Neurofibromatosis type 1

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Moises Romo M.D.

Neurofibromatosis type I (NF-1), also known as von Recklinghausen syndrome, is a common inherited disease. Along with neurofibromatosis type II (a.k.a. MISME syndrome), tuberous sclerosis, Sturge-Weber, and Von Hippel-Lindau disease, NF1 is a member of the phakomatoses or neurocutaneous syndrome, all of which have both neurologic and dermatologic lesions. This grouping is historical and based on disease pathology rather than genetic diagnosis.

Neurofibromatosis type 1 was fully described in1882 by German pathologyst Friedrich von Recklinghausen, for which the disorder was eponymously named after him (von Recklinghausen disease), although the recognition of individuals with this phenotype probably dates back from the Hellenistic era.

There is no established system for the classification of neurofibromatosis type 1.

Neurofibromatosis type 1 is an autosomal syndrome caused by a mutation in gene NF1 of chromosome 17, wich leads to a defective neurofibromin 1 protein. This mutation constitutes a phenotype with very pathognomonic features that are not always present; among them are the presence of Lisch nodules, neurofibromas, scoliosis, cognitive disabilities, vision disorders, multiple café au lait spots and epilepsy.

Neurofibromatosis type 1 can be caused 50% of the time due to an autosomal dominant inherited pattern with the other 50% beign caused due to a de novo mutation on NF1 gene. To review risk factors for the development of neurofibromatosis type 1, click here.

Neurofibromatosis type 1 should be differentiated from other genetic disorders who present with overlapping features, such as Von Hippel-Lindau syndrome, Carney complex, Li-Fraumeni syndrome, Gardner’s syndrome, Multiple endocrine neoplasia type 2, Cowden syndrome, Acromegaly/gigantism, Pituitary adenoma, Hyperparathyroidism, Pheochromocytoma/paraganglioma, Adrenocortical carcinoma.

Neurofibromatosis type 1 is the most common single gene disorder in humans, occurring in about 30 to 40 in 100,000 births worldwide.

The country with major prevalence of neurofibromatosis type 1 reported is Israel, while the one with the least reported in Denmark.

Older paternal age may increase the chances for de novo mutations in NF1 gene.

There is no race or gender predilection for neurofibromatosis type 1.

The biggest risk factor for acquiring neurofibromatosis type 1 is a family history of this disorder. Advanced paternal age increases the risk of an NF1 de novo mutation. There is no identified modifiable risk factor for acquiring neurofibromatosis type 1.

Neurofibromatosis type 1 is acquiered 50% of the time by inheritance. Screening is made by taking a family history and a physical examination, and confirmed with genetic testing. Prenatal screening is controversial.

Neurofibromatosis Type 1 manifestations vary widely among patients, from individuals with absent symptoms to rapidly progressive disorders. The most common complication of neurofibromatosis type 1 is disfigurement due to skin lesions. Prognosis will depend on the number of commorbidities, but it is usually moderately good. Life expectancy is usually reduced by 8-12 years, being malignant tumors the most common cause of death.

Neurofibromatosis type 1 is mainly diagnosed clinically. Neurofibromatosis type 1 is usually diagnosed early on in childhood. Genetic testing may be necessary in difficult cases.

Neurofibromatosis type 1 manifestations vary widely among patients, from individuals with absent symptoms to rapidly progressive disorders. The most common complication of neurofibromatosis type 1 is disfigurement due to skin lesions Prognosis will depend on the number of commorbidities, but it is usually moderately good. Life expectancy is usually reduced by 8-12 years, being malignant tumors the most common cause of death.

Neurofibromatosis type 1 physical examination may vary widely among patients. The most common features are the presence of neurofibromas, plexiform neurofibromas, Lisch nodules, cafe au lait macules (CALM), delayed puberty features, and cognitive impairment. Neurofibromatosis type 1 may be diagnosed clinically with great specificity and sensitivity by the presence of 2 characteristic features on physical examination, although many children with the NF1 gene mutation may not meet the criteria at age 1, but will do so at 8 years old in 97% of the cases.

