Cafe-au-lait spots as a clinical sign of syndromes

Authors

DOI:

https://doi.org/10.33448/rsd-v10i9.17607

Keywords:

Cafe-au-lait spots; Hyperpigmentation; Neurofibromatosis; Inborn genetic diseases; Hereditary syndromes.

Abstract

Several studies describe the frequent association of cafe-au-lait spots with neurofibromatosis. However, many other genetic diseases might be associated with the presence of café-au-lait spots. Several genetic diseases are rare. In most cases, syndromes present themselves as a set of signs and symptoms that may present varied penetrance, therefore largely reducing the percentage of final diagnosis. Exploration of clinical symptomatology is essential for the understanding and diagnosis of syndromes. In this review, we conduct an extensive literature search looking for research that investigated diseases that may be present simultaneously with the cafe-au-lait spots. A total of 60 genetic diseases were found, all of them rare. These syndromes were evaluated based on their most relevant features and described in a summary of the typical, general, and head and neck findings. The available OMIM number, mode of inheritance, chromosome, mutated genes, and affected proteins were also listed. The considerable variety of diseases associated with the presence of cafe-au-lait spots and the fact that many of these conditions affect various organ systems with diverse phenotypic presentations is a diagnostic and therapeutic challenge. The objective of this study was to provide health professionals with an instrument containing a broad spectrum of genetic diseases coincident with the presence of cafe-au-lait spots in order to facilitate the differential and final diagnosis of these syndromes.

References

Alawi, F. (2019). Using rare diseases as teaching models to increase awareness. Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology, 128(2), 99-100. DOI: 10.1016/j.oooo.2019.04.015

Allanson, J. E., Upadhyaya, M., Watson, G. H., Partington, M., MacKenzie, A., Lahey, D., … Harper, P., S. (1991). Watson syndrome: is it a subtype of type 1 neurofibromatosis? Journal of Medical Genetics, 28, 752-756. DOI: 10.1136/jmg.28.11.752

Amyere, M., Vogt, T., Hoo, J., Brandrup, F., Bygun, A., Boon, L., … Vikkula, M. (2011). KITLG mutations cause familial progressive hyper- and hypopigmentation. Journal of Investigative Dermatology, 131(6), 1234-1239. DOI: 10.1038/jid.2011.29

Aoki, Y., Niihori, T., Inoue, S., & Matsubara, Y. (2016). Recent advances in RASopathies. Journal of Human Genetics, 61(1), 33-39. DOI: 10.1038/jhg.2015.114

Arora, H., Chacon, A. H., Choudhary, S., McLeod, M. P., Meshkov, L., Nouri, K., … Izakovic, J. (2014). Bloom syndrome. International Journal of Dermatology, 53(7), 798-802. DOI: 10.1111/ijd.12408

Baas, A. F., Gabbett, M., Rimac, M., Kansikas, M., Raphael, M., Nievelstein, R. A., … Wimmer, K. (2013). Agenesis of the corpus callosum and gray matter heterotopia in three patients with constitutional mismatch repair deficiency syndrome. European Journal of Human Genetics, 21(1), 55-61. DOI: 10.1038/ejhg.2012.117

Baxter, L. L., & Pavan, W. J. (2013). The etiology and molecular genetics of human pigmentation disorders. Wiley Interdisciplinary Reviews: Developmental Biology, 2(3), 379–392. DOI: 10.1002/wdev.72

Boquett, J. A., & Ferreira, R. J. (2010). Aspectos biológicos e atividade tumorigência da família proto-oncogênica Ras. Semina: Ciências Biológicas e da Saúde, 31(2), 201-211. DOI:10.5433/1679-0359.2011v32n2p201

Brems, H., Beert, E., Ravel, T., & Legius, E. (2009). Mechanisms in the pathogenesis of malignant tumors in neurofibromatosis type 1. The Lancet Oncology, 10(5), 508-515. DOI: 10.1016/S1470-2045(09)70033-6

