Continuing Education Activity

Café au lait macules (CALMs) are common cutaneous pigmentary lesions characterized by well-circumscribed, uniformly light to dark brown patches with smooth or occasionally irregular borders. The designation derives from their resemblance in color to coffee with milk. CALMs may be present at birth or develop during early childhood, occurring either as an isolated finding or a component of an underlying genetic syndrome. Histologically, CALMs demonstrate increased melanin within basal keratinocytes with a normal or mildly elevated number of melanocytes, distinguishing them from melanocytic nevi.

Isolated CALMs are generally benign and lack clinical significance. The presence of multiple lesions, usually 6 or more, measuring greater than 5 mm in prepubertal individuals or greater than 15 mm in adults, suggests neurofibromatosis type 1. Associations also exist with other genetic conditions, including McCune-Albright syndrome, Legius syndrome, and Noonan syndrome with multiple lentigines. Therefore, a comprehensive clinical assessment for associated systemic features is essential.

Differential diagnosis includes lentigines, Becker nevus, postinflammatory hyperpigmentation, and congenital melanocytic nevus. Management is primarily conservative, emphasizing reassurance and evaluation for associated disorders when indicated. Laser therapy may be employed for cosmetic purposes, although recurrence frequently occurs. Long-term follow-up is warranted among patients with multiple CALMs to facilitate early detection of syndromic associations and guide interprofessional care.

This activity enhances healthcare professionals' competence in evaluating and managing CALMs. Participants will advance their mastery of the condition's etiology, epidemiology, pathophysiology, clinical presentation, and evidence-based diagnostic and therapeutic strategies, equipping them to collaborate with interprofessional teams caring for affected individuals.

Objectives:

• Identify the distinctive features of café au lait macules, relating morphology to underlying etiology to guide management.
• Implement personalized, evidence-based approaches for managing cafe au lait macules and their associated conditions to prevent or mitigate potential complications.
• Improve patient awareness of potential systemic associations of café au lait macules and the importance of monitoring and follow-up care.
• Apply effective strategies to improve care coordination among interprofessional team members to facilitate positive outcomes for patients diagnosed with café au lait macules associated with genetic syndromes.

Access free multiple choice questions on this topic.

Introduction

Café au lait macules (CALMs) are common, flat, hyperpigmented skin lesions observed in the general population. These marks may be congenital or arise during early childhood. Lesion number and size can increase with age. Pigmentation varies from light brown to dark brown. CALMs may appear on any body site, most frequently on the trunk and extremities (see Image.  Café au Lait Macule on the Forearm). The term café au lait is derived from French, meaning “coffee with milk.”

Two principal types of CALMs have been described. CALMs with regular, sharply demarcated margins, termed “coast of California,” are more common. Lesions range from a few millimeters to several centimeters (>20 cm) and may occur as solitary or multiple spots. The second type, characterized by irregular margins and termed “coast of Maine,” is less common and typically presents as a larger, solitary lesion. The “coast of Maine” pattern is associated with segmental pigmentary disorders, whereas the “coast of California” pattern is observed in neurofibromatosis type 1 (NF1) and related conditions.

CALMs are present in approximately 95% of patients with NF1. Solitary CALMs are common, often familial, and follow autosomal dominant inheritance. Multiple CALMs, particularly when accompanied by additional clinical features, may indicate an underlying genetic disorder and require thorough evaluation. Family history of CALMs should be assessed in all patients presenting with multiple lesions.[1][2]

Etiology

CALMs are localized areas of increased melanin deposition. The precise etiology of these lesions is unknown except when they occur in association with genetic syndromes. CALMs are observed in multiple genetic disorders, including NF1, neurofibromatosis type 2 (NF2), McCune-Albright syndrome, ring chromosome syndromes, constitutional mismatch repair deficiency, tuberous sclerosis, Fanconi anemia, Bloom syndrome, and Silver-Russell syndrome.[3] CALMs may also serve as markers for RASopathies, a group of disorders resulting from mutations in the RAS signaling pathway, and are observed in Legius syndrome, Watson syndrome, and Noonan syndrome with multiple lentigines, formerly referred to as "LEOPARD syndrome."

