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Legius Syndrome

Synonym: Neurofibromatosis Type 1-Like Syndrome

, MD, , MD, PhD, and , MD.

Author Information
, MD
Stanford University
Stanford, California
, MD, PhD
University of Utah
Salt Lake City, Utah
, MD
University of Utah
Salt Lake City, Utah

Initial Posting: ; Last Update: January 15, 2015.

Summary

Disease characteristics.

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.

Diagnosis/testing.

The diagnosis of Legius syndrome is difficult to make on clinical grounds alone. Detection of a pathogenic variant in SPRED1, the only gene known to be associated with Legius syndrome, is necessary to confirm the diagnosis.

Management.

Treatment of manifestations: Consideration of behavioral modification and/or pharmacologic therapy for those with ADHD; physical, speech, and occupational therapy for those with identified developmental delays; individualized education plans for those with learning disorders.

Surveillance: Routine screening for developmental delays and behavioral and learning problems.

Genetic counseling.

Legius syndrome is inherited in an autosomal dominant manner. Each child of an individual with Legius syndrome has a 50% chance of inheriting the pathogenic variant. Although uncommonly requested, prenatal diagnosis for pregnancies at increased risk is possible if the SPRED1 pathogenic variant has been identified in an affected family member.

Diagnosis

Suggestive Findings

Diagnosis of Legius syndrome should be suspected in an individual who:

  • Has pigmentary dysplasia consisting of café au lait macules, with or without intertriginous freckling; and
  • Lacks the non-pigmentary clinical diagnostic manifestations of neurofibromatosis type 1 (NF1) (e.g., Lisch nodules, neurofibromas, optic nerve glioma, sphenoid wing dysplasia, long bone dysplasia); and
  • Has a parent with multiple café au lait macules but no other features of NF1.

Additional clinical manifestations reported in multiple individuals are listed in Table 2.

Establishing the Diagnosis

The diagnosis of Legius syndrome is established in a proband with the identification of a heterozygous pathogenic variant in SPRED1 (see Table 1).

Molecular testing approaches can include:

  • Sequence analysis of SPRED1 first, followed by deletion/duplication analysis if no pathogenic variant is found;
  • Use of a multi-gene panel that includes SPRED1 and other genes of interest (see Differential Diagnosis). Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time.

Note: Opinions differ on the appropriate approach when clinical information and family history cannot distinguish between NF1 and Legius syndrome. The assessment of pros and cons of molecular testing requires consideration of the circumstances unique to each individual, including (but not limited to) the following:

  • Clinical findings and family history
  • Age of the individual
  • Differences in recommended clinical management when the diagnosis of NF1 or Legius syndrome is established with certainty versus when the diagnosis of neither can be established with confidence
  • Psychological burden of a diagnosis or lack thereof
  • Costs of testing and surveillance

For various approaches, see Messiaen et al [2009], Pasmant et al [2009], Stevenson & Viskochil [2009], Muram-Zborovski et al [2010], Denayer et al [2011a], Brems et al [2012].

Table 1.

Summary of Molecular Genetic Testing Used in Legius Syndrome

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
SPRED1Sequence analysis 288% 3
Deletion/duplication analysis 410% 5
Unknown 6NA
1.

See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants detected in this gene.

2.

Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3.

Of individuals evaluated for NF1 without an identifiable NF1 pathogenic variant, 3%-25% had an identifiable SPRED1 pathogenic variant [Brems et al 2007, Messiaen et al 2009, Pasmant et al 2009, Spurlock et al 2009]. Sequence analysis should identify the majority of individuals without whole gene deletions, although it is estimated that approximately 1-2% could have deep intronic mutations which could be missed, but this has not been reported.

4.

Testing that identifies exonic or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5.

Spencer et al [2011] report that deletions comprise approximately 10% of SPRED1 pathogenic variants and include multiexon deletions and whole SPRED1 gene deletions

6.

