Dermatology

Café-au-lait macules

Cafe-au-lait macules (ICD-9 code 709.09)

Are You Confident of the Diagnosis?

Solitary cafe-au-lait macules are benign lesions that are common in the general population (Figure 1, Figure 2). Multiple lesions are much less common and should raise suspicion for an associated underlying genetic syndrome, the most likely of which is neurofibromatosis type 1 (NF1).

Figure 1.

Isolated segmental cafe-au-lait macule in a young child.

Figure 2.

A typical cafe-au-lait macule (homogeneous hyperpigmentation with smooth borders) in a teenager with NF1.

What you should be alert for in the history

Cafe-au-lait macules may be present at birth or appear within the first few years of life. It is uncommon for them to appear de novo later in childhood. They enlarge proportionately with the child's growth and darken with sun exposure. In patients with multiple cafe-au-lait spots it is important to obtain a family history of similar lesions or disorders known to be associated with cafe-au-lait macules.

Characteristic findings on physical examination

Cafe-au-lait macules appear as sharply demarcated hyperpigmented macules or patches. The color ranges from tan to dark brown and is homogeneous. The borders can be smooth ("coast of California") or irregular ("coast of Maine") (Figure 3). Cafe-au-lait macules can appear anywhere on the body, but are most common on the trunk and extremities and least common on the face. They can vary in size from a few millimeters to greater than 20 centimeters.

Figure 3.

Multiple cafe-au-lait macules with irregular borders in a child who tested negative for NF1 and SPRED1 and no known underlying genetic syndrome.

Cafe-au-lait macules are usually randomly distributed, but when limited to a single body region should raise the suspicion for segmental NF1 (Figure 4). Examination with a Wood's lamp, especially in fair-skinned individuals, can be helpful.

Figure 4.

Multiple cafe-au-lait macules and inguinal freckling in a child with segmental NF1. These findings were limited to left leg and buttock.

Patients presenting with multiple cafe-au-lait macules (> 5) should have a thorough skin examination looking for other stigmata of NF1, including skin fold freckling and neurofibromas, and an ophthalmological evaluation with slit lamp examination (Figure 5).

Figure 5.

Hyperpigmentation overlying an early plexiform neurofibroma and typical cafe-au-lait macules in a child with NF1.

Expected results of diagnostic studies

A skin biopsy is usually not necessary to establish a diagnosis. If done, one would expect to see an increase amount of melanin along the basal layer. Giant melanosomes and an increased number of melanocytes have been reported in NF1-associated cafe-au-lait macules, but are not specific for NF1.

Laboratory studies and imaging are not necessary unless an associated genetic syndrome is suspected based on the presence of multiple cafe-au-lait macules, family history, or associated findings on history or physical examination. These studies should be tailored according to clinical suspicion.

Diagnosis confirmation

The differential diagnosis includes other congenital or acquired pigmented lesions:

Congenital melanocytic nevus. Differentiation may be difficult in infancy, but most congenital nevi become more raised over time and develop varying amounts of hypertrichosis and color variation.

Lentigo. Often smaller and darker than cafe-au-lait macules, with distinct histology.

Becker nevus. Typically appears in males at adolescence on upper chest or back with associated hypertrichosis and distinct histology.

Plexiform neurofibroma. Hyperpigmentation, often with a smudged or irregular border, may be the first sign of a superficial plexiform neurofibroma, but lesion will become more infiltrated over time.

Nevus spilus. Light brown patch that develops an increasing number of pigmented macules or papules, representing junctional or compound nevi.

Pigmentary mosaicism. Hyperpigmentation follows lines of Blaschko.

Segmental pigmentation disorder. Block-like hyperpigmentation with sharp midline demarcation and less distinct lateral border.

Urticaria pigmentosa. Lesions have a more yellow hue and urticate when stroked.

Postinflammatory hyperpigmentation. Receding history of inflammation or trauma).

Who is at Risk for Developing this Disease?

The prevalence of a solitary cafe-au-lait macule is estimated to be 3-36%, depending on the population studied. Multiple cafe-au-lait macules (> 5) are much less common and occur in less than 1% of the normal population. Cafe-au-lait macules are more common in African Americans than in Caucasians.

What is the Cause of the Disease?

