eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Neurofibromatosis

Author: 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
Contributor Information and Disclosures

Updated: Sep 15, 2008

Introduction

Background

Neurofibromatosis (NF) is a multisystem genetic disorder commonly associated with cutaneous, neurologic, and orthopedic manifestations. Neurofibromatosis type 1 is the most common of the conditions referred to as hamartoses.

Neurofibromatosis type 1 differs from central neurofibromatosis, also known as neurofibromatosis type 2 (NF2); patients with the latter disorder demonstrate a relative paucity of cutaneous findings but have high incidence of meningioma as well as acoustic neuromas, which are often bilateral. Patients with neurofibromatosis type 1 have a better prognosis, with fewer CNS tumors, than patients with neurofibromatosis type 2, although morbidity and mortality rates in neurofibromatosis type 1 are not negligible. Among the more severe complications associated with neurofibromatosis type 1 are visual loss secondary to optic nerve gliomas, spinal cord tumors, scoliosis, and long-bone abnormalities that sometimes require amputation.

Although neurofibromatosis type 1 is clinically apparent in almost all patients with the disorder, the manifestations of neurofibromatosis type 1 widely vary 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 neurofibromatosis type 1 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

International

Estimated incidence of neurofibromatosis type 1 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 neurofibromatosis type 1. Cutaneous or subcutaneous neurofibromas, optic nerve gliomas, dumbbell-shaped spinal cord tumors, and brain tumors are among the well-known nerve-related tumors.
    • Adolescence for boys and girls may precipitate the development of subcutaneous and cutaneous neurofibromas. Increase in the size of existing neurofibromas and appearance of new lesions is a frequent observation in women with neurofibromatosis type 1 during pregnancy.1
    • Plexiform neurofibromas, generally larger, more diffuse and locally invasive are seen in more than 25% of patients with neurofibromatosis type 1,2 and can present a surgical or medical conundrum. The wisdom of watchful waiting versus intervention is often debated, with the recognition that complete resection of a plexiform neurofibroma without residual functional deficits is rarely possible. On the other hand, debulking or partial resection of plexiform neurofibromas may be undertaken for cosmetic purposes or if progressive functional consequences are anticipated.
    • Malignant peripheral nerve sheath tumors (MPNSTs) or neurosarcomas are not uncommon in adolescents and adults with neurofibromatosis type 1. Some studies suggest a lifetime risk for development of a MPNST to be about 10%.
    • Gliomas in pediatric patients with neurofibromatosis type 1 tend to be lower grade and have a more favorable prognosis than in patients without neurofibromatosis type 1; pilocytic astrocytomas and low-grade astrocytomas (subtype intermediate) are quite common. However, diffusely infiltrating astrocytomas are also seen in a subset of patients and need to be managed accordingly.3  
    • Leukemia, especially chronic myeloid leukemia, and myelodysplasia in childhood are rare but are also associated with neurofibromatosis type 1.
  • Learning disabilities, with or without attention deficit hyperactivity disorder (ADHD), occur in approximately 40% of individuals affected with neurofibromatosis type 1. Children with ADHD are at highest risk for difficulties in social functioning. Visual-spatial motor deficits are seen in many children with neurofibromatosis type 1. A much smaller percentage of affected individuals experience more significant cognitive difficulties such as mild or moderate mental retardation.
  • Scoliosis is often 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 4-7% of individuals with neurofibromatosis type 1 and, in some cases, may be associated with intracranial lesions.
  • Bony abnormalities may not clinically appear. Radiographic evidence of intramedullary fibrosis, vertebral dural ectasias, or cortical thinning often is incidentally found. 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.
  • Osteoporosis with statistically significant decreases in bone mineral density can be identified in individuals with neurofibromatosis type 1 and may even be seen in childhood.4 Whereas numerous metabolic pathways that affect bone metabolism have been implicated in the pathogenesis of bony abnormalities in people with neurofibromatosis, studies in children and teens with neurofibromatosis type 1 have provided evidence for increased rates of bone resorption as a cause for osteopenia.5
  • Hypertension in neurofibromatosis type 1 can occur at any age. Although many adult patients have the typical essential form of hypertension, any person with neurofibromatosis type 1 and high blood pressure must be carefully evaluated for 2 alternative causes of hypertension (ie, 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 can also 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 neurofibromatosis type 1 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 neurofibromatosis type 1.
  • 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 neurofibromatosis type 1 are also noted to have clinical features of Noonan syndrome, 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, cryptorchidism) as well as typical cardiac defects (pulmonic stenosis, atrial septal defect, hypertrophic cardiomyopathy). This is sometimes referred to in the literature as the Watson phenotype and is most often associated with neurofibromatosis type 1 gene mutations.
  • Children with neurofibromatosis type 1 and severe, recurrent abdominal pain with a normal GI evaluation findings 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 equally affected, although recent evidence indicates African Americans have less risk for optic nerve glioma than whites, including Hispanics.

