Cafe Au Lait Spots

Background

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.

View Image

Axillary freckling showing café au lait spots.

View Image

Multiple irregular sized and shaped café au lait lesions.

View Image

Café au lait lesions.

View Image

Café au lait lesions.

• References

Pathophysiology

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.

• References

Etiology

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.

• References

Epidemiology

Frequency

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]

Race

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

Sex

No sexual predilection is recognized.

Age

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.

• References

Prognosis

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.

• References

History

The presence of numerous café au lait macules (CALMs) should raise the suspicion of a genetic disorder. The most common associated systemic disorder is neurofibromatosis type 1 (NF1).

The diagnostic criteria for NF1 are met if 2 or more of the following are present:

• Six or more café au lait spots larger than 5 mm in greatest diameter in prepubertal individuals and larger than 15 mm in greatest diameter in postpubertal individuals
• Two or more neurofibromas of any type or 1 plexiform neurofibroma
• Freckling in the axillary or inguinal regions
• Optic glioma
• Two or more Lisch nodules (iris hamartomas)
• A distinctive osseous lesion, such as sphenoid dysplasia or thinning of the long bone cortex, with or without pseudoarthrosis
• A first-degree relative with NF1, according to the above criteria

Characteristics of NF1 in the newborn period include the following:

• Pseudarthroses
• Congenital glaucoma
• Sphenoid wing dysplasia

Characteristics of NF1 in the early childhood period include the following:

• Embryonal tumors
• Compression injuries: Plexiform neurofibromas in the mediastinal cavity may cause compression. Back pain in a patient with café au lait lesions should always be taken seriously because this symptom may be a sign of a radiculopathy.
• Optic pathway gliomas: These occur by the time the patient is aged 3 years.

NF1 should be differentiated from neurofibromatosis type 2 (NF2). NF2 is also referred to as central neurofibromatosis because it is associated with acoustic neuroma. Patients with NF2 may also have café au lait macules. NF2 is more likely to be diagnosed in middle-aged persons, unlike NF1, which is typically diagnosed in children. The genes that are responsible for these 2 disorders are on different chromosomes: chromosome 17 in NF1 (encoding neurofibromin) and chromosome 22 in NF2.

Other syndromes associated with café au lait spots include the following:

• McCune-Albright syndrome: This syndrome often has one large, asymmetric café au lait macule with irregular borders, which is often described as being like the "coast of Maine." The syndrome is associated with polyostotic fibrous dysplasia, which leads to pathologic fractures, precocious puberty, and numerous hyperfunctional endocrinopathies.^[7] Early in life, it may present with a single, large irregular café au lait spot. Follow-up observations reveal the endocrine abnormalities.
• Fanconi anemia: Café au lait macules are present along with mental retardation, aplastic anemia, and risk for malignancy.
• Tuberous sclerosis: Café au lait spots are present along with Ash leaf spots, facial angiofibromas, hemangiomas, cardiac rhabdomyomas, and shagreen patches.
• Silver-Russell syndrome
• Ataxia telangiectasia
• Bloom syndrome
• Basal cell nevus syndrome
• Gaucher disease
• Chédiak-Higashi syndrome
• Hunter syndrome
• Legius syndrome
• Maffucci syndrome
• Multiple mucosal neuroma syndrome
• Watson syndrome

Whereas small café au lait spots are associated with various syndromes, large, solitary, light-brown patches often represent segmental lentigines that are not associated with any neurocutaneous syndromes or developmental anomalies. Mosaic presentations of neurofibromatosis can also manifest localized café au lait macules or patches.^[8]

• References

Physical Examination

Café au lait spots are flat lesions that are typically the color made by adding milk to coffee. They may vary in size from a few millimeters, as in axillary freckling, to large macules that measure more than 10 cm in size.

Large, solitary café au lait macules are larger than 0.5 cm. They are found more commonly on the buttocks than any other anatomical location. No other physical findings or syndromes are usually related to solitary CAL spots.

