 | AUTHOR INFORMATION
| Section 1 of 12    |
Authored by Beth A Pletcher, MD, Associate Professor, Co-Director of The Neurofibromatosis Center of New Jersey, Department of Pediatrics, University of Medicine and Dentistry of New Jersey
Beth A Pletcher, MD, is a member of the following medical societies:
American Academy of Pediatrics,
American College of Medical Genetics,
American Medical Association, and
American Society of Human Genetics
Edited by Ian Krantz, MD, Assistant Professor, Department of Pediatrics, University of Pennsylvania and Children's Hospital of Philadelphia; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc;
Leonard G Feld, MD, PhD, MMM, Chairman of Pediatrics, Carolinas Medical Center; Chief Medical Officer, Levine Children's Hospital, Carolinas Healthcare System;
Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System;
and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center
eMedicine Journal, May 2 2006, VOLUME 7,
Number 5
| INTRODUCTION
| Section 2 of 12  |
Background: Neurofibromatosis (NF) is a multisystem genetic disorder commonly associated with cutaneous, neurologic, and orthopedic manifestations. Neurofibromatosis type 1 (NF1) is the most common of the conditions referred to as hamartomas.
NF1 differs from central neurofibromatosis, also known as neurofibromatosis type 2 (NF2); patients with the latter disorder demonstrate a relative paucity of cutaneous findings, but they have high incidence of meningioma as well as acoustic neuromas, which often are bilateral. Patients with NF1 have a better prognosis, with fewer CNS tumors, than patients with NF2, although morbidity and mortality rates in NF1 are not negligible. Among the more severe complications associated with NF1 are visual loss secondary to optic nerve gliomas, spinal cord tumors, scoliosis, and long-bone abnormalities that sometimes require amputation.
Although NF1 is clinically apparent in almost all patients with the disorder, the manifestations of NF1 are extremely variable from person to person, even within the same family. This variation precludes accurate predictions for any affected individual about the severity of or potential for serious complications.
Pathophysiology: Manifestations of NF1 are caused by a mutation in, or a deletion of, the NF1 gene. The gene product, neurofibromin, serves as a tumor suppressor. Decreased production of this protein causes various clinical features.
Frequency:
- Internationally: Estimated incidence of NF1 is 1 case in 3000 persons, although actual frequency may be slightly higher. This disparity may be caused by incomplete identification of mildly affected individuals. Approximately half of affected individuals represent first cases in their families as the result of a new genetic event or mutation.
Mortality/Morbidity:
- Lifetime risks for benign and malignant tumors increase for individuals affected with NF1. Cutaneous or subcutaneous neurofibromas, optic nerve gliomas, dumbbell-shaped spinal cord tumors, and brain tumors are among the well-known nerve-related tumors. Leukemia, especially chronic myeloid leukemia, and myelodysplasia in childhood rarely occur but are also associated with NF1. Malignant peripheral nerve sheath tumors (MPNSTs) or neurosarcomas are not uncommon in adolescents and adults with NF1. Some studies suggest a lifetime risk for development of a MPNST to be about 10%.
- Learning disabilities, with or without attention deficit hyperactivity disorder (ADHD), occur in approximately 40% of individuals affected with NF1. Children with ADHD are at highest risk for difficulties in social functioning. Visual-spatial motor deficits are seen in many children with NF1. A much smaller percentage of affected individuals experience more significant cognitive difficulties such as mild or moderate mental retardation.
- Scoliosis often is mild, although a subset of children younger than 10 years develop a more rapidly progressive form of scoliosis that requires aggressive intervention.
- Seizures occur in between 4% and 7% of individuals with NF1 and, in some cases, they may be associated with intracranial lesions.
- Bony abnormalities may not appear clinically. Radiographic evidence of intramedullary fibrosis, vertebral dural ectasias, or cortical thinning often is found incidentally. Sphenoid bone dysplasia and long-bone bowing (pseudarthrosis) are also common. In the past, congenital tibial pseudarthrosis led to below-the-knee amputation; however, recent advances in orthopedic management with limb-sparing procedures have decreased the need for this more drastic surgical approach.
- Hypertension in NF1 can occur at any age. Although many adult patients have the typical essential form of hypertension, any person with NF1 and high BP must be carefully evaluated for 2 alternative causes of hypertension: pheochromocytomas and renal artery stenosis secondary to fibromuscular dysplasia. Children with hypertension who have NF1 require careful evaluation for both of these problems.