Brems, H., Chmara, M., Sahbatou, M., Denayer, E., Taniguchi, K., Kato, R., … Legius, E. (2007). Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. Nature Genetics, 39(9), 1120-1126. DOI: 10.1038/ng2113

Campen, R., Mankin, H., Louis, D. N., Hirano, M., & MacCollin, M. (2001). Familial occurrence of adiposis dolorosa. Journal of the American Academy of Dermatology, 44(1), 132-136. DOI: 10.1067/mjd.2001.110872

Cao, H., Alrejaye, N., Klein, O. D., Goodwin, A. F., & Oberol, S. (2017). A review of craniofacial and dental findings of the RASopathies. Orthodontics & Craniofacial Research, 20(1), 32-38. DOI: 10.1111/ocr.12144

Chatten, J., & Voorhess, M. L. (1967). Familial neuroblastoma. Report of a kindred with multiple disorders, including neuroblastomas in four siblings. The New England Journal of Medicine, 277(23), 1230-1236. DOI: 10.1056/NEJM196712072772304

Chiu, Y. E., Dugan, S., Basel, D., & Siegel, D. H. (2013). Association of Piebaldism, multiple café-au-lait macules, and intertriginous freckling: clinical evidence of a commom pathway between KIT and sprout-related, ena/vasodilator-stimulated phosphoprotein homology-1 domain containing protein 1 (SPRED1). Pediatric Dermatology, 30(3), 379-382. DOI: 10.1111/j.1525-1470.2012.01858.x

Cichorek, M., Wachulska, M., Stasiewicz, A., & Tymińska, A. (2013). Skin melanocytes: biology and development. Postepy Dermatologii Alergologii, 30(1), 30-41. DOI: 10.5114/pdia.2013.33376

Digilio, M. C., Lepri, F., Baban, A., Dentici, M. L., Versacci, P., Capolino, R., ... Dallapiccola, B. (2011). RASophaties: Clinical Diagnosis in the First Year of Life. Molecular Syndromology 1(6), 282-289. DOI: 10.1159/000331266

Elissen, W. L. (2016) Genética molecular do câncer. Latest revision: 2016 [Accessed: March 01, 2021]. Avaliable at: https://www.medicinanet.com.br › conteudos › acp-medicine

Evans, D. G. (2009). Neurofibromatosis type 2 (NF2): A clinical and molecular review. Orphanet Journal of Rare Diseases, 4, 16. DOI: 10.1186/1750-1172-4-16

Ferner, R. E. (2007). Neurofibromatosis 1 and neurofibromatosis 2: A twenty first century perspective. The Lancet Neurology, 6(4), 340-351. DOI: 10.1016/S1474-4422(07)70075-3

Fistarol, S. K., & Itin, P. H. (2010). Disorders of pigmentation. Journal der Deutschen Dermatologischen Gesellschaaft, 8(3), 187-201. DOI: 10.1111/j.1610-0387.2009.07137.x

Ghada, M. H., Abdel-Salam, M. D., Hana, H., Afifi, M. D., Maha, M., Eid, M. D., ... Kholoussi, N. (2011). Ectodermal Abnormalities in Patients with Kabuki Syndrome. Pediatric Dermatology, 28(5), 507-511. DOI: 10.1111/j.1525-1470.2011.01495.x

Giugliani, L., Vanzella, C., Zambrano, M. B., Donis, K. C., Wallau, T. K. W., & Costa, F. M. (2019). Clinical research challenges in rare genetic diseases in Brazil – Review Article. Genetics and Molecular Biology, 42(1), 305-311. DOI: http://dx.doi.org/10.1590/1678-4685-GMB-2018-0174

Guimarães, P. B., Branco, A. A., Carvalho, E., Lima, F. E., Almeida, J. R., Santos, J. B., ... De Perreli, T. (2002). Síndrome de Cowden: relato de um caso. Anais Brasileiro de Dermatologia, 77(6), 711-720. DOI: 10.1590/S0365-05962002000600009

