Clinical 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 commonly reported include intertriginous freckling, lipomas, macrocephaly, and learning disabilities, attention-deficit/hyperactivity disorder (ADHD), and developmental delays.

Diagnosis/testing.

The diagnosis of Legius syndrome is established in a proband with suggestive findings and a heterozygous pathogenic variant in SPRED1 identified by molecular genetic testing.

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; referral to dermatologist as needed for lipoma management; treatment of pectus excavatum and scoliosis per orthopedist; standard treatment for seizures per experienced neurologist; referral to otolaryngologist for those with identified hearing loss.

Surveillance: Monitor developmental progress, educational needs, and behavioral assessment at each visit; assess for pigmentary lesions, lipomas, scoliosis, and new-onset seizures at each visit; hearing evaluation as needed.

Genetic counseling.

Legius syndrome is inherited in an autosomal dominant manner. Many individuals diagnosed with Legius syndrome have an affected parent. Each child of an individual with Legius syndrome caused by a germline SPRED1 pathogenic variant has a 50% chance of inheriting the pathogenic variant. Once the SPRED1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

Legius syndrome should be suspected in a proband with the following clinical findings and family history.

Clinical findings

• Pigmentary dysplasia consisting of café au lait macules, with or without intertriginous freckling
• Lacks the nonpigmentary clinical diagnostic manifestations of neurofibromatosis type 1 (NF1) (e.g., Lisch nodules, neurofibromas, optic pathway glioma, sphenoid wing dysplasia, long bone dysplasia). Note: Lisch nodules have been reported in two individuals from one family with pathogenic variants in SPRED1 [Bixel et al 2020] but have not been reported in the vast majority of individuals with Legius syndrome.

Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnostic criteria for Legius syndrome are met if at least two of the following criteria are present:

• Five or more café au lait macules bilaterally distributed and no other NF1-related diagnostic criteria except for axillary or inguinal freckling
• A heterozygous pathogenic (or likely pathogenic) variant in SPRED1 in 100% of cells from unaffected tissue (see Table 1)
• A parent with the diagnosis of Legius syndrome by the above criteria

Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous SPRED1 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular testing approaches can include:

• Single-gene testing. Sequence analysis of SPRED1 to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
• A multigene panel that includes SPRED1 and other genes of interest (see Differential Diagnosis) may be considered to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

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, attention-deficit/hyperactivity disorder (ADHD), and developmental delays.

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. Only a few individuals (3 adults and 1 child), each with a presumed SPRED1 pathogenic variant, were reported to not have café au lait macules [Brems et al 2007, Messiaen et al 2009, Denayer et al 2011a]. The lack of pigmentary manifestations in the child was possibly a result of the child's young age. It is known that café au lait macules can fade away in older individuals with NF1. The number of café au lait macules increases with age in infants, similar to what is observed in NF1 [D Stevenson & E Legius, personal observations].

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].

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. Learning disabilities were further reported by Benelli et al [2015], Sakai et al [2015], Sekelska et al [2017], and Witkowski et al [2020] in five individuals.

The cognitive issues in individuals with Legius syndrome are likely milder than those 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 and an IQ of 68.

Multiple lipomas. Subcutaneous lipomas were reported in 32% of individuals with a SPRED1 pathogenic variant in the initial series [Brems et al 2007]; all but one individual was an adult. However, in subsequent series, lipomas were not frequently reported (e.g., lipomas were observed in two adults from one family in one series of multiple families [Pasmant et al 2009], observed in two adults in a series of 24 individuals [Denayer et al 2011a], observed in one adult in another series of 42 individuals [Messiaen et al 2009]).

Facial features. Some case series report a "Noonan facial gestalt" (14% in Brems et al [2007], 40% in Denayer et al [2011a]), although there was limited discussion of what features constituted this gestalt. Downslanted palpebral fissures, ptosis, posteriorly rotated ears, and hypertelorism were listed in the series by Denayer et al [2011a]. Noonan-like dysmorphic features were not present in individuals with Legius syndrome in one reported series [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 height was greater than the 50th centile in 52% of individuals. Growth charts for Legius syndrome have not been published.

Skeletal manifestations. Pectus/sternal abnormalities were reported in seven of 30 individuals in the series by Denayer et al [2011a]. Scoliosis was reported in six individuals [Denayer et al 2011a, Laycock-van Spyk et al 2011, Chelleri et al 2024]; one individual was reported to have congenital scoliosis, and one required surgery for scoliosis. Postaxial polydactyly was reported in four individuals [Messiaen et al 2009, Denayer et al 2011a, Gibbs et al 2025].

