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Neurofibromatosis, type 1(NF1)

MedGen UID:
18013
Concept ID:
C0027831
Neoplastic Process
Synonyms: Neurofibromatosis 1; NEUROFIBROMATOSIS, PERIPHERAL TYPE; NEUROFIBROMATOSIS, TYPE I; NF Noonan syndrome; NF1; Peripheral Neurofibromatosis; Recklinghausen Disease, Nerve; Recklinghausen's disease; Von Recklinghausen disease
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Autosomal dominant inheritance refers to genetic conditions that occur when a mutation is present in one copy of a given gene (i.e., the person is heterozygous).
SNOMED CT: [M]Von Recklinghausen's disease (81669005); Neurofibromatosis type 1 (92824003); Neurofibromatosis, type 1 (92824003); Clinical von Reclinghausen's disease (92824003); Neurofibromatosis 1 (700061007); NF1 (700061007); Neurofibromatosis (nonmalignant) type (700061007); Neurofibromatosis, peripheral type (700061007); Von Recklinghausen disease (700061007); Neurofibromatosis 1 (92824003); Neurofibromatosis, peripheral type (92824003); NF1 (92824003); Von Recklinghausen disease (92824003)
 
Gene: NF1
Cytogenetic location: 17q11.2
OMIM®: 162200
Orphanet: ORPHA636

Disease characteristics

Excerpted from the GeneReview: Neurofibromatosis 1
Neurofibromatosis 1 (NF1) is characterized by multiple café-au-lait spots, axillary and inguinal freckling, multiple cutaneous neurofibromas, and iris Lisch nodules. Learning disabilities are present in at least 50% of individuals with NF1. Less common but potentially more serious manifestations include plexiform neurofibromas, optic nerve and other central nervous system gliomas, malignant peripheral nerve sheath tumors, scoliosis, tibial dysplasia, and vasculopathy.  [from GeneReviews]
Full text of GeneReview (by section):
Summary  |  Diagnosis  |  Clinical Description  |  Differential Diagnosis  |  Management  |  Genetic Counseling  |  Resources  |  Molecular Genetics  |  References  |  Chapter Notes
Authors:
JM Friedman   view full author information

Additional descriptions

From OMIM
Neurofibromatosis type I is an autosomal dominant disorder characterized by cafe-au-lait spots, Lisch nodules in the eye, and fibromatous tumors of the skin. Individuals with the disorder have increased susceptibility to the development of benign and malignant tumors. NF1 is sometimes referred to as 'peripheral neurofibromatosis.' The worldwide incidence of NF1 is 1 in 2,500 to 1 in 3,000 individuals (reviews by Shen et al., 1996 and Williams et al., 2009). Type II neurofibromatosis (NF2; 101000) is a genetically distinct disorder caused by mutation in the gene encoding merlin (NF2; 607379) on chromosome 22q12. NF2, sometimes known as 'central neurofibromatosis,' is characterized by bilateral acoustic neuroma and meningioma, but few skin lesions or neurofibromas (Rouleau et al., 1993). Some patients with homozygous or compound heterozygous mutations in mismatch repair genes (see, e.g., MLH1; 120436 and MSH2; 609309) have a phenotype characterized by early onset malignancies and mild features of NF1, especially cafe-au-lait spots; this is known as the mismatch repair cancer syndrome (276300), sometimes referred to as brain tumor-polyposis syndrome-1 or Turcot syndrome. These patients typically do not have germline mutations in the NF1 gene, although a study by Wang et al. (2003) suggested that biallelic mutations in mismatch repair genes may cause somatic mutations in the NF1 gene, perhaps resulting in isolated features resembling NF1. See also Legius syndrome (611431), a genetically distinct disorder with a similar phenotype to NF1.  http://www.omim.org/entry/162200
From GHR
Neurofibromatosis type 1 is a condition characterized by changes in skin coloring (pigmentation) and the growth of tumors along nerves in the skin, brain, and other parts of the body. The signs and symptoms of this condition vary widely among affected people. Beginning in early childhood, almost all people with neurofibromatosis type 1 have multiple café-au-lait spots, which are flat patches on the skin that are darker than the surrounding area. These spots increase in size and number as the individual grows older. Freckles in the underarms and groin typically develop later in childhood. Most adults with neurofibromatosis type 1 develop neurofibromas, which are noncancerous (benign) tumors that are usually located on or just under the skin. These tumors may also occur in nerves near the spinal cord or along nerves elsewhere in the body. Some people with neurofibromatosis type 1 develop cancerous tumors that grow along nerves. These tumors, which usually develop in adolescence or adulthood, are called malignant peripheral nerve sheath tumors. People with neurofibromatosis type 1 also have an increased risk of developing other cancers, including brain tumors and cancer of blood-forming tissue (leukemia). During childhood, benign growths called Lisch nodules often appear in the colored part of the eye (the iris). Lisch nodules do not interfere with vision. Some affected individuals also develop tumors that grow along the nerve leading from the eye to the brain (the optic nerve). These tumors, which are called optic gliomas, may lead to reduced vision or total vision loss. In some cases, optic gliomas have no effect on vision. Additional signs and symptoms of neurofibromatosis type 1 include high blood pressure (hypertension), short stature, an unusually large head (macrocephaly), and skeletal abnormalities such as an abnormal curvature of the spine (scoliosis). Although most people with neurofibromatosis type 1 have normal intelligence, learning disabilities and attention deficit hyperactivity disorder (ADHD) occur frequently in affected individuals.  http://ghr.nlm.nih.gov/condition/neurofibromatosis-type-1