Gursoy, S., & Erçal, D. (2018). Genetic Evaluation of Common Neurocutaneous Syndromes. Pediatric Neurology, 89, 3-10. DOI: 10.1016/j.pediatrneurol.2018.08.006

Halal, F., Genrak, M. H., Baillargeon, J., & Lesage, R. (1982). Gastro-Cutaneous Syndrome: Peptic Ulcer/Hiatal Hernia, Multiple Lentigines/Café-au-lait Spots, Hypertelorism, and Myopia. American Journal of Medical Genetics, 11, 161-176. DOI: 10.1007/s00105-019-4416-6

Hamm, H., Emmerich, K., & Olk, J. (2019). Pigmentierte Flecken als mögliche Frühzeichen genetischer Syndrome. Der Hautarzt, 70, 506-513. DOI: 10.1007/s00105-019-4416-6

Hatipoglu, N., Kurtoglu, S., Kendirci, M., Keskin, M., & Per, H. (2010). Neurofibromatosis Type 1 with Overlap Turner Syndrome and Klinefelter Syndrome. Journal of Tropical Pediatrics, 56(1), 69-72. DOI: 10.1093/tropej/fmp053

Hennekam, R. C. M., Allanson, J. E., Krantz, I. D., & Gorlin, R. J. (2010). Gorlin's syndromes of the head and neck (5th ed). New York, NY: Oxford.

Jansen, S., Hoischen, A., Coe, B. P., Carvill, G. L., Van Esch, H., Bosch, D., … Vries, B. B. A. (2018). A genotype-first approach identifies an intellectual disability-overweight syndrome caused by PHIP haploinsufficiency. European journal of human genetics, 26(1), 54–63. DOI: 10.1038/s41431-017-0039-5

Klar, N., Cohen, B., & Lin, D. D. M. (2015). Neurocutaneous syndromes. Handbook of Clinical Neurology,135, 565-589. DOI: 10.1016/s0031-3955(16)38367-5

Madson, J. G. (2012). Multiple or familial café-au-lait spots is neurofibromatosis type 6: clarification of a diagnosis. Dermatology Online Journal,18(5), 4. DOI: 10.5070/D33d56c2q8

Maertens, O., De Schepper, S., Vandesompele, J., Brems, H., Heynes, I., Janssens, S., … Messiaen, L. (2007). Molecular dissection of isolated disease features in mosaic neurofibromatosis type 1. The American Journal of Human Genetics, 81(2), 243-251. DOI: 10.1086/519562

Martelli, H., Jr. (2019). In reply to: Alawi F. “Using rare diseases as teaching models to increase awareness”. Letter to the editor. Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology, 128, 690-691. DOI: 10.1016/j.oooo.2019.07.002

Mertens, D. E. (2015). Research and evaluation in education and psychology: integrating diversity with quantitative, qualitative and mixed methods (5th ed).

Chapter 3: Literature Review and Focusing the Research. Thousand Oaks, CA: Sage Publication, pp. 89-121

Mulchandani, S., Bhoj, E. J., Luo, M., Powell-Hamilton, N., Jenny, K., & Gripp, K. W. (2016). Maternal uniparental disomy of chromosome 20: a novel imprinting disorder of growth failure. Genetics in Medicine, 18, 309-315. DOI: 10.1038/gim.2015.103

Nishimura, G., Hasegawa, T., Fujino, M., Hori, N., & Tomita, Y. (2003). Microcephalic osteodysplastic primordial short stature type II with cafe‐au‐lait spots and moyamoya disease. American Journal of Medical Genetics, 117(3), 299-301. DOI: 10.1002/ajmg.a.10230

Nyström, A. M., Ekvall, S., Stromberg, B., Holmstrom, G., Thuresson, A. C., Annerén, G., … Bondeson, M. L. (2009). A severe form of Noonan syndrome and autosomal dominant café-au-lait spots–evidence for different genetic origins. Acta Paediatrica, 98, 693-698. DOI: 10.1111/j.1651-2227.2008.01170.x

Oates, J. A., & Harris, R. L. (2015). Literature Review and Focusing the Research (Chapter 3). In R. Harris & F. Williams (Eds.), Research and Evaluation in Education and Psychology, integrating diversity with quantitative, qualitative and mixed methods (5th ed). Thousand Oaks, CA: Sage Publication, pp. 89-121.

