Café-au-Lait Macules

Café-au-lait macules are well defined, uniformly light brown macules, present at birth or arising in the first years of life. Isolated lesions are common and benign, but multiple macules can signal neurofibromatosis type 1 or another genetic disorder.

One or more macules occur in 10 to 20% of children, and about 3 in 1,000 children have three or more. They are present in all populations.

Six or more macules, each over 5 mm before puberty or over 15 mm after puberty, meet one of the criteria for neurofibromatosis type 1.

Other causes of multiple macules are neurofibromatosis type 2 (few), Legius syndrome (SPRED1), McCune-Albright syndrome, tuberous sclerosis, Noonan syndrome with multiple lentigines, ring chromosome syndromes, Fanconi anaemia, Bloom syndrome, ataxia telangiectasia and constitutional mismatch repair deficiency.

Pathophysiology.

Epidermal melanocytes in the macules produce more pigment, with larger melanosomes. In neurofibromatosis type 1, loss of neurofibromin leads to RAS activation in melanocytes.

In McCune-Albright syndrome, a mosaic GNAS variant activates melanocytes and gives larger macules.

• Uniformly tan to dark brown, oval or irregular macules, 0.5 to 20 cm, with a smooth or jagged border. Number increases in the first years of life.
• Isolated lesions have no other signs.
• Neurofibromatosis type 1: axillary and inguinal freckling, cutaneous neurofibromas, Lisch nodules, optic nerve glioma, learning difficulty and bone dysplasia.
• McCune-Albright syndrome: large macules with a jagged ("coast of Maine") border that stops at the midline, with precocious puberty and fibrous dysplasia.

Red flags.

• Six or more macules of a significant size, or freckling in the armpits or groin.
• Neurological signs, developmental delay, short stature or early puberty.
• Family history of neurofibromatosis.

• Count and measure the macules, and examine the whole skin including the axillae and groin, with a Wood's lamp in fair skinned children.
• Look for neurofibromas, Lisch nodules (slit lamp), skeletal anomalies, blood pressure and head size. Ask about family history.
• Genetic testing (NF1, SPRED1) if criteria are met or suspicion is high, particularly in young children who have not yet developed other features (most meet criteria by 8 years of age).
• Further testing is directed by findings: ophthalmology, MRI of the brain and optic nerves for symptoms, and endocrine tests if puberty is early.

Differential diagnosis.

• Congenital melanocytic naevus, naevus spilus and Becker naevus.
• Mongolian spot, freckles and lentigines (including Peutz-Jeghers lentigines on the lips).
• Post-inflammatory hyperpigmentation and mastocytosis (urticaria pigmentosa).

• One to five macules without other signs: reassure, with a yearly check in children for the first years of life.
• Suspected neurofibromatosis type 1: yearly review by a paediatrician or neurofibromatosis clinic (growth, blood pressure, development, spine, eyes and skin), with MRI only when symptoms or signs call for it.
• Q-switched or picosecond lasers can lighten the macules, but recurrence is common. Test first and warn about the unpredictable outcome. Surgery is not helpful.
• Sun protection and camouflage cosmetics.
• Genetic counselling when a syndrome is diagnosed.

Special groups. Children under 2 years with six or more macules: assume possible neurofibromatosis type 1 and follow closely, since other signs appear with time.

Monitoring. Yearly clinical review for any child with three or more macules.

Referral and escalation. Paediatrics or genetics for six or more macules, or neurological, endocrine or skeletal signs.