Metabolic and chemical laboratory studies usually appear normal in individuals with neurofibromatosis type 1. NF1 gene mutation can be diagnosed using linkage analysis and gene sequencing.

There are no characteristic ECG findings associated with neurofibromatosis type 1.

There are no typical x-ray findings associated with neurofibromatosis type 1, however, X-rays may be helpful in the diagnosis of other complications such as scoliosis, slender long bones, skeletal dysplasia, tibial pseudoarthrosis, and osteoporosis.

There are no echocardiography/ultrasound findings associated with neurofibromatosis type 1.

There are no CT scan findings associated with neurofibromatosis type 1, however, a CT scan may be helpful in the diagnosis of complications. The use of routine screening brain CT scans in patients with neurofibromatosis type 1 is controversial.

There are no CT scan findings associated with neurofibromatosis type 1, however, a MRI may be helpful in the diagnosis of complications. MRI is the preferred study method when studying the central nervous system (CNS). The use of routine screening brain MRI in patients with neurofibromatosis type 1 is controversial.

There are no other diagnostic studies associated with neurofibromatosis type 1.

There is no treatment for neurofibromatosis type 1; the mainstay of therapy is supportive care. Therapy for a patient with neurofibromatosis type 1 is aimed at decreasing symptoms and improving quality of life. At every age, different problems may develop, so a specific approach is necessary for the age and presentation of the individual. Supportive therapy for neurofibromatosis type 1 includes pain relief, psychotherapy, and antidepressants.

There are no recommended therapeutic interventions for the management of neurofibromatosis type 1.

Surgery is only used as a palliative, rather than curative therapy. Surgery can be helpful for the correction of some neurofibromatosis type 1 bone malformations and for removal of painful or disfiguring tumors.

There are no established measures for the primary prevention of neurofibromatosis type 1.

Neurofibromatosis type 1 has a wide range of comorbidities, regular multidisciplinary follow-ups are mandatory. Annual mammogram and ophtalmologic examination should be made in patients with neurofibromatosis type 1. Neurocognitive evaluation and blood pressure measurements should be done regularly to record evolution and detect secondary causes of impairment.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Moises Romo M.D.

Neurofibromatosis type 1 was fully described in1882 by German pathologyst Friedrich von Recklinghausen, for which the disorder was eponymously named after him (von Recklinghausen disease), although the recognition of individuals with this phenotype probably dates back from the Hellenistic era.

• The first description of inviduals with Neurofibromatosis type 1 phenotype dates back from the XIV century, and probably even the Hellenistic era, made by Madigan, Schaw, and Masello, described as a “monstruous disease“.^[1][2]
• In 1785, English physician Mark Akensidi presents major reports about a patient, café au lait spots, rubbery lesions, cognitive imapirment, and a big head, which he named “wart man”.^[3]
• In 1830, Prusian anatomist and physician, Theodor Schwann described the nerve sheath cover that later was appreciated as the predominant cell type in neurofibromatosis.^[4]
• In 1847, Prusian pathologist, Rudolf Virchow stated that connective tissue tumors that contained nerves, should be classified apart from those that do not contain nerves, naming them “fibroma molluscum” or “elephantiasis molluscum”.^[5]
• In 1873, German ophtalmologist, Julius von Michel first reported the case of a patient with optic glioma.^[3][6]
• In 1882, German pathologist, Friedrich von Recklinghause systemically described neurofibromatosis type 1 with the presentation of two of his patients, recognizing it as a nosologic entity in his treatise “Über die multiplen Fibrome der Haut und ihre Beziehung zu den multiplen Neuromen“.^[1][4]
• In 1900, English physician A. Thomson describes Neurofibromatosis as an hereditary entity.^[4][3]
• In 1909, Suzuki was the first to describe an association between pheochromocytoma and neurofibromatosis type 1.^[4][3]
• In 1987, gene linkage studies localised the NF1 gene in chromosome 17.^[7]
• In 1987 this condition was uniformly recognized and clasified thanks to the National Institutes of Health (NIH) Consensus Development Conference.^[1]
• NF1 was cloned in 1990,^[8] and its gene product neurofibromin was identified in 1992.^[9]
• In 1999, Nielsen et al. discovered that loss of expression of p16 protein was the cause of malignant transformation in neurofibromatosis type 1.^[3][10]

