Introduction 

Legius syndrome (LEE-jus SIN-drome) also called neurofibromatosis type 1-like syndrome is a rare genetic condition characterised by café-au-lait spots (named for their colour meaning ‘coffee with milk’) on the skin. This syndrome is caused by mutations in the Sprouty-Related EVH1 Domain Containing 1 (SPRED1 gene). This gene makes a protein which regulates the cell signalling pathway that controls many important cell functions such as cell growth and division, maturation and destruction.  

The signs and symptoms of Legius syndrome are similar to another disorder called neurofibromatosis type 1 (NF1). Because of similar clinical manifestations, it can be difficult to distinguish the two disorders, especially in younger children. Tumors seen in NF-1, develop later in life, making it easier to differentiate later in life.

Background of legius syndrome 

Legius Syndrome is a rare genetic condition that was named after Professor Eric Legius who first identified it. Because of the similarities with NF1, it is also known as  “NF1-like syndrome”. The main difference between the two conditions is that Legius syndrome patients do not develop neurofibromas. As technologies such as molecular genetic testing have developed, it has become easier to distinguish between Legius syndrome (located on chromosome 15) and NF1 (located on chromosome 17).

Legius syndrome is an autosomal dominant condition that runs in families. An individual with this syndrome has a 50%  (1 in 2) chance of passing the pathogenic gene to one of their children. New mutations may occur sometimes, where the child has the condition but the parents do not. 

The onset of Legius syndrome is linked to mutations in the SPRED1 gene. The SPRED1 gene provides instructions for making the SPRED1 protein which plays an important role in controlling cell signaling pathways. This pathway is involved in the growth and division of cells (proliferation), the process of cell maturation to carry out specific functions (differentiation), cell movement, and self-destruction of cells (apoptosis). Mutations in the SPRED1 gene lead to disruption in normal functioning of protein causing an inability to regulate cell signaling pathways, resulting in overactive signaling.

Data suggests that less than 50,000 people in the United States have Legius syndrome. Legius syndrome is a rare condition with birth prevalence estimated at 1 in 46,000–75,000. With fewer than 300 molecularly confirmed diagnoses, the current understanding of Legius syndrome is limited. As more individuals with this syndrome are identified, it will be easier to understand the clinical manifestations and history of Legius syndrome.

Clinical features of legius syndrome 

The clinical features of Legius syndrome may vary from one patient to another. Children with this syndrome have changes in skin pigmentation and multiple café au lait macules which are usually visible by the time the child is 1 year old. 

Common skin manifestations in patients with Legius syndrome include:

1. Inguinal freckling (Freckles in the groin region): Presence of increased number of small circular spots on the groin region, that are darker than the surrounding skin because of melanin deposition.
2. Freckles in skin folds and armpits: The presence of small circular spots on the skin that are darker than the surrounding skin because of deposits of melanin.
3. Café au lait macules: Hyperpigmented lesions that can vary in colour from light brown to dark brown with smooth borders and size varying from 1.5 cm or more in adults and 0.5 cm or more in children. 
4. Lipomas

Non-cutaneous features include macrocephaly, hypertelorism, and a breastbone (sternum) that looks pushed in (pectus excavatum) or pushed out (pectus carinatum). Other signs and symptoms start appearing as the child grows and may include mild learning disabilities/ attention-deficit/hyperactivity disorder (ADHD)/ developmental delays. Children with Legius syndrome generally reach milestones like walking and talking slower than other children their age.

Diagnosis of legius syndrome 

Legius syndrome is commonly misdiagnosed as NF1. Patients with clinical manifestations similar to Legius syndrome or NF1 should be tested, to confirm the diagnosis. Additionally, high-risk pregnant patients with a family history or medical history of Legius syndrome should also be tested. Legius syndrome should be suspected in patients with café au lait macules with or without freckling and patients who lack nonpigmentary clinical manifestations of NF1 like neurofibromas, and optic gliomas. The presence of characteristic clinical signs helps in supporting the diagnosis. However, diagnosis based solely on the presence of clinical features like café au lait macules is not reliable due to an overlap with other disorders with similar clinical features. Molecular genetic testing is required to confirm the diagnosis of Legius syndrome and to differentiate it from NF1.¹ 

Age at diagnosis of legius syndrome 

The age at diagnosis may vary due to the difficulty in making a diagnosis based entirely on clinical features. Due to a similarity with some other syndromes which have similar features, genetic testing is needed to confirm diagnosis.

