para>In NF1, cutaneous lesions and tumors increase in size and number with age.
Pediatric Considerations
Children who have inherited the NF1 gene of an affected parent usually are identified by age 1 year, but external stigmata may be subtle. If there are no stigmata by age 2 years, NF is unlikely, but the child should be reexamined within the next few years. Definite diagnosis can be made by age 4 years using National Institute of Health (NIH) criteria (1).
Young children with multiple cafe au lait spots, but no other stigmata after careful physical and ophthalmologic evaluation, should be followed clinically as if they have NF1 (2).
Molecular confirmation may be appropriate, especially with atypical presentation (3).
DIAGNOSTIC TESTS & INTERPRETATION
- DNA sequence and deletion/duplication analysis of the NF1 gene can identify mutations in ¢ ¼96% of those with a clinical diagnosis.
- Molecular genetic testing is available, although often not necessary for diagnosis. Diagnostic laboratory information: https://www.genetests.org/
- Confirmatory genetic testing is appropriate in those who are suspected of having NF1 but do not fulfill diagnostic criteria or for prenatal diagnosis or preimplantation genetic diagnosis (PGD) (4).
Initial Tests (lab, imaging)
- Characteristic radiographic findings: sphenoid dysplasia, long bone cortical thinning, ribbon ribs, and angular scoliosis. Screening radiographs of the knees in adolescents is controversial. CT can demonstrate bony changes.
- MRI findings of the orbits, brain, or spine (86%). Routine head MRI scanning in asymptomatic individuals with NF1 is controversial. Optic gliomata (seen on MRI, 11 " 15%) may lead to blindness. Although areas of increased T2 signal intensity (unidentified bright objects) are common on brain MRI, they are not diagnostic of NF1 and likely are of no clinical significance.
- The NIH Consensus Development Conference does not recommend routine neuroimaging as a means of establishing a diagnosis, although modification of diagnostic criteria is discussed (1)[C].
Diagnostic Procedures/Other
- Ophthalmologic evaluation, including slit-lamp exam of the irides; visual field testing to evaluate optic gliomata
- Neuropsychological testing: Intelligence usually normal but may have significant deficits in language, visuospatial skills, and neuromotor skills.
TREATMENT
MEDICATION
First Line
There are no specific therapeutic agents approved; individual aspects are treated as they arise (e.g., anticonvulsants for seizures, medications for ADHD, management of blood pressure).
Second Line
- In case studies, Sirolimus, a mammalian target of rapamycin [mTOR] inhibitor, did not shrink nonprogressive plexiform neurofibromas, but did relieve pain and retard progression of inoperable plexiform neurofibromas (5)[C].
- Multiple clinical trials for NF1 are recruiting patients (see https://www.clinicaltrials.gov/).
ISSUES FOR REFERRAL
- Patients with more than minimal manifestations of NF1: Refer to a multidisciplinary NF clinic.
- Referral for psychosocial issues of family and affected individuals
- Educational intervention for children with learning disabilities or ADHD (40%)
- Early referral to orthopedics for congenital tibial bowing
ADDITIONAL THERAPIES
- Occupational therapy for children with NF1 who present with fine motor difficulties
- There is no evidence supporting laser therapy for cafe au lait spots.
- The Children 's Tumor Foundation (CTF) has established the NF Clinical Trials Consortium and the CTF NF Clinic Network to facilitate future clinical trials and help identify best practices (6).
SURGERY/OTHER PROCEDURES
Surgical treatment for severe scoliosis, plexiform neurofibromata, or malignancy
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
NF1 health supervision 2008 guidelines:
- Infancy to 1 year (7)[C]
- Growth and development: mild short stature, macrocephaly (increased brain volume); aqueductal stenosis/obstructive hydrocephalus, hydrocephalus
- Check for focal neurologic signs or asymmetric neurologic exam.
- Skeletal abnormalities, especially spine and legs
- Neurodevelopmental progress
- 1 to 5 years (7)[C]
- Cafe au lait spots and axillary freckling have no clinical significance.
- Annual ophthalmologic exam
- Brain MRI for visual changes, persistent headaches, seizures, marked increase in head size, plexiform neurofibroma of the head
- Assess speech and language: hypernasal speech due to velopharyngeal insufficiency and delayed expressive language development.
- Developmental evaluation of learning and motor abilities; may benefit from speech/language and/or motor therapy, and special education
- Monitor BP annually.
- 5 to 13 years (7)[C]
- Evaluate for skin tumors causing disfigurement and obtain consultation if surgery is desired to improve appearance or function.
- Evaluate for premature or delayed puberty. If sexual precocity is noted, evaluate for an optic glioma or hypothalamic lesion. Review the effects of puberty on NF.
- Evaluate for learning disabilities and ADHD.
- Evaluate social adjustment, development, and school placement.
- Monitor ophthalmologic status yearly until age 8 years; complete eye exam every 2 years.
- Monitor BP annually.