The underlying genetic mechanisms of conditions associated with CALMs include mutations in the NF1 tumor suppressor gene on chromosome 17 in NF1, mutations in the NF2 tumor suppressor gene on chromosome 22 in NF2, mutations in the GNAS gene in McCune-Albright syndrome, and mutations in the SPRED1 gene in Legius syndrome.

Epidemiology

Most CALMs are detected at birth or emerge during early childhood. Lesions present at birth may be difficult to visualize, although Wood lamp examination can improve identification. In patients with NF1, both the number and size of CALMs may increase over time. The prevalence of CALMs in newborns varies by race, ranging from 0.3% in White infants to 18% in African American infants. Among school-aged children, prevalence ranges from 13% in White children to 27% in African American children. CALMs occur more frequently in Black children. While most children present with 1 or 2 CALMs, 3 or more lesions are observed in 1% to 14% of the population.

Pathophysiology

The pathophysiology of CALMs is unclear. However, some studies indicate that hyperpigmentation results from abnormal expression of growth factors, including stem cell factor and hepatocyte growth factor.

Histopathology

CALMs result from increased melanin within melanocytes and basal keratinocytes. An increase in melanocyte density, elevated stem cell factor cytokines, and the presence of giant melanosomes have been observed in NF1-associated CALMs, although these findings are not specific for this genetic condition.

History and Physical

Differentiation of CALMs from other pigmented disorders is essential for accurate clinical evaluation. CALMs typically appear shortly after birth or during early childhood and may increase in size over time.[4] Lesions may be solitary or multiple, with margins that are regular or irregular (see Image. Café au Lait Macules of the Posterior Trunk). Solitary CALMs are common in the general population, whereas multiple lesions warrant a comprehensive patient evaluation. Multiple CALMs frequently indicate underlying genetic syndromes, most commonly NF1. A detailed history and physical examination can reveal findings associated with the various genetic syndromes linked to multiple CALMs.

Neurofibromatosis Type 1 

NF1, also known as von Recklinghausen disease, is the most frequently observed disorder associated with multiple CALMs. The estimated population frequency of NF1 is approximately 1 in 3,500. The condition occurs with equal frequency in male and female individuals and has been identified across all ethnic groups. NF1 results from mutations in the NF1 gene and follows an autosomal dominant pattern of inheritance. Patients presenting with hyperpigmented skin lesions, visual difficulties, neurological deficits, headaches, or pain or deformity in affected bones require prompt evaluation for NF1.[5]

At least 2 of the following features must be present to establish a diagnosis of NF1:

• 6 or more CALMs, with the greatest diameter exceeding 5 mm in prepubertal individuals and 15 mm in postpubertal individuals
• 1 plexiform neurofibroma or 2 or more neurofibromas of any type
• Axillary or inguinal freckling (Crowe sign), considered pathognomonic for NF1
• Optic glioma
• 2 or more Lisch nodules (iris hamartomas)
• A distinctive bony lesion, such as sphenoid dysplasia or cortical thickening of a long bone, with or without pseudoarthrosis
• A 1st-degree relative (parent, sibling, or offspring) with NF1 diagnosed according to the above criteria [6][7]

Evaluation for NF1 should consider both cutaneous findings and systemic manifestations, including ocular and skeletal abnormalities. Differentiation from other genetic syndromes with CALMs ensures prompt diagnosis and facilitates targeted clinical follow-up.

Neurofibromatosis Type 2

NF2 is a different disorder from NF1, both clinically and genetically. This condition results from a mutation in the NF2 gene on chromosome 22, which encodes the tumor suppressor protein merlin and follows an autosomal dominant pattern of inheritance. The frequency of NF2 is approximately 1 in 40,000 births. The clinical features of this disorder include bilateral acoustic schwannomas, cataracts, meningiomas, and ependymomas. The patient may present with a hearing problem, ringing in the ears (tinnitus), and dizziness.[8]

McCune-Albright Syndrome

As mentioned, McCune-Albright syndrome is a rare genetic disorder caused by mutations in the GNAS gene. These mutations affect G-protein signaling. The classical presentation consists of a triad of CALMs, fibrous dysplasia of bone, and precocious puberty. Additional endocrinopathies may occur, including hyperthyroidism, hypercortisolism, and hypophosphatemic rickets.[9]