- Pheochromocytomas are not rare and can cause severe, fluctuating hypertension.
- Renal artery stenosis secondary to fibromuscular dysplasia also can cause hypertension and may not respond well to standard pharmacological management.
- Other vascular lesions such as ectasias, stenoses, aneurysms, and moyamoya disease occur more often in patients with NF1 and may present with CNS symptoms.
- Short stature is common. Affected individuals often are shorter than unaffected siblings.
- Macrocephaly is common and should not cause undue alarm when seen in infants or young children unless serial head-circumference measurements increase faster than normal growth rates.
- Chiari I malformations may also be seen with increased frequency in individuals with NF1.
- Puberty usually occurs at a normal age, but precocious puberty with growth acceleration may occur in a few individuals. When precocious puberty is present, evaluate the patient for a chiasmal lesion disrupting the hypothalamic-pituitary axis.
- A subset of patients with NF1 are also noted to have clinical features of Noonan syndrome (NS), which include a combination of some typical physical features (wooly hair consistency, ptosis, downslanting palpebrae, hypertelorism, low-set posteriorly rotated ears, a short broad neck, pectus deformity, short stature, and/or cryptorchidism) as well as typical cardiac defects (pulmonic stenosis, atrial septal defect and/or hypertrophic cardiomyopathy). This is sometimes referred to in the literature as the Watson phenotype and is most often associated with NF1 gene mutations.
- Children with NF1 and severe, recurrent abdominal pain with a normal gastrointestinal evaluation may, in fact, have abdominal migraines. If abdominal migraines are suspected based on symptoms and no other identifiable etiology, such patients may respond to traditional migraine therapy.
Race: All races and ethnic backgrounds are affected equally, although recent evidence indicates African Americans have less risk for optic nerve glioma than whites, including Hispanics.
Sex: While males and females are affected equally by this autosomal dominant condition, scoliosis may be especially severe in young girls.
Age:
- The genetic change that causes NF1 is present at conception. Clinical manifestations may appear over many years.
- Diagnosis of children of parents affected with NF1 often is made earlier because the clinical criteria for diagnosis are more easily met, and the clinician may be more attuned to NF1 as a possible diagnosis.
- At-risk individuals who reach the age of 10 years without meeting the diagnostic criteria for NF1 are probably unaffected.
History: Clinical diagnosis requires the presence of at least 2 of 7 criteria to confirm the presence of NF1. Several of these manifestations do not appear until later childhood or adolescence, often delaying confirmation of the diagnosis despite suspicion of NF1.
- Clinical criteria for diagnosis
- At least 6 café au lait spots or hyperpigmented macules at least 5-mm wide in children younger than 10 years (15 mm in adults)
- Axillary or inguinal freckles
- Two or more typical neurofibromas or 1 plexiform neurofibroma
- Optic nerve glioma
- Two or more iris hamartomas (also known as Lisch nodules), often identified only through slit-lamp examination by an ophthalmologist
- Sphenoid dysplasia or typical long-bone abnormalities (eg, pseudarthrosis)
- First-degree relative with NF1
Physical:
- Cutaneous manifestations
- Café au lait spots are the earliest clinical findings in children with NF1. Spots may be present at birth or may appear over time. They frequently increase in size and number throughout childhood.
- Axillary or inguinal freckles are rare at birth but appear throughout childhood and adolescence.
- Urticaria pigmentosa resulting from a collection of mast cells within the dermis may be seen in a small subset of infants and young children with NF1. These lesions generally resolve spontaneously (personal experience).
- Neurofibromas
- Subcutaneous or cutaneous neurofibromas rarely occur in young children but appear over time in older children, adolescents, and adults. Deep lesions may be detected only by palpation, whereas cutaneous lesions may appear initially as small papules on the trunk, extremities, scalp, or face. Puberty and pregnancy may be associated with increased numbers of neurofibromas and more rapid growth of preexisting lesions.
- Plexiform neurofibromas are more diffuse growths that can be locally invasive and quite deep. They may be associated with bony erosion and pain. Plexiform neurofibromas may also be accompanied by overlying hyperpigmentation or hypertrichosis.
