Legius syndrome (LS) is an

autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

condition characterized by cafe au lait spots."Legius syndrome"
Genetics Home Reference,

National Institutes of Health The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the late ...

It was first described in 2007 and is often mistaken for neurofibromatosis type I (NF-1). It is caused by mutations in the ''

SPRED1 Sprouty-related, EVH1 domain-containing protein 1 (Spread-1) is a protein that in humans is encoded by the ''SPRED1'' gene located on chromosome 15q13.2 and has seven coding exons. Function SPRED-1 is a member of the Sprouty family of proteins ...

'' gene. It is also known as neurofibromatosis type 1-like syndrome (NFLS).

Symptoms and signs

Nearly all individuals with Legius syndrome show multiple café au lait spots on their skin. Symptoms may include: *

Freckles Freckles are clusters of concentrated melaninized cells which are most easily visible on people with a fair complexion. Freckles do not have an increased number of the melanin-producing cells, or melanocytes, but instead have melanocytes that ...

in the axillary and inguinal skin fold *

Lipoma A lipoma is a benign tumor made of fat tissue. They are generally soft to the touch, movable, and painless. They usually occur just under the skin, but occasionally may be deeper. Most are less than in size. Common locations include upper back, ...

s, developing in adulthood *

Macrocephaly Macrocephaly is a condition in which circumference of the human head is abnormally large. It may be pathological or harmless, and can be a familial genetic characteristic. People diagnosed with macrocephaly will receive further medical tests to ...

Learning disabilities Learning disability, learning disorder, or learning difficulty (British English) is a condition in the brain that causes difficulties comprehending or processing information and can be caused by several different factors. Given the "difficult ...

ADHD Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inapp ...

Developmental delay Global developmental delay is an umbrella term used when children are significantly delayed in their cognitive and physical development. It can be diagnosed when a child is delayed in one or more milestones, categorised into motor skills, speech, c ...

Features common in neurofibromatosis – like

Lisch nodules Lisch nodule, also known as iris hamartoma, is a pigmented hamartomatous nodular aggregate of dendritic melanocytes affecting the iris, named after Austrian ophthalmologist Karl Lisch (1907–1999), who first recognized them in 1937. The first ...

(iris hamartomas diagnosed on slit lamp exam), bone abnormalities,

neurofibromas A neurofibroma is a benign nerve-sheath tumor in the peripheral nervous system. In 90% of cases, they are found as stand-alone tumors (solitary neurofibroma, solitary nerve sheath tumor or sporadic neurofibroma), while the remainder are found in p ...

, optic pathway

gliomas A glioma is a type of tumor that starts in the glial cells of the brain or the spine. Gliomas comprise about 30 percent of all brain tumors and central nervous system tumours, and 80 percent of all malignant brain tumours. Signs and symptoms ...

and malignant peripheral nerve sheath tumors – are absent in Legius syndrome.

Cause

Human male karyotpe high resolution - Chromosome 15 cropped

Legius syndrome is a

phakomatosis Phakomatoses, also known neurocutaneous syndromes, are a group of multisystemic diseases that most prominently affect structures primarily derived from the ectoderm such as the central nervous system, skin and eyes. The majority of phakomatoses ar ...

and a

RASopathy The RASopathies are developmental syndromes caused by germline mutations (or in rare cases by somatic mosaicism) in genes that alter the Ras subfamily and mitogen-activated protein kinases that control signal transduction, including: * Capill ...

, a developmental syndrome due to

germline mutations A germline mutation, or germinal mutation, is any detectable variation within germ cells (cells that, when fully developed, become sperm and ova). Mutations in these cells are the only mutations that can be passed on to offspring, when either a m ...

in genes. The condition is

in regards to inheritance and caused by mutations to the ''

'' gene at

chromosome 15 Chromosome 15 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 15 spans about 102 million base pairs (the building material of DNA) and represents between 3% and 3.5% of the total DN ...

, specifically 15q14 (or (GRCh38): 15:38,252,086-38,357,248). The gene in question demonstrates almost 100 mutations.

Mechanism

A mutated SPRED1 ''protein'' adversely regulates Ras-MAPK signaling, which is a chain of proteins in a cell that sends signals from the surface of a cell to the nucleus which in turn causes the symptoms of this condition.

Diagnosis

Genetic testing Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...

is necessary to identify the syndrome. The DNA test is necessary sometimes, because symptoms may not be sufficient to definitely diagnose this condition.

Differential diagnosis

The symptoms of Legius syndrome and NF-1 are very similar; An important difference between Legius syndrome and NF-1 is the absence of tumor growths

and

which are common in NF-1.update 2015 A

genetic test Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, o ...

is often the only way to make sure a person has LS and not NF-1; the similarity of symptoms stem from the fact that the different

genes In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

affected in the two syndromes code for proteins that carry out a similar task in the same reaction pathway.

Treatment

Management of Legius syndrome is done via the following: *

Physical therapy Physical therapy (PT), also known as physiotherapy, is one of the allied health professions. It is provided by physical therapists who promote, maintain, or restore health through physical examination, diagnosis, management, prognosis, patient ...

Speech therapy Speech is a human vocal communication using language. Each language uses phonetic combinations of vowel and consonant sounds that form the sound of its words (that is, all English words sound different from all French words, even if they are th ...

* Pharmacologic therapy (e.g.

methylphenidate Methylphenidate, sold under the brand names Ritalin and Concerta among others, is the most widely prescribed central nervous system (CNS) stimulant medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser exten ...

for ADHD) The prognosis of this condition is generally considered good with appropriate treatment.

References

External links

PubMed
{{Deficiencies of intracellular signaling peptides and proteins Genodermatoses Developmental neuroscience Neuro-cardio-facial-cutaneous syndromes RASopathies Syndromes