Legius Syndrome
Summary
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 reported commonly include intertriginous freckling, lipomas, macrocephaly, and learning disabilities / attention-deficit/hyperactivity disorder (ADHD) / developmental delays. Current knowledge of the natural history of Legius syndrome is based on the clinical manifestations of fewer than 300 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 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; and 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. Many affected individuals have an affected parent. Each child of an individual with Legius syndrome has a 50% chance of inheriting the pathogenic variant and developing clinical features of the disorder. Preimplantation genetic testing or prenatal testing for pregnancies at increased risk is possible if the SPRED1 pathogenic variant has been identified in an affected family member.
Diagnosis
Suggestive Findings
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 nonpigmentary clinical diagnostic manifestations of neurofibromatosis type 1 (NF1) (e.g., Lisch nodules, neurofibromas, optic pathway glioma, sphenoid wing dysplasia, long bone dysplasia).
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 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: Identification of a heterozygous SPRED1 variant of uncertain significance does not establish or rule out the diagnosis of this disorder.
Molecular testing approaches can include:
- Single-gene testing. Sequence analysis of SPRED1 to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. 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). 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; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (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.
Note: Opinions differ on the appropriate approach when clinical information and family history cannot distinguish between NF1 and Legius syndrome. This is the case in individuals with only café au lait macules with or without freckling but no other signs of NF1. 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 vs when the diagnosis of neither can be established with confidence
- Psychological burden of a diagnosis or lack thereof
- Costs of testing and surveillance
- Odds of identifying a diagnosis of NF1 vs Legius syndrome in those with phenotype limited to pigmentary findings
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], Evans et al [2016], and Castellanos et al [2020].
Table 1.
Molecular Genetic Testing Used in Legius Syndrome
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| SPRED1 | Sequence analysis 3 | 89% 4 |
| Deletion/duplication analysis 5 | 10% 6 | |
| Unknown 7 | NA | ~1% |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
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 variants which could be missed; however, this has not been reported.
- 5.
Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
- 6.
Spencer et al [2011] report that deletions comprise approximately 10% of SPRED1 pathogenic variants and include multiexon deletions and whole SPRED1 gene deletions
- 7.
Sequence analysis in combination with deletion/duplication analysis should identify the majority of individuals, although it is estimated that approximately 1% could have deep intronic variants that could be missed; however, this has not been reported.
Clinical Characteristics
Clinical Description
Of note, the phenotype of Legius syndrome is based on the reports of relatively few (<300) individuals, in which the primary focus was on individuals with the overlapping pigmentary manifestations of neurofibromatosis type 1 (NF1).
Table 2.
Legius Syndrome: Frequency of Select Features
| Feature | % of Persons with Feature | Comment |
|---|---|---|
| Café au lait macules | >99% | |
| Skin freckling | 30%-50% | Age dependent |
| Macrocephaly | 20% | |
| Short stature | 12% | |
| Neurobehavioral/developmental issues | 30% | |
| Multiple lipomas | 18% | In adults |
| Pectus deformity | 12% | |
| Noonan-like facial features | 15% |
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 pathogenic 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 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 [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. 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 with an IQ of 68.
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].
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 individuals with Legius syndrome.
Rare features reported in more than one individual:
- Hearing loss in four individuals [Messiaen et al 2009, Denayer et al 2011a]
- Seizures in six individuals [Messiaen et al 2009, Denayer et al 2011a, Laycock-van Spyk et al 2011, Benelli et al 2015, Sakai et al 2015]
- Polydactyly in three individuals [Messiaen et al 2009, Denayer et al 2011a]
- Scoliosis in five individuals [Denayer et al 2011a, Laycock-van Spyk et al 2011]
- Pulmonic valve stenosis in three individuals [Brems et al 2007, Messiaen et al 2009, Witkowski et al 2020]
Other. 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, mitral valve prolapse, paroxysmal atrial tachycardia, tubular colonic adenoma, progressive dystonia, xanthelasmas, desmoid tumor, vestibular schwannoma, 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.
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 2015a]. 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 variant in an individual with Legius syndrome [Pasmant et al 2015a]. 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
No 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 pigment penetrance is not established. Only two individuals (a male age 60 years and a child age 2 years), 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].
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. It is not a form of neurofibromatosis because no neurofibromas have been reported. 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 NF clinics [Messiaen et al 2009, Pasmant et al 2015b, Evans et al 2016, Giugliano et al 2019].
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 (most notably neurofibromatosis type 1; see also Table 3). 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. The surveillance in neurofibromatosis type 1 is very different from the surveillance in Legius syndrome, stressing the importance of a correct diagnosis.
Neurofibromatosis type 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]. About 8% of children with six or more café au lait spots and no other clinical features of NF1 have Legius syndrome [Evans et al 2016]. Distinguishing Legius syndrome from NF1 is sometimes impossible on the basis of clinical features alone in a young child because the multiple cutaneous neurofibromas and Lisch nodules characteristic of NF1 do not usually arise until later in childhood or adolescence. Examination of the parents for signs of Legius syndrome or NF1 may distinguish the two conditions, but in simplex cases reevaluation of the proband after adolescence or molecular testing may be necessary to establish the diagnosis. The phenotypes associated with specific NF1 pathogenic variants are similar to Legius syndrome in some instances. A described genotype-phenotype correlation with the NF1 3-bp deletion resulting in removal of a methionine residue (c.2970_2972delAAT) [Koczkowska et al 2019] and missense variants of p.Arg1809 [Rojnueangnit et al 2015] result in an attenuated NF1 phenotype with relative lack of neurofibromas.
