eMedicine Specialties > Pediatrics: General Medicine > Dermatology

Café Au Lait Spots

Author: William D James, MD, Paul R Gross Professor of Dermatology, University of Pennsylvania School of Medicine; Vice-Chair, Program Director, Department of Dermatology, University of Pennsylvania Health System
Coauthor(s): Raj D Sheth, MD, Professor, Departments of Neurology and Pediatrics, Director of Comprehensive Epilepsy Program, Department of Neurology, University of Wisconsin at Madison; Nazanin Saedi, BA, George Washington University School of Medicine
Contributor Information and Disclosures

Updated: Jun 4, 2008

Introduction

Background

Café au lait (CAL) spots are hyperpigmented lesions that may vary in color from light brown to dark brown; 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 CAL skin lesions widely vary, and they are usually the earliest manifestations of neurofibromatosis.¹ The macules may be observed in infancy, although typically they are 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.

CAL spots 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, and Fanconi anemia.

CAL spots and Lisch nodules in the iris are the most characteristic markers of NF1. 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 CAL spots. 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.

Pathophysiology

CAL 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 CAL spots of patients with NF1 compared with patients who have isolated CAL spots without NF1 involvement. Also, an increase in stem cell factor cytokines is more frequently observed in NF1 CAL spots than non-NF1 CAL spots.

The diagnosis of NF1, an autosomal dominant disorder, requires the fulfillment of the Whitehouse criteria, which includes the presence of 6 or more CAL spots in children or adults. To be considered in the diagnosis of NF1, CAL lesions must be at least 15 mm in diameter in patients older than 5 years or over 5 mm in children younger than 5 years. The expression of the disorder can widely vary; members in the same family may have differing degrees of severity.

Frequency

United States

In the newborn period, solitary CAL spots may occur in 0.3% of whites, 3% of Hispanics, and in 18% of blacks.²  In childhood, solitary CAL spots occur in 13% of whites and 27% of blacks. Two or more CAL spots were not observed in any of 4000 white newborns, although they were found in 8% of black newborns.

CAL spots that confirm the diagnosis of NF1 occur at an estimated frequency of 1 in 3500 persons.³

International

Solitary CAL spots occur in 0.5% of Arab newborns and in 0.4% of Chinese newborns.²

Mortality/Morbidity

CAL spots are benign and produce no mortality or morbidity.

Race

CAL spots are more frequently observed in children of African American race.

Sex

No sexual predilection is recognized.

Age

Typically, CAL 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, CAL spots are clearly visible. The size and number of CAL spots increase with patient age in patients with NF1.

Clinical

History

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

• The diagnostic criteria for NF1 are met if 2 or more of the following are present:
• Six or more CAL macules 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 NF-1, according to the above criteria
• Characteristics of NF1 include the following:
• Newborn period
• Pseudarthroses
• Congenital glaucoma
• Sphenoid wing dysplasia
• Early childhood
• Embryonal tumors
• Compression injuries: Plexiform neurofibromas in the mediastinal cavity may cause compression. Back pain in a patient with CAL 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.
• Other syndromes associated with CAL spots include the following:
• McCune-Albright syndrome: Often one large, asymmetric CAL spot with irregular borders is present; this syndrome is associated with polyostotic fibrous dysplasia, which leads to pathologic fractures, precocious puberty, and numerous hyperfunctional endocrinopathies. Early in life, this syndrome may present with a single, large irregular CAL spot. Follow-up observations reveal the endocrine abnormalities.
• Fanconi anemia: CAL spots are present along with mental retardation, aplastic anemia, and risk for malignancy.
• Tuberous sclerosis: CAL 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
• Chiak-Higashi syndrome
• Hunter syndrome
• Maffucci syndrome
• Multiple mucosal neuroma syndrome
• Watson syndrome
• Whereas small CAL 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.

Physical

• Large, solitary CAL spots 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 CAL spots in NF1. These are large fibrous swellings of the subcutaneous tissue that may cause severe disfigurement of the face or limbs.
• CAL 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

Causes

CAL spots 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.

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