- Refer patient to a clinical psychologist or child psychiatrist for problems with self-esteem.
- Discuss growth of neurofibromata during adolescence and pregnancy.
- Counsel parents about discussing diagnosis with child.
- 13 to 21 years (7)[C]
- Examine the adolescent for abnormal pubertal development.
- Thorough skin examination for plexiform neurofibromata and a complete neurologic exam for findings suggestive of deep plexiform neurofibromata; seek surgical consultation for signs of pressure on deep structures.
- Continue to monitor BP yearly.
- Continue ophthalmologic examination every 2 years until age 18 years.
- Discuss genetics of NF1 or refer for genetic counseling.
- Discuss sexuality, contraception, and reproductive options.
- Discuss effects of pregnancy on NF1, if appropriate. Neurofibromata may enlarge and new tumors may develop during pregnancy.
- Review prenatal diagnosis or refer the patient to a geneticist.
PATIENT EDUCATION
- Genetic counseling and patient education regarding future complications about family planning
- Support groups are important: http://www.ctf.org/.
PROGNOSIS
Variable; most patients have a mild expression of NF1 and lead normal lives.
COMPLICATIONS
- Disfigurement: Skin neurofibromata develop primarily on exposed areas. The number tends to increase with puberty or pregnancy.
- Scoliosis: 10 " 30% (most cases mild); bowing of long bones, 2%; osteopenia and osteoporosis
- A large head is common but rarely associated with hydrocephalus.
- Increased risk of malignancy: malignant peripheral nerve sheath tumor (MPNST) (5 " 10%) usually in adults (1), especially within the field of previous radiotherapy for plexiform neurofibroma
- CNS tumors (5 " 15%), especially optic pathway glioma (most common CNS tumor), most often asymptomatic, but if symptomatic, usually presents before age 6 years. Symptomatic lesions are usually stable or only slowly progressive.
- High relative risk (RR) for some uncommon malignancies
- Increased risk for pheochromocytoma, rhabdomyosarcoma, leukemia, Wilms tumor
- Relative risk for cancer of the esophagus (3.3), stomach (2.8), colon (2.0), liver (3.8), lung (3.0), bone (19.6), thyroid (4.9), malignant melanoma (3.6), non-Hodgkin lymphoma (3.3), chronic myeloid leukemia (6.7), female breast (2.3), and ovary (3.7)
- Learning disability: ¢ ¼50%; may be associated with ADHD; mental retardation in 4 " 8%
- GI neurofibromata may cause GI disturbances.
- Seizures: 6 " 7%
- Hypertension is a frequent finding in adults and may occur during childhood.
- Disorders of puberty
Pregnancy Considerations
Increased risk of perinatal complications, stillbirth, intrauterine growth constriction; risk of cord compression, and outlet obstruction by pelvic neurofibromata
REFERENCES
11 DeBella K, Szudek J, Friedman JM. Use of the National Institutes of Health Criteria for diagnosis of neurofibromatosis 1 in children. Pediatrics. 2000;105(3 Pt 1):608 " 614.22 Nunley KS, Gao F, Albers AC, et al. Predictive value of cafe au lait macules at initial consultation in the diagnosis of neurofibromatosis type 1. Arch Dermatol. 2009;145(8):883 " 887.33 Burkitt Wright EM, Sach E, Sharif S, et al. Can the diagnosis of NF1 be excluded clinically? A lack of pigmentary findings in families with spinal neurofibromatosis demonstrates a limitation of clinical diagnosis. J Med Genet. 2013;50(9):606 " 613.44 National Institutes of Health Consensus Development Conference statement: neurofibromatosis. Bethesda, Md., USA, July 13 " 15, 1987. Neurofibromatosis. 1988;1(3):172 " 178.55 Hua C, Zehou O, Decassou S, et al. Sirolimus improves pain in NF1 patients with severe plexiform neurofibromas. Pediatrics. 2014:133(6): e1792 " e1797.66 Williams VC, Lucas J, Babcock MA, et al. Neurofibromatosis type 1 revisited. Pediatrics. 2009;123(1):124 " 133.77 Hersh JH. Health supervision for children with neurofibromatosis. Pediatrics. 2008;121(3):633 " 642.
SEE ALSO
Tuberous Sclerosis Complex; Von Hippel-Lindau Syndrome
CODES
ICD10
Q85.01 Neurofibromatosis, type 1
ICD9
237.71 Neurofibromatosis, type 1 [von recklinghausen 's disease]
SNOMED
- 92824003 neurofibromatosis, type 1 (disorder)
- 403815003 Axillary freckling due to neurofibromatosis (disorder)
- 403816002 multiple caf-au-lait macules due to neurofibromatosis (disorder)
CLINICAL PEARLS
- Marked clinical variability. External stigmata may be subtle or absent in young children. Minimally affected children may become severely affected adults.
- A single cafe au lait spot is of no concern in a child, but having ≥6 is a diagnostic criterion for NF1.