Oiso, N., Fukai, K., Kawada, A., & Suzuki, T. (2013). Piebaldism. The Journal of Dermatology, 40(5): 330-335. DOI: 10.1111/j.1346-8138.2012.01583.x

Online Mendelian Inheritance in Man, OMIM®: authoritative compendium of human genes and genetic phenotypes. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD). Available at: https://omim.org/

Origone, P., Defferrari, R., Mazzocco, K., Cunsolo, C. L., Bernardi, B., Tonini, G. P. (2003). Homozygous Inactivation of NF1 Gene in a Patient with Familial NF1 and Disseminated Neuroblastoma. American Journal of Medical Genetics, 118A(4), 309-313. DOI:10.1002/ajmg.a.10167

Orphanet: an online database of rare diseases and orphan drugs. Copyright, INSERM 1997. Available at: www.orpha.net

Pagnamenta, A. T., Murray, J. E., Yoon, G., Sadighi Akha, E., Harrison, V., Bicknell, L. S., … Knight, S. J. (2012). A novel nonsense CDK5RAP2 mutation in a Somali child with primary microcephaly and sensorineural hearing loss. American Journal of Medical Genetics, 158A, 2577-2582. DOI: 10.1002/ajmg.a.35558

Picardo, M., & Cardinali, G. (2011). The genetic determination of skin pigmentation: KITLG and the KITLG⁄c-Kit pathway as key players in the onset of human familial pigmentary diseases. Journal of Investigate Dermatology, 131(6), 1182-1185. DOI: 10.1038/jid.2011.67

Plana-Pla, A., Bielsa-Marsol, I., & Carrato-Monino, C. (2017). Diagnostic and Prognostic Relevant of the Cutaneous Manifestations of Neurofibromatosis Type 2. Actas Dermo-Sifiliográficas, 108(7), 630-636. DOI: 10.1016/j.adengl.2016.12.025

Plataras, C., Christianakis, E., Fostira, F., Bourikis, G., Chorti, M., Bourikas, D., … Eirekat, K. (2018). Asymptomatic Gastric Giant Polyp in a Boy with Peutz- Jeghers Syndrome Presented with Multiple Café Au Lait Traits. Case Reports in Surgery, 2018, 1-3, Article ID 6895974. DOI: 10.1155/2018/6895974

Reith, W. (2013). Phakomatosen. Der Radiologe, 53, 1075-1076. DOI: 10.1007/s00117-013-2532-3

Rinaldi, B., Vaisfeld, A., Amarri, S., Baldo C, Gobbi G, Magini P, … Crimi, M. (2017). Guideline recommendations for diagnosis and clinical management of Ring14 syndrome-first report of an ad hoc task force. Orphanet Journal of Rare Diseases, 12(1), 69. DOI: 10.1186/s13023-017-0606-4

Rivers, J. K., MacLennan, R., Kelly, J. W., Lews, A. E., Tate, B. J., Harrison, S., … McCarthy, W. H. (1985). The eastern Australian childhood nevus study: prevalence of atypical nevi, congenital nevus-like nevi, and other pigmented lesions. Journal of the American Academy of Dermatology, 32(6), 957-963. DOI: 10.1016/0190-9622(95)91331-9

Ronnstrand, L. (2004). Signal transduction via the stem cell factor receptor/c-Kit. Cellular and Molecular Life Sciences, 61(19-20), 2535-2548. DOI: 10.1007/s00018-004-4189-6

Rosales-Solis, G. M., Martínez-Longoria, C. A., Guerrero-González, G. A., Ocampo-Garza, J., & Ocampo-Candiani, J. (2016). Síndrome de Bloom. Manifestaciones clínicas y estudio cromosómico en una niña mexicana [Bloom syndrome. Clinical manifestations and cromosomal study in a Mexican child]. Gaceta medica de Mexico, 152(6), 836–837. PMID: 27861482

