Legius syndrome

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Legius syndrome
Other namesNeurofibromatosis 1-like syndrome [1]
Autosomal dominant - en.svg
This condition is inherited in an autosomal dominant manner.
Symptoms café au lait spots; +/- learning disabilities [2]
Usual onsetat birth
CausesMutations in the SPRED1 gene [3]
Diagnostic method Clinical findings, Genetic test [4]
Differential diagnosis neurofibromatosis type I
TreatmentPhysical therapy, Speech therapy [2] [1]
Prognosis good
Frequencyrare (estimated at 1:46,000-1:75,000) [2]

Legius syndrome (LS) is an autosomal dominant condition characterized by cafe au lait spots. [3] It was first described in 2007 and is often mistaken for neurofibromatosis type I. It is caused by mutations in the SPRED1 gene. [5] [6] It is also known as neurofibromatosis type 1-like syndrome. [1]

Contents

Symptoms and signs

larger cafe au lait spot on right forearm Cafe au lait fleck.jpg
larger café au lait spot on right forearm

Nearly all individuals with Legius syndrome show multiple café au lait spots on their skin. [7] Symptoms may include: [2]

Features common in neurofibromatosis – like Lisch nodules (iris hamartomas diagnosed on slit lamp exam), bone abnormalities, neurofibromas, optic pathway gliomas and malignant peripheral nerve sheath tumors – are absent in Legius syndrome. [1]

Cause

CHR 15 Human male karyotpe high resolution - Chromosome 15 cropped.png
CHR 15

Legius syndrome is a phakomatosis [8] and a RASopathy, a developmental syndrome due to germline mutations in genes. [7] [9] The condition is autosomal dominant in regards to inheritance and caused by mutations to the SPRED1 gene at chromosome 15, specifically 15q14 (or (GRCh38): 15:38,252,086-38,357,248). [10] [11] The gene in question demonstrates almost 100 mutations. [1]

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. [2] [12]

Diagnosis

Genetic testing is necessary to identify the syndrome. The DNA test is necessary sometimes, because symptoms may not be sufficient to definitely diagnose this condition. [4] [1] [13]

Differential diagnosis

The symptoms of Legius syndrome and neurofibromatosis type I are very similar; An important difference between Legius syndrome and neurofibromatosis type I is the absence of tumor growths Lisch nodules and neurofibromas which are common in neurofibromatosis type I. [2]

A genetic test is often the only way to make sure a person has Legius syndrome and not neurofibromatosis type I; the similarity of symptoms stem from the fact that the different genes affected in the two syndromes code for proteins that carry out a similar task in the same reaction pathway.[ medical citation needed ]

Treatment

Management of Legius syndrome is done via the following: [2] [1]

The prognosis of this condition is generally considered good with appropriate treatment.[ citation needed ]

See also

Related Research Articles

<span class="mw-page-title-main">Neurofibromatosis</span> Three genetic disorders involving benign tumors of the nervous system

Neurofibromatosis (NF) refers to a group of three distinct genetic conditions in which tumors grow in the nervous system. The tumors are non-cancerous (benign) and often involve the skin or surrounding bone. Although symptoms are often mild, each condition presents differently. Neurofibromatosis type I (NF1) is typically characterized by café au lait spots, neurofibromas, scoliosis, and headaches. Neurofibromatosis type II (NF2), on the other hand, may present with early-onset hearing loss, cataracts, tinnitus, difficulty walking or maintain balance, and muscle atrophy. The third type is called schwannomatosis and often presents in early adulthood with widespread pain, numbness, or tingling due to nerve compression.

<span class="mw-page-title-main">Macrocephaly</span> Abnormally large head size

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 determine whether the syndrome is accompanied by particular disorders. Those with benign or familial macrocephaly are considered to have megalencephaly.

<span class="mw-page-title-main">Noonan syndrome</span> Genetic condition involving facial, heart, blood and skeletal features

Noonan syndrome (NS) is a genetic disorder that may present with mildly unusual facial features, short height, congenital heart disease, bleeding problems, and skeletal malformations. Facial features include widely spaced eyes, light-colored eyes, low-set ears, a short neck, and a small lower jaw. Heart problems may include pulmonary valve stenosis. The breast bone may either protrude or be sunken, while the spine may be abnormally curved. Intelligence is often normal. Complications of NS can include leukemia.

<span class="mw-page-title-main">Coffin–Lowry syndrome</span> Medical condition

Coffin–Lowry syndrome is a genetic disorder that is X-linked dominant and which causes severe mental problems sometimes associated with abnormalities of growth, cardiac abnormalities, kyphoscoliosis, as well as auditory and visual abnormalities.

