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Legius syndrome(SPRED1)

MedGen UID:
370709
Concept ID:
C1969623
Disease or Syndrome
Synonyms: Neurofibromatosis type 1 like syndrome; SPRED1
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM, Orphanet
Autosomal dominant inheritance refers to genetic conditions that occur when a mutation is present in one copy of a given gene (i.e., the person is heterozygous).
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
SNOMED CT: Legius syndrome (703541007); NFLS - neurofibromatosis type 1-like syndrome (703541007); Neurofibromatosis type 1-like syndrome (703541007)
 
Gene (location): SPRED1 (15q14)
OMIM®: 611431
Orphanet: ORPHA137605

Disease characteristics

Excerpted from the GeneReview: Legius Syndrome
Legius syndrome is characterized by multiple café au lait macules without neurofibromas or other tumor manifestations of neurofibromatosis type 1 (NF1). Additional clinical manifestations reported commonly include intertriginous freckling, lipomas, macrocephaly, and learning disabilities / ADHD / developmental delays. Current knowledge of the natural history of Legius syndrome is based on the clinical manifestations of fewer than 200 individuals with a molecularly confirmed diagnosis; better delineation of the clinical manifestations and natural history of Legius syndrome will likely occur as more affected individuals are identified. [from GeneReviews]
Authors:
David Stevenson  |  David Viskochil  |  Rong Mao   view full author information

Additional descriptions

From OMIM
Legius syndrome 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).  http://www.omim.org/entry/611431
From GHR
Legius syndrome is a condition characterized by changes in skin coloring (pigmentation). Almost all affected individuals have multiple café-au-lait spots, 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.Other signs and symptoms of Legius syndrome may include an abnormally large head (macrocephaly) and unusual facial characteristics. Although most people with Legius syndrome have normal intelligence, some affected individuals have been diagnosed with learning disabilities, attention deficit disorder (ADD), or attention deficit hyperactivity disorder (ADHD).Many of the signs and symptoms of Legius syndrome also occur in a similar disorder called neurofibromatosis type 1. It can be difficult to tell the two disorders apart in early childhood. However, the features of the two disorders differ later in life.  https://ghr.nlm.nih.gov/condition/legius-syndrome

Clinical features

Muscular hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Muscular hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle), often involving reduced muscle strength. Hypotonia is characterized by a diminished resistance to passive stretching.
Macrocephaly
MedGen UID:
745757
Concept ID:
C2243051
Finding
Macrocephaly refers to an abnormally enlarged head inclusive of the scalp, cranial bones, and intracranial contents. Macrocephaly may be due to megalencephaly (true enlargement of the brain parenchyma), and the 2 terms are often used interchangeably in the genetic literature (reviews by Olney, 2007 and Williams et al., 2008). Autosomal recessive macrocephaly/megalencephaly syndrome is characterized by an enlarged cranium apparent at birth or in early childhood. Affected individuals have intellectual disability and may have dysmorphic facial features resulting from the macrocephaly (summary by Alfaiz et al., 2014).
Multiple lipomas
MedGen UID:
677074
Concept ID:
C0745730
Finding
The presence of multiple lipomas (a type of benign tissue made of fatty tissue).

Recent clinical studies

Etiology

Zhang J, Li M, Yao Z
Mol Med Rep 2016 Nov;14(5):4023-4029. Epub 2016 Sep 22 doi: 10.3892/mmr.2016.5760. PMID: 27666661Free PMC Article
Pasmant E, Gilbert-Dussardier B, Petit A, de Laval B, Luscan A, Gruber A, Lapillonne H, Deswarte C, Goussard P, Laurendeau I, Uzan B, Pflumio F, Brizard F, Vabres P, Naguibvena I, Fasola S, Millot F, Porteu F, Vidaud D, Landman-Parker J, Ballerini P
Oncogene 2015 Jan 29;34(5):631-8. Epub 2014 Jan 27 doi: 10.1038/onc.2013.587. PMID: 24469042
Schnur RE
Curr Opin Ophthalmol 2012 Sep;23(5):364-72. doi: 10.1097/ICU.0b013e3283570127. PMID: 22871881
Denayer E, Descheemaeker MJ, Stewart DR, Keymolen K, Plasschaert E, Ruppert SL, Snow J, Thurm AE, Joseph LA, Fryns JP, Legius E
Am J Med Genet C Semin Med Genet 2011 May 15;157C(2):123-8. Epub 2011 Apr 14 doi: 10.1002/ajmg.c.30297. PMID: 21495177Free PMC Article
Muram-Zborovski TM, Stevenson DA, Viskochil DH, Dries DC, Wilson AR, Rong Mao
J Child Neurol 2010 Oct;25(10):1203-9. Epub 2010 Feb 22 doi: 10.1177/0883073809359540. PMID: 20179001Free PMC Article