Sarkozy, A., Digilio, M. C., & Dallapiccola, B. (2008). Leopard Syndrome. Orphanet Journal of Rare Diseases, 3, 13. DOI: 10.1186/1750-1172-3-13

Sarnat, H. B., & Flores-Sarnat, L. (2005). Embryology of the neural crest: its inductive role in the neurocutaneous syndromes. Journal of Child Neurology, 20(8), 637-643. DOI: 10.1177/08830738050200080101

Shah, K. N. (2010). The Diagnostic and Clinical Significance of Café-au-lait Macules. Pediatric Clinics of North America, 57(5), 1131-1153. DOI: 10.1016/j.pcl.2010.07.002

Spiteri, B. S., Stafrace, Y., Calleja-Agius J. (2017). Silver-Russell Syndrome: A Review. Neonatal Network, 36(4), 206-212. DOI: 10.1891/0730-0832.36.4.206.

Tajan, M., Paccoud, R., Branks, S., Edouard, T., & Yart, A. (2018). The RASopathy Family: Consequences of Germline Activation of the RAS/MAPK Pathway. Endocrine Reviews, 39(5), 676-700. DOI: 10.1210/er.2017-00232

Tidyman, W. E., & Rauen, K. A. (2016). Expansion of the RASopathies. Current Genetic Medicine Reports, 4(3): 57-64. DOI: 10.1007/s40142-016-0100-7

Veenma, D. C. M., Eussen, H. J., Govaerts, L. C. P., de Kort, S. W. K., Odink, R. J., Wouters, C. H., … de Klein, A. (2010). Phenotype-genotype correlation in a familial IGF1R microdeletion case. Journal of Medical Genetics, 47, 492-498. DOI: 10.1136/jmg.2009.070730.

Walsh, M. F., Chang, V. Y., Kohlmann, W. K., Scott, H. S., Cunniff, C., Bourdeaut, F., … Savage, S. A. (2017). Recommendations for Childhood Cancer Screening and Surveillance in DNA Repair Disorders. Clinical Cancer Research, 23(11), 23-31. DOI: 10.1158/1078-0432.CCR-17-0465

Wimmer, K., Rosenbaum, T., & Messiaen, L. (2017). Connections between constitucional mismatch repair deficienty syndrome and neurofibromatosis type 1. Clinical genetics, 91(4), 507-519. DOI: 10.1111/cge.12904

Young I. D., Barrow, M., & Hall, C. M. (2004). Microcephalic Osteodysplastic Primordial Short Stature Type II with Café-au-lait Spots and Moyamoya Disease: Another Patient. American Journal of Medical Genetics, 127(A), 218-220. DOI: 10.1002/ajmg.a.20647

Zeng, L., Zheng, X. D., Liu L. H., Fu, L. Y., Zuo, X. B., Chen, G., … Zhang, X. J. (2016). Familial progressive hyperpigmentation and hypopigmentation without KITLG mutation. Clinical and Experimental Dermatology, 41(8), 927-929. DOI: 10.1111/ced.12923

Zhang, J., Li, M., & Yao, Z. (2016). Molecular screening strategies for NF1-like syndromes with café-au-lait macules (Review). Molecular Medicine Reports, 14(5), 4023-4029. DOI: 10.3892/mmr.2016.5760

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23/07/2021

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CARVALHO , A. A.; MARTELLI , D. R. B.; CARVALHO , M. F. A.; SWERTS , M. S. O.; MARTELLI JÚNIOR , H. Cafe-au-lait spots as a clinical sign of syndromes. Research, Society and Development, [S. l.], v. 10, n. 9, p. e14310917607, 2021. DOI: 10.33448/rsd-v10i9.17607. Disponível em: https://rsdjournal.org/index.php/rsd/article/view/17607. Acesso em: 23 sep. 2021.

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