Messiaen et al [2009] reported on a cohort of familial cases with similar phenotypes and 73% had mutations in NF1 and 19% had a SPRED1 mutation, suggesting that other loci are possible for an overlapping pigmentary phenotype. In addition, several families with multiple café au lait macules inherited in an autosomal dominant pattern have been described [Brunner et al 1993, Charrow et al 1993, Arnsmeier et al 1994, Abeliovich et al 1995, Nyström et al 2009b].

Clinical Description

Natural History

The natural history of Legius syndrome is based on the clinical manifestations of a few series of individuals with SPRED1 pathogenic variants and their extended families. Additional less common manifestations are listed in Table 2. Better delineation of the clinical manifestations and natural history of Legius syndrome will likely occur as more affected individuals are identified and followed prospectively.

Of note, the phenotype of Legius syndrome is based on the reports of relatively few (<200) individuals, in which the primary focus was on individuals with the overlapping pigmentary manifestations of neurofibromatosis type 1 (NF1).

Skin findings. Almost invariably, individuals with Legius syndrome present with café au lait macules. In some instances, freckling of the axillary/groin region is present. Two individuals (a male age 60 years and a child age 2 years), each with a presumed pathologic SPRED1 variant, have been reported with no café au lait macules or freckling [Brems et al 2007, Messiaen et al 2009]. The lack of pigmentary manifestations in the two-year-old was possibly a result of the child’s young age. The number of café au lait macules increases with age in childhood, similar to what is observed in NF1 [Author, personal observation].

Macrocephaly. Absolute or relative macrocephaly has been seen in children and adults with Legius syndrome. However, the frequency of macrocephaly varied in different reports: head circumference was at or above the 97th centile in approximately 40% of individuals in one cohort [Brems et al 2007] but above the 95th centile in only one of 18 individuals in another cohort [Pasmant et al 2009].

Stature. Absolute short stature has not been frequently noted in most series (although Denayer et al [2011a] reported it in 31%). Brems et al [2007] reported that in 52% of individuals, height was greater than the 50th centile. Growth charts for Legius syndrome have not been published.

Neurobehavioral and developmental problems are observed in individuals with Legius syndrome, but in many instances detailed descriptions are lacking. Messiaen et al [2009] reported three individuals who had hyperactivity and two who had attention deficits. Of the six individuals with developmental abnormalities described by Messiaen et al [2009], all had speech and/or language delays as the primary or only delay. In the 12 individuals with Legius syndrome described by Spurlock et al [2009], no learning or developmental problems were noted in the probands. Denayer et al [2011a] described five children with motor delay and five with speech delay, three individuals with ADHD, and 14 of 25 individuals with learning difficulties.

The cognitive phenotype in Legius syndrome is likely milder than that observed in NF1. A study of 15 individuals with Legius syndrome by Denayer et al [2011b] showed a lower performance IQ in children with Legius syndrome compared to their unaffected family members, although the full-scale IQ did not differ. Laycock-van Spyk et al [2011] reported one individual with cognitive impairment with an IQ of 68.

Brain imaging. Two individuals had T2 hyperintense lesions on brain imaging; thus, the presence of such lesions cannot be used to differentiate between Legius syndrome and NF1 [Denayer et al 2011a].

Vascular anomalies. A small number of vascular anomalies have been reported, but the descriptions are incomplete and different in each instance. The vascular abnormalities were listed as “tuberous hemangioma,” “inguinal hemangioma,” “large right temporal venous anomaly in brain,” and “vascular anomaly left lower leg.” Additional data are needed to determine if these reported vascular anomalies are tumors or malformations, and whether there is an increase of vascular anomalies in Legius syndrome.