Axillary freckling (known as Crowe sign) and inguinal freckling are characteristic diagnostic features of NF1.

Plexiform neurofibromas may underlie café au lait macules in NF1. These are large fibrous swellings of the subcutaneous tissue that may cause severe disfigurement of the face or limbs.^[9]

Café au lait spots are associated with underlying disorders, and physical findings indicative of those disorders include the following:

• Scoliosis
• Hypoplastic bowing of the legs
• Osseous lesions in the ribs
• Pseudoarthrosis of the tibia
• Spina bifida
• Scalloping of the vertebral body
• Lisch nodules
• Neurofibromas
• Lipomata
• Angiomata
• Ptosis
• Ocular abnormalities (including glaucoma and corneal opacifications)
• Pheochromocytoma

• References

Laboratory Studies

The presence of multiple café au lait macules (CALMs) should prompt a search for features suggestive of an underlying genetic disorder. Early diagnosis and genetic testing/counseling are important because of the genetic transmission of the underlying systemic disorders, if one is present. Genetic testing is available for the diagnosis of neurofibromatosis type 1 (NF1)–associated CALMs.

• References

Histologic Findings

Hyperpigmentation of basilar keratinocytes is noted. Giant melanosomes may be present within keratinocytes.

• References

Medical Care

Café au lait macules (CALMs) do not require medical care. When café au lait spots are associated with neurofibromatosis (NF) or another underlying condition, monitoring of associated conditions is required.

• References

Surgical Care

Although treatment of these lesions is not necessary, several lasers have been used to treat café au lait macules with variable responses. The lasers that have been used to treat café au lait macules include PDL, Er:YAG, Q-switched, and picosecond lasers.^{[10, 11, 12]}

The risks of the procedures must be discussed with the patient and the family. The risks of laser surgery include transient hyperpigmentation, hypopigmentation, slight scarring, permanent hyperpigmentation, and recurrence.^[13]

The data for the use of repeated Q-switched laser treatments are not consistent, with approximately 50% experiencing total clearance and with the other half developing recurrence and patchy pigmentation.^[14] The reported responses to frequency-doubled Nd:YAG vary.^{[15, 16]} One patient was treated with the Er:YAG and achieved almost complete clearance of the café au lait macules.^[17] In one study, complete clearance of 34 café au lait macules was reported using a pulsed dye laser for 4-14 treatments, with no recurrences at 12 months follow-up.^[18]

In 2012, Wang et al treated 48 Chinese patients with the Q-switched alexandrite laser and found that 26 patients (51.4%) had good-to-excellent responses after an average of 3.2 treatments with a low rate of recurrence (10.4%). The results are usually favorable, and when substantial clearing is achieved, the recurrence rate is low; however, where clearance is partial, recurrence is as high as 50%. The risk of postinflammatory hyperpigmentation is as high as 50% per treatment. When this develops, it is essential to wait until it clears before resuming laser treatment.^[19]

In 2017, Belkin et al reported a retrospective study of 45 patients treated with the picosecond 755-nm alexandrite picosecond laser, Q-switched ruby laser, Q-switched alexandrite laser, or Q-switched 1064-nm Nd:YAG laser for irregularly bordered café au lait macules of the “coast of Maine” subtype and smooth-bordered “coast of California” subtype.^[12] The irregularly bordered lesions received a mean visual analog score (VAS) of 3.67, corresponding to an excellent response on average (76-100% clearance) (P  <  .001).The smooth-bordered lesions, however, received a mean VAS of 1.76, corresponding to a fair response on average (26-50% pigmentary clearance). Based on their study, café au lait macules with jagged or ill-defined boarders of the coast of Maine subtype tend to respond better to laser treatment.

• References

Prevention

Guidelines for genetic counseling in patients with neurofibromatosis type 1 (NF1) have been established.^[20]

• References