• Probably the most famous case of neurofibromatosis type 1 was described in 1888, in England, with Joseph Merrick, the “elephant man“. This man had a difficult life, and was cruelly exhibited in circuses as a phenomenon. Joseph was born as a healthy child in 1862, but started to develop typical characteristics of the disease at age 2.^[11] By age 22, Merrick presented dysmorphic facies, macrocephaly, skin and bone deformities, but surprisingly, no cognitive impairment. He quoted:

“The deformity I am exhibiting now is because an elephant scared my mother; she walked down the street as a procession of animals paraded. A huge crowd gathered to watch them, and unfortunately, they pushed my mother under the feet of an elephant. She was very scared. She was pregnant with me, and this misfortune was the cause of my deformity“.

“Is true that my form is something odd, but blaming me is blaming God; Could I create myself anew would not fail pleasing you.If I could reach from pole to pole or grasp the ocean with a span, I would be measured by the soul. The mind´s the standard of the man.^[12]

• This patient was the inspiration for the 1980 movie “The Elephant Man“, by David Lynch.

• Society’s acceptance and understanding for neurofibromatosis type 1 has changed drastically over the time; from being a so-called a “monstrous disease”, to a well-known entity now in the day, compassion has grown for those individuals suffering from this condition thanks to the many research behind its behavior and characteristics. Advances in its treatment have made a great impact in the natural history of this disease, decreasing mortality and now focusing on a more multidysciplinary management.^[5]

• Joseph Merrick (the elephant man)^[13][12][11]
• Munya Yassir (actress)^[14]
  

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Moises Romo M.D.

There is no established system for the classification of neurofibromatosis type 1.

• There is no established system for the classification of neurofibromatosis type 1.
  

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Moises Romo M.D.

Neurofibromatosis type 1 is an autosomal syndrome caused by a mutation in gene NF1 of chromosome 17, wich leads to a defective neurofibromin 1 protein. This mutation constitutes a phenotype with very pathognomonic features that are not always present; among them are the presence of Lisch nodules, neurofibromas, scoliosis, cognitive disabilities, vision disorders, multiple café au lait spots and epilepsy.

• Neurofibromin 1 (NF1) gene, is a large multi-domain protein, of approximately 250 KDa, containing 2,818 amino acids,^[1][2] located in chromosome 17,^[3] codes for the GTPase-activating protein, neurofibromin.^[4][5] This protein, is a tumor suppressor expressed in many cells, primarily in neurons, glial, immune cells, endothelial cellls of the adrenal medulla, Schwann cells and early in melanocyte development.^[6][7]
• Neurofibromin works by downregulating the RAS/MAPK pathway, by accelerating hydrolisis and preventing cell proliferation.^{[5][6] [8][9]}
• Neurofibromin interacts cytoskeletal microtubular and microfilaments for proper neuronal development.^[1][10]
  

• Neurofibromatosis type 1 is an autosomal syndrome, although, roughly 50% of gene mutations arise from de novo events.^[1]
• The large size of the NF1 gene (350 kb with 60 exons) predisposes to a high mutation rate, with approximately one mutation occurring per 10,000 gametes.^[11]
• NF1 mutations lead to protein truncation (loss of neurofibromin expression), which in turn produces increased cell growth and survival through expression of RAS to ultimately increase chances for malignant transformation.^[7][12][1]
• More than 3,000 NF1 gene mutations have been recognised.^[7]
• Loss of neurofibromin leads to formation of skin lesions, tumours and skeletal abnormalities.^[7]
• Patients with neurofibromatosis type 1 syndrome have a higher incidence of GI, liver, lung, bone, thyroid, breast and ovarian cancers.^[1][13]
• Nerve sheath tumours can arise from benign neurofibromas and these compose the first cause of death in individuals with neurofibromatosis type 1.^[1]
• Patients with neurofibromatosis type 1 can present a wide variability of clinical features, even in the same family since mutation mechanisms are so vast. Interestingly, patients can present traits limited to a part of their body (mosaicism).^[7]
• Therapies are focused to inhibit RAS phenylation to block oncogenic RAS signalling.^[1]
  