Table 3.
Disorders with Multiple Café au Lait Macules of Interest in the Differential Diagnosis of Legius Syndrome
| Gene(s) | Disorder | MOI | Additional Clinical Features Not Associated w/Legius Syndrome |
|---|---|---|---|
| BLM | Bloom syndrome | AR | Pre- & postnatal severe growth retardation, susceptibility to infections, high incidence of hematological malignancies |
| BRAF HRAS KRAS LZTR1 MAP2K1 NRAS PTPN11 RAF1 RAF1 RIT1 SOS1 1 | Costello syndrome | AD | Coarse facial features, ulnar deviation of wrist & fingers, ↑ incidence of cardiomyopathy, arrhythmia, rhabdomyosarcoma, neuroblastoma, bladder transitional cell carcinoma |
| Noonan syndrome 2 | AD (AR) 3 | Hypertrophic cardiomyopathy | |
| Noonan syndrome w/multiple lentigines | AD | Lentigines, hypertrophic cardiomyopathy | |
| Cardiofaciocutaneous syndrome | AD | Moderate to severe intellectual disability, skin abnormalities (hyperkeratosis), sparse hair | |
| BRCA2 BRIP1 FANCA FANCB FANCC FANCD2 FANCE FANCF FANCG FANCI (21 genes) 4 | Fanconi anemia | AR AD XL | Bone marrow failure, skeletal limb malformations, microcephaly, malignancies |
| GNAS | Fibrous dysplasia/McCune-Albright syndrome | See footnote 5. | Fibrous bone dysplasia, precocious puberty, hyperpigmentation w/irregular borders |
| MLH1 MSH2 MSH6 PMS2 | CMMRD (see Lynch Syndrome) | AR | High frequency of childhood malignancies, pilomatricomas |
| NF1 | Neurofibromatosis 1 | AD | Optic pathway & other brain glioma, Lisch nodules, choroidal abnormalities, neurofibromas, congenital bowing of limbs, pseudarthrosis, sphenoid bone dysplasia |
| PTEN | Bannayan-Riley-Ruvalcaba syndrome (see PTEN Hamartoma Tumor Syndrome) | AD | Extreme macrocephaly, ↑ risk for cancer & benign skin tumors, hamartomatous polyps |
| TSC1 TSC2 | Tuberous sclerosis complex | AD | Angiofibromas, shagreen patches, ungual fibromas, brain abnormalities (nodules, dysplasia, astrocytomas), renal angiomyolipomas, cardiac rhabdomyomas |
AD = autosomal dominant; AR = autosomal recessive; CMMRD = constitutional mismatch repair deficiency; MOI = mode of inheritance; XL = X-linked
- 1.
Genes associated with RASopathies are grouped together in this table to avoid redundancy. See the linked GeneReviews for specific gene-phenotype relationships.
- 2.
At least one individual with Legius syndrome was previously diagnosed as having Noonan syndrome [Brems et al 2007].
- 3.
Noonan syndrome is most often inherited in an autosomal dominant manner. Noonan syndrome caused by pathogenic variants in LZTR1 can be inherited in either an autosomal dominant or an autosomal recessive manner.
- 4.
Listed genes represent the most common genetic causes; see Fanconi Anemia for additional associated genes.
- 5.
Fibrous dysplasia/McCune-Albright syndrome, a sporadically occurring disorder, is caused by an early embryonic postzygotic somatic activating (gain-of-function) pathogenic variant in GNAS (encoding the cAMP pathway-associated G-protein, Gsα).
Other disorders with multiple café au lait macules
- Silver-Russell syndrome. Additional clinical features include marked prenatal and postnatal growth restriction and body asymmetry.
- 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. 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 2009].
Management
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.
Table 4.
Recommended Evaluations Following Initial Diagnosis in Individuals with Legius Syndrome
| System/Concern | Evaluation | Comment |
|---|---|---|
| Development | Developmental assessment |
|
| Psychiatric/ Behavioral | Neuropsychiatric eval | Persons age >12 mos: screening for behavior concerns incl ADHD |
| Genetic counseling | By genetics professionals 1 | To inform affected persons & their families re nature, MOI, & implications of Legius syndrome to facilitate medical & personal decision making |
ADHD = attention-deficit/hyperactivity disorder; MOI = mode of inheritance
- 1.
Geneticist, certified genetic counselor, or certified advanced genetic nurse
Treatment of Manifestations
Table 5.
Treatment of Manifestations in Individuals with Legius Syndrome
| Manifestation/Concern | Treatment |
|---|---|
| Developmental delay / Intellectual disability |
|
| Psychiatric/Behavioral | Consideration of behavioral modification or pharmacologic adjuvant therapy for individuals w/ADHD |
ADHD = attention-deficit/hyperactivity disorder; OT = occupational therapy; PT = physical therapy
Surveillance
Table 6.
Recommended Surveillance for Individuals with Legius Syndrome
| System/Concern | Evaluation | Frequency |
|---|---|---|
| Development | Monitor developmental progress & educational needs. | At each visit |
| Psychiatric/Behavioral | Behavioral assessment for ADHD | |
| Vascular anomalies 1 | Blood pressure assessment |
ADHD = attention-deficit/hyperactivity disorder
- 1.
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
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.