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Neurofibromatosis, type 1(NF1)

MedGen UID:
18013
Concept ID:
C0027831
Neoplastic Process
Synonyms: NEUROFIBROMATOSIS, PERIPHERAL TYPE; NEUROFIBROMATOSIS, TYPE I; NEUROFIBROMATOSIS, TYPE I, SOMATIC; Neurofibromatosis-Noonan syndrome; NF1; Recklinghausen's disease; Von Recklinghausen disease
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM, Orphanet
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).
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
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 (location): NF1 (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]
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.  https://ghr.nlm.nih.gov/condition/neurofibromatosis-type-1

Clinical features

Hypertension
MedGen UID:
6969
Concept ID:
C0020538
Disease or Syndrome
Blood pressure is the force of your blood pushing against the walls of your arteries. Each time your heart beats, it pumps blood into the arteries. Your blood pressure is highest when your heart beats, pumping the blood. This is called systolic pressure. When your heart is at rest, between beats, your blood pressure falls. This is called diastolic pressure. . Your blood pressure reading uses these two numbers. Usually the systolic number comes before or above the diastolic number. A reading of. -119/79 or lower is normal blood pressure. -140/90 or higher is high blood pressure. -Between 120 and 139 for the top number, or between 80 and 89 for the bottom number is called prehypertension. Prehypertension means you may end up with high blood pressure, unless you take steps to prevent it. High blood pressure usually has no symptoms, but it can cause serious problems such as stroke, heart failure, heart attack and kidney failure. You can control high blood pressure through healthy lifestyle habits such as exercise and the DASH diet and taking medicines, if needed. . NIH: National Heart, Lung, and Blood Institute.
Renal Artery Stenosis
MedGen UID:
19727
Concept ID:
C0035067
Disease or Syndrome
The presence of stenosis of the renal artery.
Pheochromocytoma
MedGen UID:
18419
Concept ID:
C0031511
Neoplastic Process
Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are characterized by paragangliomas (tumors that arise from neuroendocrine tissues symmetrically distributed along the paravertebral axis from the base of the skull to the pelvis) and by pheochromocytomas (paragangliomas that are confined to the adrenal medulla). Sympathetic paragangliomas hypersecrete catecholamines; parasympathetic paragangliomas are most often nonsecretory. Extra-adrenal parasympathetic paragangliomas are located predominantly in the skull base, neck, and upper medistinum; approximately 95% of such tumors are nonsecretory. In contrast, sympathetic extra-adrenal paragangliomas are generally confined to the lower mediastinum, abdomen, and pelvis, and are typically secretory. Pheochromocytomas, which arise from the adrenal medulla, typically hypersecrete catecholamines. Symptoms of PGL/PCC result either from mass effects or catecholamine hypersecretion (e.g., sustained or paroxysmal elevations in blood pressure, headache, episodic profuse sweating, forceful palpitations, pallor, and apprehension or anxiety). The risk for malignant transformation is greater for extra-adrenal sympathetic paragangliomas than for pheochromocytomas or skull base and neck paragangliomas.
Parathyroid adenoma
MedGen UID:
75502
Concept ID:
C0262587
Neoplastic Process
A benign tumor of the parathyroid gland that can cause hyperparathyroidism.
Glaucoma
MedGen UID:
42224
Concept ID:
C0017601
Disease or Syndrome