Etiology

The etiology of sporadic cafe-au-lait macules is unknown.

Pathophysiology

NF1-associated macules have recently been shown to be caused by a loss of both NF1 alleles in cultured melanocytes, although what role this plays in the hyperpigmentation is unclear. Aberrant expression of certain growth factors, such as stem cell factor and hepatocyte growth factor, and their receptors may play a role in the epidermal hyperpigmentation.

Systemic Implications and Complications

Cafe-au-lait macules themselves are harmless, but when multiple or segmental, may be a marker for a number of genetic syndromes. Six or more cafe-au-lait macules fulfills one of the seven National Institutes of Health (NIH) diagnostic criteria for NF1. Other syndromes definitely associated with multiple cafe-au-lait macules include: (1) neurofibromatosis type 2 (NF2); (2) Legius syndrome (NF1-like syndrome); (3) autosomal dominant multiple cafe-au-lait macules; (4) Watson syndrome; (5) McCune-Albright syndrome; (6) LEOPARD syndrome; (7) ring chromosome syndromes; and (8) constitutional mismatch repair deficiency syndrome (CMMR-D).

NF1 is by far the most common disorder associated with multiple cafe-au-lait macules. Two studies found that approximately 75% of young children who presented with at least six cafe-au-lait macules only eventually met diagnostic criteria for NF1.

NF2 usually presents with fewer cafe-au-lait macules than NF1, along with bilateral vestibular schwannomas and other central nervous system (CNS) tumors. Work-up and management of NF1 and NF2 is detailed in the chapter entitled “Neurofibromatosis".

Legius syndrome is a newly defined disorder characterized by multiple cafe-au-lait macules, axillary freckling, and macrocephaly. Patients may meet diagnostic criteria for NF1, but do not appear to develop Lisch nodules, neurofibromas, or CNS tumors. Legius syndrome should be considered when multiple family members have cafe-au-lait macules and axillary freckling, but lack neurofibromas or when a patient meets diagnostic criteria for NF1 based on pigmentary features, but molecular testing for NF1 is negative. Legius syndrome is due to mutations in SPRED-1 and genetic testing is available.

Several reports have described families with multiple cafe-au-lait macules without other stigmata of NF1. NF1 testing is negative in these families. Some may have in fact have Legius syndrome, while others have a yet unidentified molecular defect. This diagnosis should only be made when there is a clear family history of multiple cafe-au-lait macules, but not neurofibromas, and testing for NF1 and SPRED1 is negative.

Watson syndrome is allelic to NF1 and in addition to multiple cafe-au-lait macules presents with pulmonary stenosis, short stature and dull intelligence.

The cafe-au-lait macules in McCune-Albright syndrome tend to be large, unilateral, and follow the lines of Blaschko They are often described as having jagged borders. Other cardinal features include fibrous dysplasia, precocious puberty and other endocrinopathies, such as hyperthyroidism. This disorder is sporadic and due to postzygotic mutations in the gene GNAS1. Genetic testing of blood or skin biopsy from cafe-au-lait macules is available, but sensitivity is low.

In LEOPARD syndrome, the cafe-au-lait macules are often dark brown (cafe-noir macules). Additionally, LEOPARD syndrome is associated with multiple lentigenes, cardiac conduction defects, ocular hypertelorism, pulmonary stenosis, growth retardation, genital abnormalities and hearing loss. Most commonly LEOPARD syndrome is due to a mutation in PTPN11, but other genes of the RAS/MAPK pathway have also been reported. Genetic testing is available.

Multiple cafe-au-lait macules in patients with ring chromosome syndromes involving chromosomes 7, 11, 12, 15 and 17 have been reported. These children also have a number of other congenital anomalies, such as facial dysmorphism and microcephaly. Karyotyping can confirm the diagnosis.

CMMR-D is caused by homozygosity for one of the genes causing hereditary non-polyposis colon cancer. Typical features are adenomatous colonic polyps, early-onset colorectal cancer and an increased risk for various pediatric malignancies. Recently, the presence of multiple cafe-au-lait macules, often described as irregular, has been reported in these patients. Skin-fold freckling, Lisch nodules, and neurofibromas have also been described. This condition can be distinguished from NF1 in that one or both parents has clinical findings or a family history of non-polyposis colorectal cancer and lacks features of NF1. NF1 testing is negative.