Seizures have been reported in seven individuals [Messiaen et al 2009, Denayer et al 2011a, Laycock-van Spyk et al 2011, Benelli et al 2015, Romanisio et al 2021, Medina Lemus et al 2024]. Medina Lemus et al [2024] discuss that seizures appear to be more common in individuals with Legius syndrome compared to the general population, but this is based on limited data.

Hearing loss was reported in four individuals and described as "mild" in two [Messiaen et al 2009, Denayer et al 2011a].

Vascular anomalies. A small number of vascular anomalies have been reported, but the descriptions are incomplete and differ in each instance. The vascular abnormalities were listed as "tuberous hemangioma," "inguinal hemangioma," "large right temporal venous anomaly in brain," “moyamoya syndrome", 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 individuals with Legius syndrome.

Brain imaging. Two individuals had T₂-weighted 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]. However, in a study comparing imaging of individuals with NF1 (n=130) and individuals with Legius syndrome (n=16), 89% of individuals with NF1 had focal areas of signal intensity compared to 0% of individuals with Legius syndrome [Petrak et al 2025].

Cardiac abnormalities. Pulmonic valve stenosis has been reported in four individuals [Brems et al 2007, Messiaen et al 2009, Witkowski et al 2020, Gibbs et al 2025]. There are single reports of other cardiac findings such as mitral valve prolapse [Messiaen et al 2009] and paroxysmal atrial tachycardia [Brems et al 2007].

Tumor risk. Single reports of various tumors include:

• Wilms tumor and colon tubular adenoma (both in one individual) [Brems et al 2007]
• Non-small cell lung cancer [Brems et al 2007]
• Tenosynovial giant cell tumor [Messiaen et al 2009]
• Dermoid tumor of ovary [Messiaen et al 2009]
• Desmoid tumor of the abdominal wall [Denayer et al 2011a]
• Unilateral vestibular schwannoma [Denayer et al 2011a]

One group suggested that individuals with Legius syndrome are at an increased risk for leukemia [Pasmant et al 2009, Pasmant et al 2015a]. There has been a report of acute myeloblastic leukemia in one individual [Pasmant et al 2009]. This group subsequently screened 230 pediatric lymphoblastic and acute myeloblastic leukemias and found a loss-of-function frameshift SPRED1 variant in an individual with Legius syndrome [Pasmant et al 2015a].

A review by Ney et al [2022] concluded that tumor surveillance was not recommended in individuals with Legius syndrome. Further studies are needed to assess the potential risk for cancers in individuals with Legius syndrome, particularly given that SPRED1 is part of the Ras-MAPK signal transduction pathway, a pathway involved in several neoplasms.

Genotype-Phenotype Correlations

No clinically relevant genotype-phenotype correlations have been identified.

Penetrance

The vast majority of individuals with SPRED1 pathogenic variants have café au lait macules and/or freckling; however, the age of penetrance of these pigmentary features is not established. Only a few individuals (3 adults and 1 child), each with a presumed SPRED1 pathogenic variant, were reported to not have café au lait macules [Brems et al 2007, Messiaen et al 2009, Denayer et al 2011a].

Some very young children may not have developed café au lait macules yet, and in older individuals the café au lait macules may have faded away. Some adolescents or young adults show only two or three café au lait macules, and the syndrome may be underdiagnosed.

Nomenclature

The majority of individuals with SPRED1 pathogenic variants share the pigmentary manifestations but lack the tumor findings associated with NF1. Legius syndrome is not a form of neurofibromatosis, although it is a RASopathy. To clearly delineate this point in counseling sessions and to avoid confusion between NF1 and NF1-like syndrome, the name "Legius syndrome" was chosen and fulfills its purpose.

Prevalence

The prevalence of Legius syndrome is estimated at 1:46,000-1:75,000 based on the fraction of children with a SPRED1 pathogenic variant in cohorts of children followed at neurofibromatosis clinics [Messiaen et al 2009, Pasmant et al 2015b, Evans et al 2016, Giugliano et al 2019].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual with Legius syndrome, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.

