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Neurofibromatosis Type 1

NF 1

Neurofibromatosis type 1 (NF1) is an inherited systemic disorder that predominantly affects the skin, nervous system and musculoskeletal system. There is no cure for the disorder.


Presentation

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 pregnancyPlexiform 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.

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]
Jaundice
  • We report the case of a patient with NF1 who presented with obstructive jaundice due to multiple firm nodules around the ampulla of Vater.[ncbi.nlm.nih.gov]
  • An 11-month-old boy, who was recently diagnosed with NF-1, presented to the outpatient clinic with a 3-month history of prolonged jaundice, and failure to thrive.[ncbi.nlm.nih.gov]
  • A 66-year-old lady with neurofibromatosis type 1 presented with painless progressive jaundice for six months. Laboratory investigations revealed iron deficiency anemia and conjugated hyperbilirubinemia. Tumor markers were normal.[ncbi.nlm.nih.gov]
  • Caplin , Obstructive jaundice secondary to neuroendocrine tumour in a patient with von Recklinghausen??s disease , European Journal of Gastroenterology & Hepatology , 10.1097/00042737-200511000-00012 , 17 , 11 , (1229-1232) , (2005) .[doi.org]
Periodontitis
  • The extension of the diagnostic criteria including radiologically-healthy teeth and a widened periodontal gap in the periapical area only marginally increased the number of considered cases.[ncbi.nlm.nih.gov]
Ectopia Lentis
  • He was referred by his paediatrician with decreased vision secondary to ectopia lentis.[ncbi.nlm.nih.gov]
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]
  • Additionally, NF1-like cafe-au-lait spots have been described in biallelic mismatch repair deficiency, another condition featuring gastrointestinal polyps.[ncbi.nlm.nih.gov]
  • 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]
  • A disease characterized by patches of skin pigmentation (cafe-au- lait spots), Lisch nodules of the iris, tumors in the peripheral nervous system and fibromatous skin tumors.[genome.ucsc.edu]
  • The dark brown areas are called cafe-au-lait spots. The multiple cutaneous and subcutaneous tumors are nerve sheath neoplasms, called neurofibromas. They can develop anywhere along the peripheral nerve fibers.[icd9data.com]
Axillary Freckling
  • 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]
  • 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]
  • 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]
  • 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]
  • She had multiple subcutaneous fibromatoses (30 cm 20 cm) in the right hip joint and pelvic region, subcutaneous nodules (1 cm 5 cm) in the left hip joint, and limited range of motion in the right hip joint (Fig 2 ).[journal.ac]
Subcutaneous Mass
  • Physical examination showed numerous cafe-au-lait-spots, subcutaneous masses, scoliosis, and a baby's head-sized fixed mass in the left abdomen. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed a 9 x 9 cm retroperitoneal mass.[repository.kulib.kyoto-u.ac.jp]
  • Multiple subcutaneous masses are seen in the right pelvic region. No abnormal bones or internal organs are observed.[journal.ac]

Workup

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].

Pneumoperitoneum
  • At the end of the procedure, a chest tube was left in place and therapeutic pneumoperitoneum was performed to decrease the dead space as the lung did not fully expand with positive-pressure ventilation.[ncbi.nlm.nih.gov]

Treatment

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.

Prognosis

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.

Etiology

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.

Epidemiology

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.

Sex distribution
Age distribution

Pathophysiology

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.

Prevention

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.

Summary

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

Patient Information

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.

References

Article

  1. Peltonen S, Pöyhönen M, Koillinen H, Valanne L, Peltonen J. [How to recognize neurofibromatosis?]. Duodecim. 2014;130(6):619-25.
  2. Abramowicz A, Gos M. Neurofibromin in neurofibromatosis type 1 - mutations in NF1gene as a cause of disease. Dev Period Med. 2014 Jul-Sep;18(3):297-306.
  3. Karajannis MA, Ferner RE. Neurofibromatosis-related tumors: emerging biology and therapies. Curr Opin Pediatr. 2015 Feb;27(1):26-33.
  4. Vranceanu AM, Merker VL, Park ER, Plotkin SR. Quality of life among children and adolescents with neurofibromatosis 1: a systematic review of the literature. J Neurooncol. 2015 Feb 7.
  5. Rolston JD, Han SJ, Cotter JA, El-Sayed IH, Aghi MK. Gangliogliomas of the optic pathway. J Clin Neurosci. 2014 Dec;21(12):2244-9.
  6. Schwetye KE, Gutmann DH. Cognitive and behavioral problems in children with neurofibromatosis type 1: challenges and future directions. Expert Rev Neurother. 2014 Oct;14(10):1139-52.
  7. Tadini G, Milani D, Menni F, Pezzani L, Sabatini C, Esposito S. Is it time to change the neurofibromatosis 1 diagnostic criteria? Eur J Intern Med. 2014 Jul;25(6):506-10.
  8. Zimmer A. Neurofibromatoses] Radiologe. 2013 Dec;53(12):1077-83.
  9. Hirbe AC, Gutmann DH. Neurofibromatosis type 1: a multidisciplinary approach to care. Lancet Neurol. 2014 Aug;13(8):834-43.
  10. Kahn J, Gillespie A, Tsokos M, Ondos J, Dombi E, Camphausen K, Widemann BC, Kaushal A. Radiation therapy in management of sporadic and neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors. Front Oncol. 2014 Nov 17;4:324

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Last updated: 2019-07-11 20:38