Cafe Au Lait Spots

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Café au lait spots, or café au lait (CAL) macules (CALMs), are hyperpigmented lesions that may vary in color from light brown to dark brown; [1] this is reflected by the name of the condition, which means “coffee with milk.” The borders may be smooth or irregular.

The size and number of café au lait skin lesions widely vary and are usually the earliest manifestations of neurofibromatosis. [2] The macules may be observed in infancy, although they are typically very light in infants and can be difficult to appreciate. The skin lesions develop in early infancy, and they may enlarge in size and become obvious after age 2 years.

Café au lait macules are observed in 95% of patients with neurofibromatosis type 1 (NF1), which is the most frequently occurring neurocutaneous syndrome. These spots may also be observed in patients without NF1. Other conditions in which they may be observed include McCune-Albright syndrome, tuberous sclerosis, Fanconi anemia, and Coffin-Siris syndrome (MIM 135900), characterized by developmental delay, speech impairment, distinctive facial features, hypertrichosis, hypoplasia of the distal phalanx of the fifth digit, and agenesis of the corpus callosum. [3]  Café au lait macules may be a marker for RASopathies, disorders related to RAS mutations. [4]

The images below depict various café au lait lesions.

Café au lait spots are caused by an increase in melanin content, often with the presence of giant melanosomes. A significant increase in melanocyte density is noted in the café au lait macules of patients with NF1 compared with patients who have isolated café au lait macules without NF1 involvement. Also, an increase in stem cell factor cytokines is more frequently observed in NF1 café au lait macules than non-NF1 café au lait macules.

Café au lait macules associated with NF1 result from an autosomal dominant disorder with high penetrance and variability in the expression of clinical features.

The NF1 gene is localized to the pericentromeric region of the long arm of chromosome 17. The gene encodes for neurofibromin, which is a GTP-ase activating protein that downregulates cellular proto-oncogene, p21-ras.

About 50% of individuals with NF1 have a spontaneous mutation. The high incidence of new mutations is thought to result from the large size of the gene, which increases the likelihood of spontaneous mutations.

Occasionally, patients who have larger gene deletions have a higher incidence of mental retardation and earlier appearance of cutaneous neurofibromas.

United States

In the newborn period, solitary café au lait spots may occur in 0.3% of whites, 3% of Hispanics, and in 18% of blacks. [5] In childhood, solitary café au lait macules occur in 13% of whites and 27% of blacks. Two or more café au lait macules were not observed in any of 4000 white newborns, although they were found in 8% of black newborns. Café au lait spots that confirm the diagnosis of NF1 occur at an estimated frequency of 1 in 3500 persons. [6]

International

Solitary café au lait spots occur in 0.5% of Arab newborns and in 0.4% of Chinese newborns. [5]

Café au lait spots are more frequently observed in black children.

No sexual predilection is recognized.

Typically, café au lait spots are present at birth, although they may be difficult to appreciate. A Wood lamp may improve the ability to visualize these faint spots. By the time the child is aged 2-3 years, café au lait macules are clearly visible. The size and number of café au lait macules increase with patient age in patients with NF1.

No reports indicate that café au lait macules undergo malignant change. Café au lait macules are benign and produce no mortality or morbidity, although the associated syndromes may have significant manifestations.

Plensdorf S, Martinez J. Common pigmentation disorders. Am Fam Physician. 2009 Jan 15. 79(2):109-16. [Medline].

Abeliovich D, Gelman-Kohan Z, Silverstein S, et al. Familial café au lait spots: a variant of neurofibromatosis type 1. J Med Genet. 1995 Dec. 32(12):985-6. [Medline]. [Full Text].

Sonmez FM, Uctepe E, Gunduz M, Gormez Z, Erpolat S, Oznur M, et al. Coffin-Siris syndrome with café-au-lait spots, obesity and hyperinsulinism caused by a mutation in the ARID1B gene. Intractable Rare Dis Res. 2016 Aug. 5 (3):222-6. [Medline].

Gilbert-Dussardier B, Briand-Suleau A, Laurendeau I, Bilan F, Cavé H, Verloes A, et al. Copy number variants and rasopathies: germline KRAS duplication in a patient with syndrome including pigmentation abnormalities. Orphanet J Rare Dis. 2016 Jul 22. 11 (1):101. [Medline].

Tekin M, Bodurtha JN, Riccardi VM. Cafe au lait spots: the pediatrician’s perspective. Pediatr Rev. 2001 Mar. 22(3):82-90. [Medline].

De Schepper S, Boucneau J, Vander Haeghen Y, Messiaen L, Naeyaert JM, Lambert J. Cafe-au-lait spots in neurofibromatosis type 1 and in healthy control individuals: hyperpigmentation of a different kind?. Arch Dermatol Res. 2006 Apr. 297(10):439-49. [Medline].

Medina YN, Rapaport R. Evolving diagnosis of McCune-Albright syndrome. atypical presentation and follow up. J Pediatr Endocrinol Metab. 2009 Apr. 22(4):373-7. [Medline].