Glaucoma is a group of eye disorders in which the optic nerves connecting the eyes and the brain are progressively damaged. This damage can lead to reduction in side (peripheral) vision and eventual blindness. Other signs and symptoms may include bulging eyes, excessive tearing, and abnormal sensitivity to light (photophobia). The term "early-onset glaucoma" may be used when the disorder appears before the age of 40.In most people with glaucoma, the damage to the optic nerves is caused by increased pressure within the eyes (intraocular pressure). Intraocular pressure depends on a balance between fluid entering and leaving the eyes.Usually glaucoma develops in older adults, in whom the risk of developing the disorder may be affected by a variety of medical conditions including high blood pressure (hypertension) and diabetes mellitus, as well as family history. The risk of early-onset glaucoma depends mainly on heredity.Structural abnormalities that impede fluid drainage in the eye may be present at birth and usually become apparent during the first year of life. Such abnormalities may be part of a genetic disorder that affects many body systems, called a syndrome. If glaucoma appears before the age of 5 without other associated abnormalities, it is called primary congenital glaucoma.Other individuals experience early onset of primary open-angle glaucoma, the most common adult form of glaucoma. If primary open-angle glaucoma develops during childhood or early adulthood, it is called juvenile open-angle glaucoma.
Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Congenital Abnormality
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (145410), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).
Lisch nodules
MedGen UID:
395461
Concept ID:
C1860334
Finding
The presence of pigmented, oval and dome-shaped raised hamartomatous nevi of the iris..
Tibial pseudoarthrosis
MedGen UID:
869786
Concept ID:
C4024216
Anatomical Abnormality
Pseudarthrosis, or \
Astrocytoma
MedGen UID:
438
Concept ID:
C0004114
Neoplastic Process
Neoplasms of the brain and spinal cord derived from glial cells which vary from histologically benign forms to highly anaplastic and malignant tumors. Fibrillary astrocytomas are the most common type and may be classified in order of increasing malignancy (grades I through IV). In the first two decades of life, astrocytomas tend to originate in the cerebellar hemispheres; in adults, they most frequently arise in the cerebrum and frequently undergo malignant transformation. (From Devita et al., Cancer: Principles and Practice of Oncology, 5th ed, pp2013-7; Holland et al., Cancer Medicine, 3d ed, p1082)
Hydrocephalus
MedGen UID:
9335
Concept ID:
C0020255
Disease or Syndrome
Autosomal recessive nonsyndromic hydrocephalus is characterized by onset in utero of enlarged ventricles due to a disturbance of cerebrospinal fluid accumulation. Affected individuals may have neurologic impairment (summary by Drielsma et al., 2012). Hydrocephalus can also be caused by Arnold-Chiari malformation, atresia of foramen of Magendie, stenosis of aqueduct of Sylvius (307000), toxoplasmosis, hydranencephaly, etc. Furthermore, it develops in infancy or childhood in achondroplasia (100800) and in Hurler disease (607014). Genetic Heterogeneity of Congenital Hydrocephalus See also autosomal recessive HYC2 (615219), caused by mutation in the MPDZ gene (603785) on chromosome 9p. An X-linked form (307000) is caused by mutation in the L1CAM gene on (308840) on chromosome Xq28.
Meningioma
MedGen UID:
7532
Concept ID:
C0025286
Neoplastic Process
The presence of a meningioma, i.e., a benign tumor originating from the dura mater or arachnoid mater.
Pheochromocytoma
MedGen UID:
18419
Concept ID:
C0031511
Neoplastic Process
Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are characterized by paragangliomas (tumors that arise from neuroendocrine tissues symmetrically distributed along the paravertebral axis from the base of the skull to the pelvis) and by pheochromocytomas (paragangliomas that are confined to the adrenal medulla). Sympathetic paragangliomas hypersecrete catecholamines; parasympathetic paragangliomas are most often nonsecretory. Extra-adrenal parasympathetic paragangliomas are located predominantly in the skull base, neck, and upper medistinum; approximately 95% of such tumors are nonsecretory. In contrast, sympathetic extra-adrenal paragangliomas are generally confined to the lower mediastinum, abdomen, and pelvis, and are typically secretory. Pheochromocytomas, which arise from the adrenal medulla, typically hypersecrete catecholamines. Symptoms of PGL/PCC result either from mass effects or catecholamine hypersecretion (e.g., sustained or paroxysmal elevations in blood pressure, headache, episodic profuse sweating, forceful palpitations, pallor, and apprehension or anxiety). The risk for malignant transformation is greater for extra-adrenal sympathetic paragangliomas than for pheochromocytomas or skull base and neck paragangliomas.