- Neurofibromas rarely grow rapidly; such growth can suggest malignant transformation.
- Ophthalmologic examination
- Optic nerve tumors primarily occur in children younger than 5 years and may not be evident clinically. The most common presenting symptom is asymmetric noncorrectable visual loss. Optic nerve gliomas (ONGs) occasionally become symptomatic in older children or even adults; ONGs can also undergo spontaneous regression.
- Subtle peripheral field defects, color discrimination difficulties, optic nerve pallor, or proptosis may occur in association with an optic glioma, in the absence of visual acuity deficits.
- Lisch nodules may not be readily visible except by slit lamp, although they occasionally can be seen with an ophthalmoscope, especially in individuals with light-colored irises.
- Patchy choroidal abnormalities and corkscrew retinal vascular changes are described on occasion in patients with NF1.
- Orthopedic examination
- Sphenoid dysplasia usually is asymptomatic but occasionally can be associated with herniation through the bony defect. Patients with plexiform neurofibroma of the eyelid or temporal region often have ipsilateral sphenoid dysplasia.
- Congenital pseudarthrosis may be evident at birth. Bowing of the tibia is the most typical presentation. Thinning and angulation of long bones with prominence of the anterior tibia and progressive deformity can occur throughout early childhood. Bowing of the forearm is less common.
- Thoracic cage asymmetry with flaring or prominence of the inferior ribs is seen in some children with NF1 but rarely requires surgical intervention.
- Scoliosis, with or without kyphosis, may become evident in childhood or adolescence. In a child younger than 10 years, scoliosis is associated with a poorer prognosis and is likely to progress rapidly. Scoliosis detected in adolescence should be followed clinically but is less likely to require orthopedic intervention.
- Other assessments
- Check BP at every clinical visit because of concerns about alternative causes of hypertension in patients with NF1.
- Measure head circumference through the first 3 years of life, as with any pediatric patient. Relative macrocephaly should not cause alarm unless serial measurements suggest rapid growth (ie, growth rates increasing across 2 or more percentile lines).
Causes:
- NF1 is an autosomal dominant condition caused by decreased production of the protein neurofibromin, which has a putative tumor suppressor function. Only 1 deleted or mutated NF1 gene is required to affect individuals.
- The NF1 gene is located within the long arm of chromosome 17. More than 250 mutations that lead to protein truncation have been identified in affected individuals. A more severe phenotype occurs in a subset of patients who have a complete gene deletion.
- The precise role of neurofibromin is not yet fully elucidated, but neurofibromin deficiency causes multiple clinical effects, suggesting this gene product has diverse functions in a variety of tissues.
- The NF1 phenotype is highly penetrant (ie, almost all individuals with an NF1 gene mutation have some clinical manifestation of NF), but it has widely variable expressivity (ie, varying degrees of severity of the clinical manifestations even within families).
| DIFFERENTIALS
| Section 4 of 12 |
Café Au Lait Spots
McCune-Albright Syndrome
Other Problems to be Considered:
Neurofibromatosis type 2
Lab Studies:
- Genetic testing
- Improved understanding of the genetic cause of NF1 has led to development of a protein truncation assay (PTA) that identifies a proportion of individuals with NF1.
- Detection rates using the PTA vary from 65-70% in people who clearly have NF1 by clinical criteria. This testing methodology has limited usefulness as a diagnostic test because a negative result does not exclude NF1.
- Protein truncation test results, when positive, can help diagnose patients who have a single clinical finding (eg, multiple café au lait spots) but who have no family history of NF1.
- Sequencing of the neurofibromin gene has a much higher detection rate and may ultimately be the preferred molecular diagnostic study for individuals suspected to have NF1.
- Prenatal diagnosis
- In a family with multiple affected members and no recognizable mutation, linkage analysis can be used to track the NF1 gene through the generations to determine which chromosome 17 region the fetus received.
- For a parent with NF1 who is the only affected family member, PTA can determine whether a specific gene mutation can be identified. This may be augmented or replaced by gene sequencing information with a mutation detection rate approaching 95% in clinically affected individuals. Once a mutation is identified in an affected parent, prenatal diagnosis using amniocytes or chorionic villi may be feasible.
- For at-risk couples including a parent with an identified gene mutation, preimplantation genetic diagnosis may also be possible if the couple is willing and able to undergo in vitro fertilization followed by transfer of unaffected embryos.
