Clinical characteristics.

Neurofibromatosis 1 (NF1) is characterized by multiple café au lait spots, axillary and inguinal freckling, multiple cutaneous neurofibromas, iris Lisch nodules, and choroidal freckling. About half of people with NF1 have plexiform neurofibromas, but most are internal and not suspected clinically. Learning disabilities are present in at least 50% of individuals with NF1. Less common but potentially more serious manifestations include optic nerve and other central nervous system gliomas, malignant peripheral nerve sheath tumors, scoliosis, tibial dysplasia, and vasculopathy.

Diagnosis/testing.

The diagnosis of NF1 is usually based on clinical findings. Heterozygous pathogenic variants in NF1 are responsible for neurofibromatosis 1. Molecular genetic testing of NF1 is rarely needed for diagnosis.

Management.

Treatment of manifestations: Referral to specialists for treatment of complications involving the eye, central or peripheral nervous system, cardiovascular system, endocrine system, spine, or long bones; surgical removal of disfiguring or uncomfortable discrete cutaneous or subcutaneous neurofibromas. Surgical treatment of plexiform neurofibromas is often unsatisfactory. Complete surgical excision, when possible, of malignant peripheral nerve sheath tumors. Treatment of optic gliomas is generally unnecessary as they are usually asymptomatic and clinically stable. Dystrophic scoliosis often requires surgical management, whereas nondystrophic scoliosis can usually be treated conservatively. Methylphenidate treatment often benefits children with attention deficit hyperactivity disorder.

Surveillance: Annual physical examination by a physician familiar with the disorder; annual ophthalmologic examination in children, less frequently in adults; regular developmental assessment of children; regular blood pressure monitoring; MRI for follow up of clinically suspected intracranial tumors and other internal tumors. Begin annual mammography in women at age 30 with consideration of annual breast MRI in women between ages 30 and 50 years.

Genetic counseling.

NF1 is inherited in an autosomal dominant manner. Half of affected individuals have NF1 as the result of a de novo NF1 pathogenic variant. The offspring of an affected individual are at a 50% risk of inheriting the altered NF1 allele, but the disease manifestations are extremely variable, even within a family. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant in a family is known.

Suggestive Findings

Neurofibromatosis 1 (NF1) should be suspected in individuals who have any of the following findings:

• Six or more café au lait macules (Figure 1) >5 mm in greatest diameter in prepubertal individuals and >15 mm in greatest diameter in postpubertal individuals
• Two or more neurofibromas (Figure 2) of any type or one plexiform neurofibroma (Figure 3)
• Freckling in the axillary or inguinal regions
• Optic glioma
• Two or more Lisch nodules (iris hamartomas)
• A distinctive osseous lesion such as sphenoid dysplasia or tibial pseudarthrosis
• A first-degree relative (parent, sib, or offspring) with NF1 as defined by the above criteria

Figure 1.

Café au lait macules

Figure 2.

Neurofibromas

Figure 3.

Plexiform neurofibroma

Establishing the Diagnosis

The diagnosis of NF1 is established in a proband who meets the diagnostic criteria for neurofibromatosis 1 (NF1) developed by the National Institutes of Health [NIH 1988]. The NIH diagnostic criteria for NF1 are met in an individual who has two or more of the features listed in Suggestive Findings.

Note: As described below (Children), care must be taken in assigning the diagnosis of NF1 to a child with no known family history of NF1 since the diagnostic pigmentary findings overlap other disorders.

Adults. The NIH diagnostic criteria are both highly specific and highly sensitive in adults with NF1 [Ferner et al 2011, Ferner & Gutmann 2013].

Children

• Only about half of children with NF1 and no known family history of NF1 meet the NIH criteria for diagnosis by age one year; almost all do by age eight years [DeBella et al 2000a] because many features of NF1 increase in frequency with age.
• Children who have inherited NF1 from an affected parent can usually be identified within the first year of life because diagnosis requires just one feature in addition to a positive family history. This feature is usually multiple café au lait spots, which develop in infancy in more than 95% of individuals with NF1 [DeBella et al 2000b, Nunley et al 2009].
• Young children with multiple café au lait spots and no other NF1 features whose parents do not show signs of NF1 on careful physical and ophthalmologic examination should be strongly suspected of having NF1 and followed clinically as though they do [Nunley et al 2009].
• A definite diagnosis of NF1 can be made in most of these children by age four years using the NIH criteria.
• Young children who present with six or more café au lait macules and freckling in axillary or inguinal regions and who have no known family history of NF1 will meet the diagnostic criteria for NF1, but diagnoses of Legius syndrome or constitutional mismatch repair syndrome are also possible and need to be considered especially if no additional findings of NF1 develop with increasing age. See Differential Diagnosis.

