Cafe Au Lait Spots Clinical Presentation

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.^[5] 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
• Chiak-Higashi syndrome
• Hunter 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.

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.

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

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.