• Neurofibromatosis type 2 is a genetic condition which may be inherited or may arise spontaneously. It is caused by NF2 gene(Merlin gene) mutation in chromosome 22 and presents with bilateral vestibular schwannomas(acoustic neuromas).^[14]
• Neurofibromatosis type 1 is part of the group of neurocutaneous disorders called phakomatoses, some of the most famous conditions from this group are:
  • Tuberous sclerosis
  • Sturge-Weber
  • Von Hippel-Lindau disease
  • Ataxia telangiectasia

• The most common non-­neoplastic manifestations are cafe-au-lait macules, which is a very sensitive finding when they appear in large quantities.^[7][15][16]
• Dysplasia of the long bones and sphenoid wings, fractures, and pseudoarthrosis are common findings in patients with neurofibromatosis type 1.^[16][17] They occur due to osteoblastic and osteoclastic dysfunction which lead to decreased mineralization.^[7]
• The defects in bone observed in individuals with neurofibromatosis type 1 are due to the loss of both copies of NF1 in osteoclasts and/or osteoblasts.Osteoblast dysfunction following NF1 loss results in an increased generation of pyrophosphate, which inhibits bone mineral (hydroxyapatite) production and bone mineralization, causing reduced bone density and a higher risk of bone fracture.^[7][18]
• Lisch nodules are hyperpigmented hamartomas of the iris, which are seen in 95–100% of adults with neurofibromatosis type 1.^[16][17]
• Neurofibromas are benign peripheral nerve sheath tumors that arise from Schwann cells, and represent the most frequent type of tumors in patients with neurofibromatosis type 1; they can be divided as dermal and plexiform neurofibromas.^[7][19]
• Optic gliomas are the most common brain tumors in neurofibromatosis type 1, they are observed in 15–20% of children younger than 7 years.^[16][20]
• Several types of cerebrovascular disease, including stenotic or occlusive disease, vascular dilatation or aneurysm, arteriovenous fistula, moyamoya syndrome, or vascular proliferation have been consistently found in biopsies of patients with neurofibromatosis type 1.^[16][21]
  

• Cafe au-lait macules consist of a dense population of melanocytes with biallelic NF1 inactivation.^[7][15]
• Neurofibromas are benign peripheral nerve sheath tumors composed of neoplastic Schwann cells, fibroblasts, blood vessels, and mast cells.^[16]
• Optic pathway gliomas are composed of astrocytes, oligodendrocytes, neurons, microglia and progenitor or stem cells.^[7][22]
  

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Moises Romo M.D.

Neurofibromatosis type 1 can be caused 50% of the time due to an autosomal dominant inherited pattern with the other 50% beign caused due to a de novo mutation on NF1 gene. To review risk factors for the development of neurofibromatosis type 1, click here.

• Neurofibromatosis type 1 is a relatively common inherited disorder. The development of this disease is always due to a mutation in the NF1 gene from chromosome 17, which in turn, produces a defective neurofibromin protein.
• 50% of cases of neurofibromatosis type 1 are inherited, with the remainder beign de novo NF1 mutation.^[1][2]

• Neurofibromatosis type 1 due to de novo mutations of NF1, occur in the absence of a family history of the disease, usually from a paternal germline cell mutation.^[3][1]
• Multiple de novo pathogenic varients is possible in a same family of individuals with neurofibromatosis type 1.^[4][5]
• Causes for NF1 gene mutation are the following:

Causes for NF1 gene mutation	Percentage
Small deletions	22.4%[6]
Non-sense mutations	17.5%[6]
Deletion of several exons	15.5%[6]
Missense mutations	11.8%[6]
Small insertions	11%[6]
Intronic mutations affecting RNA splicing	10.2%[6]
Deletions of the entire NF1 gene	7.2%[6]
Chromosomal anomalies	1.6%[6]
3-UTR region mutations	1.6%[6]
Large insertions	1.2%[6]