Molecular genetic testing for identification of a heterozygous pathogenic variant in NF1 may be indicated in some individuals:

• Testing is indicated for individuals in whom NF1 is suspected but who do not fulfill the NIH diagnostic criteria. This is rarely necessary after early childhood.
• Testing may be useful in a young child with a serious tumor (e.g., optic glioma) in whom establishing a diagnosis of NF1 immediately would affect management.
• Testing of an adult with NF1 is necessary if prenatal or preimplantation genetic diagnosis in a current or future pregnancy is anticipated.
• In some families with spinal NF1 [Burkitt Wright et al 2013] or the NF1 c.2970-2972 delAAT pathogenic variant [Upadhyaya et al 2007, Quintáns et al 2011], affected individuals may not meet the NIH diagnostic criteria, especially in childhood. In such families, molecular testing is indicated for diagnosis of at-risk relatives.

Revision of the NIH diagnostic criteria has been recommended to take into account the availability of molecular testing for pathogenic variants of NF1 as well as clinical features (e.g., choroidal freckling, nevus anemicus, "unidentified bright objects") that often occur in childhood but were not known at the time of NIH Consensus Conference [Curless et al 1998, Ferrari et al 2014, Tadini et al 2014, Parrozzani et al 2015].

Single-gene testing. Sequence analysis of NF1 genomic DNA (gDNA) and/or cDNA (complementary DNA, copied from mRNA) is performed in association with gene-targeted deletion analysis.

• A multistep pathogenic variant detection protocol that combines analysis of genomic DNA and cDNA (mRNA) and testing for whole-gene or exon copy number changes is recommended if molecular genetic testing is indicated [Wimmer et al 2006, Messiaen & Wimmer 2008, Valero et al 2011, Sabbagh et al 2013]. This approach identifies more than 95% of NF1 pathogenic variants in individuals fulfilling the NIH diagnostic criteria. Because of the the variety and rarity of individual pathogenic variants found in people with NF1 and the frequency of pathogenic variants that affect splicing (22%-30%, more than 1/3 of which are not detected by gDNA sequencing) [Evans et al 2016], methods that include cDNA sequencing have higher detection rates than methods based solely on analysis of gDNA (Table 1).
• A multistep detection protocol that includes only cDNA (mRNA) sequencing and testing for whole-gene or exon copy number changes has been described that also has a diagnostic sensitivity of more than 95% [Evans et al 2016]. In this protocol, targeted gDNA sequencing is used to confirm that the pathogenic variants are in fact genomic.
• gDNA-only variant detection protocols are also available. These approaches, which involve sequencing of the entire NF1 coding region and adjacent splice sites from genomic DNA, have a somewhat lower diagnostic sensitivity, even if testing for whole-gene or exon copy number changes is also included [Maruoka et al 2014, van Minkelen et al 2014, Pasmant et al 2015, Zhang et al 2015, Calì et al 2017].

Chromosomal microarray analysis (CMA) may be performed to detect NF1 whole-gene deletions if the NF1 microdeletion phenotype is suspected clinically [Mautner et al 2010, Pasmant et al 2010, Kehrer-Sawatzki & Cooper 2012].

A multigene panel that includes NF1 and other genes of interest (see Differential Diagnosis) may also be considered. However, with the exception of SPRED1, the clinical phenotypes associated with constitutional variants of other genes on rasopathy, Noonan syndrome, or hereditary cancer panels are unlikely to overlap with that of NF1, and the detection frequency of pathogenic variants in NF1 on any panel performed by genomic DNA sequencing alone is likely to be stubstantially lower than that obtained by cDNA (mRNA) and targeted gDNA sequencing and copy number testing of NF1 with a multistep protocol. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Note: Cytogenetic testing may be considered if a clinical diagnosis of NF1 is certain but no pathogenic variant is found on analysis of NF1 cDNA (mRNA), gDNA, and copy number. Cytogenetic rearrangements are responsible for NF1 in fewer than 1% of affected individuals, and many of the pathogenic changes that occur in these cases can probably be detected using multistep cDNA-based testing, as described above.