Imaging Studies:
- Radiography
- Plain-film radiography may detect a variety of subtle and not-so-subtle bony abnormalities associated with NF1. Dural ectasias are often seen incidentally on vertebral radiographs in individuals with NF1 or Marfan syndrome and may be harbingers of progressive scoliosis yet to come.
- Obtain radiographs when the following or similar clinical findings exist:
- Possible modeling defects of the long bones or ribs
- Concerns about bony erosion secondary to an adjacent plexiform neurofibroma
- Signs of scoliosis
- Bone pain
- MRI or CT scans
- In the past, head MRI or CT scans were ordered routinely for patients with NF1. Recently, many clinicians have deviated from standard screening and have opted to use head imaging only for specific indications.
- Some clinicians perform a baseline CT or MRI head scan in children at the time of diagnosis, then do not recommend another unless neurologic problems arise. Other clinicians believe baseline studies have limited value because even detection of an asymptomatic optic nerve glioma does not necessarily prompt medical intervention. Some groups in Europe still advocate for annual brain MRIs in children with NF1.
- MRI has become the preferred diagnostic head imaging study in NF1. Experience over the past decade has shown MRI often detects unidentified bright objects (UBOs) in the brain parenchyma of patients with NF1. These bright spots, seen on T2-weighted images, generally do not enhance, cause no mass effect, and often resolve as the individual ages. UBOs are believed to represent benign hamartomas in NF1 and are seen more often in children with NF1-related learning disabilities and fine motor difficulties.
- Consider CT or MRI scans to evaluate ventricular size when increasing head circumferences are noted in an infant. Hydrocephalus rarely occurs in children with NF1.
- MRI is a valuable tool to evaluate the optic nerves or optic chiasm. MRI is indicated for patients with optic nerve pallor, visual changes, proptosis, or precocious puberty. Clinicians should communicate their concerns about optic nerve pathology when ordering this test so that special orbital views are obtained.
- Consider MRI scans of the head for patients with headaches that increase in frequency or intensity over time. Although brain tumors are less common in patients with NF1 than in those with NF2, they do occur.
- MRI scans also have proven useful to evaluate internal lesions (eg, mediastinal masses, spinal cord tumors, deep plexiform neurofibromas, abdominopelvic lesions, neurofibromas of the brachial or sacral plexus).
- MRI using short T1-inversion recovery may be helpful in providing accurate volumetric measurements of plexiform neurofibromas at initial diagnosis and serially over time.
- PET
- F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) may be used to stage and follow MPNSTs.
Other Tests:
- EEGs are indicated for patients who exhibit symptoms that suggest a seizure disorder. Seizures are reported more often in children and adults with NF1.
- Myelography occasionally is needed to clarify the extent of a spinal cord tumor. MRI scans alone generally suffice for making medical or surgical decisions.
- Visual evoked potentials (VEPS) may prove helpful in detecting ONGs or assessing tumor progression in patients with previously diagnosed optic pathway tumors.
Procedures:
- Slit-lamp examination
- Slit-lamp examination by an experienced ophthalmologist provides essential diagnostic information in older children and adults who present with only 1 clinical criterion (eg, multiple café au lait spots).
- Lisch nodule occurrence appears to depend on age; more than 95% of NF1-affected individuals older than 10 years exhibit this finding.
- Slit-lamp examination is also valuable in determining whether the parents of an affected child carry the NF1 mutation, even when the parent has no other signs of the condition.
- Laser treatment
- Laser removal of neurofibromas (whether medically or cosmetically indicated) is a common procedure for individuals with NF1.
- Recent advances in laser technology allow nonsurgical removal of small cutaneous neurofibromas; however, careful surgical resection of small or large neurofibromas may leave a smaller, less prominent scar.
- Although laser treatment has been used to remove a variety of cutaneous hyperpigmented lesions (eg, port wine stains, tattoos), it has not proven effective in permanent removal of café au lait spots.
Histologic Findings: Neurofibromas typically are well-differentiated tumors containing elongated spindle-shaped cells and pleomorphic fibroblastlike cells. Inflammatory cells rarely occur in these otherwise benign-appearing lesions. Optic gliomas are also quite indolent and generally are low-grade lesions; optic nerve lesions associated with NF1 are less aggressive than optic nerve tumors in the general population and respond better to current therapies.
