Characteristics of Café-au-lait Macules and their Association with the Neurofibromatosis type I Genotype in a Cohort of Greek Children

Authors

  • Lamprini Nasi Unit of Pediatric Dermatology, First Department of Pediatrics, Medical School, National and Kapodistrian University of Athens, Agia Sophia Children's Hospital, Athens, Greece
  • Alexios Alexopoulos Unit of Pediatric Dermatology, First Department of Pediatrics, Medical School, National and Kapodistrian University of Athens, Agia Sophia Children's Hospital, Athens, Greece
  • Eleftheria Kokkinou Division of Pediatric Neurology, First Department of Pediatrics, Medical School, National and Kapodistrian University of Athens, Agia Sophia Children's Hospital, Athens, Greece
  • Kleoniki Roka Division of Pediatric Hematology-Oncology, First Department of Pediatrics, Medical School, National and Kapodistrian University of Athens, Agia Sophia Children's Hospital, Athens, Greece
  • Maria Tzetis Laboratory of Medical Genetics, Medical School, National and Kapodistrian University of Athens, Agia Sophia Children's Hospital, Athens, Greece
  • Maria Tsipi Laboratory of Medical Genetics, Medical School, National and Kapodistrian University of Athens, Agia Sophia Children's Hospital, Athens, Greece
  • Talia Kakourou Unit of Pediatric Dermatology, First Department of Pediatrics, Medical School, National and Kapodistrian University of Athens, Agia Sophia Children's Hospital, Athens, Greece
  • Christina Kanaka-Gantenbein First Department of Pediatrics, Medical School, National and Kapodistrian University of Athens, Agia Sophia Children's Hospital, Athens, Greece
  • George Chrousos First Department of Pediatrics, Medical School, National and Kapodistrian University of Athens, Agia Sophia Children's Hospital, Athens, Greece
  • Antonis Kattamis Division of Pediatric Hematology-Oncology, First Department of Pediatrics, Medical School, National and Kapodistrian University of Athens, Agia Sophia Children's Hospital, Athens, Greece
  • Roser Pons Division of Pediatric Neurology, First Department of Pediatrics, Medical School, National and Kapodistrian University of Athens, Agia Sophia Children's Hospital, Athens, Greece

DOI:

https://doi.org/10.2340/actadv.v103.5758

Keywords:

neurofibromatosis, café-au-lait macules, pigment intensity, melanin, genotype

Abstract

Cafe-au-lait macules are the most distinctive clinical finding in neurofibromatosis type I. The aim of this prospective study of Greek children diagnosed with neurofibromatosis type I was to describe the dermatological phenotype and to analyse the characteristics of cafe-au-lait macules and their association with genotype. Pigment intensity and melatonin content of cafe-au-lait macules were measured with a narrowband spectrophotometer. A total of 63 children aged 6 months to 16 years old were studied. Mean melanin content varied, both among patients, and within each patient (p < 0.001). Females had a higher number of cafe-au-lait macules than did males (p = 0.025), and the melanin content of cafe-au-lait macules was lower in females than males (p < 0.001). Patients with protein-truncating variants in the neurofibromatosis type I gene had higher melanin content of cafe-au-lait macules than other types of genetic variants t (55) = 2.196, p = 0.032. Plexiform neurofibromas were also detected in the majority of patients with protein- truncating variants, while juvenile xanthogranulomas were detected equally in patients with protein-truncating and non-protein-truncating variants. In conclusion, cafe-au-lait macules with high melatonin content are associated with patients carrying non-protein-truncating variants. Therefore, measurement of cafe-au-lait macule pigment intensity might provide useful information for initial assessment of patients with neurofibromatosis type I and the severity of their future phenotype.

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References

Bergqvist C, Servy A, Valeyrie-Allanore L, Ferkal S, Combemale P, Wolkenstein P, et al. NF France Network. Neurofibromatosis 1 French national guidelines based on an extensive literature review since 1966. Orphanet J Rare Dis 2020; 15: 37.

https://doi.org/10.1186/s13023-020-1310-3 DOI: https://doi.org/10.1186/s13023-020-1310-3

Kallionpää RA, Uusitalo E, Leppävirta J, Pöyhönen M, Peltonen S, Peltonen J. Prevalence of neurofibromatosis type 1 in the Finnish population. Genet Med 2018; 20: 1082-1086.

https://doi.org/10.1038/gim.2017.215 DOI: https://doi.org/10.1038/gim.2017.215

Yao R, Wang L, Yu Y, Wang J, Shen Y. Diagnostic value of multiple café-au-lait macules for neurofibromatosis 1 in Chinese children. J Dermatol 2016; 43: 537-542.

https://doi.org/10.1111/1346-8138.13169 DOI: https://doi.org/10.1111/1346-8138.13169