Cafe-au-lait macules may also occur at a higher frequency in other syndromes, including Cowden syndrome, Banayan-Riley-Ruvalcalba syndrome, Bloom syndrome, Noonan syndrome, ataxia-telangiectasia, Russell-Silver syndrome, Fanconi anemia, tuberous sclerosis complex, Turner syndrome, multiple mucosal neuroma syndrome 1 or 2b, Rubinstein-Taybi syndrome and Kabuki syndrome, although the strength of this association varies among studies.

Treatment Options

Treatment options are summarized in Table I.

Table I.

Treatment options for cafe-au-lait macules
Medical Surgical Physical
None Laser therapy Sun protection
Q-switched Nd:YAG (532 nm, 1064 nm)
Q-switched alexandrite (755 nm)
Q-switched ruby (694 nm)
Copper vapor laser (511 nm)
Pigmented lesion dye laser (510 nm)

Optimal Therapeutic Approach for this Disease

Cafe-au-lait macules are benign lesions and treatment is not required. However, treatment may be requested to improve cosmesis. Multiple lasers have been reported to be efficacious, although success is variable and repigmentation occurs in up to half of all treated lesions. To date, no studies comparing these lasers in a randomized fashion exists; therefore, it is not possible to recommend one modality over another.

The main risks of laser treatment of cafe-au-lait macules are hypo- and hyperpigmentation. It is important to counsel patients prior to laser treatments that only about half of cafe-au-lait macules lighten with treatment, multiple treatment sessions may be necessary, and about half of lesions that do respond will gradually darken over time.

There is currently no accepted medical treatment for cafe-au-lait macules. A topical vitamin D3 analog (tacalcitol ointment) was described in two patients as an effective treatment for improving the pigmentation of NF1-associated cafe-au-lait macules.

Sun protection may be helpful to decrease the darkening that occurs with sun exposure.

Patient Management

All patients presenting with a cafe-au-lait macule should have a complete skin examination looking for other lesions. Patients with one or two cafe-au-lait macules and no other findings can be reassured that these are likely isolated and no further treatment or workup is needed.

Patients with three or more cafe-au-lait macules will need a more detailed history and physical examination to exclude an underlying associated genetic syndrome.

Patients should be questioned about other family members with multiple cafe-au-lait macules, neurofibromatosis, skin tumors, brain or spinal cord tumors, deafness, and colon cancer (for CMMR-D) They should also be questioned about any personal history of tumors or cancer, learning disabilities, deafness, fractures, and hypertension.

Physical examination should be focused on the number, size, distribution and morphology of the cafe-au-lait macules, associated skin findings (freckling of the axilla or groin, lentigines, cutaneous neurofibromas, plexiform neurofibromas), skeletal system (macrocephaly, short stature, scoliosis, bowing of long bones, facial asymmetry), signs of precocious puberty and presence of other congenital anomalies.

Skin examination of first-degree relatives may be useful if an autosomal dominant disorder, such as NF1, is suspected. When an associated genetic syndrome is suspected, patients should be referred to an appropriate specialist.

Patients with six or more cafe-au-lait macules or with other findings suggestive of NF1 should be have a baseline ophthalmologic evaluation with slit lamp examination. Children with 6 or more cafe-au-lait macules and no other findings should be followed yearly with physical examination and ophthalmologic evaluation until at least the age of 10 or until another diagnosis becomes apparent.

Genetic testing is available for many of the syndromes associated with multiple cafe-au-lait macules and could be considered for clinical confirmation of a suspected diagnosis or when prenatal testing is desired. Molecular NF1 testing may allow an earlier diagnosis of NF1 in a young child presenting with six or more cafe-au-lait macules, no family history of NF1, and no other findings on exam. The sensitivity of this test is 95%. If the NF1 testing is negative, SPRED-1 testing should be considered.

Unusual Clinical Scenarios to Consider in Patient Management

Multiple cafe-au-lait macules localized to one body region suggests segmental NF1. These macules are often superimposed over an area of hyperpigmentation that is sharply demarcated from the surrounding skin. Freckling and neurofibromas can appear in the region. More serious complications of NF1 are generally absent.