Clinical Description

The clinical manifestations of neurofibromatosis 1 (NF1) are extremely variable [Ferner et al 2011, Ferner & Gutmann 2013, Dunning-Davies & Parker 2016].

Genotype-Phenotype Correlations

NF1 is characterized by extreme clinical variability, not only between unrelated individuals and among affected individuals within a single family but even within a single person with NF1 at different times in life. Only a few clear correlations have been observed between particular pathogenic NF1 alleles and consistent clinical phenotypes [Shofty et al 2015]:

• NF1 whole-gene deletion is associated with large numbers and early appearance of cutaneous neurofibromas, more frequent and more severe cognitive abnormalities, somatic overgrowth, large hands and feet, and dysmorphic facial features [Mautner et al 2010, Pasmant et al 2010, Kehrer-Sawatzki & Cooper 2012].
• A 3-bp in-frame deletion of exon 17 (c.2970-2972 delAAT) (NF Consortium nomenclature; exon 22 of NCBI nomenclature) is associated with typical pigmentary features of NF1 but no cutaneous or surface plexiform neurofibromas [Upadhyaya et al 2007].
• Any one of several missense variants affecting NF1 codon Arg1809 (see Table 2) in exon 29 (NF Consortium nomenclature; exon 38 of NCBI nomenclature) is associated with multiple café au lait spots, learning disabilities, short stature, and pulmonic stenosis but absence of cutaneous neurofibromas or clinically apparent plexiform neurofibromas [Pinna et al 2015, Rojnueangnit et al 2015].

Persons with NF1 (including those with NF1/Noonan syndrome or Watson syndrome phenotypes) who also have pulmonic stenosis appear to have non-truncating NF1 variants more frequently than the truncating variants that are found more often in other persons with NF1 [Ben-Shachar et al 2013].

The consistent familial transmission of NF1 variants such as Watson syndrome (multiple café au lait spots, pulmonic stenosis, and intellectual disability) [Allanson et al 1991, Tassabehji et al 1993] and familial spinal neurofibromatosis [Upadhyaya et al 2009, Burkitt Wright et al 2013, Ruggieri et al 2015] also indicates that allelic heterogeneity plays a role in the clinical variability of NF1. Statistical analysis of the NF1 phenotype within and between families [Sabbagh et al 2009, Sabbagh et al 2013] and observations on 23 half-sibs fathered by a sperm donor with mosaic NF1 [Ejerskov et al 2016] suggest that the NF1 pathogenic allele itself accounts for only a small fraction of phenotypic variation. Differences in expression of the normal NF1 allele may account for some of the phenotypic variability [Jentarra et al 2012]. Statistical analysis of clinical features in affected families [Pasmant et al 2012] and studies of polymorphisms in putative epistatic loci [Pemov et al 2014] suggest that modifying genes at other loci influence many aspects of the NF1 phenotype.

The extreme clinical variability of NF1 suggests that random events are important in determining the phenotype of affected individuals. Evidence in support of this interpretation is provided by the occurrence of acquired "second hit" variants or loss of heterozygosity at the NF1 locus in some neurofibromas, malignant peripheral nerve sheath tumors, pheochromocytomas, astrocytomas, gastrointestinal stromal tumors, myeloid malignancies, mandibular giant cell granulomas, and glomus tumors from patients with NF1 [Upadhyaya et al 2012, Emmerich et al 2015]. NF1 loss of heterozygosity has also been observed in some instances in melanocytes grown from café au lait spots [Maertens et al 2007, De Schepper et al 2008], macronodular adrenal hyperplasia, and tissue associated with tibial pseudarthrosis [Kobus et al 2015] from patients with NF1 [Lee et al 2012, Paria et al 2014, Sant et al 2015].

It seems likely that the clinical variability of NF1 results from a combination of genetic, non-genetic, and stochastic factors. Such complexity and the diversity of constitutional NF1 pathogenic variants that occur in this disease will continue to make genotype-phenotype correlation difficult.

Penetrance

Penetrance is virtually complete after childhood.

Nomenclature

NF1 was previously referred to as peripheral neurofibromatosis, to distinguish it from NF2 (central neurofibromatosis) – although central nervous system involvement may also occur in NF1.

"Neurofibromatosis" without further specification is sometimes used in the literature to refer to NF1, but this usage is confusing because other authors employ the term "neurofibromatosis" to designate a group of conditions that includes (in addition to NF1) NF2, schwannomatosis, and other clinically similar disorders.