Clinical features

Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
Overgrowth
MedGen UID:
376550
Concept ID:
C1849265
Finding
Lisch nodules
MedGen UID:
395461
Concept ID:
C1860334
Finding
Pheochromocytoma
MedGen UID:
505323
Concept ID:
CN002423
Finding
Pheochromocytomas (also known as chromaffin tumors) produce, store, and secrete catecholamines. Pheochromocytomas usually originate from the adrenal medulla but may also develop from chromaffin cells in or about sympathetic ganglia. A common symptom of pheochromocytoma is hypertension owing to release of catecholamines.
Meningioma
MedGen UID:
505374
Concept ID:
CN002583
Finding
The presence of a meningioma, i.e., a benign tumor originating from the dura mater or arachnoid mater.
Rhabdomyosarcoma
MedGen UID:
505375
Concept ID:
CN002584
Finding
Parathyroid adenoma
MedGen UID:
505395
Concept ID:
CN002620
Finding
A benign tumor of the parathyroid gland that can cause hyperparathyroidism.
Astrocytoma
MedGen UID:
506296
Concept ID:
CN008457
Finding
Astrocytoma is a neoplasm of the central nervous system derived from astrocytes. Astrocytes are a type of glial cell, and thus astrocytoma is a subtype of glioma.
Plexiform neurofibroma
MedGen UID:
506304
Concept ID:
CN008592
Finding
A neurofibroma in which Schwann cells proliferate inside the nerve sheath, producing an irregularly thickened, distorted, tortuous structure.
Optic glioma
MedGen UID:
506306
Concept ID:
CN008594
Finding
A glioma originating in the optic nerve or optic chiasm.
Spinal neurofibromas
MedGen UID:
429015
Concept ID:
CN008595
Finding
Neurofibromas originating in the spine.
Neurofibrosarcoma
MedGen UID:
451960
Concept ID:
CN117588
Finding
A form of malignant cancer of the connective tissue surrounding nerves. Given its origin and behavior, it is classified as a sarcoma.
Renal artery stenosis
MedGen UID:
505007
Concept ID:
CN001737
Finding
The presence of stenosis of the renal artery.
Overgrowth
MedGen UID:
376550
Concept ID:
C1849265
Finding
Hypertelorism
MedGen UID:
504419
Concept ID:
CN000296
Finding
Interpupillary distance more than 2 SD above the mean (alternatively, the appearance of an increased interpupillary distance or widely spaced eyes).
Lisch nodules
MedGen UID:
395461
Concept ID:
C1860334
Finding
Glaucoma
MedGen UID:
409541
Concept ID:
C1962986
Finding
Hypertelorism
MedGen UID:
504419
Concept ID:
CN000296
Finding
Interpupillary distance more than 2 SD above the mean (alternatively, the appearance of an increased interpupillary distance or widely spaced eyes).
Hypsarrhythmia
MedGen UID:
195766
Concept ID:
C0684276
Finding
Seizures
MedGen UID:
409523
Concept ID:
C1959629
Finding
Hydrocephalus
MedGen UID:
369747
Concept ID:
C1963137
Finding
Intellectual disability, mild
MedGen UID:
504770
Concept ID:
CN001151
Finding
Mild intellectual disability is defined as an intelligence quotient (IQ) in the range of 50-69.
Specific learning disability
MedGen UID:
504802
Concept ID:
CN001216
Finding
Impairment of certain skills such as reading or writing, coordination, self-control, or attention that interfere with the ability to learn. The impairment is not related to a global deficiency of intelligence.
Aqueductal stenosis
MedGen UID:
505228
Concept ID:
CN002189
Finding
Stenosis of the cerebral aqueduct (also known as the mesencephalic duct, aqueductus mesencephali, or aqueduct of Sylvius), which connects the third cerebral ventricle in the diencephalon to the fourth ventricle, which is between the pons and cerebellum.
Spina bifida
MedGen UID:
505230
Concept ID:
CN002193
Finding
Incomplete closure of the embryonic neural tube, whereby some vertebral arches remain unfused and open. The mildest form is spina bifida occulta, followed by meningocele and meningomyelocele.
