Alternative titles; symbols
SNOMEDCT: 703541007; ORPHA: 137605; DO: 0070484;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 15q14 | Legius syndrome | 611431 | Autosomal dominant | 3 | SPRED1 | 609291 |
A number sign (#) is used with this entry because of evidence that Legius syndrome (LGSS) is caused by heterozygous mutation in the SPRED1 gene (609291) on chromosome 15q14.
Legius syndrome (LGSS) is an autosomal dominant disorder that shows some similarities to neurofibromatosis type I (NF1; 162200), which is caused by mutation in the neurofibromin gene (613113); however, Legius syndrome is less severe. Individuals with Legius syndrome typically have multiple cafe-au-lait spots, sometimes associated with skin fold freckling, variable dysmorphic features such as hypertelorism or macrocephaly, lipomas, and mild learning disabilities or attention problems. Legius syndrome is not associated with neurofibromas, optic gliomas, Lisch nodules, or tumor predisposition. The SPRED1 gene encodes a negative regulator of the RAS-MAPK pathway, similar to neurofibromin, and thus may be considered a RASopathy (review by Brems et al., 2012).
Brems et al. (2007) described 5 families with an autosomal dominant trait consisting of multiple cafe-au-lait spots, axillary freckling, macrocephaly, and a Noonan (163950)-like facial dysmorphism in some individuals. Despite the phenotypic similarities to neurofibromatosis type I, none of the patients had mutations in the neurofibromin gene. Some patients had learning difficulties or hyperactivity. Although none of the patients had neurofibromas or central nervous system tumors, several had lipomas, and 3 additional tumors (lung cancer, childhood renal cancer, and colon adenoma) were observed among 37 patients.
Pasmant et al. (2009) reported 5 unrelated French families with NFLS. Inheritance was autosomal dominant. The phenotype included a high prevalence of cafe-au-lait spots and axillary and groin freckling. Other variable features included lipomas and learning disabilities. Facial dysmorphism was not observed. As none of the patients had neurofibromas or Lisch nodules, Pasmant et al. (2009) suggested that the condition be named 'Legius syndrome.'
Spurlock et al. (2009) reported 6 probands with Legius syndrome. All had pigmentary skin changes, but none had neurofibromas, Lisch nodules, dysmorphic features, or learning disabilities. Two patients had head circumferences in the 90th and 98th percentiles, respectively. The 6 probands were identified from a cohort of 85 probands with pigmentary skin changes consistent with NF1 but no neurofibromas. Spurlock et al. (2009) noted that the mild pigmentary phenotype is clinically indistinguishable from NF1 in childhood, and that the absence of major physical complications and neurofibromas greatly reduces any NF1 disease related morbidity, especially in adults. This has major implications for genetic counseling of NF1 families.
Laycock-van Spyk et al. (2011) reported a mother and her 4 children with Legius syndrome. The mother had perioral and ocular hyperpigmentation, hypertelorism, mild ptosis, and hypotonia. All patients had decreased IQ or learning difficulties, and most had hypotonia. All had skin pigmentary abnormalities, but none had Lisch nodules or neurofibromas.
By genomewide linkage analysis in 2 families with Legius syndrome, Brems et al. (2007) found linkage of the disorder to chromosome 15 (maximum multipoint parametric lod score of 4.8).
In affected members of 5 unrelated families with an autosomal dominant phenotype referred to as neurofibromatosis type 1-like syndrome (NFLS), Brems et al. (2007) identified 4 different heterozygous mutations in the SPRED1 gene (609291.0001-609291.0004). Screening of 86 additional patients who had undergone NF1 (162200) testing with negative results identified 7 additional SPRED1 mutations (see, e.g., 609291.0005).
Pasmant et al. (2009) identified 5 heterozygous truncating mutations in the SPRED1 gene (see, e.g., 609291.0005; 609291.0006) in affected members of 5 unrelated French families with Legius syndrome. One patient developed a childhood monoblastic acute leukemia, but cancer cells did not show somatic alteration of SPRED1. SPRED1 mutations occurred in 0.5% in the entire series of 561 probands with a clinical diagnosis of NF1.