Prevalence

NF1 is one of the most common dominantly inherited genetic disorders, occurring with an incidence at birth of approximately one in 3000 individuals [Lammert et al 2005, Evans et al 2010].

Almost half of all affected individuals have the disorder as the result of de novo mutation. The mutation rate for NF1 (~1:10,000) is among the highest known for any gene in humans. The cause of the unusually high mutation rate is unknown.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with neurofibromatosis 1 (NF1), the following evaluations are recommended:

• Personal medical history with particular attention to features of NF1
• Physical examination with particular attention to the skin, skeleton, cardiovascular system, and neurologic systems
• Ophthalmologic evaluation including slit lamp examination of the irides and infrared reflectance imaging or optical coherence tomography of the fundus
• Developmental assessment in children
• Other studies as indicated on the basis of clinically apparent signs or symptoms
• Consultation with a clinical geneticist and/or genetic counselor

In addition, a family history with particular attention to features of NF1 should be obtained, and physical examinations and ophthalmologic examinations (including slit lamp exams and infrared reflectance imaging or optical coherence tomography of the fundus) should be performed on both parents to determine if the condition in the affected individual was inherited or occurred de novo. This determination is necessary for genetic counseling and may help identify patients who have a condition that is not caused by pathogenic variants in NF1, such as Legius syndrome or constitutive mismatch repair deficiency (see Differential Diagnosis).

Treatment of Manifestations

Patient management guidelines for NF1 have been put forward by the American Academy of Pediatrics [Hersh 2008] and various expert groups [Ferner & Gutmann 2013, Dunning-Davies & Parker 2016].

Individuals with NF1 who have abnormalities involving the eye, central or peripheral nervous system, spine or long bones, cardiovascular system, or endocrine system should be referred to an appropriate specialist for treatment. Malignant tumors that develop in individuals with NF1 should be managed by surgical and/or medical oncologists who are familiar with the unusual molecular oncogenic mechanisms and inherent tumor predispositions (e.g., with radiotherapy [Evans et al 2002, Sharif et al 2006]; see Agents/Circumstances to Avoid) that may be associated with this genetic condition.

Neurofibromas. Discrete cutaneous or subcutaneous neurofibromas that are disfiguring or in inconvenient locations (e.g., at belt or collar lines) can be removed surgically, or, if small, by laser or electrocautery.

• Surgical removal of individual cutaneous neurofibromas is generally straightforward, but the large numbers of such tumors that occur in many affected adults may limit the extent of treatment that is practical or possible. Laser ablation is a rapid and effective method of removing larger numbers of cutaneous neurofibromas with satisfactory cosmetic results [Kriechbaumer et al 2014, Rosenbaum & Wimmer 2014, Méni et al 2015].
• Surgical treatment of plexiform neurofibromas is often unsatisfactory because of their intimate involvement with nerves and their tendency to grow back at the site of removal [Prada et al 2012, Nguyen et al 2013a, Rosenbaum & Wimmer 2014, Safaee et al 2015, Safaee et al 2017].
• In one small series in which surgical removal of superficial plexiform neurofibromas was undertaken in children while the tumors were still relatively small, it was possible to resect the neurofibromas without producing any neurologic deficit [Friedrich et al 2005].
• Recommendations for clinical management of orbital/periorbital plexiform neurofibromas in children with NF1 have been made by a multidisciplinary expert task force [Avery et al 2017].
• Clinical trials for several different medical treatments of plexiform and spinal neurofibromas are currently under way [Blakeley & Plotkin 2016, Karajannis & Ferner 2015] (see Therapies Under Investigation).
• Radiotherapy of plexiform neurofibromas is contraindicated because of the risk of inducing malignant peripheral nerve sheath tumors in these genetically predisposed individuals [Evans et al 2002].