Segmental NF1 is due to a somatic or post-zygotic mutation in the NF1 gene. The risk of transmitting full-blown NF1 to offspring is low, but has been reported. An NF1 mutation will not be identified in blood, but can be detected from skin biopsy of a cafe-au-lait macule.

Multiple cafe-au-lait macules and freckling of the axilla or groin were once thought to be pathognomonic for NF1. It is now known that Legius syndrome can present with the same pigmentary features. The more serious tumorigenic manifestations do not appear to occur in patients with Legius syndrome. Recognizing this disorder may have important prognostic and monitoring implications for patients. It is estimated that 1- 2% of patients that fulfill NIH diagnostic criteria met solely by pigmentary findings will actually have Legius syndrome.

What is the Evidence?

Shah, KN. "The diagnostic and clinical significance of cafe-au-lait ". Pediatr Clin N Am. vol. 57. 2010. pp. 1131-53.

(A well-referenced and thorough review of cafe-au-lait macules and associated syndromes. Tables summarizing the differential diagnosis and associated syndromes are provided.)

Nunley, KS, Gao, F, Albers, AC, Bayliss, SJ, Gutmann, DH. "Predictive value of cafe-au-lait macules at initial consultation in the diagnosis of neurofibromatosis type 1". Arch Dermatol. vol. 145. 2009. pp. 883-7.

(A retrospective study examining 110 children referred for evaluation of cafe-au-lait macules. This study found that 77% of children with 6 or more macules eventually fulfilled diagnostic criteria for NF1 and this likelihood increased with an increasing number and typical morphology of cafe-au-lait macules.)

Korf, BR. "Diagnostic outcome in children with multiple cafe-au-lait ". Pediatrics . vol. 90. 1992. pp. 924-7.

(A prospective study that clinically followed 41 children presenting with six or more cafe-au-lait macules. Seventy-three percent went on to meet diagnostic criteria of NF1.)

De Schepper, S, Bouncneau, J, Lambert, J, Messiaen, L, Naeyaert, JM. "Pigment cell-related manifestations in neurofibromatosis type 1: an ". Pigment Cell Res . vol. 18. 2004. pp. 13-24.

(A thorough review of the known etiology and pathophysiology of cafe-au-lait macules in patients with NF1.)

De Schepper, S, Maertens, O, Callens, T, Naeyaert, JM, Lambert, J, Messiaen, L. "Somatic mutation analysis in NF1 cafe-au-lait spots reveals two NF1 hits in the ". J Invest Dermatol . vol. 128. 2008. pp. 1050-53.

(The first report that showed cafe-au-lait macules in NF1 are caused by loss of both NF1 alleles.)

(Denayer, E, Chmara, M, Brems, H, Maat Kievit, A, van Bever, Y. "Legius syndrome in fourteen ". Hum Mutat. vol. 32. 2011. pp. E1985-1998.

(A review of the clinical and genetic features of 30 individuals with Legius or NF1-like syndrome.)

Muram-Zborovski, TM, Stevenson, DA, Viskochil, DH, Dries, DC, Wilson, AR, Mao, R. "SPRED1 mutations in a neurofibromatosis ". J Child Neurol. vol. 25. 2010. pp. 1203-9.

(A prospective study that found 1.3% of patients referred to an NF Clinic who met NIH diagnostic criteria for NF1 harbor SPRED1 mutations. This likelihood increases with age if nonpigmentary NF1 findings are absent.)

Carpo, BG, Grevelink, JM, Grevelink, SV. "Laser treatment of pigmented lesions in ". Semin Cutan Med Surg . vol. 18. 1999. pp. 233-43.

(A review of laser treatments for pigmented lesions, including cafe-au-lait macules.)

Nakayama, J, Kiryu, H, Urabe, K, Matsuo, S, Shibata, S. "Vitamin D3 analogues improve cafe-au-lait spots in patients with von Recklinghausen's disease: experimental and clinical ". Eur J Dermatol . vol. 9. 1999. pp. 202-5.

(This case report described two patients with large cafe-au-lait macules who were treated with topical tacalcitol. The cafe-au-lait macules appeared lighter after 6 months of therapy.)
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