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.
• Some individuals diagnosed with Legius syndrome have the disorder as the result of a de novo pathogenic variant. The proportion of individuals with Legius syndrome caused by a de novo pathogenic variant is unknown. One report stated that six of 23 probands with SPRED1 pathogenic variants in a clinical cohort had de novo pathogenic variants [Messiaen et al 2009].
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, early death of the parent before the onset of manifestations, or late onset of the disease in the affected parent. Therefore, de novo occurrence of a SPRED1 pathogenic variant cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
    * Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic/gonadal mosaicism for the pathogenic variant and may be mildly/minimally affected. (Segmental distribution of café au lait macules as a result of somatic mosaicism for a SPRED1 pathogenic variant has been observed in two individuals but is very rare [Jobling et al 2017; D Stevenson & E Legius, unpublished data].)

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 and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• All sibs who inherit a pathogenic SPRED1 variant are expected to develop some clinical features of Legius syndrome, but there is high variability in the number and age of onset of café au lait macules (see Penetrance).
• If the SPRED1 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the SPRED1 pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for Legius syndrome because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism.

Offspring of a proband

• Each child of an individual with Legius syndrome caused by a germline SPRED1 pathogenic variant has a 50% chance of inheriting the pathogenic variant.
• Each child of an individual with Legius syndrome caused by a postzygotic mosaic SPRED1 pathogenic variant has up to a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the SPRED1 pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

Once the SPRED1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for Legius syndrome are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

SPRED1 encodes Sprouty-related, EVH1 domain-containing protein 1 (Spred1), a protein that negatively regulates Ras-MAPK signaling. Functional domains in Spred1 include:

• N-terminal EVH-1 domain
• Central KIT binding domain
• 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]. Specific interacting domains in Spred1 and neurofibromin have been identified [Dunzendorfer-Matt et al 2016, Hirata et al 2016].

Additional SPRED genes are linked to related phenotypes (e.g., SPRED2 pathogenic variants result in a Noonan syndrome-like phenotype without café au lait macules [Motta et al 2021]). Given the overlapping function of the Spred family of proteins in many cell types [Lorenzo & McCormick 2020], other SPRED genes can likely compensate for lack of Spred1 in some organ systems, potentially explaining the milder phenotype in Legius syndrome compared to other RASopathies.

Disease-associated variants result in Spred1 proteins incapable of inhibiting Raf1 kinase activation, resulting 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 neurofibromatosis type 1 (NF1) and likely results in the clinical overlap of these two conditions.

Mechanism of disease causation. Loss of function with a second acquired SPRED1 pathogenic variant occurring in affected tissue similar to the mechanism in NF1 [Brems et al 2007, Jouhilahti et al 2011]

Acknowledgments

David Viskochil, MD, PhD
John Carey, MD
Ludwine Messiaen, PhD
Talia Muram, MD

Author History

Eric Legius, MD, PhD (2020-present)
Rong Mao, MD; University of Utah (2010-2020)
Talia Muram-Zborovski, MD, University of Utah (2010-2015)
David Stevenson, MD (2010-present)
David Viskochil, MD, PhD; University of Utah (2010-2020)

Revision History

• 4 December 2025 (sw) Comprehensive update posted live
• 6 August 2020 (sw) Comprehensive update posted live
• 15 January 2015 (me) Comprehensive update posted live
• 14 October 2010 (me) Review posted live
• 29 April 2010 (ds) Original submission