Neurofibromas, typically of the large or deep plexiform variety, sometimes undergo malignant transformation to neurofibrosarcomas. Unlike benign neurofibromas, neurofibrosarcomas characteristically are hypercellular with giant cells, an increased number of mitoses, and vascular proliferation. Because rests of malignant cells may embed between larger masses of benign cells in a plexiform neurofibroma, careful examination of a plexiform tumor is important; take samples from multiple regions to confirm the lesion is benign.
| TREATMENT
| Section 6 of 12 |
Medical Care:
- Medical care consists of routine examinations, focusing on some of the possible complications of NF1.
- Biannual examinations for children younger than 5 years, and annual examinations thereafter, provide the best early detection of problems, which can decrease morbidity and improve the patient's quality of life.
- Annual eye examinations, especially in children younger than 5 years, are essential for early detection of optic nerve lesions. However, since symptomatic ONGs may also appear in older children and young adults, annual examinations should be part of ongoing care for all individuals with NF1.
- Perform a cutaneous examination to search for new neurofibromas and progression of preexisting lesions.
- Plexiform neurofibromas may be locally invasive; direct clinical evaluation at determining the extent of involvement and detecting evidence of bony erosion or nerve entrapment.
- The examination should include a careful search for skeletal involvement, including scoliosis, hemihypertrophy, and long-bone modeling defects.
- Check BP at every visit and take prompt action if hypertension is detected.
- Ask parents about the child's neurodevelopmental progress, so that any learning disabilities can be addressed in a timely manner. For children and adolescents with ADD or ADHD, psychostimulant medication may improve academic performance and social skills.
- Individuals and families may benefit from involvement in a local or national support group or organization committed to the service of NF patients (see Patient Education).
Surgical Care:
- Neurofibromas
- Any competent surgeon can accomplish surgical resection, although consultation with a plastic surgeon is advisable for areas of greater cosmetic concern (eg, the face).
- Neurofibromas that press on vital structures, obstruct vision, or grow rapidly deserve immediate attention.
- Plexiform neurofibromas may be extremely difficult to approach surgically. Plexiform neurofibromas often recur after resection because of residual cell rests deep in soft tissues.
- Surgeons must recognize that removal of some of these lesions can cause substantial blood loss, and they should plan accordingly.
- For many patients, neurofibromas on the scalp, along the hairline, or around the waist (where clothes rub) can cause significant irritation and discomfort. Removal of these lesions should be considered a necessary medical procedure, not a cosmetic procedure.
- Peripheral nerve sheath tumors may occur in the brachial or pelvic plexuses; most are benign, although they may cause significant neurologic symptoms.
- Spinal cord tumors
- Resection of spinal cord tumors is quite difficult but often is necessary to prevent progressive paraplegia or quadriplegia. Prompt action is important when neurologic symptoms appear to maximize operative success.
- For some patients, surgical intervention may not guarantee a complete resection of the tumor but may serve a palliative function.
- Orthopedic intervention
- Orthopedic treatment is indicated for rapidly progressive scoliosis and for some severe bony defects.
- Referral as soon as scoliosis is detected is advisable, so that the orthopedic specialist may use nonsurgical approaches to avoid future spinal fusion procedures.
- Limb-sparing procedures, along with new bracing and casting technologies, have decreased the need for amputation. The best treatment for patients with long-bone defects involves ongoing orthopedic care.
- Vascular lesions
- Percutaneous transluminal renal artery angioplasty (PTRAA) may be effective in treating some cases of stenosis secondary to fibromuscular dysplasia.
- Patients who fail (PTRAA) or are not candidates for this procedure based on their specific vascular lesion may require surgical repair and anastomosis of the renal artery.
Consultations:
- An ophthalmologist is a valuable member of the NF consultation team, evaluating patients on an annual basis for visual acuity changes, for field defects, and for Lisch nodules.
- A neurologist serves as a core consultant, performing a complete focused neurological examination to provide valuable information about neurologic changes.
- A neurosurgeon provides expert consultation when a spinal cord tumor or brain tumor is identified. The neurosurgeon works closely with the neurologist to determine the optimal timing for surgery and the ideal surgical approach.