Legius Syndrome

Legius syndrome, an NF1-like condition, is characterized by multiple CALMs, macrocephaly, axillary freckling, lipomas, learning disabilities, and Noonan-like facies. Facial features indicative of Noonan-like facies include hypertelorism, a flat nasal bridge, downward-slanting palpebral fissures, thin lips, low-set posteriorly rotated ears, excess nuchal skin, webbed neck, and swelling of the hands and feet. Neurofibromas and cranial nervous system tumors typical of NF1 are absent in Legius syndrome.[10]

Watson Syndrome

Watson syndrome follows an autosomal dominant pattern of inheritance and shares features with NF1. The condition is characterized by CALMs, pulmonic stenosis, intellectual disability, and short stature.[11]

Noonan Syndrome with Multiple Lentigines

Noonan syndrome with multiple lentigines, formerly known as LEOPARD syndrome, is an autosomal dominant RASopathy. The acronym "LEOPARD" denotes key clinical features essential for diagnosis: lentigines, electrocardiographic conduction defects, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, growth retardation, and sensorineural deafness.

Evaluation

CALMs are diagnosed on clinical grounds. Evaluation of a child with multiple CALMs requires assessment of whether the lesions indicate an underlying systemic disorder. The presence of 6 or more CALMs should raise suspicion for a genetic syndrome, most commonly NF1. A thorough skin examination may reveal axillary or inguinal freckling and cutaneous neurofibromas. Ophthalmological evaluation using a slit lamp is essential to detect Lisch nodules and signs of optic glioma. CALMs are generally distributed in a random pattern. However, lesions confined to a single body region suggest the possibility of segmental NF1 (see Image. Multiple Café au Lait Macules with Truncal Distribution).

Patients with CALMs require careful examination for features of associated syndromes. Assessment of developmental history and academic progression is important for identifying syndromes linked to CALMs. Genetic testing can confirm suspected underlying genetic disorders. In confirmed cases, evaluation of family members is recommended to identify findings such as multiple CALMs, cutaneous neurofibromas, learning disabilities, skin tumors, or central nervous system tumors. 

Suspected cases of NF2 should undergo magnetic resonance imaging of the brain to locate vestibular schwannomas and identify other tumors associated with NF2, including meningiomas and ependymomas. Skin biopsy is generally unnecessary for diagnosis. When performed, NF1-associated CALMs demonstrate increased melanin in the basal layer and the presence of giant melanosomes.[12]

Treatment / Management

CALMs have no reported risk of malignant transformation. Treatment is generally unnecessary unless requested by the patient for cosmetic reasons. No effective medical therapy for CALMs existed until recent advancements, and laser therapy is the primary treatment modality.[13] CALMs may be treated with various lasers, including Q-switched neodymium:yttrium-aluminum-garnet (Nd:YAG), alexandrite, and ruby lasers, as well as copper vapor and pigmented lesion dye lasers.[14] Multiple treatment sessions are typically required for lesion clearance. Potential risks of laser therapy include hypopigmentation, transient or permanent hyperpigmentation, scarring, and incomplete lesion clearance.[15]

Patients with CALMs associated with genetic syndromes benefit from an interprofessional team approach. Management involves evaluation by a pediatric neurologist, dermatologist, ophthalmologist, geneticist, specialized nurse, and orthopedic surgeon. Genetic counseling for the patient and family members constitutes an essential component of the treatment plan in confirmed cases of CALMs linked to genetic syndromes such as NF1 and NF2.[16][17]

Differential Diagnosis

The differential diagnosis of CALMs includes the following:

• Congenital melanocytic nevus
• Becker nevus
• Nevus spilus
• Lentigo
• Urticaria pigmentosa
• Postinflammatory hyperpigmentation
• Plexiform neurofibroma
• Segmental pigmentation disorder
• Mastocytoma
• Phytophotodermatitis

CALMs should first be distinguished from diffuse causes of hyperpigmentation, such as Addison disease, hemochromatosis, and phototoxic or allergic reactions. These conditions lack the well-demarcated, round borders characteristic of most CALMs.