Other. See Table 2. Examples of other findings reported in isolated or only a few individuals include fifth finger clinodactyly, Chiari I malformation, hypotonia, cataract, nephrolithiasis, urethral meatal stenosis, pulmonic stenosis and mitral valve prolapse, paroxysmal atrial tachycardia, tubular colonic adenoma, progressive dystonia, xanthelasmas, desmoid tumor, vestibular schwanomma, tenosynovial giant cell tumor, dermoid tumor of the ovary, non-small cell lung cancer, Wilms tumor, and monoblastic acute leukemia. Observations of clinical findings in a single individual should be taken with caution because chance occurrence cannot be distinguished from specific disease associations.

Table 2.

Additional Findings Reported in Multiple Individuals in Studies of Legius Syndrome

Finding Study
Brems et al [2007] (n=44)Pasmant et al [2009] (n=18)Spurlock et al [2009] (n=12)Messiaen et al [2009] (n=40) 1Muram-Zborovski et al [2010] (n=2)Denayer et al [2011a] (n=30)Spencer et al [2011] (n=7)Laycock-van Spyk et al [2011] (n=10)
Number of persons by study in whom the finding was observed 2
Macrocephaly13118113
Short stature (<5th centile)31081
Noonan-syndrome-like facies51121
Pectus anomalies33711
Depigmented macules31
Vascular lesions112
Lipomas142321
Learning disabilities / ADHD / developmental delays 85921646
Headaches42
Hearing loss21
Seizures211
Polydactyly12
Scoliosis41

ADHD = attention deficit hyperactivity disorder

1.

Clinical cohort (cohort 1). Data from Anonymous cohort are not included due to potential overlap.

2.

Absence of clinical findings was not always reported; hence, numbers represent only data that were reported in the respective articles.

3.

Includes angiolipoma

Tumor risk. Legius syndrome in general lacks the tumor manifestations typically observed in NF1 (i.e., Lisch nodules, neurofibromas, and central nervous system tumors). One group has suggested that individuals with Legius syndrome are at an increased risk for leukemia [Pasmant et al 2009, Pasmant et al 2014]. There has been a report of acute myeloblastic leukemia in one individual by Pasmant et al [2009], and this group subsequently screened 230 pediatric lymphoblastic and acute myeloblastic leukemias and found a loss-of-function frameshift SPRED1 mutation in a patient with Legius syndrome, but no other SPRED1 mutation in the cohort [Pasmant et al 2014]. However, in the one patient, the karyotype of white blood cell blasts showed a SPRED1 loss of heterozygosity [Pasmant et al 2014]. In addition, SPRED1 protein and SPRED1 mRNA levels were decreased in the majority of acute myeloblastic leukemias at diagnosis [Pasmant et al 2014]. Further studies are needed to assess the potential risk for cancers in Legius syndrome, particularly given that SPRED1 is part of the RAS-MAPK signal transduction pathway, a pathway involved in several neoplasms.

Genotype-Phenotype Correlations

To date no genotype-phenotype correlations have been documented.

Penetrance

The vast majority of individuals with SPRED1 pathogenic variants have café au lait macules and/or freckling; however, the age of pigment penetrance is not established. Only two individuals (a 60-year-old male and a 2-year-old child), each with a presumed SPRED1 pathogenic variant, were reported not to have café au lait macules or freckling [Brems et al 2007, Messiaen et al 2009].

Anticipation

No evidence for anticipation exists.

Nomenclature

Individuals with SPRED1 pathogenic variants were initially described as having “neurofibromatosis type 1-like syndrome” (NFLS) – primarily because of the observation that the findings in many fulfilled the current NIH NF1 clinical diagnostic criteria, even though based solely on pigmentary findings [Brems et al 2007]. Although NF1 and SPRED1 interact within the same signal transduction pathway, the majority of individuals with SPRED1 pathogenic variants share the pigmentary manifestations but lack the tumor findings associated with NF1. To clearly delineate this point in counseling sessions and to avoid confusion between NF1 and NF1-like syndrome, experts at the 13th European Neurofibromatosis Meeting (2008) suggested that the disorder be named “Legius syndrome” after Eric Legius, the senior author of the publication that first described the phenotype of SPRED1 pathogenic variants in humans [Brems et al 2007].