Literature Cited

• Ablain J, Xu M, Rothschild H, Jordan RC, Mito JK, Daniels BH, Bell CF, Joseph NM, Wu H, Bastian BC, Zon LI, Yeh I. Human tumor genomics and zebrafish modeling identify SPRED1 loss as a driver of mucosal melanoma. Science. 2018;362:1055–60. [PMC free article: PMC6475924] [PubMed: 30385465]
• Benelli E, Bruno I, Belcaro C, Ventura A, Berti I. Legius syndrome: case report and review of literature. Ital J Pediatr. 2015;41:8. [PMC free article: PMC4323213] [PubMed: 25883013]
• Bixel KD, Cano MJ, Johnson DM, Gomez B, Lobsinger LV, Valentin FE, Hsieh DT, Rohena LO. Lisch nodules and iris mammillations in two siblings with familial Legius syndrome. Clin Case Rep. 2020;8:1867-71. [PMC free article: PMC7562883] [PubMed: 33088508]
• Brems H, Chmara M, Sahbatou M, Denayer E, Taniguchi K, Kato R, Somers R, Messiaen L, De Schepper S, Fryns JP, Cools J, Marynen P, Thomas G, Yoshimura A, Legius E. Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. Nat Genet. 2007;39:1120–6. [PubMed: 17704776]
• Chelleri C, Brolatti N, De Marco P, Ognibene M, Diana MC, Madia F, Duca MD, Santangelo A, Capra V, Striano P, Zara F, Scala M. Novel causative variants in Legius syndrome: SPRED1 Genotype spectrum expansion. Am J Med Genet A. 2024;194:e63824. [PubMed: 39031930]
• 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. Legius syndrome in fourteen families. Hum Mutat. 2011a;32:E1985–98. [PMC free article: PMC3038325] [PubMed: 21089071]
• Denayer E, Descheemaeker MJ, Stewart DR, Keymolen K, Plasschaert E, Ruppert SL, Snow J, Thurm AE, Joseph LA, Fryns JP, Legius E. Observations on intelligence and behavior in 15 patients with Legius syndrome. Am J Med Genet C Semin Med Genet. 2011b;157C:123–8. [PMC free article: PMC3081633] [PubMed: 21495177]
• Dunzendorfer-Matt T, Mercado EL, Maly K, McCormick F, Scheffzek K. The neurofibromin recruitment factor Spred1 binds to the GAP related domain without affecting Ras inactivation. Proc Natl Acad Sci U S A. 2016;113:7497–502. [PMC free article: PMC4941445] [PubMed: 27313208]
• Evans DG, Bowers N, Burkitt-Wright E, Miles E, Garg S, Scott-Kitching V, Penman-Splitt M, Dobbie A, Howard E, Ealing J, Vassalo G, Wallace AJ, Newman W, Huson SM, et al. Comprehensive RNA analysis of the NF1 gene in classically affected NF1 affected individuals meeting NIH criteria has high sensitivity and mutation negative testing is reassuring in isolated cases with pigmentary features only. EBioMedicine. 2016;7:212–20. [PMC free article: PMC4909377] [PubMed: 27322474]
• Gibbs A, Holder-Espinasse M, Ramachandran V, Chandler NJ. Post-axial polydactyly and postnatal pulmonary stenosis observed with a SPRED1 pathogenic variant. Prenat Diagn. 2025;45:1066-9. [PMC free article: PMC12254426] [PubMed: 40437629]
• Giugliano T, Santoro C, Torella A, Del Vecchio Blanco F, Grandone A, Onore ME, Melone MAB, Straccia G, Melis D, Piccolo V, Limongelli G, Buono S, Perrotta S, Nigro V, Piluso G. Clinical and genetic findings in children with neurofibromatosis type 1, Legius syndrome, and other related neurocutaneous disorders. Genes (Basel). 2019;10:580. [PMC free article: PMC6722641] [PubMed: 31370276]
• Gutmann DH, Aylsworth A, Carey JC, Korf B, Marks J, Pyeritz RE, Rubenstein A, Viskochil D. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA. 1997;278:51–7. [PubMed: 9207339]
• Hirata Y, Brems H, Suzuki M, Kanamori M, Okada M, Morita R, Llano-Rivas I, Ose T, Messiaen L, Legius E, Yoshimura A. Interaction between a domain of the negative regulator of the Ras-ERK pathway, SPRED1 protein, and the GTPase-activating protein-related domain of neurofibromin is implicated in Legius syndrome and neurofibromatosis type 1. J Biol Chem. 2016;291:3124–34. [PMC free article: PMC4751360] [PubMed: 26635368]
