Cafe-au-lait macule

Author: Made Ananda Krisna, General Practitioner Cipto Mangunkusumo Hospital, Faculty of Medicine Universitas, Indonesia; Chief Editor: Dr Amanda Oakley, Dermatologist, Hamilton, New Zealand, November 2015.

What is a café-au-lait macule?

A café-aut-lait macule is a common birthmark, presenting as a hyperpigmented skin patch with a sharp border and diameter of > 0.5 cm. Also known as circumscribed café-aut-lait hypermelanosis or Recklinghausen spot, it is often abbreviated as CALM.

More images of café-au-lait macules ...

Who gets café-au-lait macules?

Café-au-lait macules are usually present at birth (congenital) or appear in early infancy. They sometimes become apparent later in infancy, especially after exposure to the sun, which darkens the colour.

They may be isolated or associated with systemic diseases such as neurofibromatosis (NF), McCune Albright syndrome, Legius syndrome, and LEOPARD syndrome.

Overall prevalence of café-au-lait macules varies with race:

Isolated café-au-lait macules are invariably solitary. More than 3 in a Caucasian or > 5 in an African American are uncommon and should lead to systemic evaluation, referral and/or close follow-up.

What causes café-au-lait macules?

Histologically, isolated café-au-lait macules have excessive numbers of melanosomes (intracellular pigment granules). These are produced by normal numbers of epidermal melanocytes (epidermal melanotic hypermelanosis). In contrast, café-au-lait macules associated with NF type 1 and Leopard syndrome have increased proliferation of epidermal melanocytes (epidermal melanocytic hyperplasia).

Multiple café-au-lait macules are related to several genetic syndromes.

Neurofibromatosis type 1

About half of those with neurofibromatosis type 1 (NF1) have an inherited mutation of NF1 gene on chromosome 17. NF1 gene codes for neurofibromin, a tumor suppressor gene. Others have a sporadic mutation of the same gene.

Neurofibromatosis type 2

Like NF1, autosomal dominant and sporadic mutations of the NF2 gene are equally common. NF2 gene codes for Merlin protein, whose physiologic function is still under investigation.

Legius syndrome

Legius syndrome is caused by SPRED gene mutation, which normally controls RAS pathway and interacts with neurofibromin.

McCune Albright syndrome

McCune Albright syndrome is caused by mutation of Gs protein, activating adenylate cyclase.

LEOPARD syndrome

LEOPARD syndrome is due to autosomal dominant inheritance of mutated PTPN11 gene on chromosome 12. The gene codes protein tyrosine phosphatase SHP-2.

The next three syndromes are much rarer than those described above.

Watson syndrome

Watson syndrome is linked to mutation of NF1 gene, or is at least allelic to NF1, or is caused by mutation of contiguous genes to NF1.

Bloom syndrome

Bloom syndrome is due to autosomal recessive mutation in BLM gene on chromosome 15. The gene product is DNA helicase, an enzyme essential to DNA repair to prevent chromosomal breakage.

Silver-Russel syndrome

There are several genetic abnormalities associated with Silver-Russel syndrome. The 2 most common are:

What are the clinical features of café-au-lait macules?

Café-au-lait macules:

The distribution and configuration of café-au-lait macules can be a clue to an underlying syndrome.

NF1

NF1 is highly variable in appearance. The main 2 National Institute of Health (NIH) Consensus criteria for diagnosis of NF1 are:

There are 5 other NIH criteria:

At least two criteria are required to make a working diagnosis of neurofibromatosis. The definitive diagnosis is made by confirming the presence of genetic mutation.

NF type 2

NF2 presents with unilateral or bilateral acoustic schwannoma (vestibular schwannoma). Patients develop hearing problems, ringing in the ears (tinnitus), and dizziness. By the age of 30, nearly all patients with NF2 have bilateral vestibular schwannoma.

Legius syndrome

Patients with Legius syndrome have multiple café-au-lait macules (> 5mm in children and > 15 mm in adults). Axillary freckling less common.

They may rarely have macrocephaly, cognitive disabilities, and several congenital malformations such as Noonan-like facies, pectus excavatum/carinatum, and lipomas.

McCune Albright syndrome

Café-au-lait macules in McCune Albright syndrome are fewer than in NF1, with more irregular borders. They are classically found on the midline.

The clinical diagnosis of McCune Albright syndrome is established by a triad of abnormalities:

LEOPARD syndrome

The L of LEOPARD syndrome refers to prominent lentigines. These are multiple < 5 mm, well-demarcated, brown macules presenting on the whole skin without mucous membrane involvement. They appear at birth and continue increasing in number until puberty.

LEOPARD is an acronym referring to the clinical findings required to make the diagnosis:

Patients with LEOPARD syndrome may also develop café-au-lait macules, nail malformation, and hyperelastic skin.

Watson syndrome

Watson syndrome is extremely rare with only 4 families described between 1960s to early 1990s. Their café-au-lait macules in Watson syndrome had similar characteristics to NF1. Other features of Watson syndrome are:

Bloom syndrome

Café-au-lait macules are not the main clinical finding in Bloom syndrome. Key characteristics of Bloom syndrome are:

Silver-Russel syndrome

Even though café-au-lait macules are not essential for diagnosis, they are common in children with Silver-Russel syndrome. They are mainly located on chest, stomach, and extremities.

The main features of Silver-Russel syndrome are:

How is a café-aut-lait macule diagnosed?

Café-aut-lait macules are diagnosed clinically. If significant in number and size, a complete clinical examination should be undertaken to determine whether an associated syndrome may be present.

Syndromes may be diagnosed from their clinical manifestations or by genetic testing.

What is the treatment for café-aut-lait macules?

No medical care is required to treat café-aut-lait macules. Lasers reported to have successfully faded café-aut-lait macules include:

Risks for laser surgery inclucde transient/permanent hyperpigmentation, hypopigmentation, and scarring.

Treatment of underlying syndromes may be complex and require multidisciplinary care.

What is the outcome for café-aut-lait macules?

Without treatment, café-aut-lait macules persist lifelong. Results from lasers are not consistent. However, for those who responded to initial treatment, recurrence rates are reported to be low.

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