• Advanced paternal age increases probability of an NF1 de novo mutation.^[1]
• The mutation rate for the NF1 gene, 4.37 (± 0.72) per 100,0000.^[7]
  

• Heterozygous pathogenic variants in NF1 gene are responsible for the developement of neurofibromatosis 1 disease.^[8]
• Neurofibromatosis type 1 is inherited in an autosomal dominant fashion.^[9][10]
• Inherited neurofibromatosis type 1 has 100% penetrance (no skipping generations).^[4][11]
• Unlike many autosomal dominant disorders, where one defective copy of a gene can produce the phenotype, in neurofibromatosis type 1, mutation of two copies are necessary to develope the presentation, this means that many people who inherit only one copy mutation need for a second mutation during lifetime for neurofibromas and other characteristics to arise.^[9]
• Due to neurofibromatosis type 1 high prevalence, other concomittant autosomal dominant disorders have been reported, such as Noonan syndrome, multiple endocrine neoplasia type 2, and Huntington disease.^[12]
• Neurofibromatosis type 1 mosaicism may also appear and be limited to one segment of the body.^[8]
• Parents with mosaicism of neurofibromatosis type 1 have less 50% of chance to transmit the condition to its child, but if transmitted, the mutation will be present in every cell of the newborn, presenting a severe variant.^[4]
  

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Moises Romo M.D.

Neurofibromatosis type 1 should be differentiated from other genetic disorders who present with overlapping features, such as Von Hippel-Lindau syndrome, Carney complex, Li-Fraumeni syndrome, Gardner’s syndrome, Multiple endocrine neoplasia type 2, Cowden syndrome, Acromegaly/gigantism, Pituitary adenoma, Hyperparathyroidism, Pheochromocytoma/paraganglioma, Adrenocortical carcinoma.

Neurofibromatosis type 1 can be differentitated from other genetic disorders by the following characteristics:^{[1][2][3][4][5][6][7][8][9][10][11]}

