How is Legius syndrome inherited?

Legius syndrome follows an autosomal dominant inheritance pattern. This means inheriting just one copy of the altered gene from either parent can cause the condition.

How rare is Legius syndrome?

Legius syndrome is classified as not well established. The estimated prevalence is approximately Unknown. Because rare disease data can be limited, actual numbers may differ from published estimates.

How is Legius syndrome diagnosed?

Information about diagnosis is currently limited for this condition.

Are there treatments for Legius syndrome?

Information about treatment is currently limited for this condition.

What complications can arise from Legius syndrome?

Legius syndrome mainly affects skin pigmentation, and while it does not typically lead to serious health issues, monitoring is important. Some individuals may have a higher risk of developing certain tumors, but this is less common than in neurofibromatosis type 1. Regular check-ups with a healthcare provider can help manage any potential complications.

How does Legius syndrome affect daily life?

Living with Legius syndrome often means managing the appearance of café-au-lait spots and possible freckling. While these skin changes are harmless, they can affect self-esteem and body image. It's important for individuals to have support and to talk about their feelings regarding their skin changes with family and friends.

What is the life expectancy for someone with Legius syndrome?

Currently, there is limited information about the life expectancy of individuals with Legius syndrome. Most people with this condition lead normal lives, as it primarily affects skin pigmentation and does not typically lead to severe health problems. Regular medical care can help ensure that any potential issues are addressed early.

Should my family see a specialist if we have Legius syndrome?

Yes, it can be helpful for families affected by Legius syndrome to consult with a geneticist or a dermatologist. These specialists can provide guidance on managing the skin changes and any related concerns. They can also offer support and resources for families navigating this condition together.

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Legius syndrome - Clinical Profile, Genes & Research | Kisho | Kisho

Rare Disease

Legius syndrome

MONDO:0012669

Also known as:NF1-like syndromeneurofibromatosis 1-like syndromeneurofibromatosis type 1 like syndrome

Find Clinical TrialsTrials

Overview

Legius syndrome, also known as NF1-like syndrome, is a rare, genetic skin pigmentation disorder characterized by multiple cafC)-au-lait macules with or without axillary or inguinal freckling.

GeneticsAutosomal dominant · SPRED1 (chr 15)

Clinical Trials4 registered · 3 recruiting

Clinical Presentation

Built from Human Phenotype Ontology (HPO) phenotype annotations and GeneReviews clinical descriptions. Features represent findings documented across known cases — not an exhaustive list of possible symptoms.

Features include always present findings: Cafe-au-lait spot; and common findings: Axillary freckling, Freckling, and Inguinal freckling. 24 total HPO annotations.

Organ System	Phenotype Count	Example Features
Head and neck	4	High palate, Macrocephaly, High, narrow palate

Genetic Landscape

Assembled from HGNC gene records, ClinGen gene-disease validity evidence, and ClinVar pathogenic variant data. Validity classifications reflect the strength of published evidence linking each gene to this disease.

SPRED1 function has not been fully characterized.

Legius syndrome is caused by mutations in the SPRED1 gene on chromosome 15.

GeneReviews

Clinical Guidance

No clinically relevant genotype-phenotype correlations have been identified.

Diagnosis

Drawn from GeneReviews diagnostic guidelines, newborn screening panel status (RUSP), and ClinGen gene-disease validity classifications. Reflects current clinical evidence and consensus where available.

GeneReviews

Diagnostic Criteria

Suggestive Findings

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

Clinical findings

Pigmentary dysplasia consisting of caf 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 but have not been reported in the vast majority of individuals with Legius syndrome.

Treatment

Compiled from FDA-approved drug records, orphan drug designations, and FDA Adverse Event Reporting System (FAERS) safety data. GeneReviews management guidance is included where available.

No approved treatments are currently available for Legius syndrome. The disease remains an area of unmet medical need.

GeneReviews

Management Guidelines

No clinical practice guidelines for Legius syndrome have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

Evaluations Following Initial Diagnosis

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

Prognosis

Based on GeneReviews surveillance recommendations, HPO phenotype frequency and severity annotations, and published prevalence estimates from Orphanet and OMIM.

GeneReviews

Surveillance Guidelines

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

Table 6.

Legius Syndrome: Recommended Surveillance

System/Concern | Evaluation | Frequency

Development

| Monitoring of developmental progress educational needs | At each visit

Research Landscape

Sourced from ClinicalTrials.gov and PubMed. Publication types are classified using NLM-curated article metadata; research type breakdowns reflect the nature of published work for this disease.

4 clinical trials registered, 3 recruiting. Interventions under study include other interventions. Pipeline includes 1 NA. Research is primarily sponsored by academic and government institutions.

17 publications have been identified in PubMed for Legius syndrome. Research spans Case Report / Case Series (29%), Basic Science / Preclinical (29%), and Review / Meta-Analysis (18%).