What is the differential diagnosis for legius syndrome?

There are other conditions with similar skin markings to Legius syndrome, making it crucial to pinpoint the correct diagnosis for effective treatment and monitoring.

Legius syndrome is often misdiagnosed as Neurofibromatosis type 1 (NF1) because they share some clinical features like café au lait macules and freckling. However, Legius syndrome doesn't have certain tumours and eye issues that NF1 does. This mix-up can be especially tricky in kids because the usual signs of NF1 show up later in life.²

Another possible misdiagnosis is Noonan syndrome which can also look like Legius syndrome but involves cardiovascular, ocular, and genetic abnormalities, which are not seen in Legius syndrome.

Other conditions with similar skin markings are café-au-lait macules and McCune–Albright syndrome, but they have their distinct features.

Management and treatment 

Prenatal genetic counselling and genetic testing may be helpful for parents and family members of children or adults with Legius syndrome.

There is no known cure for Legius syndrome. Treatment usually focuses on managing symptoms and may include; drug therapy for the behavioral manifestations of the disorder (ADHD);  physical, speech, and occupational therapy for developmental delays; and extra educational support for those with learning difficulties.

Prognosis

Patients with Legius syndrome have a favourable prognosis, based on the current knowledge of the disease. Children with this syndrome do not need close medical monitoring. They have a full life expectancy and their activities do not need to be limited. A developmental assessment should be undertaken to ensure that appropriate resources are in place to support the child if necessary. Additionally, an affected individual carries a 50% risk of genetic transmission to each child.

FAQs 

What type of cancers can develop in patients with Legius syndrome?

Legius syndrome occurs as a result of changes in a specific signalling pathway. Any changes in this pathway can result in an increased risk of developing cancer or other malignant diseases. Incidents of various kinds of cancers have been reported in patients with Legius syndrome, however, due to the rarity of the condition, the risk of developing cancer is uncertain. Regular examinations to determine developmental delays, changes in behaviour, and learning disability should be conducted. Clinical examinations with blood pressure measurements can be conducted regularly to check for any vascular abnormalities. Patients should be informed about the increased risk of cancer.

Conclusion 

Legius syndrome, a rare genetic condition often misdiagnosed as neurofibromatosis type 1 (NF1), presents with distinct clinical features such as café-au-lait macules and freckling. With advancements in molecular genetic testing, distinguishing Legius syndrome from NF1 has become more feasible. Despite its rarity, Legius syndrome affects individuals in diverse ways, with variable clinical manifestations and onset. While there is no cure for Legius syndrome, management primarily involves symptom control and supportive care, including drug therapy for behavioural manifestations and developmental delays. The prognosis for patients with Legius syndrome remains promising, with a normal life expectancy and minimal medical monitoring required. As our understanding of Legius syndrome grows through further research and clinical experience, early recognition and intervention will continue to improve the quality of life for affected individuals and their families.

Summary 

Legius syndrome, also known as Neurofibromatosis type 1-like syndrome (NFLS), is a rare genetic disorder characterised by multiple café-au-lait spots with or without freckling in the axilla or groin. Patients with this syndrome may have additional clinical manifestations like, macrocephaly, learning difficulties, and developmental delay. Due to overlapping clinical features between NF1 and Legius syndrome, clinical differentiation between the two is difficult. A distinctive difference between the two is the absence of other features such as neurofibromas, optic gliomas, and typical bone changes, that are commonly seen in NF1. Legius syndrome, on the other hand, involves subcutaneous lipomas occurring in adulthood.

Confirmation of Legius syndrome involves identifying a pathogenic variant in the SPRED1 gene. In sporadic cases of Legius syndrome, the detection rate of pathogenic variants in the SPRED1 gene is approximately 2%. However, this rate increases significantly, up to 19%, in patients with positive family history and the presence of café-au-lait spots accompanied by freckling, even without meeting other clinical criteria for NF1.