DeBella K, Szudek J, Friedman JM. Use of the National Institutes of Health criteria for diagnosis of neurofibromatosis 1 in children. Pediatrics 2000; 105: 608-614.

https://doi.org/10.1542/peds.105.3.608 DOI: https://doi.org/10.1542/peds.105.3.608

Ozarslan B, Russo T, Argenziano G, Santoro C, Piccolo V. Cutaneous findings in neurofibromatosis type 1. Cancers (Basel) 2021; 13: 463.

https://doi.org/10.3390/cancers13030463 DOI: https://doi.org/10.3390/cancers13030463

Boyd KP, Korf BR, Theos A. Neurofibromatosis type 1. J Am Acad Dermatol 2009; 61: 1-16.

https://doi.org/10.1016/j.jaad.2008.12.051

Landau M, Krafchik BR. The diagnostic value of café-au-lait macules. J Am Acad Dermatol 1999; 40: 877-892.

https://doi.org/10.1016/S0190-9622(99)70075-7 DOI: https://doi.org/10.1016/S0190-9622(99)70075-7

Friedman JM. Neurofibromatosis 1: clinical manifestations and diagnostic criteria. J Child Neurol 2002; 17: 548-651.

https://doi.org/10.1177/088307380201700802 DOI: https://doi.org/10.1177/088307380201700802

Nunley KS, Gao F, Albers AC, Bayliss SJ, Gutmann DH. Predictive value of café au lait macules at initial consultation in the diagnosis of neurofibromatosis type 1. Arch Dermatol 2009; 145: 883-887.

https://doi.org/10.1001/archdermatol.2009.169 DOI: https://doi.org/10.1001/archdermatol.2009.169

Ortonne JP, Brocard E, Floret D, Perrot H, Thivolet J. Valeur diagnostique des taches café-au-lait (T.C.L.). Ann Dermatol Venereol 1980; 107: 313-327.

Abeliovich D, Gelman-Kohan Z, Silverstein S, Lerer I, Chemke J, Merin S, et al. Familial café au lait spots: a variant of neurofibromatosis type 1. J Med Genet 1995; 32: 985-986.

https://doi.org/10.1136/jmg.32.12.985 DOI: https://doi.org/10.1136/jmg.32.12.985

Viskochil D. Genetics of neurofibromatosis 1 and the NF1 gene. J Child Neurol 2002; 17: 562-651.

https://doi.org/10.1177/088307380201700804 DOI: https://doi.org/10.1177/088307380201700804

Legius E, Brems H. Genetic basis of neurofibromatosis type 1 and related conditions, including mosaicism. Childs Nerv Syst 2020; 36: 2285-2295.

https://doi.org/10.1007/s00381-020-04771-8 DOI: https://doi.org/10.1007/s00381-020-04771-8

Farschtschi S, Mautner VF, McLean ACL, Schulz A, Friedrich RE, Rosahl SK. The Neurofibromatoses. Dtsch Arztebl Int 2020; 117: 354-360.

https://doi.org/10.3238/arztebl.2020.0354 DOI: https://doi.org/10.3238/arztebl.2020.0354

Tsipi M, Poulou M, Fylaktou I, Kosma K, Tsoutsou E, Pons MR, et al. Phenotypic expression of a spectrum of neurofibromatosis type 1 (NF1) mutations identified through NGS and MLPA. J Neurol Sci 2018; 395: 95-105.

https://doi.org/10.1016/j.jns.2018.10.006 DOI: https://doi.org/10.1016/j.jns.2018.10.006

Frenk E, Marazzi A. Neurofibromatosis of von Recklinghausen: a quantitative study of the epidermal keratinocyte and melanocyte populations. J Invest Dermatol 1984; 83: 23-25.

https://doi.org/10.1111/1523-1747.ep12261648 DOI: https://doi.org/10.1111/1523-1747.ep12261648

De Schepper S, Maertens O, Callens T, Naeyaert JM, Lambert J, Messiaen L. Somatic mutation analysis in NF1 café au lait spots reveals two NF1 hits in the melanocytes. J Invest Dermatol 2008; 128: 1050-1053.

https://doi.org/10.1038/sj.jid.5701095 DOI: https://doi.org/10.1038/sj.jid.5701095

Boyd KP, Gao L, Feng R, Beasley M, Messiaen L, Korf BR, et al. Phenotypic variability among café-au-lait macules in neurofibromatosis type 1. J Am Acad Dermatol 2010; 63: 440-447.

https://doi.org/10.1016/j.jaad.2009.09.042 DOI: https://doi.org/10.1016/j.jaad.2009.09.042

Kokkinou E, Roka K, Alexopoulos A, Tsina E, Nikas I, Krallis P, et al. Development of a multidisciplinary clinic of neurofibromatosis type 1 and other neurocutaneous disorders in Greece. A 3-year experience. Postgrad Med 2019; 131: 445-452.