Tanito K, Ota A, Kamide R, Nakagawa H, Niimura M. Clinical features of 58 Japanese patients with mosaic neurofibromatosis 1. J Dermatol. 2014 Aug. 41(8):724-8. [Medline].

Ben-Shachar S, Dubov T, Toledano-Alhadef H, Mashiah J, Sprecher E, Constantini S, et al. Predicting neurofibromatosis type 1 risk among children with isolated café-au-lait macules. J Am Acad Dermatol. 2017 Jun. 76 (6):1077-1083.e3. [Medline].

Polder KD, Landau JM, Vergilis-Kalner IJ, Goldberg LH, Friedman PM, Bruce S. Laser eradication of pigmented lesions: a review. Dermatol Surg. 2011 May. 37(5):572-95. [Medline].

Artzi O, Mehrabi JN, Koren A, Niv R, Lapidoth M, Levi A. Picosecond 532-nm neodymium-doped yttrium aluminium garnet laser-a novel and promising modality for the treatment of café-au-lait macules. Lasers Med Sci. 2018 May. 33 (4):693-697. [Medline].

Belkin DA, Neckman JP, Jeon H, Friedman P, Geronemus RG. Response to Laser Treatment of Café au Lait Macules Based on Morphologic Features. JAMA Dermatol. 2017 Nov 1. 153 (11):1158-1161. [Medline].

Carpo BG, Grevelink JM, Grevelink SV. Laser treatment of pigmented lesions in children. Semin Cutan Med Surg. 1999 Sep. 18(3):233-43. [Medline].

Stratigos AJ, Dover JS, Arndt KA. Laser treatment of pigmented lesions–2000: how far have we gone?. Arch Dermatol. 2000 Jul. 136(7):915-21. [Medline].

Goldberg DJ. Laser treatment of pigmented lesions. Dermatol Clin. 1997 Jul. 15(3):397-407. [Medline].

Kim HR, Ha JM, Park MS, Lee Y, Seo YJ, Kim CD, et al. A low-fluence 1064-nm Q-switched neodymium-doped yttrium aluminium garnet laser for the treatment of café-au-lait macules. J Am Acad Dermatol. 2015 Sep. 73 (3):477-83. [Medline].

Alora MB, Arndt KA. Treatment of a cafe-au-lait macule with the erbium:YAG laser. J Am Acad Dermatol. 2001 Oct. 45(4):566-8. [Medline].

Alster TS. Complete elimination of large café-au-lait birthmarks by the 510-nm pulsed dye laser. Plast Reconstr Surg. 1995 Dec. 96(7):1660-4. [Medline].

Wang Y, Qian H, Lu Z. Treatment of café au lait macules in Chinese patients with a Q-switched 755-nm alexandrite laser. J Dermatolog Treat. 2012 Dec. 23(6):431-6. [Medline].

Radtke HB, Sebold CD, Allison C, Haidle JL, Schneider G. Neurofibromatosis type 1 in genetic counseling practice: recommendations of the National Society of Genetic Counselors. J Genet Couns. 2007 Aug. 16(4):387-407. [Medline].

Benedict PH, Szabo G, Fitzpatrick TB, Sinesi SJ. Melanotic macules in Albright’s syndrome and in neurofibromatosis. JAMA. 1968 Aug 26. 205(9):618-26. [Medline].

Cohen JB, Janniger CK, Schwartz RA. Cafe-au-lait spots. Cutis. 2000 Jul. 66(1):22-4. [Medline].

William D James, MD Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology, Society for Investigative Dermatology

Disclosure: Received income in an amount equal to or greater than $250 from: Elsevier; WebMD.

Raj D Sheth, MD Chief, Division of Pediatric Neurology, Nemours Children’s Clinic; Professor of Neurology, Mayo College of Medicine; Professor of Pediatrics, University of Florida College of Medicine

Raj D Sheth, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Pediatrics, American Epilepsy Society, American Neurological Association, Child Neurology Society

Disclosure: Nothing to disclose.

Nazanin Saedi, MD Assistant Professor, Director of Laser Surgery and Cosmetic Dermatology, Department of Dermatology and Cutaneous Biology, Jefferson Medical College of Thomas Jefferson University

Nazanin Saedi, MD is a member of the following medical societies: American Academy of Dermatology, American Society for Dermatologic Surgery

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH Professor and Head of Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, Rutgers New Jersey Medical School; Visiting Professor, Rutgers University School of Public Affairs and Administration

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, New York Academy of Medicine, American Academy of Dermatology, American College of Physicians, Sigma Xi

Disclosure: Nothing to disclose.

Dirk M Elston, MD Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Kevin P Connelly, DO Clinical Assistant Professor, Department of Pediatrics, Division of General Pediatrics and Emergency Care, Virginia Commonwealth University School of Medicine; Medical Director, Paws for Health Pet Visitation Program of the Richmond SPCA; Pediatric Emergency Physician, Emergency Consultants Inc, Chippenham Medical Center

Kevin P Connelly, DO is a member of the following medical societies: American Academy of Pediatrics, American College of Osteopathic Pediatricians, American Osteopathic Association

Disclosure: Nothing to disclose.

Cafe Au Lait Spots

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