Disease	Gene	Chromosome	Differentiating Features	Components of MEN			Diagnosis
				Parathyroid	Pitutary	Pancreas
Von Hippel-Lindau syndrome[1]	Von Hippel–Lindau tumor suppressor[1]	3p25.3[1]	Angiomatosis,[1] Hemangioblastomas,[1] Pheochromocytoma,[1] Renal cell carcinoma,[1] Pancreatic cysts (pancreatic serous cystadenoma)[1] Endolymphatic sac tumor,[1] Bilateral papillary cystadenomas of the epididymis (men) or broad ligament of the uterus (women)[1]	–	–	+	Clinical diagnosis[1] In hereditary VHL, disease techniques such as Southern blotting and gene sequencing can be used to analyse DNA and identify mutations.[1]
Carney complex[2]	PRKAR1A[2]	17q23-q24[2]	Myxomas of the heart[2] Hyperpigmentation of the skin (lentiginosis)[2] Endocrine (ACTH-independent Cushing’s syndrome due to primary pigmented nodular adrenocortical disease)[2]	–	–	–	Clinical diagnosis[2]
Neurofibromatosis type 1[12]	NF1[12]	17[12]	Scoliosis[12] Learning disabilities[12] Vision disorders[12] Cutaneous lesions[12] Epilepsy.[12]	–	–	–	Prenatal Chorionic villus sampling or amniocentesis can be used to detect NF-1 in the fetus.[12] Postnatal Cardinal Clinical Features” are required for positive diagnosis.[12] Six or more café-au-lait spots over 5 mm in greatest diameter in pre-pubertal individuals and over 15 mm in greatest diameter in post-pubertal individuals.[12] Two or more neurofibromas of any type or 1 plexiform neurofibroma[12] Freckling in the axillary (Crowe sign) or inguinal regions[12] Optic glioma[12] Two or more Lisch nodules (pigmented iris hamartomas)[12] A distinctive osseous lesion such as sphenoid dysplasia, or thinning of the long bone cortex with or without pseudarthrosis.[12]
Li-Fraumeni syndrome[3]	TP53[3]	17[3]	Early onset of diverse amount of cancers such as Sarcoma Cancers of Breast Brain Adrenal glands[3]	–	–	–	Criteria Sarcoma at a young age (below 45)[3] A first-degree relative diagnosed with any cancer at a young age (below 45)[3] A first or second degree relative with any cancer diagnosed before age 60.[3]
Gardner’s syndrome[4]	APC[4]	5q21[4]	Multiple polyps in the colon[4] Osteomas of the skull[4] Thyroid cancer,[4] Epidermoid cysts,[4] Fibromas[4] Desmoid tumors[4]	–	–	–	Clinical diagnosis[4] Colonoscopy[4]
Multiple endocrine neoplasia type 2[5]	RET[5]	–	Medullary thyroid carcinoma (MTC)[5] Pheochromocytoma[5] Primary [5]hyperparathyroidism[5]	+	–	–	Hypercalcemia[5] Hypophosphatemia,[5] Elevated parathyroid hormone,[5] Elevated norepinephrine[5] Criteria Two or more specific endocrine tumors Medullary thyroid carcinoma Pheochromocytoma Parathyroid hyperplasia[5]
Cowden syndrome[6]	PTEN[6]	–	Hamartomas[6]	–	–	–	PTEN mutation probability risk calculator[6]
Acromegaly/gigantism[7]	GNAS1[7]	20[7]	Enlargement of the hands, feet, nose, lips and ears, and a general thickening of the skin[7] Hypertrichosis[7] Hyperpigmentation[7] Hyperhidrosis[7] Carpal tunnel syndrome.[7]	–	+	–	An elevated concentration of serum growth hormone (GH) and insulin-like growth factor 1(IGF-1) levels is diagnostic of acromegaly.[7]
Pituitary adenoma[8]	–	–	Visual field defects classically bitemporal hemianopsia[8] Increased intracranial pressure[8] Migraine[8] Lateral rectus palsy[8]	–	+	–	Elevated serum level of prolactin[8] Elevated or decreased serum level of adrenocorticotropic hormone (ACTH)[8] Elevated or decreased serum level of growth hormone (GH)[8] Elevated or decreased serum level of thyroid-stimulating hormone (TSH)[8] Elevated or decreased serum level of follicle-stimulating hormone (FSH)[8] Elevated or decreased serum level of luteinizing hormone (LH)[8]
Hyperparathyroidism[9]	–	–	– Kidney stones[9] Hypercalcemia,[9] Constipation[9] Peptic ulcers[9] Depression[9]	+	–	–	An elevated concentration of serum calcium with elevated parathyroid hormone level is diagnostic of primary hyperparathyroidism.[9] Most consistent laboratory findings associated with the diagnosis of secondary hyperparathyroidism include elevated serum parathyroid hormone level and low to normal serum calcium.[9] An elevated concentration of serum calcium with elevated parathyroid hormone level in post renal transplant patients is diagnostic of tertiary hyperparathyoidism.[9]
Pheochromocytoma/paraganglioma[10]	VHL RET NF1  SDHB SDHD[10]	–	Characterized by Episodic hypertension[10] Palpitations[10] Anxiety[10] Diaphoresis[10] Weight loss[10]	–	–	–	Increased catecholamines and metanephrines in plasma (blood) or through a 24-hour urine collection.[10]
Adrenocortical carcinoma[11]	p53[11] Retinoblastoma h19[11] Insulin-like growth factor II (IGF-II)[11] p57kip2[11]	17p, 13q[11]	Cushing syndrome (cortisol hypersecretion)[11] Conn syndrome (aldosterone hypersecretion)[11] virilization (testosterone hypersecretion)[11]	–	–	–	Increased serum glucose[11] Increased urine cortisol[11] Serum androstenedione and dehydroepiandrosterone[11] Low serum potassium[11] Low plasma renin activity[11] High serum aldosterone.[11] Excess serum estrogen.[11]
Adapted from Toledo SP, Lourenço DM, Toledo RA. A differential diagnosis of inherited endocrine tumors and their tumor counterparts, journal=Clinics (Sao Paulo), volume= 68, issue= 7, 07/24/2013[13]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Moises Romo M.D.

Neurofibromatosis type 1 is the most common single gene disorder in humans, occurring in about 30 to 40 in 100,000 births worldwide.