Spurlock et al. (2009) identified 6 different heterozygous SPRED1 mutations (see, e.g., 609291.0007; 609291.0008) in 6 of 85 probands with a mild NF1 phenotype and no neurofibromas. Five of the 6 mutations resulted in a truncated protein.
Laycock-van Spyk et al. (2011) identified 6 different heterozygous nonsense or frameshift mutations in the SPRED1 gene in 6 of 115 patients with an NF1-like syndrome but without mutations in the NF1 gene. The largest family in their study carried a heterozygous frameshift mutation (609291.0009). Combining their data with those from their earlier study (Spurlock et al., 2009), Laycock-van Spyk et al. (2011) estimated that SPRED1 mutations are found in about 6% of such patients.
Spencer et al. (2011) used multiplex ligation-dependent probe amplification (MLPA) to screen 510 NF1-negative patients with multiple cafe-au-lait spots with or without freckling and no other signs of NF1 for deletions in the SPRED1 gene. Four different deletions were detected, including 2 that segregated with the phenotype in 2 families and 2 that were apparently sporadic. All the deletions had different breakpoints, with 1 including 2 neighboring genes. Point mutations or 1- to 4-bp insertion/deletion mutations were found in 36 of the 510 individuals. Thus, deletions accounted for about 10% of the 40 detected SPRED1 mutations in this cohort, suggesting that dosage analysis of this gene should be performed in candidate patients.
Brems, H., Chmara, M., Sahbatou, M., Denayer, E., Taniguchi, K. Kato, R., Somers, R., Messiaen, L., De Schepper, S., Fryns, J.-P., Cools, J., Marynen, P., Thomas, G., Yoshimura, A., Legius, E. Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. (Letter) Nature Genet. 39: 1120-1126, 2007. [PubMed: 17704776] [Full Text: https://doi.org/10.1038/ng2113]
Brems, H., Pasmant, E., Van Minkelen, R., Wimmer, K., Upadhyaya, M., Legius, E., Messiaen, L. Review and update of SPRED1 mutations causing Legius syndrome. Hum. Mutat. 33: 1538-1546, 2012. [PubMed: 22753041] [Full Text: https://doi.org/10.1002/humu.22152]
Laycock-van Spyk, S., Jim, H. P., Thomas, L., Spurlock, G., Fares, L., Palmer-Smith, S., Kini, U., Saggar, A., Patton, M., Mautner, V., Pilz, D. T., Upadhyaya, M. Identification of five novel SPRED1 germline mutations in Legius syndrome. (Letter) Clin. Genet. 80: 93-96, 2011. [PubMed: 21649642] [Full Text: https://doi.org/10.1111/j.1399-0004.2010.01618.x]
Pasmant, E., Sabbagh, A., Hanna, N., Masliah-Planchon, J., Jolly, E., Goussard, P., Ballerini, P., Cartault, F., Barbarot, S., Landman-Parker, J., Soufir, N., Parfait, B., Vidaud, M., Wolkenstein, P., Vidaud, D., France, R. N. F. SPRED1 germline mutations caused a neurofibromatosis type 1 overlapping phenotype. J. Med. Genet. 46: 425-430, 2009. [PubMed: 19366998] [Full Text: https://doi.org/10.1136/jmg.2008.065243]
Spencer, E., Davis, J., Mikhail, F., Fu, C., Vijzelaar, R., Zackai, E. H., Feret, H., Meyn, M. S., Shugar, A., Bellus, G., Kocsis, K., Kivirikko, S., Poyhonen, M., Messiaen, L. Identification of SPRED1 deletions using RT-PCR, multiplex ligation-dependent probe amplification and quantitative PCR. Am. J. Med. Genet. 155A: 1352-1359, 2011. [PubMed: 21548021] [Full Text: https://doi.org/10.1002/ajmg.a.33894]
Spurlock, G., Bennett, E., Chuzhanova, N., Thomas, N., Jim, H.-P., Side, L., Davies, S., Haan, E., Kerr, B., Huson, S. M., Upadhyaya, M. SPRED1 mutations (Legius syndrome): another clinically useful genotype for dissecting the neurofibromatosis type 1 phenotype. J. Med. Genet. 46: 431-437, 2009. [PubMed: 19443465] [Full Text: https://doi.org/10.1136/jmg.2008.065474]