Diagnosis

Benelli E, Bruno I, Belcaro C, Ventura A, Berti I
Ital J Pediatr 2015 Feb 8;41:8. doi: 10.1186/s13052-015-0115-9. PMID: 25883013Free PMC Article
Pasmant E, Gilbert-Dussardier B, Petit A, de Laval B, Luscan A, Gruber A, Lapillonne H, Deswarte C, Goussard P, Laurendeau I, Uzan B, Pflumio F, Brizard F, Vabres P, Naguibvena I, Fasola S, Millot F, Porteu F, Vidaud D, Landman-Parker J, Ballerini P
Oncogene 2015 Jan 29;34(5):631-8. Epub 2014 Jan 27 doi: 10.1038/onc.2013.587. PMID: 24469042
Stevens CA, Chiang PW, Messiaen LM
Am J Med Genet A 2012 May;158A(5):1195-9. Epub 2012 Mar 21 doi: 10.1002/ajmg.a.35297. PMID: 22438235
Denayer E, Chmara M, Brems H, Kievit AM, van Bever Y, Van den Ouweland AM, Van Minkelen R, de Goede-Bolder A, Oostenbrink R, Lakeman P, Beert E, Ishizaki T, Mori T, Keymolen K, Van den Ende J, Mangold E, Peltonen S, Brice G, Rankin J, Van Spaendonck-Zwarts KY, Yoshimura A, Legius E
Hum Mutat 2011 Jan;32(1):E1985-98. doi: 10.1002/humu.21404. PMID: 21089071Free PMC Article
Spurlock G, Bennett E, Chuzhanova N, Thomas N, Jim HP, Side L, Davies S, Haan E, Kerr B, Huson SM, Upadhyaya M
J Med Genet 2009 Jul;46(7):431-7. Epub 2009 May 13 doi: 10.1136/jmg.2008.065474. PMID: 19443465

Therapy

Rauen KA, Huson SM, Burkitt-Wright E, Evans DG, Farschtschi S, Ferner RE, Gutmann DH, Hanemann CO, Kerr B, Legius E, Parada LF, Patton M, Peltonen J, Ratner N, Riccardi VM, van der Vaart T, Vikkula M, Viskochil DH, Zenker M, Upadhyaya M
Am J Med Genet A 2015 Jan;167A(1):1-10. Epub 2014 Nov 12 doi: 10.1002/ajmg.a.36793. PMID: 25393061Free PMC Article

Prognosis

Sakai N, Maeda T, Kawakami H, Uchiyama M, Harada K, Tsuboi R, Mitsuhashi Y
J Dermatol 2015 Jul;42(7):703-5. Epub 2015 May 18 doi: 10.1111/1346-8138.12862. PMID: 25981987
Niemeyer CM
Haematologica 2014 Nov;99(11):1653-62. doi: 10.3324/haematol.2014.114595. PMID: 25420281Free PMC Article
Muram TM, Stevenson DA, Watts-Justice S, Viskochil DH, Carey JC, Mao R, Jackson B
Am J Med Genet A 2013 Mar;161A(3):467-72. Epub 2013 Feb 7 doi: 10.1002/ajmg.a.35718. PMID: 23401230
Gripp KW, Lin AE
Genet Med 2012 Mar;14(3):285-92. doi: 10.1038/gim.0b013e31822dd91f. PMID: 22261753
Muram-Zborovski TM, Vaughn CP, Viskochil DH, Hanson H, Mao R, Stevenson DA
Am J Med Genet A 2010 Aug;152A(8):1973-8. doi: 10.1002/ajmg.a.33525. PMID: 20602485Free PMC Article

Clinical prediction guides

Spatola M, Wider C, Kuntzer T, Croquelois A
BMC Neurol 2015 Apr 16;15:55. doi: 10.1186/s12883-015-0310-8. PMID: 25884655Free PMC Article
Pasmant E, Gilbert-Dussardier B, Petit A, de Laval B, Luscan A, Gruber A, Lapillonne H, Deswarte C, Goussard P, Laurendeau I, Uzan B, Pflumio F, Brizard F, Vabres P, Naguibvena I, Fasola S, Millot F, Porteu F, Vidaud D, Landman-Parker J, Ballerini P
Oncogene 2015 Jan 29;34(5):631-8. Epub 2014 Jan 27 doi: 10.1038/onc.2013.587. PMID: 24469042
Krejci P
Mutat Res Rev Mutat Res 2014 Jan-Mar;759:40-8. Epub 2013 Dec 1 doi: 10.1016/j.mrrev.2013.11.001. PMID: 24295726
Gripp KW, Lin AE
Genet Med 2012 Mar;14(3):285-92. doi: 10.1038/gim.0b013e31822dd91f. PMID: 22261753
Denayer E, Descheemaeker MJ, Stewart DR, Keymolen K, Plasschaert E, Ruppert SL, Snow J, Thurm AE, Joseph LA, Fryns JP, Legius E
Am J Med Genet C Semin Med Genet 2011 May 15;157C(2):123-8. Epub 2011 Apr 14 doi: 10.1002/ajmg.c.30297. PMID: 21495177Free PMC Article

Recent systematic reviews

Brems H, Pasmant E, Van Minkelen R, Wimmer K, Upadhyaya M, Legius E, Messiaen L
Hum Mutat 2012 Nov;33(11):1538-46. Epub 2012 Aug 1 doi: 10.1002/humu.22152. PMID: 22753041

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