Malignant peripheral nerve sheath tumors. Pain, development of a neurologic deficit, or enlargement of a preexisting plexiform neurofibroma may signal a malignant peripheral nerve sheath tumor and require immediate evaluation [Valeyrie-Allanore et al 2005]. Examination by MRI, PET, or PET/CT [Combemale et al 2014, Hirbe & Gutmann 2014, Salamon et al 2015, Van Der Gucht et al 2016] is useful in distinguishing benign and malignant peripheral nerve sheath tumors, but definitive differentiation can only be made by histologic examination of the tumor. Complete surgical excision, when possible, is the only treatment that offers the possibility of cure of malignant peripheral nerve sheath tumors [Dunn et al 2013, Valentin et al 2016]. Adjuvant chemotherapy or radiotherapy is sometimes used as well and appears to have benefitted some (but not most) patients with NF1 [Chaudhary & Borker 2012, Zehou et al 2013, Valentin et al 2016]. Clinical trials for malignant peripheral nerve sheath tumors are currently under way [Karajannis & Ferner 2015] (see Therapies Under Investigation).

Optic gliomas. Optic gliomas tend to occur at a younger age but to follow a more benign course in children with NF1 than in children who do not have NF1 [Nicolin et al 2009, Stokland et al 2010, Goodden et al 2014]. Most optic pathway gliomas found on MRI in people with NF1 are asymptomatic and do not require treatment [Blanchard et al 2016, Friedrich & Nuding 2016, Parkhurst & Abboy 2016, Sellmer et al 2017b]. Chemotherapy is the treatment of choice for progressive optic pathway gliomas in children with NF1, although the results are mixed [Rosenfeld et al 2010, Ardern-Holmes & North 2011, Fisher et al 2012, Shofty et al 2015]. Children with NF1 and low grade progressive gliomas (most of which were located in the optic pathways) had better survival after treatment with carboplatin and vincristine than children with similar tumors who did not have NF1 [Ater et al 2016]. Surgical treatment of optic nerve glioma is usually reserved for cosmetic palliation in a blind eye, and radiotherapy is usually avoided because of the risk of inducing malignancy or moya-moya in the exposed field [Evans et al 2002, Ullrich et al 2007a, Murphy et al 2015]. Clinical trials for optic pathway gliomas are currently under way [Karajannis & Ferner 2015] (see Therapies Under Investigation).

Brain tumors. Non-optic gliomas in people with NF1 tend to follow a less aggressive course than in those who do not have NF1 [Ullrich et al 2007a, Sellmer et al 2017a]. Most such tumors are asymptomatic, and they usually grow slowly or not at all over many years [Sellmer et al 2017a].

Orthopedic issues. Dystrophic scoliosis in children with NF1 often requires surgical management, which may be complex and difficult [Stoker et al 2012, Kawabata et al 2013, Deng et al 2017]. Nondystrophic scoliosis in persons with NF1 can be treated in a manner similar to idiopathic scoliosis.

Surgical treatment of tibial pseudarthrosis is difficult and often unsatisfactory [Stevenson et al 2013, Borzunov et al 2016].

Bisphosphonate treatment may benefit patients with NF1 who have osteoporosis, but the effect may be smaller than is usually seen in patients who do not have NF1 [Heervä et al 2014].

Neurobehavioral problems. Methylphenidate treatment often benefits children with attention deficit hyperactivity disorder and NF1 [Lion-François et al 2014].

Breast cancer. Although women with NF1 who develop breast cancer tend to have more aggressive disease than other women, the author is not aware of any evidence or recommendations that they should be treated differently from others with similar pathology and tumor markers. The author is not aware of any secondary tumors related to radiotherapy for breast cancer in women with NF1, however avoiding radiotherapy, if possible, is reasonable.

Surveillance

Patient management guidelines for NF1 have been put forward by the American Academy of Pediatrics [Hersh 2008] and various expert groups [Ferner & Gutmann 2013, Dunning-Davies & Parker 2016].

The following are recommended:

• Annual physical examination by a physician who is familiar with the individual and with the disease
• Annual ophthalmologic examination in early childhood; less frequent examination in older children and adults
• Regular developmental assessment by screening questionnaire (in childhood)
• Regular blood pressure monitoring
• Other studies (e.g., MRI) only as indicated on the basis of clinically apparent signs or symptoms
• Monitoring of those who have abnormalities of the central nervous system, skeletal system, or cardiovascular system by an appropriate specialist

Because of the increased risk of developing breast cancer before age 50 years among women with NF1 [Madanikia et al 2012, Wang et al 2012, Seminog & Goldacre 2015], US National Comprehensive Cancer Network Guidelines recommend that mammography be performed annually beginning at age 30 and that breast MRI be considered between ages 30 and 50 years in women with NF1 [Daly et al 2017]. However, the efficacy and cost-effectiveness of such screening have not yet been demonstrated [Howell et al 2017].

