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Paediatrics

Presentation: Child with multiple café-au-lait macules

Café-au-lait macules are pigmented lesions (patches) that can be found anywhere on the body and typically range from light to dark brown in colour. The appearance of one or two is common within the general population. However, 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 café-au-lait macules is neurofibromatosis type 1 (NF1). Revised diagnostic criteria (see our resources list below) suggest that a diagnosis of NF1 can be made in a patient without a family history when two or more of the following features are present:

  • six or more café-au-lait macules (over 5mm in pre-pubertal individuals, over 15mm in post-pubertal individuals);
  • axillary or inguinal freckling;
  • two or more neurofibromas or one plexiform neurofibroma;
  • optic pathway glioma;
  • two or more iris Lisch nodules on slit lamp examination, or two or more choroidal anomalies imaged by optical coherence tomography (OCT) or near-infrared reflectance (NIR) imaging;
  • a distinctive osseous lesion such as sphenoid dysplasia, tibial bowing or pseudoarthrosis of a long bone; and
  • a heterozygous pathogenic NF1 variant with an allele fraction of 50%.

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.

  • RASopathies: Including Legius syndrome, Noonan syndrome, Noonan syndrome with multiple lentigines (formerly called LEOPARD syndrome), Costello syndrome and cardio-facio-cutaneous (CFC) syndrome. Clinical features of this group of conditions include normal or high birth weight, early feeding difficulties, congenital heart disease and cryptorchidism in boys. For information about testing, see Clinical suspicion of Noonan syndrome.
    • Legius syndrome is an important differential diagnosis of NF1. It is caused by variants in the SPRED1 gene and should be considered in a child who presents with multiple café-au-lait macules but no neurofibromas or any of the other tumour manifestations seen in NF1. Relative macrocephaly, axillary or inguinal freckling and neurodevelopmental associations are also frequently observed. For information about testing for Legius syndrome, see What do you need to do?
  • Tuberous sclerosis (TS): Caused by variants affecting the TSC1 and TSC2 genes and characterised by an increased predisposition to hamartoma formation. Children with TS can present with developmental delay, skin manifestations (including café-au-lait macules and hypopigmented macules), seizures and a range of other clinical features. For information about testing, see Clinical suspicion of tuberous sclerosis complex.
  • McCune-Albright syndrome: Caused by a somatic variant in the GNAS gene. Children with McCune-Albright syndrome typically present with polyostotic fibrous dysplasia, endocrinopathies and café-au-lait macules that usually have jagged borders (known as ‘coast of Maine’) and stop abruptly in the midline. For information about testing, see Clinical suspicion of McCune-Albright syndrome.
  • Chromosome breakage conditions: Including Fanconi anaemia, Bloom syndrome and ataxia telangiectasia. Clinical features of these conditions include short stature, microcephaly, café-au-lait macules and sun sensitivity. They are associated with immunodeficiency and a predisposition to malignancy. For information about testing, see Clinical suspicion of Bloom syndrome, Clinical suspicion of Fanconi anaemia and Clinical suspicion of ataxia telangiectasia.
  • Silver-Russell syndrome (SRS): Children with SRS typically present with intrauterine growth restriction with relative macrocephaly and may have body asymmetry. For information about testing, see Clinical suspicion of Silver-Russell syndrome.
  • Turner syndrome (monosomy X (45,X)): If this condition is not detected antenatally, girls typically present with short stature, either in early childhood or in later years, due to absence of puberty. For information about testing, see Clinical suspicion of Turner syndrome.
  • Genodermatoses: These can include the below.
    • Familial progressive hyperpigmentation (FPH): Caused by a variant affecting the KITLG gene. FPH typically presents at birth or in early infancy with irregular patches of hyperpigmented skin, which increase in size and number with age. No systemic diseases are associated.
    • PTEN hamartoma tumour syndrome: Including Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome, this is a spectrum of conditions caused by variants affecting the PTEN gene. Children typically present with macrocephaly, mildly delayed motor milestones and characteristic skin findings. There is an increased risk of multiple cancers, typically from adulthood. For information about testing, see Clinical suspicion of PTEN hamartoma tumour syndrome.

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 MLPA, 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 a large whole genome sequencing (WGS) ‘super panel’ (a panel comprised of several different constituent panels forming one large panel), and requesting it currently requires authorisation from clinical genetics services.
  • 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 (purple-topped tube) is required. Exceptions include karyotype testing and DNA repair defect testing (for chromosome breakage), which require lithium heparin (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: 21/03/2024
  • Next review due: 21/03/2025
  • Authors: Dr Danielle Bogue
  • Reviewers: Dr Lianne Gompertz, Dr Eleanor Hay, Dr Emile Hendriks

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