Dermatology: Practical and Conceptual


Image Letter | Dermatol Pract Concept. 2025;15(4):5771 1

Legius Syndrome: A Clinical Observation  
of a Father-Son Pair

Lin Wang1,2, Yiyun Wu2, Wenting Xu2, Cheng Tan2

1 Yancheng TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Yancheng, Jiangsu, China

2 Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China

Key words: Pigmentary Disorder, Legius Syndrome

Citation: Wang L, Wu Y, Xu W, Tan C. Legius Syndrome: A Clinical Observation of a Father-Son Pair. Dermatol Pract Concept. 
2025;15(4):5771. DOI: https://doi.org/10.5826/dpc.1504a5771

Accepted: April 22, 2025; Published: October 2025

Copyright: ©2025 Wang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-
NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, 
distribution, and reproduction in any medium, provided the original authors and source are credited.

Funding: None.

Competing Interests: None.

Authorship: All authors have contributed significantly to this publication.

Corresponding Author: Cheng Tan, MD, affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, Nanjing, 
China, 210029. ORCID: 0000-0002-8764-2078. E-mail: tancheng@yeah.net

Case Presentation

A 3-year-old male was referred to our clinic to evaluate mul-

tiple café-au-lait macules (CALMs) present since birth. His 

growth and developmental milestones were age-appropriate, 

with no other abnormality observed. (Figure 1A). The 

family history was significant as the patient’s father exhib-

ited multiple CALMs, axillary freckling (Figures 1B and 

1D), and several subcutaneous lipomas confirmed by ul-

trasound (Figure 1E). Genetic testing revealed a heterozy-

gous frameshift mutation in exon 7 of the  SPRED1  gene 

(NM_152594:c .1149_1152delAGAG, p.G385Ifs*20). This 

mutation was also detected in the affected father, but absent 

in the mother (Figures 1F–H), confirming Legius syndrome.

Teaching Point

Legius syndrome is an autosomal dominant disorder caused 

by germline loss-of-function mutations in the SPRED1 gene. 

The clinical features include multiple CALMs, with or 

without associated intertriginous freckling [1]. Associated 

findings may encompass lipomas, macrocephaly, or neuro-

developmental manifestations, including learning disabili-

ties, attention-deficit/hyperactivity disorder (ADHD), and 

mild developmental delays [2]. In contrast to neurofibro-

matosis type 1 (NF1), Legius syndrome is characterized by 

the absence of tumorigenic manifestations such as neuro-

fibromas and optic pathway gliomas, and it is associated 

with a milder clinical phenotype. Current clinical guide-

lines highlight the importance of monitoring and managing 

neurodevelopmental issues, given that there is no targeted 

therapy available for cutaneous lesions. Accurate diagnosis 

is essential for distinguishing Legius syndrome from NF1, 

thereby preventing unnecessary surveillance measures such 

as tumor screening and mitigating familial anxiety associ-

ated with NF1-related complications. Genetic counseling 

and prenatal testing should be made available to affected 

families.



2 Image Letter | Dermatol Pract Concept. 2025;15(4):5771

Figure 1. Clinical features included café-au-lait macules in the patient (A) and café-au-lait macules with 

facial freckles in the father (B–D).Ultrasound examination of the father’s right flank revealed a slightly 

hyperechoic region (28 mm × 7 mm) with well-defined margins and clear demarcation from surround-

ing tissues, consistent with lipomas (E). The patient harbored a heterozygous frameshift mutation, 

c.1149_1152delAGAG (p.G385Ifs*20), in exon 7 of the SPRED1 gene (F). This mutation was identified 

in his father (G) but absent in his mother (H).

References

1. Legius E, Messiaen L, Wolkenstein P, et al. Revised diagnos-

tic criteria for neurofibromatosis type 1 and Legius syndrome: 

an international consensus recommendation. Genet Med. 

2021;23(8):1506-1513.DOI:10.1038/s41436-021-01170-5. 

PMID: 34012067.

2. Pabst L, Carroll J, Lo W, Truxal KV. Moyamoya syndrome in a child 

with Legius syndrome: Introducing a cerebral vasculopathy to the 

SPRED1 phenotype? Am J Med Genet A. 2021;185(1):223-227.  

DOI: 10.1002/ajmg.a.61921. PMID: 33078527.