Prevalence

The prevalence of Legius syndrome is not known, but in two studies approximately 2% of individuals fulfilling diagnostic criteria for NF1 have had SPRED1 pathogenic variants [Messiaen et al 2009, Muram-Zborovski et al 2010]. The incidence of NF1 is reported to be 1:3000 [Friedman & Birch 1997].

Differential Diagnosis

Of primary importance in the clinical delineation of Legius syndrome is establishing the absence of other manifestations associated with the large number of other syndromes with multiple café au lait macules. Although the diagnosis of Legius syndrome is difficult to make clinically with certainty without identification of a SPRED1 pathogenic variant, the lack of additional clinical features, especially in older individuals, can help to differentiate Legius syndrome from other conditions.

Neurofibromatosis 1 (NF1) is most frequently confused with Legius syndrome, as some individuals with Legius syndrome fulfill the clinical diagnostic criteria for NF1 [NIH 1988, Gutmann et al 1997]. Approximately 3%-25% of individuals being evaluated for NF1 who do not have an identifiable NF1 pathogenic variant have a SPRED1 pathogenic variant [Brems et al 2007, Messiaen et al 2009, Pasmant et al 2009, Spurlock et al 2009]. The vast majority of individuals with NF1 eventually develop Lisch nodules and neurofibromas, but these manifestations are age-related, making the clinical distinction of NF1 from Legius syndrome very difficult in young children. The non-pigmentary manifestations outlined in the NIH NF1 diagnostic criteria (e.g., Lisch nodules, neurofibromas, optic pathway gliomas, sphenoid wing dysplasia, long-bone dysplasia) have not been observed in individuals with Legius syndrome, and the presence of one of these manifestations differentiates NF1 from Legius syndrome. Caution is needed when trying to establish a diagnosis of NF1 based purely on pigmentary findings [Stevenson & Viskochil 2009].

The phenotypes associated with specific NF1 pathogenic variants are similar to Legius syndrome in many cases. A described genotype-phenotype correlation with the NF1 three-base-pair deletion resulting in removal of a methionine residue (c.2970_2972delAAT in exon 22 using NCBI nomenclature) results in an attenuated NF1 phenotype with relative lack of neurofibromas [Stevenson et al 2006, Upadhyaya et al 2007]. An NF1 missense mutation (p.Leu1390Phe) was observed in a single multigenerational family that lacked neurofibromas and had features of Noonan syndrome with variable presence of Lisch nodules; however, the possible contribution of other modifiers cannot be excluded [Nyström et al 2009a].

Noonan syndrome. While individuals with Noonan syndrome occasionally have café au lait macules, they do not typically have them in large numbers. Some individuals with SPRED1 pathogenic variants have been reported to have facial features consistent with Noonan syndrome, and at least one individual with Legius syndrome was previously diagnosed as having Noonan syndrome [Brems et al 2007]. Congenital heart disease is common in Noonan syndrome but has not been a consistent finding in Legius syndrome.

Autosomal dominant café au lait spots (OMIM 114030). Several families with multiple café au lait macules inherited in an autosomal dominant pattern have been described [Brunner et al 1993, Charrow et al 1993, Arnsmeier et al 1994, Abeliovich et al 1995, Nyström et al 2009b]. It is possible that some of these families harbor a SPRED1 pathogenic variant, although this phenotype in at least one family did not segregate with markers within the SPRED1 locus [Nyström et al 2009b].

