The clinical features of NF1 are often not present at birth or in early childhood and the diagnosis is made based on the history of the affected parent or sibling. In most cases, a child who is born to a family with NF1 and does not present with any clinical features by age 10, will most likely be unaffected by the disorder [1]. The presentation of a patient with NF1 is quite variable. In children, the most frequent initial finding is presence of multiple café-au-lait spots. These skin lesions may be present at birth and become more obvious with time. In most infants, the café-au-lait spots do increase in size and number with advancing age.

Freckles in the inguinal or axillary region are very rarely seen at birth. However, as the child gets older and passes puberty, these skin lesions become more obvious. The neurofibromas are rarely seen in infants and young children. These lesions tend to occur past the age of puberty and become prominent by the adolescent years. The skin lesions initially start off as papules on the face, scalp, extremities and scalp. Some individuals may only have deeper neurofibromas that may only be felt via palpation. Some neurofibromas may not only be deep but also be locally invasive and produce pain with even mild palpation. The skin lesions often show rapid growth just after puberty or during pregnancy. Plexiform neurofibromas may also be associated with excess hair growth and darkening of skin. The growth of these neurofibromas can be rapid and that may be indicative of a malignant lesion.

The optic nerve gliomas are usually low grade and occur in 1/5th of patients with NF1. These lesions are often silent but can present with symptoms in young children. Females are more likely to develop visual problems compared to males. Besides vision loss, others may develop peripheral visual field deficits, proptosis and difficulty discriminating color. The visual loss is often unilateral and often not correctable. Rarely a neurofibroma may encroach on nerve pathways of the hypothalamus-pituitary axis and present as precocious puberty in children.

The Lisch nodules are usually not visible to the naked eye and require a slit lamp exam or use of an ophthalmoscope. Fundoscopic exam may reveal choroidal abnormalities. A variety of musculoskeletal defects may be seen in NF1 include bowing of the tibia/ulna, angulation and bowing of the long bones. Bony dysplasia of the sphenoid bone may be obvious but is often asymptomatic. Scoliosis may first become obvious in childhood and may be associated with kyphosis. Most individuals do not have progression of scoliosis but when it does progress it can be deforming and requires surgical intervention.

At every visit, the blood pressure must be measured because of the possibility of primary hypertension or developing secondary hypertension from a pheochromocytoma or renal artery stenosis. In all children with NF1, head circumference needs to be monitored for the first few years of life. Head enlargement may occur rapidly and may be appear abnormal. Most individuals with NF1 tend to have short stature.

• Epilepsy

  RESULTS: Of the 184 NF1 patients seen during that period, 26 had epilepsy and three had febrile seizures. Of the 26, 17 (65%) had localization-related epilepsy, seven of whom (41%) were drug resistant. [ncbi.nlm.nih.gov]

  Neurofibromatosis type 1 and Epilepsy Epilepsy is seen in about 4 to 7% of patients with NF1. This is double the risk factor compared to the general population. The onset of epilepsy can occur at any age. [epilepsy.com]

• Developmental Disorder

  As a developmental disorder, NF1 can also cause cognitive disability, skeletal deformities, and cardiovascular malfunction. While symptoms appear early in life, they may get worse over time or new ones may arise. [philanthropy.milkeninstitute.org]

  Abstract Background Proteus syndrome is a rare developmental disorder of unknown aetiology. It is a disorder characterized by postnatal overgrowth affecting multiple tissues. Proteus syndrome is most frequently manifested in skeletal changes. [ncbi.nlm.nih.gov]

  Disorders, University Hospital Eppendorf, Martinistr. 52, 20246 Hamburg, Germany. [atlasgeneticsoncology.org]

  Treatment may include surgery, radiation +/- steroids, or chemotherapy (in children).[13] Neurobehavioral developmental disorder[edit] The most common complication in patients with NF-1 is cognitive and learning disability. [en.wikipedia.org]

• Coarctation of the Aorta

  In most patients, the hypertension is essential, but vascular dysplasia can occur in association with NF1 and may produce renal artery stenosis, coarctation of the aorta, or other vascular lesions associated with severe hypertension in adult patients [emedicine.com]

• Hepatomegaly

  Hepatomegaly (4 cm below the costal margin) was additionally observed. His father was diagnosed with NF-1. Radiologic imaging studies showed a 6×5×5 cm in diameter cystic mass with multiple septations in the segment 4A of the liver. [ncbi.nlm.nih.gov]

• Macroglossia

  […] recognized pre‐operatively, elective awake fibreoptic tracheal intubation may fail because of a grossly distorted anatomy. 113 However, successful intubation after inhalation anaesthesia with sevoflurane has been described. 107 In addition, the presence of macroglossia [academic.oup.com]