The country with major prevalence of neurofibromatosis type 1 reported is Israel, while the one with the least reported in Denmark.

Older paternal age may increase the chances for de novo mutations in NF1 gene.

There is no race or gender predilection for neurofibromatosis type 1.

• The incidence of neurofibromatosis type 1 is approximately 33.33 per 100,000 individuals worldwide.^[1]
• The incidence of neurofibromatosis type 1 is approximately 14-26 per 100,000 individuals in the United States.^[2][3]

• The prevalence of neurofibromatosis type 1 is approximately 33.33 per 100,000 individuals worldwide.^[1][4]
• Prevalence can can vary from one country to another, beign 104.1 per 100,000 individuals in Israel to 12.8 per 100,000 individuals in Russia.^[1][4]
• The highest prevalence of neurofibromatosis type 1 is in the population between 10 to 19 years old.^[2]

• Neurofibromatosis type 1 decreases life expectancy in approximately 15-20 years from a normal person.^[5][6]
• The mean annual frequency of neurofibromatosis type 1-associated deaths was 9.3 per 100,000 deaths.^[6][7]
• The mean annual mortality rate associated with neurofibromatosis type 1 is 0.092 per 100,000 people.^[7]

• The median age of diagnosis for neurofibromatosis type 1 is usually around 20 years old, although it can range from 3 months to 60 years old.^[2]
• Since its a hereditary disorder, patients of all age groups may develop neurofibromatosis type 1 symptoms.
• Prevalence of neurofibromatosis has been found to be increased in individuals born from parents with advanced age.^[2][8][9]
• The mean age of mothers who give to birth of a child with neurofibromatosis type 1 is 30 years , while the paternal age is 33.^[2]

• There is no racial predilection to neurofibromatosis type 1.^[10]
• There seems to be a lower incidence of optic nerve glioma in African-American population.^[10]

• Neurofibromatosis type 1 affects men and women equally.^[11]

• The majority of neurofibromatosis type 1 cases are reported in Israel.^[2][12]
• The country with less cases of neurofibromatosis type 1 reported is Denmark.^[2][13]

• Many countries lack a proper electronic patient record, so many times, researcher have to rely on death certificates and non-population-based cohorts to estimate risks of neurofibromatosis type 1.^[1][14]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Moises Romo M.D.

The biggest risk factor for acquiring neurofibromatosis type 1 is a family history of this disorder. Advanced paternal age increases the risk of an NF1 de novo mutation. There is no identified modifiable risk factor for acquiring neurofibromatosis type 1.

• Since neurofibromatosis type 1 is an inherited or de novo mutation disease, there is hardly any modifiable risk factors.^[1]
• The biggest risk factor for neurofibromatosis type 1 is a family history of the disorder.^[2][3]
• Children of individuals with neurofibromatosis type 1 have 50% of inheriting the mutation in NF1 gene.^[4]
• Neurofibromatosis type 1 is inherited in an autosomal dominant manner, with 100% penetrance.^[5]
• Advanced paternal age increases the risk of an NF1 de novo mutation.^[3]
• Parents with mosaicism of neurofibromatosis type 1 have less than 50% of chance to transmit the condition to its child, but if transmitted, the mutation will be present in every cell of the newborn, presenting a severe variant.^[6]

• The risk of inheriting schwannomatosis from an affected parent with neurofibromatosis type 1 is approximately 15%.^[2]
• The cumulative risk to develope any kind of malignancy during life in patients with neurofibromatosis type 1 is approximately 60%, especially brain tumors.^[7]
• The risk of developing a nerve sheath tumor is increased more than 1000-fold times than the general population.^[7]
• Serum level of vitamin D inversely correlates with the number of neurofibromas.^[8]
• Neurofibromatosis type 1 patients have higher risk of developing depression and social anxiety.^[9]
• Associated risk factors for death in patients with neurofibromatosis type 1 are the presence of subcutaneous neurofibromas, the absence of cutaneous neurofibromas, and facial asymmetry.^[10]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Moises Romo M.D.

