi.org/10.1111/ddg.13416

    Article  Google Scholar 

  50. Dertlioğlu SB, Çalık M, Çiçek D (2014) Demographic, clinical, and radiologic signs and treatment responses of lipoid proteinosis patients: a 10-case series from Şanlıurfa. Int J Dermatol 53:516–523. https://doi.org/10.1111/ijd.12254

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors would like to thank the patient V.D. who motivated the deep research in Lipoid Proteinosis.

Author information

Authors and Affiliations

  1. Department of Sense Organs, Sapienza University of Rome, 00185, Rome, Italy

    Chiara Cocchi & Lucia Longo

  2. Otorhinolaryngology Unit, Hesperia Hospital, 41125, Modena, Italy

    Chiara Cocchi

  3. Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185, Rome, Italy

    Alberto Milanese & Anna Rita Vestri

  4. Independent Researcher, Modena, Italy

    Line Abdul-Messie

Authors
  1. Chiara Cocchi
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  2. Alberto Milanese
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  3. Line Abdul-Messie
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  5. Lucia Longo
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Contributions

Study concept and design: Cocchi, Milanese, Longo; Acquisition, analysis and interpretation of data: Cocchi, Milanese, Longo; Drafting of the manuscript: Cocchi, Abdul-Messie, Milanese; Statistical analysis: Milanese, Vestri; Study supervision: Vestri, Longo; Critical revision of the manuscript for important intellectual content: all authors.

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Correspondence to Chiara Cocchi.

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Authors have no relevant financial or non-financial interests to disclose. No funding was received for conducting this study.

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No ethical approval or informed consent was required for the present study because all analysed data were already published in scientific journals.

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The present study didn’t involve any patients in its phases (collection, analysis and interpretation of data).

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Cocchi, C., Milanese, A., Abdul-Messie, L. et al. Laryngeal features in Lipoid proteinosis: a systematic review and meta-analysis of individual participant data. Eur Arch Otorhinolaryngol (2024). https://doi.org/10.1007/s00405-024-08713-x

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