Café-au-lait macules

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.

Figure 2.

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.

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.

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.

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.