Sex

While males and females are equally affected by this autosomal dominant condition, scoliosis may be especially severe in young girls.

Age

The genetic change that causes neurofibromatosis type 1 is present at conception. Clinical manifestations may appear over many years. Diagnosis of children of parents affected with neurofibromatosis type 1 is often made earlier because the clinical criteria for diagnosis are more easily met, and the clinician may be more attuned to neurofibromatosis type 1 as a possible diagnosis. At-risk individuals who reach the age of 10 years without meeting the diagnostic criteria for neurofibromatosis type 1 are probably unaffected.

Clinical

History

Clinical diagnosis requires the presence of at least 2 of 7 criteria to confirm the presence of neurofibromatosis type 1 (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 include the following:

  • 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 neurofibromatosis type 1

Physical

  • Cutaneous manifestations
    • Café au lait spots are the earliest clinical findings in children with neurofibromatosis type 1. 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 neurofibromatosis type 1. These lesions generally spontaneously resolve.
  • 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 initially appear 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 clinically evident. The most common presenting symptom is asymmetric noncorrectable visual loss. Optic nerve gliomas occasionally become symptomatic in older children or even adults; optic nerve gliomas 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 can occasionally 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 neurofibromatosis type 1.
  • Orthopedic examination
    • Sphenoid dysplasia is usually asymptomatic but can occasionally 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 neurofibromatosis type 1 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 rapidly progress. Scoliosis detected in adolescence should be clinically followed but is less likely to require orthopedic intervention.
  • Other assessments
    • Check blood pressure at every clinical visit because of concerns about alternative causes of hypertension in patients with neurofibromatosis type 1.
    • 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

  • Neurofibromatosis type 1 is an autosomal dominant condition caused by decreased production of the protein neurofibromin, which has a putative tumor suppressor function. Only one 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 neurofibromatosis type 1 phenotype is highly penetrant (ie, almost all individuals with an NF1 gene mutation have some clinical manifestation of neurofibromatosis), but it has widely variable expressivity (ie, varying degrees of severity of the clinical manifestations even within families).

More on Neurofibromatosis

Overview: Neurofibromatosis
Differential Diagnoses & Workup: Neurofibromatosis
Treatment & Medication: Neurofibromatosis
Follow-up: Neurofibromatosis
Multimedia: Neurofibromatosis
References
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Further Reading

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Keywords

neurofibromatosis, NF, classic neurofibromatosis, neurofibromatosis type 1, NF1, neurofibromatosis type 2, NF2, von Recklinghausen disease, hamartomas, optic nerve gliomas, spinal cord tumors, scoliosis, long-bone abnormalities, malignant peripheral nerve sheath tumors, MPNSTs, neurosarcoma, leukemia, chronic myeloid leukemia, myelodysplasia, attention deficit hyperactivity disorder, ADHD, osteoporosis, osteopenia, pheochromocytomas, renal artery stenosis secondary to fibromuscular dysplasia, Moyamoya disease, short stature, macrocephaly, precocious puberty, Noonan syndrome, wooly hair consistency, ptosis, downslanting palpebrae, hypertelorism, low-set posteriorly rotated ears, a short broad neck, pectus deformity, short stature, cryptorchidism, pulmonic stenosis, atrial septal defect, hypertrophic cardiomyopathy

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Contributor Information and Disclosures

Author

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
Disclosure: Nothing to disclose.

Medical Editor

Ian Krantz, MD, Department of Pediatrics, Assistant Professor, University of Pennsylvania and Children's Hospital of Philadelphia
Ian Krantz, MD is a member of the following medical societies: American Society of Human Genetics
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

Leonard G Feld, MD, PhD, MMM, Chairman of Pediatrics, Carolinas Medical Center; Chief Medical Officer, Levine Children's Hospital, Carolinas Healthcare System
Leonard G Feld, MD, PhD, MMM is a member of the following medical societies: American Academy of Pediatrics, American College of Physician Executives, American Society of Nephrology, American Society of Pediatric Nephrology, International Society of Nephrology, and Juvenile Diabetes Foundation International
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics and Rehabilitation, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

 
 
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