<span class="mw-page-title-main">Neurofibromatosis type I</span> Type of neurofibromatosis disease

Neurofibromatosis type I (NF-1), or von Recklinghausen syndrome, is a complex multi-system human disorder caused by the mutation of neurofibromin 1 (NF-1), a gene on chromosome 17 that is responsible for production of a protein (neurofibromin) which is needed for normal function in many human cell types. NF-1 causes tumors along the nervous system which can grow anywhere on the body. NF-1 is one of the most common genetic disorders and is not limited to any person's race or sex. NF-1 is an autosomal dominant disorder, which means that mutation or deletion of one copy of the NF-1 gene is sufficient for the development of NF-1, although presentation varies widely and is often different even between relatives affected by NF-1.

<span class="mw-page-title-main">Neurofibromatosis type II</span> Type of neurofibromatosis disease

Neurofibromatosis type II is a genetic condition that may be inherited or may arise spontaneously, and causes benign tumors of the brain, spinal cord, and peripheral nerves. The types of tumors frequently associated with NF2 include vestibular schwannomas, meningiomas, and ependymomas. The main manifestation of the condition is the development of bilateral benign brain tumors in the nerve sheath of the cranial nerve VIII, which is the "auditory-vestibular nerve" that transmits sensory information from the inner ear to the brain. Besides, other benign brain and spinal tumors occur. Symptoms depend on the presence, localisation and growth of the tumor(s). Many people with this condition also experience vision problems. Neurofibromatosis type II is caused by mutations of the "Merlin" gene, which seems to influence the form and movement of cells. The principal treatments consist of neurosurgical removal of the tumors and surgical treatment of the eye lesions. Historically the underlying disorder has not had any therapy due to the cell function caused by the genetic mutation.

<span class="mw-page-title-main">Mitochondrial myopathy</span> Medical condition

Mitochondrial myopathies are types of myopathies associated with mitochondrial disease. Adenosine triphosphate (ATP), the chemical used to provide energy for the cell, cannot be produced sufficiently by oxidative phosphorylation when the mitochondrion is either damaged or missing necessary enzymes or transport proteins. With ATP production deficient in mitochondria, there is an over-reliance on anaerobic glycolysis which leads to lactic acidosis either at rest or exercise-induced.

<span class="mw-page-title-main">Neurofibroma</span> Benign nerve-sheath tumor in the peripheral nervous system

A neurofibroma is a benign nerve-sheath tumor in the peripheral nervous system. In 90% of cases, they are found as stand-alone tumors, while the remainder are found in persons with neurofibromatosis type I (NF1), an autosomal-dominant genetically inherited disease. They can result in a range of symptoms from physical disfiguration and pain to cognitive disability.

Phakomatoses, also known as 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 are single-gene disorders that may be inherited in an autosomal dominant, autosomal recessive or X-linked pattern. Presentations may vary dramatically between patients with the same particular syndrome due to mosaicism, variable expressivity, and penetrance.

The Crowe sign or Crowe's sign is the presence of axillary (armpit) freckling in people with neurofibromatosis type I. These freckles occur in up to 30% of people with the disease and their presence is one of six diagnostic criteria for neurofibromatosis. Freckles can also be present in the intertriginous area in neurofibromatosis, such as the inguinal fold, submammary areas, and nape of the neck.

<span class="mw-page-title-main">Costello syndrome</span> Medical condition

Costello syndrome, also called faciocutaneoskeletal syndrome or FCS syndrome, is a rare genetic disorder that affects many parts of the body. It is characterized by delayed development and intellectual disabilities, distinctive facial features, unusually flexible joints, and loose folds of extra skin, especially on the hands and feet. Heart abnormalities are common, including a very fast heartbeat (tachycardia), structural heart defects, and overgrowth of the heart muscle. Infants with Costello syndrome may be large at birth, but grow more slowly than other children and have difficulty feeding. Later in life, people with this condition have relatively short stature and many have reduced levels of growth hormones. It is a RASopathy.

<span class="mw-page-title-main">Noonan syndrome with multiple lentigines</span> Rare autosomal dominant multi-system genetic condition

Noonan syndrome with multiple lentigines (NSML) which is part of a group called Ras/MAPK pathway syndromes, is a rare autosomal dominant, multisystem disease caused by a mutation in the protein tyrosine phosphatase, non-receptor type 11 gene (PTPN11). The disease is a complex of features, mostly involving the skin, skeletal and cardiovascular systems, which may or may not be present in all patients. The nature of how the mutation causes each of the condition's symptoms is not well known; however, research is ongoing. It is a RASopathy.

<span class="mw-page-title-main">Neurofibromin</span> Mammalian protein found in humans

Neurofibromin (NF-1) is a protein that is encoded in the human by the NF1 gene. NF1 is located on chromosome 17. Neurofibromin, a GTPase-activating protein that negatively regulates RAS/MAPK pathway activity by accelerating the hydrolysis of Ras-bound GTP. NF1 has a high mutation rate and mutations can alter cellular growth control, and neural development, resulting in neurofibromatosis type 1. Symptoms of NF1 include disfiguring cutaneous neurofibromas (CNF), café au lait pigment spots, plexiform neurofibromas (PN), skeletal defects, optic nerve gliomas, life-threatening malignant peripheral nerve sheath tumors (MPNST), pheochromocytoma, attention deficits, learning deficits and other cognitive disabilities.

