Definition and Clinical Features
|Image courtesy of U.S. National Library of Medicine Opens in new window|
Legius syndrome, initially described as a neurofibromatosis type 1-like syndrome, is a rare autosomal dominant disorder Opens in new window characterized by multiple café-au-lait macules associated with changes in skin coloring (pigmentation).
Patients present with Legius syndrome have multiple café-au-lait spots Opens in new window, which are flat patches on the skin that are darker than the surrounding area. Another pigmentation change, freckles in the armpits and groin, may occur in some affected individuals.
Legius syndrome, caused by SPRED1 mutations, has phenotypic overlap with neurofibromatosis type 1 (NF1) Opens in new window, but the phenotype is milder (Table X-1).
Typical NF1-associated features such as neurofibromas, iris Lisch nodules, malignant peripheral nerve sheath tumors, optic pathway gliomas, and typical osseous lesions (sphenoid wing dysplasia, pseudarthrosis, and vertebral body dysplasia) are not reported in Legius syndrome.
|Table X-1 | Differences in Clinical Signs and Features of Legius Syndrome and NF1|
|NIH NF1 diagnostic criteria: fulfill 2 or more of following featurs||Legius syndrome||NF1|
|√ ≥ 6 café-au-lait spots (> 5 mm diameter in children, > 15 mm in adults)||+||+|
|√ ≥ 2 cutaneous or subcutaneous neurofibromas or 1 plexiform neurofibroma||-||+|
|√ axillary or inguinal freckling||+||+|
|√ optic pathway glioma||-||+|
|√ ≥ 2 Lisch nodules||-||+|
|√ bone dysplasia (pseudarthrosis, tibial bowing, …)||-||+|
|√ first degree relative with clinical diagnosis of NF1, according to these criteria||+||+|
|Table X-1 Continues|
|Associated features||Legius syndrome||NF1|
|√ specific malignancies||-(?)||+|
|√ short stature||+||+|
|√ learning disabilities||+||+|
|√ attention deficit||+||+|
Signs and Clinical Features
Café-au-lait macules Opens in new window with or without axillary or inguinal freckling are present in more than 90% of individuals with Legius syndrome. Macrocephaly Opens in new window was present in several individuals as well as a Noonan-like Opens in new window facial morphology.
A relatively large head is often described, and it is not clear yet if lipomas reported in some of the adults are part of the spectrum, since lipomas are frequent in the general population. Headaches, scoliosis, short stature, pectus excavatum/carinatum, and depigmented macules are less frequent.
Seizures Opens in new window, polydactyly, vascular malformations, and pulmonic valve stenosis were seen more than once in individuals with Legius syndrome. Learning and/or attention problems as well as developmental delay were noticed in some affected children.
The following neoplasias were noticed only once: lung cancer, childhood renal cancer, and colonadenoma, monoblastic acute leukemia, giant cell tumor, dermoid tumor of the ovary, and breast cancer, and unilateral vestibular schwannoma and desmoids tumor.
Learning disabilities, developmental delay, Noonan-like characteristics Opens in new window, ADHD Opens in new window, hyperactivity, autistic behavior, and concentration problems are often mentioned in children with Legius syndrome.
Descriptive detail in intelligence and behavior has been reported in 15 children with Legius syndrome (Denayer et al., 2011b). The mean full-scale IQ is normal, but several children in this group showed learning disabilities.
Legius syndrome is associated with mutations Opens in new window in SPRED 1 gene, a gene that encodes a protein that operates in the same biological pathway as the NF1 gene product. Thus Legius syndrome is a member of the RASopathies.
SPRED 1 is a negative regulator of the Ras/MAPK pathway, and SPRED 1 mutations result in decreased inhibition of the pathway. Legius syndrome is the result of increased activity of the Ras/MAPK pathway in a number of cell types. Spred 1 gene expression Opens in new window has been found in interleukin-3-dependent mouse hematopoietic cell lines as well as bone marrow-derived mast cells (Nonami et al., 2004).
Spred 1 is enriched in the CNS germinal zones; it dampens neural stem-cell proliferation and maintains ventricular zone structure (Phoenix and Temple, 2010). Human SPRED 1 is highly expressed in lung, brain, spinal cord, and spleen. Lower expression levels are seen in liver, pancreas, prostate, kidney, heart, thymus, muscle, and bone marrow (Shmueli et al., 2003; Yanai et al., 2005).
Café-au-lait macules Opens in new window in individuals with Legius syndrome result from biallelic SPRED 1 inactivation in melanocytes. SPRED 1 is a negative regulator of the Ras/MAPK pathway at the level of RAS-RAF interaction. The EVH1 domain binds to neurofibromin and recruits neurofibromin to the cell membrane.
The diagnosis of Legius syndrome is suspected in patients with multiple café-au-lait maculae with or without freckling and no other NF1 diagnostic criteria in whom an NF1 mutation was excluded by mutation analysis (Messianen et al., 2009).
The diagnosis of Legius syndrome can only be made by SPRED 1 mutation analysis. Legius syndrome can be confused with NF1, since many individuals with Legius syndrome fulfill the NF1 diagnostic criteria (Table X-1).
A correct diagnosis is important, since the diagnosis of Legius syndrome may relieve a psychological burden in families who are worried about NF1-associated features like benign and malignant tumors.
Some specific clinical phenotypes in NF1 Opens in new window patients can be very similar to those associated with Legius syndrome. An example is the phenotype seen in individuals with a specific 3-bp deletion in exon 17 of the NF1 gene (c.2970-2972delAAT). These individuals present with a mild NF1 phenotype with freckles and café-au-lait spots but without neurofibromas (Upadhyaya et al., 2007).
In some sporadic cases the clinical picture of generalized mosaic NF1 can be very similar to that of Legius syndrome. Therefore NF1 mutation analysis on peripheral blood and melanocytes derived from café-au-lait maculae can be important for a correct diagnosis (Maertens et al., 2007).
- Stevenson D, Viskochil D. Pigmentary findings in neurofibromatosis type 1-like syndrome (Legius syndrome): potential diagnostic dilemmas. JAMA. 2009; 302:2150-2151.