• Progressive Hearing Loss

  Case Report A 20 year old male born of consaingous marriage (2 nd degree) having normal birth and developmental history was presented with two year history of progressive hearing loss. [medical-case-reports.imedpub.com]

  Although the tumors are usually benign (noncancerous), they often lead to progressive hearing loss as they grow. Other complications. [orthoinfo.aaos.org]

• Freckles

  Von Recklinghausen's disease or neurofibromatosis 1 is an autosomal dominant disorder with multiple neurofibromas and schwannomas, along with cafe au lait spots and axillary freckling. [medical-dictionary.thefreedictionary.com]

  A child with NF1 is likely to have at least six or more of these spots that are larger than freckles. [clevelandclinic.org]

  The following symptoms appear in people with NF1: Several (usually 6 or more) café au lait spots Multiple freckles in the armpit or groin area Tiny growths in the iris (colored area) of the eye ; these are called Lisch nodules and usually do not affect [webmd.com]

  Intertriginous freckling develops starting at 5 years of age. Multiple cutaneous and subcutaneous neurofibromas develop in adults. In older patients, they continue to increase in number and size. Cutaneous neurofibromas do not become malignant. [orpha.net]

• Cafe-Au-Lait Spots

  Von Recklinghausen's disease or neurofibromatosis 1 is an autosomal dominant disorder with multiple neurofibromas and schwannomas, along with cafe au lait spots and axillary freckling. [medical-dictionary.thefreedictionary.com]

  Neurofibromatosis type I is 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. [flybase.org]

  The cafe au lait spots increase in number and size with age. Ninety-seven percent of people with NF1 have 6 or more cafe au lait spots by age 20. The skin neurofibromas appear later, usually in the second decade of life. [medicinenet.com]

  Signs and symptoms include: Flat, light brown spots on the skin (cafe au lait spots). These harmless spots are common in many people. Having more than six cafe au lait spots is a strong indication of NF1. [mayoclinic.org]

  NF1 is characterized by “cafe-au-lait spots” (light brown skin patches) as well as neurofibromas (benign skin tumors). These neurofibromas can grow on nerves and organs and need to be surgically removed. [weillcornellbrainandspine.org]

• Axillary Freckling

  Von Recklinghausen's disease or neurofibromatosis 1 is an autosomal dominant disorder with multiple neurofibromas and schwannomas, along with cafe au lait spots and axillary freckling. [medical-dictionary.thefreedictionary.com]

  Axillary freckling Axillary freckling (as well as freckling on the perineum), known as the Crowe sign, is a helpful diagnostic feature in neurofibromatosis (see the image below). [emedicine.com]

  Physical examination revealed no cafè au lait spots, axillary freckling, Lisch nodules, or clinical signs of NF. Her family history was negative for NF. Physical and neurologic examinations revealed no abnormalities. Figure 1. [mdedge.com]

• Subcutaneous Nodule

  Multiple subcutanous nodules (neurofibromas) were also present all over the body. Chest examination revealed stony dull note on percussion and absent breath sounds over right hemithorax. [academic.oup.com]

  Diffuse plexiform neurofibromas (subcutaneous nodules or amorphous overgrowth of underlying bone or Schwann cells) can be disfiguring and may cause deficits distal to the neurofibroma. [merckmanuals.com]

  Cutis. 2014 September;94(3):149-152 We report the case of a 5-year-old girl who presented with 2 blue-red atrophic plaques on the left leg as well as subcutaneous nodules that were present since infancy. [mdedge.com]

  Subcutaneous neurofibromas present as firm, spherical subcutaneous nodules that are frequently painful. Plexiform neurofibromas ( Figure 5 ) are a distinctive type of neurofibroma. [dermatologyadvisor.com]

• Macula

  One large café-au-lait macula under the breasts, and a lot of small, brown neurofibromas Figure 3. Patient No. 3. A lot of small neurofibromas on the trunk Figure 5. [deepdyve.com]

  Café au lait spots are hyperpigmented maculae that may vary in color from light brown to dark brown Their borders may be smooth or irregular. They may appear anywhere on the skin, but they are less common on the face (1). [scielo.isciii.es]

  Maculae conditions misdiagnosed with CAL LEOPARD Syndrome Multiple lentigines, hypertelorism, sensorineural deafness, hypertrophic cardiomyopathy; autosomal dominant. [doi.org]

• Hypertelorism

  (large café-au-lait spots with irregular margins, polyostotic fibrous dysplasia) Noonan syndrome (short stature, unusual facies, pulmonic stenosis) A Noonan syndrome phenotype occurs in about 12% of patients with NF1 and features may include ocular hypertelorism [en.wikibooks.org]

  Maculae conditions misdiagnosed with CAL LEOPARD Syndrome Multiple lentigines, hypertelorism, sensorineural deafness, hypertrophic cardiomyopathy; autosomal dominant. [doi.org]