Spina bifida
MedGen UID:
38283
Concept ID:
C0080178
Congenital Abnormality
Spina bifida is a condition in which the neural tube, a layer of cells that ultimately develops into the brain and spinal cord, fails to close completely during the first few weeks of embryonic development. As a result, when the spine forms, the bones of the spinal column do not close completely around the developing nerves of the spinal cord. Part of the spinal cord may stick out through an opening in the spine, leading to permanent nerve damage. Because spina bifida is caused by abnormalities of the neural tube, it is classified as a neural tube defect.Children born with spina bifida often have a fluid-filled sac on their back that is covered by skin, called a meningocele. If the sac contains part of the spinal cord and its protective covering, it is known as a myelomeningocele. The signs and symptoms of these abnormalities range from mild to severe, depending on where the opening in the spinal column is located and how much of the spinal cord is affected. Related problems can include a loss of feeling below the level of the opening, weakness or paralysis of the feet or legs, and problems with bladder and bowel control. Some affected individuals have additional complications, including a buildup of excess fluid around the brain (hydrocephalus) and learning problems. With surgery and other forms of treatment, many people with spina bifida live into adulthood.In a milder form of the condition, called spina bifida occulta, the bones of the spinal column are abnormally formed, but the nerves of the spinal cord usually develop normally. Unlike in the more severe form of spina bifida, the nerves do not stick out through an opening in the spine. Spina bifida occulta most often causes no health problems, although rarely it can cause back pain or changes in bladder function.
Plexiform neurofibroma
MedGen UID:
64640
Concept ID:
C0206728
Neoplastic Process
A neurofibroma in which Schwann cells proliferate inside the nerve sheath, producing an irregularly thickened, distorted, tortuous structure.
Optic glioma
MedGen UID:
138056
Concept ID:
C0346326
Neoplastic Process
Glial cell derived tumors arising from the optic nerve, usually presenting in childhood.
Spinal neurofibromas
MedGen UID:
869787
Concept ID:
C4024217
Neoplastic Process
Neurofibromas originating in the spine.
Rhabdomyosarcoma
MedGen UID:
20561
Concept ID:
C0035412
Neoplastic Process
A malignant mesenchymal neoplasm arising from skeletal muscle.
Tibial pseudoarthrosis
MedGen UID:
869786
Concept ID:
C4024216
Anatomical Abnormality
Pseudarthrosis, or \
Plexiform neurofibroma
MedGen UID:
64640
Concept ID:
C0206728
Neoplastic Process
A neurofibroma in which Schwann cells proliferate inside the nerve sheath, producing an irregularly thickened, distorted, tortuous structure.
Spinal neurofibromas
MedGen UID:
869787
Concept ID:
C4024217
Neoplastic Process
Neurofibromas originating in the spine.

Professional guidelines

PubMed

Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH, Naruse M, Pacak K, Young WF Jr; Endocrine Society.
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Recent clinical studies

Etiology

Ogle SK, Rose MM, Wildes CT
J Pediatr Oncol Nurs 2002 Jul-Aug;19(4):122-6. doi: 10.1177/104345420201900403. 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. 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. doi: 10.1177/104345420201900403. PMID: 12203191
Kayl AE, Moore BD 3rd
Ment Retard Dev Disabil Res Rev 2000;6(2):117-24. doi: 10.1002/1098-2779(2000)6:2<117::AID-MRDD5>3.0.CO;2-X. PMID: 10899804

Therapy

Ogle SK, Rose MM, Wildes CT
J Pediatr Oncol Nurs 2002 Jul-Aug;19(4):122-6. doi: 10.1177/104345420201900403. 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. PMID: 22678692
Ogle SK, Rose MM, Wildes CT
J Pediatr Oncol Nurs 2002 Jul-Aug;19(4):122-6. doi: 10.1177/104345420201900403. 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. 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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