Pheochromocytoma
MedGen UID:
505323
Concept ID:
CN002423
Finding
Pheochromocytomas (also known as chromaffin tumors) produce, store, and secrete catecholamines. Pheochromocytomas usually originate from the adrenal medulla but may also develop from chromaffin cells in or about sympathetic ganglia. A common symptom of pheochromocytoma is hypertension owing to release of catecholamines.
Meningioma
MedGen UID:
505374
Concept ID:
CN002583
Finding
The presence of a meningioma, i.e., a benign tumor originating from the dura mater or arachnoid mater.
Astrocytoma
MedGen UID:
506296
Concept ID:
CN008457
Finding
Astrocytoma is a neoplasm of the central nervous system derived from astrocytes. Astrocytes are a type of glial cell, and thus astrocytoma is a subtype of glioma.
Plexiform neurofibroma
MedGen UID:
506304
Concept ID:
CN008592
Finding
A neurofibroma in which Schwann cells proliferate inside the nerve sheath, producing an irregularly thickened, distorted, tortuous structure.
Optic glioma
MedGen UID:
506306
Concept ID:
CN008594
Finding
A glioma originating in the optic nerve or optic chiasm.
Spinal neurofibromas
MedGen UID:
429015
Concept ID:
CN008595
Finding
Neurofibromas originating in the spine.
Pheochromocytoma
MedGen UID:
505323
Concept ID:
CN002423
Finding
Pheochromocytomas (also known as chromaffin tumors) produce, store, and secrete catecholamines. Pheochromocytomas usually originate from the adrenal medulla but may also develop from chromaffin cells in or about sympathetic ganglia. A common symptom of pheochromocytoma is hypertension owing to release of catecholamines.
Parathyroid adenoma
MedGen UID:
505395
Concept ID:
CN002620
Finding
A benign tumor of the parathyroid gland that can cause hyperparathyroidism.
Overgrowth
MedGen UID:
376550
Concept ID:
C1849265
Finding
Spina bifida
MedGen UID:
505230
Concept ID:
CN002193
Finding
Incomplete closure of the embryonic neural tube, whereby some vertebral arches remain unfused and open. The mildest form is spina bifida occulta, followed by meningocele and meningomyelocele.
Scoliosis
MedGen UID:
427922
Concept ID:
CN002409
Finding
The presence of an abnormal lateral curvature of the spine.
Genu valgum
MedGen UID:
505373
Concept ID:
CN002582
Finding
The legs angle inward, such that the knees are close together and the ankles far apart.
Tibial pseudoarthrosis
MedGen UID:
429435
Concept ID:
CN008596
Finding
Pseudarthrosis, or \
Cafe-au-lait spot
MedGen UID:
113157
Concept ID:
C0221263
Finding
Light brown pigmented macules associated with NEUROFIBROMATOSIS and Albright's syndrome (see FIBROUS DYSPLASIA, POLYOSTOTIC).
Inguinal freckling
MedGen UID:
320315
Concept ID:
C1834297
Finding
Axillary freckling
MedGen UID:
348082
Concept ID:
C1860335
Finding
Plexiform neurofibroma
MedGen UID:
506304
Concept ID:
CN008592
Finding
A neurofibroma in which Schwann cells proliferate inside the nerve sheath, producing an irregularly thickened, distorted, tortuous structure.
Spinal neurofibromas
MedGen UID:
429015
Concept ID:
CN008595
Finding
Neurofibromas originating in the spine.
Hypertension
MedGen UID:
635666
Concept ID:
C0497247
Finding
A finding of increased blood pressure; not necessarily hypertensive disorder
Renal artery stenosis
MedGen UID:
505007
Concept ID:
CN001737
Finding
The presence of stenosis of the renal artery.
Rhabdomyosarcoma
MedGen UID:
505375
Concept ID:
CN002584
Finding
Genu valgum
MedGen UID:
505373
Concept ID:
CN002582
Finding
The legs angle inward, such that the knees are close together and the ankles far apart.
Tibial pseudoarthrosis
MedGen UID:
429435
Concept ID:
CN008596
Finding
Pseudarthrosis, or \