<span class="mw-page-title-main">RAPADILINO syndrome</span> Medical condition

RAPADILINO syndrome is an autosomal recessive disorder characterized by:

<span class="mw-page-title-main">SPRED2</span> Protein-coding gene in the species Homo sapiens

Sprouty-related, EVH1 domain-containing protein 2 is a protein that in humans is encoded by the SPRED2 gene.

<span class="mw-page-title-main">Orofaciodigital syndrome 1</span> Medical condition

Orofaciodigital syndrome 1 (OFD1), also called Papillon-Léage and Psaume syndrome, is an X-linked congenital disorder characterized by malformations of the face, oral cavity, and digits with polycystic kidney disease and variable involvement of the central nervous system.

<span class="mw-page-title-main">Parkes Weber syndrome</span> Medical condition

Parkes Weber syndrome (PWS) is a congenital disorder of the vascular system. It is an extremely rare condition, and its exact prevalence is unknown. It is named after British dermatologist Frederick Parkes Weber, who first described the syndrome in 1907.

<span class="mw-page-title-main">SPRED1</span> Protein-coding gene in the species Homo sapiens

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.

The RASopathies are a group of developmental syndromes caused by germline mutations in genes belonging to the Ras/MAPK pathway. Common features include intellectual disability, congenital heart defects, skin abnormalities, and craniofacial abnormalities.

<span class="mw-page-title-main">Familial multiple cafe-au-lait spots</span> Medical condition

Familial multiple cafe au lait spots, also known as autosomal dominant multiple cafe au lait spots or neurofibromatosis type 6, is a rare, cutaneous genetic disorder which is characterized by the hereditary cutaneous presence of several cafe-au-lait spots without any other symptoms of neurofibromatosis. Sporadic cases may be called "sporadic multiple cafe au lait spots". Few cases have been described in medical literature, although it is estimated that the presence of multiple cafe au lait spots without NF1 is rare among the general population.

References

  1. 1 2 3 4 5 6 7 RESERVED, INSERM US14 -- ALL RIGHTS. "Orphanet: Legius syndrome". www.orpha.net. Retrieved 2017-06-01.{{cite web}}: CS1 maint: numeric names: authors list (link)
  2. 1 2 3 4 5 6 7 Stevenson, David; Viskochil, David; Mao, Rong (1993). "Legius Syndrome". GeneReviews. PMID   20945555 . Retrieved 1 June 2017.update 2015
  3. 1 2 "Legius syndrome", Genetics Home Reference, National Institutes of Health
  4. 1 2 "Legius syndrome | Genetic and Rare Diseases Information Center". rarediseases.info.nih.gov. Retrieved 2017-06-01.
  5. "SPRED1", Genetics Home Reference, National Institutes of Health
  6. "Legius Syndrome Often Mistaken for Neurofibromatosis Type 1", by Allison Gandley, November 18, 2009, Medscape
  7. 1 2 "OMIM Entry - # 611431 - LEGIUS SYNDROME". omim.org. Retrieved 2017-06-01.
  8. Rosser, Tena (February 2018). "Neurocutaneous Disorders". Continuum (Minneapolis, Minn.). 24 (1, Child Neurology): 96–129. doi:10.1212/CON.0000000000000562. ISSN   1538-6899. PMID   29432239. S2CID   4107835.
  9. Tidyman, William (2009). "The RASopathies: Developmental syndromes of Ras/MAPK pathway dysregulation". Current Opinion in Genetics & Development. 19 (3): 230–236. doi:10.1016/j.gde.2009.04.001. PMC   2743116 . PMID   19467855.
  10. "OMIM Entry - * 609291 - SPROUTY-RELATED EVH1 DOMAIN-CONTAINING PROTEIN 1; SPRED1". www.omim.org. Retrieved 2017-06-01.
  11. "Homo sapiens sprouty related EVH1 domain containing 1 (SPRED1), RefSeq - Nucleotide - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2017-06-01.
  12. Molina, Julian R.; Adjei, Alex A. (2006-01-01). "The Ras/Raf/MAPK Pathway". Journal of Thoracic Oncology. 1 (1): 7–9. doi: 10.1016/S1556-0864(15)31506-9 . PMID   17409820.
  13. "SPRED1 sprouty related EVH1 domain containing 1 - Gene - GTR - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2017-06-01.
  14. Storebø, Ole Jakob; Storm, Maja Rosenberg Overby; Pereira Ribeiro, Johanne; Skoog, Maria; Groth, Camilla; Callesen, Henriette E.; Schaug, Julie Perrine; Darling Rasmussen, Pernille; Huus, Christel-Mie L.; Zwi, Morris; Kirubakaran, Richard; Simonsen, Erik; Gluud, Christian (2023-03-27). "Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD)". The Cochrane Database of Systematic Reviews. 2023 (3): CD009885. doi:10.1002/14651858.CD009885.pub3. ISSN   1469-493X. PMC   10042435 . PMID   36971690.

Further reading