• Horn S, Neuhann T, Hennig C, Abad-Perez A, Prott EC, Cardellini L, Potratz C, Leubner J, Eichhorn B, Merkel M, Abicht A, Kaindl AM. LZTR1 loss-of-function variants associated with café au lait macules with or without freckling. Front Neurol. 2024 Aug 27;15:1391425. [PMC free article: PMC11383758] [PubMed: 39258154]
• Jobling RK, Lara-Corrales I, Hsiao MC, Shugar A, Hedges S, Messiaen L, Kannu P. Mosaicism for a SPRED1 deletion revealed in a patient with clinically suspected mosaic neurofibromatosis. Br J Dermatol. 2017;176:1077–8. [PubMed: 27423141]
• Jouhilahti EM, Peltonen S, Heape AM, Peltonen J. The pathoetiology of neurofibromatosis 1. Am J Pathol. 2011;178:1932-9. [PMC free article: PMC3081157] [PubMed: 21457932]
• Koczkowska M, Callens T, Gomes A, Sharp A, Chen Y, Hicks AD, Aylsworth AS, Azizi AA, Basel DG, Bellus G, Bird LM, Blazo MA, Burke LW, Cannon A, Collins F, DeFilippo C, Denayer E, Digilio MC, Dills SK, Dosa L, Greenwood RS, Griffis C, Gupta P, Hachen RK, Hernández-Chico C, Janssens S, Jones KJ, Jordan JT, Kannu P, Korf BR, Lewis AM, Listernick RH, Lonardo F, Mahoney MJ, Ojeda MM, McDonald MT, McDougall C, Mendelsohn N, Miller DT, Mori M, Oostenbrink R, Perreault S, Pierpont ME, Piscopo C, Pond DA, Randolph LM, Rauen KA, Rednam S, Rutledge SL, Saletti V, Schaefer GB, Schorry EK, Scott DA, Shugar A, Siqveland E, Starr LJ, Syed A, Trapane PL, Ullrich NJ, Wakefield EG, Walsh LE, Wangler MF, Zackai E, Claes KBM, Wimmer K, van Minkelen R, De Luca A, Martin Y, Legius E, Messiaen LM. Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation. Genet Med. 2019;21:867–76. [PMC free article: PMC6752285] [PubMed: 30190611]
• Laycock-van Spyk S, Jim HP, Thomas L, Spurlock G, Fares L, Palmer-Smith S, Kini U, Saggar A, Patton M, Mautner V, Pilz DT, Upadhyaya M. Identification of five novel SPRED1 germline mutations in Legius syndrome. Clin Genet. 2011;80:93–6. [PubMed: 21649642]
• Legius E, Messiaen L, Wolkenstein P, Pancza P, Avery RA, Berman Y, Blakeley J, Babovic-Vuksanovic D, Cunha KS, Ferner R, Fisher MJ, Friedman JM, Gutmann DH, Kehrer-Sawatzki H, Korf BR, Mautner VF, Peltonen S, Rauen KA, Riccardi V, Schorry E, Stemmer-Rachamimov A, Stevenson DA, Tadini G, Ullrich NJ, Viskochil D, Wimmer K, Yohay K; International Consensus Group on Neurofibromatosis Diagnostic Criteria (I-NF-DC); Huson SM, Evans DG, Plotkin SR. Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation. Genet Med. 2021;23:1506-13. [PMC free article: PMC8354850] [PubMed: 34012067]
• Lorenzo C, McCormick F. SPRED proteins and their roles in signal transduction, development, and malignancy. Genes Dev. 2020;34:1410-21. [PMC free article: PMC7608746] [PubMed: 33872193]
• Mastromoro G, Santoro C, Motta M, Sorrentino U, Daniele P, Peduto C, Petrizzelli F, Tripodi M, Pinna V, Zanobio M, Rotundo G, Bellacchio E, Lepri F, Farina A, D'Asdia MC, Piceci-Sparascio F, Biagini T, Petracca A, Castori M, Melis D, Accadia M, Traficante G, Tarani L, Fontana P, Sirchia F, Paparella R, Currò A, Benedicenti F, Scala I, Dentici ML, Leoni C, Trevisan V, Cecconi A, Giustini S, Pizzuti A, Salviati L, Novelli A, Zampino G, Zenker M, Genuardi M, Digilio MC, Papi L, Perrotta S, Nigro V, Castellanos E, Mazza T, Trevisson E, Tartaglia M, Piluso G, De Luca A. Heterozygosity for loss-of-function variants in LZTR1 is associated with isolated multiple café-au-lait macules. Genet Med. 2024;26:101241. [PubMed: 39140257]