  NS is a disorder characterized by dysmorphic facial features, short stature, hypertelorism, cardiac anomalies, deafness, motor delay, and a bleeding diathesis. DISEASE: Defects in NF1 may be a cause of colorectal cancer (CRC) [MIM:114500]. [genome.ucsc.edu]

• Seizure

  BACKGROUND: Neurofibromatosis type 1 (NF1) is related to a generally increased prevalence of seizures. The mechanism underlying the increased predisposition to seizures has not been fully elucidated. [ncbi.nlm.nih.gov]

  […] inherited Some of the things I'm looking for in your family history include: Birth defects History of pregnancy losses learning difficulties or MR chronic health problems unusual skin findings or birth marks hearing loss underarm freckling scoliosis seizures [en.wikibooks.org]

  Different seizure types and syndromes have been described in NF1. These include generalized onset seizures ( tonic-clonic and atonic ), as well as focal ( partial ) onset seizures with and without secondary generalization. [epilepsy.com]

• Average Intelligence

  One way of measuring intelligence is using a scoring system known as an intelligence quotient (IQ). Average intelligence is set at an IQ of 100. [web.archive.org]

  Children with NF1 who have a learning difficulty may have normal or slightly lower-than-average intelligence, but they can usually be taught at a mainstream school. [nhs.uk]

  Functional assessment Children with NF-1 may exhibit reduced intellectual capacity, with a slight reduction seen in average Intelligence Quotient (IQ) scores. [now.aapmr.org]

• Convulsions

  Benign brain tumors may put pressure on parts of the brain and cause convulsions, eyesight problems, and balance problems. Some become cancerous. [medicalnewstoday.com]

The initial clue to the presence of NF1 is made from a clinical exam. Over the years, criteria have been established to help clinicians make an early diagnosis of NF1 [7]. The reason for the criteria is that not all clinical features appear until adolescence and often the diagnosis is delayed. For clinical diagnosis, there must be at least two of the seven criteria listed below.

• Presence 2 or more axillary or inguinal freckles.
• Presence of 6 or more café-au-lait spots or hyperpigmented skin lesions measuring 5 mm in diameter in prepubertal children and 15 mm postpubertal children.
• At least 2 or more neurofibromas or one plexiform neurofibroma.
• Optic nerve glioma.
• Two or more Lisch nodules.
• Presence of sphenoid dysplasia or classical long-bone angulation of bowing.
• Presence of NF1 in a first-degree relative.

However, in young children without clinical features, molecular testing may be of help. Today the NF1 gene can be tracked though linkage analysis and any mutation can be detected during the prenatal period via chorionic villus sampling or amniocentesis. Urinary levels of epinephrine and norepinephrine are measured if there is suspicion of a pheochromocytoma.
Plain X-rays are used to detect musculoskeletal abnormalities. CT scans and MRI are also used to image the brain to detect optic gliomas, presence of hydrocephalus, spinal cord lesions, acoustic neuromas and pheochromocytomas [8].

Neurofibromatosis has no cure. The majority of patients are monitored for life for development of complications resulting from the disease [9]. Patients need to be examined every 6-12 months for the following clinical features:

• Checking skin to look for presence of any new neurofibromas or to determine if the older lesions are progressing in size.
• Monitor blood pressure
• Assessment of growth and development
• A thorough eye exam
• Assess for any bony alterations or worsening of any existing abnormalities
• Evaluate for learning development

At each visit the patient should be asked about any neurological symptoms like urinary or fecal incontinence, pain, tingling, weakness or paresthesia. Symptoms of spinal cord neurofibroma often develop slowly and are best treated when diagnosed early. Painful or ulcerated neurofibromas can be treated with chemotherapy and/or radiation. However, clinicians should try and avoid radiation therapy, as there is a potential for increased risk of secondary malignancies [10].

Surgery

Sometimes for isolated neurofibroma that are ulcerated, causing pain or loss of function, surgery can be used to excise the lesions. Neurofibromas may compress important nerves and affect vision or may be growing rapidly and invading important structures. These lesions usually required emergency surgical therapy. Because of the need to excise large lesions, consultation with a plastic surgeon is recommended to cover the resulting wound. In some patients who develop sudden progression of scoliosis or other bony defects, an orthopedic consultation is required.

If pheochromocytoma is diagnosed, surgical excision is required. Some patients with hypertension due to renal artery stenosis may benefit from angioplasty or surgical repair of the renal artery lesion. Orthopedic intervention is indicated for rapidly progressive or severe bony defects. Laser is now used to treat the pigmented skin lesions but has not proven to be successful for café-au-lait spots.

Compared to the general population, the life expectancy of individuals with NF1 is slightly lower. Follow up studies show that on average NF1 individuals have 8-10 year decrease in their life span compared to the general population. However, it is important to know that patients with NF1 have a continuing risk of developing both malignant and benign tumors, which may occur on critical areas of the body and can severely impair function and quality of life [3] [4].