https://doi.org/10.1080/00325481.2019.1659708 DOI: https://doi.org/10.1080/00325481.2019.1659708

Taylor SC. Skin of color: biology, structure, function, and implications for dermatologic disease. J Am Acad Dermatol 2002; 46: S41-S62.

https://doi.org/10.1067/mjd.2002.120790 DOI: https://doi.org/10.1067/mjd.2002.120790

Albaghdadi M, Thibodeau ML, Lara-Corrales I. Updated approach to patients with multiple café au lait macules. Dermatol Clin 2022; 40: 9-23.

https://doi.org/10.1016/j.det.2021.08.002 DOI: https://doi.org/10.1016/j.det.2021.08.002

Boyd KP, Korf BR, Theos A. Neurofibromatosis type 1. J Am Acad Dermatol 2009; 61: 1-16.

https://doi.org/10.1016/j.jaad.2008.12.051 DOI: https://doi.org/10.1016/j.jaad.2008.12.051

Diggs-Andrews KA, Brown JA, Gianino SM, Rubin JB, Wozniak DF, Gutmann DH. Sex is a major determinant of neuronal dysfunction in neurofibromatosis type 1. Ann Neurol 2014; 75: 309-316.

https://doi.org/10.1002/ana.24093 DOI: https://doi.org/10.1002/ana.24093

Pasmant E, Vidaud M, Vidaud D, Wolkenstein P. Neurofibromatosis type 1: from genotype to phenotype. J Med Genet 2012; 49: 483-489.

https://doi.org/10.1136/jmedgenet-2012-100978 DOI: https://doi.org/10.1136/jmedgenet-2012-100978

Koczkowska M, Chen Y, Callens T, Gomes A, Sharp A, Johnson S, et al. Genotype-phenotype correlation in NF1: evidence for a more severe phenotype associated with missense mutations affecting NF1 codons 844-848. Am J Hum Genet 2018; 102: 69-87.

https://doi.org/10.1016/j.ajhg.2017.12.001 DOI: https://doi.org/10.1016/j.ajhg.2017.12.001

Kehrer-Sawatzki H, Mautner VF, Cooper DN. Emerging genotype-phenotype relationships in patients with large NF1 deletions. Hum Genet 2017; 136: 349-376.

https://doi.org/10.1007/s00439-017-1766-y DOI: https://doi.org/10.1007/s00439-017-1766-y

Kang E, Kim YM, Seo GH, Oh A, Yoon HM, Ra YS, et al. Phenotype categorization of neurofibromatosis type I and correlation to NF1 mutation types. J Hum Genet 2020; 65: 79-89.

https://doi.org/10.1038/s10038-019-0695-0 DOI: https://doi.org/10.1038/s10038-019-0695-0

Pemov A, Li H, Patidar R, Hansen NF, Sindiri S, Hartley SW, et al. The primacy of NF1 loss as the driver of tumorigenesis in neurofibromatosis type 1-associated plexiform neurofibromas. Oncogene 2017; 36: 3168-3177.

https://doi.org/10.1038/onc.2016.464 DOI: https://doi.org/10.1038/onc.2016.464

De Schepper S, Boucneau J, Lambert J, Messiaen L, Naeyaert JM. Pigment cell-related manifestations in neurofibromatosis type 1: an overview. Pigment Cell Res 2005; 18: 13-24.

https://doi.org/10.1111/j.1600-0749.2004.00206.x DOI: https://doi.org/10.1111/j.1600-0749.2004.00206.x

Stamatas GN, Zmudzka BZ, Kollias N, Beer JZ. Non-invasive measurements of skin pigmentation in situ. Pigment Cell Res 2004; 17: 618-626.

https://doi.org/10.1111/j.1600-0749.2004.00204.x DOI: https://doi.org/10.1111/j.1600-0749.2004.00204.x

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Published

2023-06-05

How to Cite

Nasi, L., Alexopoulos, A., Kokkinou, E., Roka, K. ., Tzetis, . M., Tsipi, M., Kakourou, T., Kanaka-Gantenbein, C., Chrousos, G., Kattamis, A., & Pons, R. (2023). Characteristics of Café-au-lait Macules and their Association with the Neurofibromatosis type I Genotype in a Cohort of Greek Children. Acta Dermato-Venereologica, 103, adv5758. https://doi.org/10.2340/actadv.v103.5758

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Vol. 103 (2023)

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Copyright (c) 2023 Lamprini Nasi, Alexios Alexopoulos, Eleftheria Kokkinou, Kleoniki Roka, Maria Tzetis, Maria Tsipi, Talia Kakourou, Christina Kanaka-Gantenbein, George Chrousos, Antonis Kattamis, Roser Pons

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