Other conditions associated with multiple café au lait macules include multiple lentigines syndrome (also known as LEOPARD syndrome), McCune-Albright syndrome (OMIM 174800), homozygous mismatch repair cancer syndrome (see Hereditary Non-Polyposis Colon Cancer), Bloom syndrome, Fanconia anemia, Russell-Silver syndrome, Bannayan-Riley-Ruvalcaba syndrome (see PTEN Hamartoma Tumor Syndrome), Costello syndrome, cardiofaciocutaneous syndrome, and tuberous sclerosis complex.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to SimulConsult®, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual with a confirmed molecular diagnosis of Legius syndrome, the following evaluations are recommended:

  • Age-appropriate developmental assessment
  • Neuropsychiatric evaluation on entry into school system or sooner based on clinical findings
  • Detailed dermatologic evaluation for supportive findings
  • Medical genetics consultation

Treatment of Manifestations

The following are appropriate:

  • Consideration of behavioral modification or pharmacologic adjuvant therapy for individuals with ADHD
  • Adjuvant therapies such as physical, speech, and occupational therapy for individuals with identified developmental delays
  • Individualized education plans for learning disorders and school performance issues

Prevention of Secondary Complications

Age-appropriate developmental assessment and neuropsychiatric evaluations could potentially result in the initiation of therapies to prevent developmental and behavioral complications.

Surveillance

Consider periodic evaluation by a clinical geneticist to discuss manifestations associated with disorders of the Ras/MAPK pathway that may eventually be associated with Legius syndrome

Routine screening for developmental delays and behavioral and learning problems is appropriate.

Although vascular abnormalities have been reported in a few individuals with Legius syndrome, hypertension has not been reported. However, given the prevalence of vascular abnormalities and hypertension in NF1, it would seem appropriate to have regular blood pressure monitoring at each physician visit.

Evaluation of Relatives at Risk

Using molecular genetic testing for the SPRED1 pathogenic variant found in the proband, it is appropriate to evaluate relatives at risk (e.g., parents, younger and older sibs of a proband) with café au lait macules to identify as early as possible those who could benefit from institution of treatment and preventive measures.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Legius syndrome is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Many individuals diagnosed with Legius syndrome have an affected parent.
  • A proband with Legius syndrome may have the disorder as the result of de novo gene mutation. Because the majority of simplex cases (i.e., a single occurrence in a family) have not been evaluated sufficiently to determine if the mutation occurred de novo, the proportion of Legius syndrome caused by de novo mutation is not well elucidated. However, one report states that six of 23 probands with SPRED1 pathogenic variants in a clinical cohort had de novo mutation [Messiaen et al 2009].
  • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or de novo mutation in the proband. Although no instances of germline mosaicism have been reported, as with any autosomal dominant condition, it remains a possibility.
  • The family history of some individuals diagnosed with Legius syndrome may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless physical examination by a clinical geneticist and SPRED1 molecular genetic testing has been performed on the parents of the proband.

Note: If the parent is the individual in whom the pathogenic variant first occurred s/he may have somatic mosaicism for the pathogenic variant and may be mildly/minimally affected, although this has not been reported to date for Legius syndrome.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
  • The sibs of a proband with clinically unaffected parents are still at increased risk for Legius syndrome because of the possibility of reduced penetrance in a parent.
  • If the SPRED1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Each child of an individual with Legius syndrome has a 50% chance of inheriting the SPRED1 pathogenic variant.

Other family members

  • The risk to other family members depends on the status of the proband's parents.
  • If a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with apparent de novo mutation. When neither parent of a proband with Legius syndrome has the pathogenic variant or clinical evidence of the disorder, it is likely that mutation occurred de novo in the proband. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the SPRED1 pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Requests for prenatal testing for conditions which (like Legius syndrome) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the SPRED1 pathogenic variant has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • RASopathiesNet
    244 Taos Road
    Atlandena CA 91001
    Phone: 626-676-7694
    Email: lisa@rasopathies.org
  • Children's Tumor Foundation
    95 Pine Street
    16th Floor
    New York NY 10005
    Phone: 800-323-7938 (toll-free); 212-344-6633
    Fax: 212-747-0004
    Email: info@ctf.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Legius Syndrome: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Legius Syndrome (View All in OMIM)

609291SPROUTY-RELATED EVH1 DOMAIN-CONTAINING PROTEIN 1; SPRED1
611431LEGIUS SYNDROME

Molecular Genetic Pathogenesis

SPRED1 encodes a protein that negatively regulates Ras-MAPK signaling. Loss-of-function mutations in SPRED1 create mutant Spred1 proteins incapable of inhibiting Raf1 kinase activation. This results in attenuated inhibition of downstream Raf-MEK-ERK signaling [Brems et al 2007]. This uninhibited signaling and consequent increase in Ras signal propagation is similar to that observed in NF1 and likely results in the clinical overlap of these two conditions.