Neurofibromatosis type 1 is acquiered 50% of the time by inheritance. Screening is made by taking a family history and a physical examination, and confirmed with genetic testing. Prenatal screening is controversial.

• Approximately 50% of individuals with neurofibromatosis type 1 acquiere this condition by inheritance.^[1][2][3]
• Screening is made by taking a family history and a physical examination, and confirmed with genetic testing.^[3]
• It is important to take into account that family history may be negative in a patient with neurofibromatosis type 1 due to death of parents at an early age.^[1]
• There is a general consensus for genetic testing in children presenting with typical features of neurofibromatosis type 1 (neurofibromas, more than 6 cafe au lait macules, Lisch nodules).^[4][3]
• Finding of 6 or more cafe au lait macules in patients of young age (less than 8 years old), is highly correlated with the diagnosis of neurofibromatosis type 1 verified by genetic testing.^[5][6][3]
• Mutations in NF1 gene can be determined using a combination of molecular techniques, such as dHPLC, direct sequencing, FISH, MLPA and array CGH.^[7][8][2]
• Prenatal ultrasound is usually of no utility, but has been reported positive in pregnant patients with severe neurofibromatosis type 1 features.^[9]
• Prenatal screening has been controversial due to ethical issues of pregnancy termination in this condition.^[1][10]
• Prenatal diagnosis of neurofibromatosis type 1 can be made using cells of embryos as early as 3 day old^[2]

• Parents of patients with neurofibromatosis type 1 should be screened with a medical history, ophtalmologic and general physical examination paying particular attention to dermatologic features.^[1] If examination results normal in both parents, a de novo mutation is concluded, since mosaicisms are rare.^{[1][11][12][13]}
• Genetic counseling should be offered to all individuals of reproductive age planning to conceive.^[1][14][15]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Moises Romo M.D.

Neurofibromatosis Type 1 manifestations vary widely among patients , from individuals with absent symptoms to rapidly progressive disorders. The most common complication of neurofibromatosis type 1 is disfigurement due to skin lesions. Prognosis will depend on the number of commorbidities, but it is usually moderately good. Life expectancy is usually reduced by 8-12 years, being malignant tumors the most common cause of death.

• Manifestations vary widely among patients with neurofibromatosis type 1, from individuals with absent symptoms to rapidly progessive disorders.^[1]
• Characteristics of neurofibromatosis type 1 appear at different ages,^[1][2][3][4] among them:
  • Bone manifestations appear from birth.^[1]
  • Plexiform neurofibromas appear usually around 1 year of age.^[1]
  • Cafe au lait spots appear in the first 5 years of life.^[1]
  • Optic gliomas develope in the first 6 years of life.^[1]
  • Scoliosis develops between age 6 and 10.^[1]
  • Malignant peripheral nerve sheath tumors usually appear around adolescence or adulthood.^[1]
• People with neurofibromatosis type 1 tend to grow below average in height and above average in head circumference.^[5][6][7][1]
• Precocious puberty and delayed puberty is more common in individuals with neurofibromatosis type 1 than the general population.^{[8][9][10][1]}

• Common complications of neurofibromatosis type 1 include:
  • Depression and social anxiety^[11]
  • Chronic pain, numbness, and/or paralysis due to the peripheral nerve sheath tumors^[11]
  • Blindness due to optic nerve gliomas^[11]
  • Amputation due to a tibial pseudarthrosis^[11]
  • Disfigurement due to skin lesions^[11]
  • Brain tumors^[11]
  • Wandering problems due to scoliosis and/or kyphosis^[11]
  • Malignant degeneration of neurofibromas into malignant peripheral nerve sheath tumor (this occurs in 10-12% of the cases)^[11]

• Depending on the extent of the disease progression and the time of diagnosis, the prognosis may vary. However, the prognosis is generally regarded as moderately good.
• Quality of life is lower in children and adults with neurofibromatosis type 1, due to the several commorbidities and complications, many times having an incapacitating depression.^[12]
• Life expectancy in patients with neurofibromatosis type 1 is usually reduced 8-21 years from the normal population.^[13]
• The most common cause of death in these type of patients is due to malignant neoplasm.^{[13][14][15][16][17][18]}

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