Prognosis

CALMs are challenging to treat. Laser therapy may achieve partial lesion clearance, although recurrence is frequent. CALMs are benign and have no reported morbidity or mortality. However, associated genetic syndromes can predispose patients to the development of malignant tumors.

Complications

Solitary or 2 CALMs in the absence of features of genetic syndromes are considered benign. Multiple or segmental CALMs may indicate an underlying genetic syndrome. NF1 can predispose to malignancies such as nerve sheath tumors, optic gliomas, and leukemias.[18] Tuberous sclerosis may be associated with cardiac tumors, including rhabdomyomas.[19]

Consultations

Children suspected of having NF1 or NF2 require evaluation by an interprofessional team. This team should include a pediatric neurologist, dermatologist, ophthalmologist, geneticist, and orthopedic surgeon.

Deterrence and Patient Education

Parents should seek prompt evaluation if a child has an undiagnosed pigmented lesion, 6 or more CALMs, CALMs accompanied by cutaneous nodules, CALMs associated with learning, language, or developmental delays, or a family history of multiple CALMs or a diagnosis of NF1. Patients diagnosed with NF2 require annual history and physical examination, including cutaneous, ophthalmologic, and audiologic assessments. An annual brain magnetic resonance imaging is recommended for early detection of tumors associated with NF2 beginning at age 10 years.

Children with NF1 frequently experience learning difficulties, writing impairments, and attention deficits. Parents should receive education regarding these challenges and strategies for management. Rehabilitation programs should be considered for individuals with more severe functional impairment.

Pearls and Other Issues

Legius syndrome may present with clinical features similar to those of NF1. An estimated 1% to 2% of patients who meet the diagnostic criteria for NF1 are found to have Legius syndrome. Negative results on NF1 molecular testing should prompt SPRED1 gene analysis to confirm a diagnosis of Legius syndrome.[20]

Enhancing Healthcare Team Outcomes

CALMs are benign lesions without inherent clinical significance and are common in the general population. Multiple CALMs may indicate an underlying genetic disorder, warranting evaluation by an interprofessional team. Management should involve a pediatric neurologist, dermatologist, ophthalmologist, geneticist, orthopedic surgeon, and specialized nurse. Annual follow-up is recommended to monitor disease progression.

Review Questions

• Access free multiple choice questions on this topic.
• Click here for a simplified version.
• Comment on this article.

References

1.

Hamm H, Emmerich K, Olk J. [Pigmented macules as possible early signs of genetic syndromes]. Hautarzt. 2019 Jul;70(7):506-513. [PubMed: 31076812]

2.

Shah KN. The diagnostic and clinical significance of café-au-lait macules. Pediatr Clin North Am. 2010 Oct;57(5):1131-53. [PubMed: 20888463]

3.

Nicolaides NC, Kontou M, Vasilakis IA, Binou M, Lykopoulou E, Kanaka-Gantenbein C. McCune-Albright Syndrome: A Case Report and Review of Literature. Int J Mol Sci. 2023 May 09;24(10) [PMC free article: PMC10218573] [PubMed: 37239810]

4.

Albaghdadi M, Thibodeau ML, Lara-Corrales I. Updated Approach to Patients with Multiple Café au Lait Macules. Dermatol Clin. 2022 Jan;40(1):9-23. [PubMed: 34799039]

5.

Moodley M, Lopez KR. Neurofibromatosis type 1 - an update. Semin Pediatr Neurol. 2024 Dec;52:101172. [PubMed: 39622609]

6.

Friedman JM. Neurofibromatosis 1. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews^® [Internet]. University of Washington, Seattle; Seattle (WA): Oct 2, 1998. [PubMed: 20301288]

7.

Bernier A, Larbrisseau A, Perreault S. Café-au-lait Macules and Neurofibromatosis Type 1: A Review of the Literature. Pediatr Neurol. 2016 Jul;60:24-29.e1. [PubMed: 27212418]

8.