Research Type	Count	% of Total
Patient case studies	5	29%

Data assembled from 9 of 12 sources · Last updated Sep 20, 2026, 3:00 PM UTC

MONDOHPOClinicalTrials.govFDAPubMedHGNCClinVarClinGenGeneReviewsOrphanetOMIMRUSP

Medical References

External Resources

OMIM

Online Mendelian Inheritance in Man

OMIM:611431

Orphanet

European rare disease database

Orphanet:137605

GARD

Genetic and Rare Diseases Info Center

GARD:10714

Questions for Your Care Team

→Are any of the 4 active clinical trials a good fit for my situation?
→Should I pursue genetic testing for SPRED1, and what would the results mean for my family?
→Are there specialists or centers of excellence for this condition in my area?
→Is there a patient registry I should consider joining?

FAQ

Frequently Asked Questions

Common questions about Legius syndrome

Legius syndrome is a rare genetic condition that primarily affects skin pigmentation. People with Legius syndrome tend to have multiple café-au-lait spots. In some cases, there may also be freckling in the armpit or groin areas. The condition is sometimes referred to as NF1-like syndrome, which highlights its similarity to neurofibromatosis type 1, though the two disorders are distinct. This syndrome is considered uncommon and is identified through its skin findings. The primary characteristic is the presence of café-au-lait spots, which are light brown patches on the skin. Although these skin changes are the hallmark of Legius syndrome, the overall appearance and number of spots may vary between individuals.

People with Legius syndrome often have multiple café-au-lait macules. In some cases, there may also be freckling in areas such as the armpits and groin. These skin changes are the most common signs observed in this condition.

Legius syndrome is a genetic condition caused by variations in the SPRED1 gene. Since the condition is inherited, the changes in the DNA that affect the SPRED1 gene are considered the main cause of the disorder. Associated genes include SPRED1.

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GeneReviews

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 caf au lait macules, most notably neurofibromatosis type 1 (NF1). The diagnosis of Legius syndrome cannot be established 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 NF1 is different from the surveillance in Legius syndrome, stressing the importance of a correct diagnosis. NF1 is most frequently confused with Legius syndrome, as some individuals with Legius syndrome fulfill the pigmentary clinical diagnostic criteria for NF1 . About 8% of children with six or more caf au lait macules and no other clinical features of NF1 have Legius syndrome . 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 help 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. For example, a described genotype-phenotype correlation with the NF1 3-bp deletion resulting in removal of a methionine residue (c.2970_2972delAAT) and missense variants of p.Arg1809 result in an attenuated NF1 phenotype with relative lack of neurofibromas. Table 3. Legius Syndrome: Differential Diagnosis

Gene(s)	Disorder	MOI	Additional Clinical Features of Disorder Not Commonly Associated w/Legius Syndrome
Bloom syndrome	AR	Pre- postnatal severe growth deficiency, susceptibility to infections, high incidence of hematologic malignancies BRAFHRASKRASLZTR1MAP2K1MAP2K2MRASNRASPTPN11RAF1RASA2RIT1RRAS2SOS1SOS21	—
HRAS-related Costello syndrome	AD	Coarse facial features, ulnar deviation of wrist fingers, cardiac involvement (e.g., arrhythmia, hypertrophic cardiomyopathy), rhabdomyosarcoma, neuroblastoma, transitional cell carcinoma of bladder	—
Noonan syndrome2	AD(AR)3	Hypertrophic cardiomyopathy	—
Noonan syndrome w/multiple lentigines	AD	Lentigines, hypertrophic cardiomyopathy	—
Cardiofaciocutaneous syndrome	AD	Mild-to-severe intellectual disability, skin abnormalities (hyperkeratosis), sparse hair 23 genes incl:BRCA2BRIP1FANCAFANCBFANCCFANCD2FANCEFANCFFANCGFANCI4	—
Fanconi anemia	ARADXL	Bone marrow failure, skeletal limb malformations, microcephaly, malignancies GNAS	Fibrous dysplasia/ McCune-Albr...

Source: GeneReviews — "Legius Syndrome"

Legius syndrome

Overview

Clinical Presentation

Genetic Landscape

Clinical Guidance

Diagnosis

Diagnostic Criteria

Suggestive Findings

Treatment

Management Guidelines

Evaluations Following Initial Diagnosis

Prognosis

Surveillance Guidelines

Development

Research Landscape

Medical References

External Resources

OMIM

Orphanet

GARD

Related Diseases

Questions for Your Care Team

Questions for Your Care Team

FAQ

Frequently Asked Questions

What is Legius syndrome?

What are the symptoms of Legius syndrome?

What causes Legius syndrome?

How is Legius syndrome inherited?

How rare is Legius syndrome?

How is Legius syndrome diagnosed?

Are there treatments for Legius syndrome?

What complications can arise from Legius syndrome?

How does Legius syndrome affect daily life?

What is the life expectancy for someone with Legius syndrome?

Should my family see a specialist if we have Legius syndrome?

Clinical Guidance

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Penetrance

Differential Diagnosis

Development

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Neurologic

Therapies Under Investigation

Clinical Trials

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