• Gliomas are common in patients with NF1 and often occur on the spinal cord, optic nerve or in subcutaneous tissues. Even though these gliomas are usually of low grade and have a good prognosis, they often invade local tissue and management requires good clinical judgement to avoid complications [5].
• Plexiform neurofibromas tend be multiple, diffuse and much larger than the usual neurofibromas. They are often locally invasive and difficult to treat. Surgical resection may be done for symptomatic lesions but post-surgical neurological deficits are common.
• Malignant nerve tumors occur in about 10% of patients with NF1 and usually occur in peripheral nerves. The prognosis for large lesions is poor because the lesions are difficult to resect and often resistant to other treatments.
• Even in the absence of neurofibromas, at least 1-3% of individuals with NF1 develop some type of sensory or polyneuropathy, which may present with pain, paresthesias and radiculopathy.
• NF1 patients may also develop GI tract stromal tumors that often occur in the proximal small bowel. These tumors often present with GI bleeding or bowel obstruction, and require surgical intervention.
• Some degree of learning deficits or behavior problems occur in nearly 2/5th of all patients with NF1. Besides intellectual impairment, many experience cognitive difficulties which limits their ability to attend school or work. There is a 30% prevalence of autism spectrum disorder in NF1 patients [6].
• Scoliosis in NF1 is mild but in some children can progress rapidly and may require surgical intervention.
• The limb dysplasias were once treated with below knee amputation but recent advances in orthopedic surgery has led to development of limb sparing procedures. Nevertheless, as the child grows the angulation or bowing of deformities continues to progress.
• Premature osteoporosis is also identified early in some children with NF1, which may explain the bone angulation and bowing. Liberal use of vitamin D supplements are recommended.
• Essential hypertension may occur at any age in NF1. In addition, renal artery stenosis and pheochromocytomas may also be other causes of secondary hypertension.
• Arnold Chiari malformation type 1 is also seen in NF1 patients and a few need neurosurgical intervention to provide relief from hydrocephalus.

The precise cause of NF1 is not known but thought to be related to the protein molecule neurofibromin. Neurofibromin has many diverse functions and controls overgrowth of certain nerve and other cells. It appears that neurofibromin prevents uncontrolled growth of several cell types. When there is a decrease in neurofibromin, the clinical features of neurofibromatosis predominate.

The incidence of NF1 is about 3 in every 10,000 births. However, these numbers are underestimates because there are some individuals who have no symptoms or clinical features of the disorder and never come to medical attention. NF1 occurs with equal frequency in all races. Newer data indicates that the risk for developing optic glioma is slightly less in African Americans compared to Hispanics and Caucasians. However, optic gliomas are more likely to occur in females compared to males. Similarly, the degree of scoliosis is more severe in young females compared to males.

Neurofibromatosis is an inherited genetic disorder caused by a deletion or a mutation of the NF1 gene. The gene product of the NF1 gene known as neurofibromin, normally suppresses growth of nerve and many other related cells. When gene mutation occurs, there is uncontrolled overgrowth of certain nerve and other cells. Recent evidence indicates that the NF1 gene is localized the long arm of chromosome 17. Over the years, several hundred mutations of the gene have been identified in patients with NF1.

There is no way to prevent NF1 because it is a genetically inherited disorder. However, early detection during pregnancy can help determine if the infant has the disorder. Families with NF1 should be referred for genetic counseling.

Neurofibromatosis type 1 (NF1) is an autosomal dominant medical disorder that primarily affects the skin, bone and nerve tissues. The disorder often presents with freckles in the axilla, café-au-lait spots (milky white lesions), bone dysplasia and growth of benign and malignant nerve tumors known as neurofibromas. Many individuals also develop essential or secondary hypertension due to renal artery stenosis or pheochromocytomas. The neurofibromas are usually multiple and often occur in critical areas of the body, leading to nerve compression. The one major difference between NF1 and NF2 is the former has a lower incidence of brain tumors, whereas patients with NF2 have fewer skin lesions but have a higher frequency of brain lesions like meningiomas and bilateral acoustic neuromas. 

Neurofibromatosis type 1 (NF1) is an inherited disorder that primarily affects the skin, bones and nerves. It is caused by a mutation of a gene on chromosome 17. The disorder is characterized by changes in skin coloring and the growth of tumors along nerves, brain, and in other body parts. When NF1 is diagnosed, the patient and the family should be referred to the national or local support group for both emotional support and continuous updates on the advances in treatment. Patients should be educated about possible symptoms that may require surgery. In addition, patients should be told about potential neurological symptoms that may indicate spinal cord compression. All patients and their families should be referred for genetic counseling should they desire to have children in future. Patients should be told to have continuous follow up with their healthcare provider and be cognizant of any new symptoms that may arise.

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