Legius syndrome

Author: Dr Daniel Mazzoni, Junior Medical Officer, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia. DermNet NZ Editor-in-Chief: Adjunct A/Prof. Amanda Oakley, Dermatologist, Hamilton, New Zealand. Copy edited by Gus Mitchell. January 2019.


What is Legius syndrome?

Legius syndrome is a rare genetic disorder first described in 2007 [1]. It is also known as neurofibromatosis type 1-like syndrome [2].

Legius syndrome is classically characterised by multiple light brown macules, known as café-au-lait macules [3]. Unlike neurofibromatosis type 1, there are no tumours in Legius syndrome.

Café au lait macules

Who gets Legius syndrome?

Legius syndrome may occur in anyone with at least one biological parent with genetically confirmed Legius syndrome [2]. The prevalence of Legius syndrome is unknown, but may be higher than expected due to misdiagnosis as neurofibromatosis type 1 [4].

What causes Legius syndrome?

Legius syndrome is a genetic condition inherited in an autosomal dominant manner that involves a SPRED1 gene mutation on chromosome 15q14. This results in the abnormal function of the SPRED1 protein, which is responsible for regulating specific cell signalling pathways involved in cell proliferation, differentiation and apoptosis. No other pathogenic variants have been found to cause Legius syndrome [2,3].

As an autosomal dominant condition, Legius syndrome may occur in anyone with at least one biological parent who has genetically confirmed Legius syndrome. Rarely, it may occur de novo, but these cases have not been evaluated sufficiently to confirm this [2]. Each child that has a parent with genetically confirmed Legius syndrome has a 50% risk of inheritance.

What are the clinical features of Legius syndrome?

The clinical features of Legius syndrome vary significantly in nature and severity from one person to another.

Almost all patients with Legius syndrome present with multiple café-au-lait macules [2,3]. The number of these macules tends to increase during childhood [4].

Other common cutaneous features may include:

Non-cutaneous features may include:

  • Macrocephaly
  • Unusual facial characteristics, similar to Noonan syndrome
  • Short stature
  • Pectus excavatum (sunken breastbone) or pectus carinatum (protruding breastbone) [2–4].

Neuropsychiatric features may include:

  • Learning difficulties
  • Developmental delay
  • Attention deficit hyperactivity disorder (ADHD) [2–4].

The intellectual disabilities are generally less severe in patients with Legius syndrome compared to those with neurofibromatosis type 1 [5].

Importantly, Legius syndrome does not cause neurofibromas and Lisch nodules, which are typically seen in neurofibromatosis type 1 [2,3].

How is Legius syndrome diagnosed?

Legius syndrome is difficult to diagnose on a clinical basis alone given the similar cutaneous clinical presentation to other disorders with multiple café-du-lait macules.

Where Legius syndrome is suspected, genetic testing can be used to confirm the diagnosis. This involves:

  • Sequence analysis of SPRED1
  • Deletion/duplication analysis (if sequence analysis is unremarkable)
  • Multi-gene panel (SPRED1 and other genes of interest) [2,3].

Suspicious findings that may warrant genetic testing include:

  • Café-au-lait macules without other clinical features suggesting neurofibromatosis type 1
  • A parent with café-au-lait macules without clinical features suggesting neurofibromatosis type 1 [2].

What is the differential diagnosis for Legius syndrome?

Legius syndrome is often misdiagnosed because the pigmentary manifestations are very similar to other syndromes with multiple lentigines. Correct diagnosis is critical to guide long-term monitoring and management.

Neurofibromatosis type 1

  • Neurofibromatosis type 1 is the most common misdiagnosis due to similar clinical diagnostic criteria [2–4].
  • Neurofibromas, Lisch nodules, bone abnormalities, and optic gliomas do not occur in Legius syndrome.
  • These two conditions are difficult to differentiate in younger children, as characteristic tumours of neurofibromatosis usually do not develop until later in life.

Noonan syndrome with multiple lentigines

Other syndromes characterised by multiple lentigines include:

What is the treatment for Legius syndrome?

Children with Legius syndrome should be under regular screening and evaluation for developmental delay, cognitive impairment, and behavioural issues [2].

Treatment of Legius syndrome is primarily supportive and should be focused on the specific problems of the affected individual.

Appropriate management if indicated may include:

  • Physical, speech and/or occupational therapy
  • Behavioural modification therapy and pharmacologic therapy (ie, for ADHD) [2].

What is the outcome for Legius syndrome?

Patients with Legius syndrome have a generally good prognosis with appropriate problem-based management.

An affected individual must consider the 50% risk of genetic transmission to each child.

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References

  1. Brems H, Chmara M, Sahbatou M, et al. Germ-line los of function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. Nat Genet 2007; 39(9): 1120–6. DOI: 10.1038/ng2113. PubMed
  2. Stevenson D, Viskochil D, Mao R. Legius Syndrome. GeneReviews. University of Washington, Seattle; 1993–2008. PubMed Books
  3. National Institutes of Health. SPRED1 gene. Genetics Home Reference. Available at: https://ghr.nlm.nih.gov/condition/legius-syndrome#resources (accessed 28 November 2018).
  4. Legius E. Legius syndrome. Orphanet. Available at: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=137605 (accessed 28 November 2018).
  5. Benelli E, Bruno I, Belcaro C, et al. Legius syndrome: a case report and review of literature. Ital J Paediatr 2015; 41: 8. DOI: 10.1186/s13052-015-011509. PubMed
  6. Ngan V. Noonan syndrome with multiple lentigines. DermNet New Zealand. Updated 2017.

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