Professional guidelines

PubMed

Robson ME, Storm CD, Weitzel J, Wollins DS, Offit K; American Society of Clinical Oncology
J Clin Oncol 2010 Feb 10;28(5):893-901. Epub 2010 Jan 11 doi: 10.1200/JCO.2009.27.0660. [Epub ahead of print] PMID: 20065170
Toriello HV, Meck JM; Professional Practice and Guidelines Committee
Genet Med 2008 Jun;10(6):457-60. doi: 10.1097/GIM.0b013e318176fabb. PMID: 18496227Free PMC Article
Radtke HB, Sebold CD, Allison C, Haidle JL, Schneider G
J Genet Couns 2007 Aug;16(4):387-407. Epub 2007 Jul 17 doi: 10.1007/s10897-007-9101-8. [Epub ahead of print] PMID: 17636453
Trepanier A, Ahrens M, McKinnon W, Peters J, Stopfer J, Grumet SC, Manley S, Culver JO, Acton R, Larsen-Haidle J, Correia LA, Bennett R, Pettersen B, Ferlita TD, Costalas JW, Hunt K, Donlon S, Skrzynia C, Farrell C, Callif-Daley F, Vockley CW; National Society of Genetic Counselors
J Genet Couns 2004 Apr;13(2):83-114. doi: 10.1023/B:JOGC.0000018821.48330.77. PMID: 15604628
Am J Hum Genet 1995 Nov;57(5):1233-41. PMID: 7485175Free PMC Article

Recent clinical studies

Etiology

Ogle SK, Rose MM, Wildes CT
J Pediatr Oncol Nurs 2002 Jul-Aug;19(4):122-6. PMID: 12203191

Diagnosis

Kantaputra PN, van den Ouweland A, Sangruchi T, Limwongse C
Am J Med Genet A 2012 Jul;158A(7):1750-3. Epub 2012 Jun 7 doi: 10.1002/ajmg.a.35422. [Epub ahead of print] PMID: 22678692
Goldgar C
JAAPA 2011 Mar;24(3):75-6, 78. PMID: 21434506
Moore BD
Dev Disabil Res Rev 2009;15(1):45-51. doi: 10.1002/ddrr.53. PMID: 19213018
Ogle SK, Rose MM, Wildes CT
J Pediatr Oncol Nurs 2002 Jul-Aug;19(4):122-6. PMID: 12203191
Side LE, Emanuel PD, Taylor B, Franklin J, Thompson P, Castleberry RP, Shannon KM
Blood 1998 Jul 1;92(1):267-72. PMID: 9639526

Therapy

Ogle SK, Rose MM, Wildes CT
J Pediatr Oncol Nurs 2002 Jul-Aug;19(4):122-6. PMID: 12203191

Prognosis

Kantaputra PN, van den Ouweland A, Sangruchi T, Limwongse C
Am J Med Genet A 2012 Jul;158A(7):1750-3. Epub 2012 Jun 7 doi: 10.1002/ajmg.a.35422. [Epub ahead of print] PMID: 22678692
Ogle SK, Rose MM, Wildes CT
J Pediatr Oncol Nurs 2002 Jul-Aug;19(4):122-6. PMID: 12203191

Clinical prediction guides

Kantaputra PN, van den Ouweland A, Sangruchi T, Limwongse C
Am J Med Genet A 2012 Jul;158A(7):1750-3. Epub 2012 Jun 7 doi: 10.1002/ajmg.a.35422. [Epub ahead of print] PMID: 22678692
Shannon KM, Watterson J, Johnson P, O'Connell P, Lange B, Shah N, Steinherz P, Kan YW, Priest JR
Blood 1992 Mar 1;79(5):1311-8. PMID: 1536955

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