Halliday D, Parry A, Evans DG. Neurofibromatosis type 2 and related disorders. Curr Opin Oncol. 2019 Nov;31(6):562-567. [PubMed: 31425178]

9.

Jibbe N, Jibbe A, Rajpara A. McCune Albright Syndrome. Kans J Med. 2020;13:49-50. [PMC free article: PMC7053411] [PubMed: 32190188]

10.

Giugliano T, Santoro C, Torella A, Del Vecchio Blanco F, Grandone A, Onore ME, Melone MAB, Straccia G, Melis D, Piccolo V, Limongelli G, Buono S, Perrotta S, Nigro V, Piluso G. Clinical and Genetic Findings in Children with Neurofibromatosis Type 1, Legius Syndrome, and Other Related Neurocutaneous Disorders. Genes (Basel). 2019 Jul 31;10(8) [PMC free article: PMC6722641] [PubMed: 31370276]

11.

Foster JL, Bradley SM, Ikonomidis JS. Pulmonary artery aneurysm and coronary artery disease in the clinical presentation of watson syndrome. Ann Thorac Surg. 2006 Aug;82(2):740-2. [PubMed: 16863806]

12.

Zhang J, Li M, Yao Z. Molecular screening strategies for NF1-like syndromes with café-au-lait macules (Review). Mol Med Rep. 2016 Nov;14(5):4023-4029. [PMC free article: PMC5112360] [PubMed: 27666661]

13.

Guo ZZ, Wang ZC, Wang D, Ge LL, Li YH, Gu YH, Wang W, Wei CJ, Gu B, Yao M, Dong JY, Li QF. Laser treatment for Cafe-au-lait Macules: a systematic review and meta-analysis. Eur J Med Res. 2023 Jun 08;28(1):185. [PMC free article: PMC10249291] [PubMed: 37291616]

14.

Wang T, Lin Y, Mao L, Yu X, Wang Z, Liu H, Zhang F. Treatment of café-au-lait macules with picosecond and nanosecond 1064-nm nd: YAG laser: a retrospective study. Lasers Med Sci. 2025 Jan 30;40(1):54. [PubMed: 39883241]

15.

Passeron T, Genedy R, Salah L, Fusade T, Kositratna G, Laubach HJ, Marini L, Badawi A. Laser treatment of hyperpigmented lesions: position statement of the European Society of Laser in Dermatology. J Eur Acad Dermatol Venereol. 2019 Jun;33(6):987-1005. [PubMed: 30873649]

16.

Plensdorf S, Livieratos M, Dada N. Pigmentation Disorders: Diagnosis and Management. Am Fam Physician. 2017 Dec 15;96(12):797-804. [PubMed: 29431372]

17.

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. [PubMed: 21492309]

18.

Kara B, Koksal Y. Pediatric Lymphoma and Solid Tumors Associated With Cancer Susceptibility Syndromes. J Pediatr Hematol Oncol. 2020 Oct;42(7):438-445. [PubMed: 32282651]

19.

Lee E, Mahani MG, Lu JC, Dorfman AL, Srinivasan A, Agarwal PP. Primary cardiac tumors associated with genetic syndromes: a comprehensive review. Pediatr Radiol. 2018 Feb;48(2):156-164. [PubMed: 29214333]

20.

Legius E, Messiaen L, Wolkenstein P, Pancza P, Avery RA, Berman Y, Blakeley J, Babovic-Vuksanovic D, Cunha KS, Ferner R, Fisher MJ, Friedman JM, Gutmann DH, Kehrer-Sawatzki H, Korf BR, Mautner VF, Peltonen S, Rauen KA, Riccardi V, Schorry E, Stemmer-Rachamimov A, Stevenson DA, Tadini G, Ullrich NJ, Viskochil D, Wimmer K, Yohay K, International Consensus Group on Neurofibromatosis Diagnostic Criteria (I-NF-DC). Huson SM, Evans DG, Plotkin SR. Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation. Genet Med. 2021 Aug;23(8):1506-1513. [PMC free article: PMC8354850] [PubMed: 34012067]

Disclosure: Suman Jha declares no relevant financial relationships with ineligible companies.

Disclosure: Hasnain Syed declares no relevant financial relationships with ineligible companies.