• Medina Lemus A, Boelman C, Myers KA. Epilepsy in Legius syndrome: coincidence or causation? Am J Med Genet A. 2024;194:e63547. [PubMed: 38268057]
• Messiaen L, Yao S, Brems H, Callens T, Sathienkijkanchai A, Denayer E, Spencer E, Arn P, Babovic-Vuksanovic D, Bay C, Bobele G, Cohen BH, Escobar L, Eunpu D, Grebe T, Greenstein R, Hachen R, Irons M, Kronn D, Lemire E, Leppig K, Lim C, McDonald M, Narayanan V, Pearn A, Pederson R, Powell B, Shapiro L, Skidmore D, Tegay D, Thiese H, Zackai E, Vijzelaar R, Taniguchi K, Ayada R, Okamoto F, Yoshimura A, Parret A, Korf B, Legius E. Clinical and mutational spectrum of neurofibromatosis type 1-like syndrome. JAMA. 2009;302:2111–8. [PubMed: 19920235]
• Motta M, Fasano G, Gredy S, Brinkmann J, Bonnard AA, Simsek-Kiper PO, Gulec EY, Essaddam L, Utine GE, Guarnetti Prandi I, Venditti M, Pantaleoni F, Radio FC, Ciolfi A, Petrini S, Consoli F, Vignal C, Hepbasli D, Ullrich M, de Boer E, Vissers LELM, Gritli S, Rossi C, De Luca A, Ben Becher S, Gelb BD, Dallapiccola B, Lauri A, Chillemi G, Schuh K, Cavé H, Zenker M, Tartaglia M. SPRED2 loss-of-function causes a recessive Noonan syndrome-like phenotype. Am J Hum Genet. 2021;108:2112-29. [PMC free article: PMC8595899] [PubMed: 34626534]
• Newell F, Kong Y, Wilmott JS, Johansson PA, Ferguson PM, Cui C, Li Z, Kazakoff SH, Burke H, Dodds TJ, Patch AM, Nones K, Tembe V, Shang P, van der Weyden L, Wong K, Holmes O, Lo S, Leonard C, Wood S, Xu Q, Rawson RV, Mukhopadhyay P, Dummer R, Levesque MP, Jönsson G, Wang X, Yeh I, Wu H, Joseph N, Bastian BC, Long GV, Spillane AJ, Shannon KF, Thompson JF, Saw RPM, Adams DJ, Si L, Pearson JV, Hayward NK, Waddell N, Mann GJ, Guo J, Scolyer RA. Whole-genome landscape of mucosal melanoma reveals diverse drivers and therapeutic targets. Nat Commun. 2019;10:3163. [PMC free article: PMC6639323] [PubMed: 31320640]
• Ney G, Gross A, Livinski A, Kratz CP, Stewart DR. Cancer incidence and surveillance strategies in individuals with RASopathies. Am J Med Genet C Semin Med Genet. 2022;190:530-40. [PMC free article: PMC9825668] [PubMed: 36533693]
• NIH. National Institutes of Health Consensus Development Conference Statement: neurofibromatosis. Bethesda, Md, USA, July 13-15, 1987. Neurofibromatosis. 1988;1:172–8. [PubMed: 3152465]
• Nyström AM, Ekvall S, Strömberg B, Holmström G, Theuresson AC, Annerén G, Bondeson ML. A severe form of Noonan syndrome and autosomal dominant café-au-lait spots – evidence for different genetic origins. Acta Paediatr. 2009;98:693–8. [PubMed: 19120036]
• Pasmant E, Ballerini P, Lapillonne H, Perot C, Vidaud D, Leverger G, Landman-Parker J. SPRED1 disorder and predisposition to leukemia in children. Blood. 2009;114:1131. [PubMed: 19643996]
• 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. SPRED1, a RAS MAPK pathway inhibitor that causes Legius syndrome, is a tumor suppressor downregulated in paediatric acute myeloblastic leukaemia. Oncogene. 2015a;34:631–8. [PubMed: 24469042]
• Pasmant E, Parfait B, Luscan A, Goussard P, Briand-Suleau A, Laurendeau I, Fouveaut C, Leroy C, Montadert A, Wolkenstein P, Vidaud M, Vidaud D. Neurofibromatosis type 1 molecular diagnosis: what can NGS do for you when you have a large gene with loss of function mutations? Eur J Hum Genet. 2015b;23:596–601. [PMC free article: PMC4402624] [PubMed: 25074460]
• Petrak B, Kraus J, Bendova S, Dvorakova M, Pourova RK, Ebel M, Glombova M, Jakoubek V, Musova Z, Hedvicakova P, Santova A, Maminak M, Tesner P. Significance of the absence of focal areas of signal intensity on brain magnetic resonance imaging examinations in Legius syndrome. Pediatr Neurol. 2025;169:142-7. [PubMed: 40516232]
• Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–33. [PMC free article: PMC4731925] [PubMed: 26656846]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Rojnueangnit K, Xie J, Gomes A, Sharp A, Callens T, Chen Y, Liu Y, Cochran M, Abbott MA, Atkin J, Babovic-Vuksanovic D, Barnett CP, Crenshaw M, Bartholomew DW, Basel L, Bellus G, Ben-Shachar S, Bialer MG, Bick D, Blumberg B, Cortes F, David KL, Destree A, Duat-Rodriguez A, Earl D, Escobar L, Eswara M, Ezquieta B, Frayling IM, Frydman M, Gardner K, Gripp KW, Hernández-Chico C, Heyrman K, Ibrahim J, Janssens S, Keena BA, Llano-Rivas I, Leppig K, McDonald M, Misra VK, Mulbury J, Narayanan V, Orenstein N, Galvin-Parton P, Pedro H, Pivnick EK, Powell CM, Randolph L, Raskin S, Rosell J, Rubin K, Seashore M, Schaaf CP, Scheuerle A, Schultz M, Schorry E, Schnur R, Siqveland E, Tkachuk A, Tonsgard J, Upadhyaya M, Verma IC, Wallace S, Williams C, Zackai E, Zonana J, Lazaro C, Claes K, Korf B, Martin Y, Legius E, Messiaen L. High incidence of Noonan syndrome features including short stature and pulmonic stenosis in patients carrying NF1 missense mutations affecting p.Arg1809: genotype-phenotype correlation. Hum Mutat. 2015;36:1052–63. [PMC free article: PMC5049609] [PubMed: 26178382]
• Romanisio G, Chelleri C, Scala M, Piccolo G, Carlini B, Gatti L, Capra V, Zara F, Bersano A, Pavanello M, De Marco P, Diana MC. RNF213 variant in a patient with Legius syndrome associated with moyamoya syndrome. Mol Genet Genomic Med. 2021;9:e1669. [PMC free article: PMC8222830] [PubMed: 33939317]
• Sakai N, Maeda T, Kawakami H, Uchiyama M, Harada K, Tsuboi R, Mitsuhashi Y. Family with Legius syndrome (neurofibromatosis type 1-like syndrome). J Dermatol. 2015;42:703–5. [PubMed: 25981987]
• Sekelska M, Briatkova L, Olcak T, Bolcekova A, Ilencikova D, Kadasi L, Zatkova A. The first Slovak Legius syndrome patient carrying the SPRED1 gene mutation. Gen Physiol Biophys. 2017;36:205–10. [PubMed: 28150585]
• Spurlock G, Bennett E, Chuzhanova N, Thomas N, Jim HP, Side L, Davies S, Haan E, Kerr B, Huson SM, Upadhyaya M. SPRED1 mutations (Legius syndrome): another clinically useful genotype for dissecting the NF1 phenotype. J Med Genet. 2009;46:431–7. [PubMed: 19443465]
• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197-207.. [PMC free article: PMC7497289] [PubMed: 32596782]
• Stowe IB, Mercado EL, Stowe TR, Bell EL, Oses-Prieto JA, Hernández H, Burlingame AL, McCormick F. A shared molecular mechanism underlies the human rasopathies Legius syndrome and Neurofibormatosis-1. Genes Dev. 2012;26:1421–6. [PMC free article: PMC3403010] [PubMed: 22751498]
• Tidyman WE, Rauen KA. The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. Curr Opin Genet Dev. 2009;19:230–6. [PMC free article: PMC2743116] [PubMed: 19467855]
• Wakioka T, Sasaki A, Kato R, Shouda T, Matsumoto A, Miyoshi K, Tsuneoka M, Komiya S, Baron R, Yoshimura A. Spred is a Sprouty-related suppressor of Ras signaling. Nature. 2001;412:647–51. [PubMed: 11493923]
• Witkowski L, Dillon MW, Murphy E. S Lebo M, Mason-Suares H. Expanding the Noonan spectrum/RASopathy NGS panel: benefits of adding NF1 and SPRED1. Mol Genet Genomic Med. 2020;8:e1180. [PMC free article: PMC7196473] [PubMed: 32107864]
• Yeh I, Jorgenson E, Shen L, Xu M, North JP, Shain AH, Reuss D, Wu H, Robinson WA, Olshen A, von Deimling A, Kwok PY, Bastian BC, Asgari MM. Targeted genomic profiling of acral melanoma. J Natl Cancer Inst. 2019;111:1068–77. [PMC free article: PMC6792090] [PubMed: 30657954]