For example, neurobehavioral problems are reported in individuals with Legius syndrome and NF1; this finding in Legius syndrome is biologically consistent with data in the mouse model showing that Spred1 protein is required for synaptic plasticity [Denayer et al 2008]. In addition, vascular anomalies are seen in other syndromes of the Ras-MAPK pathway (i.e., capillary malformation-arteriovenous malformation syndrome with RASA1 pathogenic variants), providing potential biologic support for an association with Legius syndrome.

Gene structure. SPRED1 spans 104.4 kb of genomic sequence. It consists of seven exons. The transcript is 7255 bp in length (NM_152594.2) and encodes 444 amnio acids (NP_689807.1). For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. Twenty-four benign or suspected benign variants have been reported in two locus-specific databases. Ten are missense mutations, eleven are silent variants, and three are spice site variants.

Muram-Zborovski et al [2010] identified a common SPRED1 haplotype matching GenBank reference sequence NG_008980 in 17.9% of their NF1 cohort and 12.5% of an unselected normal population. This haplotype differs from the more common reference sequence NC_000015 by four single nucleotide allelic variants (SNPs). Two of these normal variants are exonic, one in exon 3 and one in exon 7; the other two SNPs are within intron 5. See Table 3.

Table 3.

Selected SPRED1 Benign Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.291A>Gp.Lys97LysNM_152594​.2
NP_689807​.1
c.1044C>Tp.Val348Val
c.424-8A>CNA
c.424-98C>TNA

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

NA = not applicable

Pathogenic allelic variants. Pathogenic variants have been identified throughout SPRED1, without a discernible mutation hotspot. Most of the pathogenic variants identified are nonsense mutations, splice site mutations, small insertions/deletions, and gross gene rearrangements. They are predicted to be protein truncating. A few missense mutations have also been identified within families; however, only a portion of these have been confirmed as pathogenic using functional studies [Messiaen et al 2009].

Normal gene product. Spred1 protein is a 444-amino acid sprouty-related protein. It comprises an N-terminal EVH-1 domain, a central KIT binding domain, and a C-terminal SPRY domain. Spred1 belongs to a family of proteins that are negative regulators of the Ras/ERK pathway. Spred1 negatively regulates the Ras/ERK pathway by inhibiting Raf1 kinase activation [Wakioka et al 2001, Tidyman & Rauen 2009]. Spred1 has also been shown to interact with neurofibromin to bring it to plasma membrane-bound Ras peptides [Stowe et al 2012].

Abnormal gene product. Pathogenic variants in SPRED1 that result in Spred1 loss of function disrupt its ability to inhibit Raf1 kinase activation, leading to increased downstream ERK signaling. Pathogenic variants in SPRED1 have been identified within the N-terminal EVH-1 domain, the KIT binding domain, and the C-terminal SPRY domain of the spred1 protein.

References

Literature Cited

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Chapter Notes

Acknowledgments

John Carey, MD; Ludwine Messiaen, PhD; Talia Muram, MD

Author History

Rong Mao, MD (2010-present)
Talia Muram-Zborovski, MD, University of Utah (2010-2015)
David Stevenson, MD (2010-present)
David Viskochil, MD, PhD (2010-present)

Revision History

  • 15 January 2015 (me) Comprehensive update posted live
  • 12 May 2011 (cd) Revision: Testing Strategy; Table 2
  • 14 October 2010 (me) Review posted live
  • 29 April 2010 (ds) Original submission
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