- A geneticist provides information about diagnosis, diagnostic testing, inheritance, and recurrence risk in future children. A geneticist may also address family planning options and prenatal diagnosis.
- An orthopedic surgeon is a key consultant for the many bone abnormalities that occur in NF (eg, scoliosis, pseudarthrosis, hemihypertrophy, bony erosion by plexiform neurofibromas).
- A developmental pediatrician may be an invaluable resource for evaluating a child with learning disabilities. Speech delay and hypotonia are among the most common signs of developmental delay in NF. Early intervention with appropriate services may help maximize a child's potential. A developmental specialist can determine which services are needed and may recommend early intervention programs.
- The patient may benefit from consultation with several other specialists to address specific NF concerns, including the following:
- A nephrologist to exclude renal vascular lesions
- A general or plastic surgeon to remove neurofibromas
- An oncologist for management and treatment of ONGs, other intracranial gliomas, neurosarcomas, or MPNSTs
- An otolaryngologist for suspected hearing loss or acoustic nerve lesions
- A dermatologist for cutaneous lesions
- An oculoplastic surgeon for orbital plexiform neurofibromas
Activity:
- NF1 requires no general activity restrictions with the exception of individuals with specific orthopedic concerns whose consulting physicians may recommend activity restrictions.
- Patients with spinal fusion procedures and individuals with significant long-bone weakness or pseudarthrosis may need to limit specific athletic activities.
| MEDICATION
| Section 7 of 12 |
NF1 has no known medical therapy. Researchers have initiated several drug trials in search of medications that slow or halt the growth of neurofibromas. A recent trial used a retinoic acid derivative in an attempt to slow the growth of plexiform neurofibromas. To date, none of these medications has demonstrated significant benefit.
For a small subset of patients with pruritus caused by cutaneous neurofibromas, diphenhydramine administration may provide limited temporary relief. Encourage patients with this condition to avoid hot showers and baths because heat may exacerbate itching.
Chemotherapy trials with carboplatin have proven efficacy in controlling the growth of visually significant optic gliomas.
| FOLLOW-UP
| Section 8 of 12 |
Further Inpatient Care:
- Hospitalization may be required for major surgical procedures and for clinical evaluation of uncontrolled hypertension.
Further Outpatient Care:
- Many minor surgical procedures (eg, cutaneous neurofibroma removal) may be performed in an outpatient setting.
- Although treatment of the patient with NF can be accomplished in the primary care setting, a number of additional medical concerns should be addressed on a routine basis. Some practitioners believe it best for patients to be seen on an annual basis in a comprehensive NF center; other practitioners believe they can provide the annual care themselves and refer to consultants for specific needs.
- Patients younger than 5 years should receive biannual examinations, then annual examinations thereafter. Clinicians should devote special attention to complications of NF. Each biannual examination should include the following:
- BP estimation
- Head circumference measurement, at least during the first 3 years of life
- Examination of the skin for typical lesions, including early or growing neurofibromas
- Brief, age-appropriate visual acuity check
- Examination of the eyes for evidence of proptosis or strabismus
- Examination of the spine and extremities for abnormalities
- Neurodevelopmental assessment and Tanner staging to exclude precocious puberty
- Annual ophthalmologic examinations should look for optic nerve pallor, visual acuity changes, visual field defects, and Lisch nodules. Promptly refer young children to a pediatric ophthalmologist for concerns about visual acuity, evidence of proptosis, or palpebral plexiform neurofibromas obstructing vision.
- Referral to an orthopedic surgeon may be necessary for deformities of the extremities, including significant hemihypertrophy, or for scoliosis. Orthopedic referral for scoliosis is particularly urgent for children younger than 10 years.
- Referral to a pediatric neurologist may be necessary for concerns about neurologic symptomatology such as significant headaches, weakness or asymmetry, severe hypotonia, rapidly increasing head size, and possible seizures.
- Referral to a developmental specialist may be indicated for a child with motor, speech, or cognitive delays.
Complications:
- Locally invasive plexiform neurofibromas
- Dumbbell-shaped spinal cord neurofibromas or neurofibromas of the brachial or sacral plexus
- Optic nerve gliomas, especially in children younger than 5 years
- Scoliosis, which may be particularly aggressive in children younger than 10 years
- Bony modeling defects that may lead to pseudarthrosis, thoracic cage asymmetry, or pathologic fractures
- Hypertension due to pheochromocytoma or renal vascular stenosis secondary to fibromuscular dysplasia
- Increased risk for brain tumors, leukemia, and other malignancies of neural crest origin, including neurofibrosarcomas
- Occasionally, peripheral nerve sheath tumors undergo malignant transformation and are clinically challenging.
