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Paediatrics

Presentation: Child with multiple café-au-lait macules

Café-au-lait macules are flat pigmented patches that can be found anywhere on the body. They are typically light to dark brown in colour. While having one or two is generally common, multiple café-au-lait macules in children, especially when accompanied by other suggestive features, may indicate an underlying genetic condition.

Example clinical scenario

A family is concerned that their four-year-old daughter seems much shorter than her classmates at school. She is always ‘on the go’ and has a short attention span. On examination, you notice multiple widespread café-au-lait macules on her skin.

When to consider genomic testing

The most common cause of multiple café-au-lait macules is neurofibromatosis type 1 (NF1). Diagnosis requires two from:

  • at least 6 café-au-lait macules (at least 0.5cm in a child and 1.5cm in an adult);
  • at least 2 subcutaneous or cutaneous neurofibromas;
  • plexiform neurofibroma;
  • optic glioma;
  • at least 2 Lisch nodules;
  • bony dysplasia (sphenoid wing, long bone bowing, pseudarthrosis); and
  • a family history of NF1.

Revised diagnostic criteria (see our resources list below) suggest that if only café-au-lait macules and axillary/inguinal freckling are present, the diagnosis is most likely NF1 but exceptionally the person might have another diagnosis such as Legius syndrome. Legius syndrome, described below, is the most common differential for NF1.

Young children who only present with café-au-lait macules, short stature and relative macrocephaly may still be eligible for testing on discussion with your local genomics laboratory or clinical genetics service.

Note that the child of a parent who meets diagnostic criteria and has one or more of the features outlined above also meets the revised diagnostic criteria of an NF1 diagnosis.

Other conditions or families of conditions that can present with multiple café-au-lait macules are listed below.

What do you need to do?

  • Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria, which provides information about individual tests and their associated eligibility criteria. You can also access a spreadsheet containing details of all available tests.
  • To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
  • Decide which of the panels best suits the needs of your patient or family.
    • If you suspect NF1 or Legius syndrome, the correct test to order is:
    • If the clinical features are suggestive of segmental or atypical NF1, the correct test to order is:
      • R376 Segmental or atypical neurofibromatosis type 1 testing: This includes a single-gene test and MLPA for the NF1 gene.
    • If a member of the family already has a known NF1 variant, cascade testing can be offered to first-degree relatives. In this situation, the laboratory will test for the known familial variant only through R240 Diagnostic testing for known mutation(s).
  • If you feel there are other likely alternative diagnoses, or if NF1 testing is negative, you may also wish to consider the following tests.
    • R236 Pigmentary skin disorders: To be considered when clinical features are atypical and a broader range of genes is potentially causative. It includes whole exome sequencing or gene panel sequencing and MLPA for the SPRED1 gene. Testing for familial progressive hyperpigmentation is eligible.
    • R343 Chromosomal mosaicism – microarray: To be considered when there is hyperpigmentation or hypopigmentation following Blaschko’s lines, with associated anomalies such as neurodevelopmental delay, seizures and/or asymmetry. The sample submitted for this test can be either a skin biopsy or a blood sample.
    • R327 Mosaic skin disorders (deep sequencing): To be considered when there is likely to be a mosaic single-gene cause. This clinical indication includes gene panel sequencing, and testing for McCune-Albright syndrome is eligible.
    • R27 Paediatric disorders or R89 Ultra-rare and atypical monogenic disorders: These tests should be used in individuals with congenital malformations, dysmorphism or other complex syndromic presentations.
  • R27 is an amalgamation of over 10 panels of genes known to be associated with a broad range of paediatric developmental disorders. It may now be ordered directly by paediatricians, though a discussion with clinical genetics services may be beneficial.
  • For tests that are undertaken using WGS, including R27 and R89, you will need to:
  • For tests that do not include WGS, including R222, R376, R240, R236, R343 and R327:
    • you can use your local Genomic Laboratory Hub test order and consent (RoD) forms; and
    • parental samples may be needed for interpretation of the child’s result. Parental samples can be taken alongside that of the child, and their DNA stored, or can be requested at a later date if needed.
  • The majority of tests are DNA based, and an EDTA sample (typically a purple-topped tube) is required. Exceptions include karyotype testing and DNA repair defect testing (for chromosome breakage), which require lithium heparin (typically a green-topped tube).
  • Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 25/04/2025
  • Next review due: 25/04/2026
  • Authors: Dr Danielle Bogue
  • Reviewers: Dr Lianne Gompertz, Dr Eleanor Hay, Dr Emile Hendriks

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