- Learning disabilities, attention deficit disorder, ADHD, or, rarely, mental retardation
Prognosis:
- Although most individuals with NF1 lead relatively long and healthy lives, NF1 may reduce overall life expectancy as much as 15 years. The major causes for this increased morbidity and subsequent mortality are hypertension and cancer.
- Prompt attention to complications of NF1 and early detection of medical problems may reduce overall morbidity and mortality significantly.
Patient Education:
- Ensure children and their parents are aware of symptoms that require immediate medical attention; these include onset of strabismus, headaches that increase in intensity or frequency, signs of precocious puberty, and focal neurologic deficits.
- The following organizations are among the resources for patients with NF and their families:
- In addition to emotional support, these organizations provide the following services:
- Periodic updates on advances in NF research
- Contact information for regional support groups and local medical resources
- Newsletters for patients and families
| MISCELLANEOUS
| Section 9 of 12 |
Medical/Legal Pitfalls:
- Failure to identify scoliosis sufficiently early to institute nonsurgical approaches
- Failure to identify optic gliomas sufficiently early to intervene before they cause permanent visual loss
- Failure to identify and appropriately treat alternative causes of hypertension
- Failure to provide appropriate genetic counseling
| TEST QUESTIONS
| Section 10 of 12 |
CME Question 1: Which of the following is not a clinical criterion used to confirm the diagnosis of neurofibromatosis type 1 (NF1)?
A: Café au lait spots
B: Plexiform neurofibroma
C: Scoliosis
D: Optic nerve glioma
E: Family history of NF1
The correct answer is C: Because scoliosis is common in the general population, it has limited use as a diagnostic sign for NF1.
CME Question 2: The young woman pictured here has a plexiform neurofibroma of the eyelid. Which of the following additional lesions is most likely to accompany this lesion?
A: Lisch nodules
B: Tibial pseudarthrosis
C: Optic nerve glioma
D: Sphenoid dysplasia
E: CNS astrocytoma
The correct answer is D: Although Lisch nodules are quite common in older children and adults with neurofibromatosis, an association appears to exist between palpebral plexiform neurofibromas and sphenoid dysplasia. The other findings are relatively rare complications of neurofibromatosis and would be unrelated to the orbital lesion.
Pearl Question 1 (T/F): Pheochromocytoma is a likely cause for hypertension in an adolescent with neurofibromatosis type 1 (NF1).
The correct answer is True: Both pheochromocytoma and renal vascular stenosis are found more often in patients with NF1 and must be considered in any patient with this condition. Essential hypertension also occurs with NF1 but in this case is a diagnosis of exclusion.
Pearl Question 2 (T/F): Scoliosis that begins in adolescence is associated with the worst prognosis for patients with neurofibromatosis type 1 (NF1).
The correct answer is False: Scoliosis detected in a child younger than 10 years is by far the most significant concern. Early diagnosis often is associated with rapidly progressive and difficult-to-treat scoliosis or kyphoscoliosis. Dural ectasias often are seen incidentally on vertebral radiographs in individuals with NF1 or Marfan syndrome and may be harbingers of progressive scoliosis yet to come.
Pearl Question 3 (T/F): Leukemia is a hematologic malignancy associated with neurofibromatosis type 1 (NF1).
The correct answer is True: Both leukemia and myelodysplasia occur more often in patients with NF1. Despite the well-known association with tumors of neural crest origin (eg, neurosarcoma, optic glioma, glioma), these hematologic malignancies also may occur but less often.
Pearl Question 4 (T/F): Plexiform neurofibromas pose a more serious health risk when compared to subcutaneous or cutaneous neurofibromas.
The correct answer is True: Plexiform neurofibromas, although generally benign lesions, can grow deep into soft tissue and even can erode through bone. These locally invasive lesions can cause nerve entrapment, pain, and loss of function of a limb, in addition to significant cosmetic disfigurement.
| PICTURES
| Section 11 of 12 |
| BIBLIOGRAPHY
| Section 12 of 12 |
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