Agents/Circumstances to Avoid

No limitations are necessary for most individuals with NF1. Limitations may be required if certain particular features such as tibial dysplasia or dysplastic scoliosis are present; in these instances the limitation is determined by the feature, not by the presence of NF1 itself.

Radiotherapy of individuals with NF1 appears to be associated with a high risk of developing malignant peripheral nerve sheath tumors within the field of treatment [Evans et al 2002, Sharif et al 2006].

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Although most pregnancies in women with NF1 are normal, serious complications can occur [Chetty et al 2011, Terry et al 2013].

• Many women with NF1 experience a rapid increase in the number and size of neurofibromas during pregnancy.
• Hypertension may first become symptomatic or, if preexisting, may be greatly exacerbated during pregnancy.
• Large pelvic or genital neurofibromas can complicate delivery, and cesarean section appears to be necessary more often in pregnant women with NF1 than in other women.

Therapies Under Investigation

Various medical treatments for plexiform and spinal neurofibromas are being evaluated in clinical trials [Blakeley & Plotkin 2016, Karajannis & Ferner 2015]. A 20% or greater decrease in tumor volume was observed in 17 of 24 children with inoperable symptomatic or health-threatening plexiform neurofibromas who received long-term treatment with selumetinib, a MEK inhibitor, in a Phase I clinical trial [Dombi et al 2016]. Tumor progression did not occur in any case, and toxicity was considered to be acceptable in this trial (see Note).

Radiofrequency therapy has shown promise for treatment of facial diffuse plexiform neurofibromas and café au lait spots in small clinical series [Baujat et al 2006, Yoshida et al 2007].

Controlled trials of several therapeutic approaches to malignant peripheral nerve sheath tumors are available to individuals with NF1 [Karajannis & Ferner 2015] (see Note).

Several controlled trials for treatment of optic pathway gliomas are available to individuals with NF1 [Karajannis & Ferner 2015] (see Note).

Clinical trials have been undertaken for the learning and behavioral problems that occur in people with NF1 [Lion-François et al 2014, van der Vaart et al 2016] (see Note).

Note: NIH ClinicalTrials.gov has a list of current clinical trials for NF1.

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Other

Hormonal contraception appears not to stimulate the growth of neurofibromas in women with NF1 [Lammert et al 2006].

Mode of Inheritance

Neurofibromatosis 1 (NF1) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Approximately 50% of individuals diagnosed with NF1 have an affected parent.
• Approximately 50% of individuals diagnosed with NF1 have the disorder as the result of a de novo NF1 pathogenic variant.
• Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant (i.e., neither parent is known to have NF1) include medical history and physical examination with particular attention to dermal and other features of NF1. In addition, an ophthalmologic examination (including slit lamp examination and infrared reflectance imaging or optical coherence tomography) should be performed on both parents to look for Lisch nodules, choroidal freckling, or other ophthalmologic signs of NF1.
• If neither parent of an individual with NF1 meets the clinical diagnostic criteria for NF1 after careful medical history, physical examination, and ophthalmologic examination, a de novo pathogenic variant occurring in the proband is the most likely explanation. Germline mosaicism in a parent with no clinical signs of NF1 is possible but much less likely [Lázaro et al 1995, Bottillo et al 2010, Trevisson et al 2014].
• The family history may appear to be negative because of failure to recognize NF1 in family members or early death of a parent before the recognition of signs or symptoms.
• Note: An individual in whom NF1 appears to have arisen as the result of de novo mutation may have somatic mosaicism associated with segmental or unusually mild disease manifestations [Messiaen et al 2011, García-Romero et al 2016]. The risk of a parent with mosaicism for an NF1 pathogenic variant transmitting the disease to his or her child may be less than 50%, but if the pathogenic variant is transmitted, it will be present in every cell in the child's body and s/he may be much more severely affected.

Sibs of a proband

• The risk to the sibs of the proband depends on the clinical status of the proband's parents.
• If a parent is affected, the risk to the sibs is 50%; a sib who inherits an NF1 pathogenic variant will develop features of NF1, but the disease may be considerably more (or less) severe in an affected sib than in the proband.
• If neither parent of an individual with NF1 meets the clinical diagnostic criteria for NF1 after careful medical history, physical examination, and ophthalmologic examination, the risk to the sibs of the affected individual of having NF1 is low but greater than that of the general population because of the possibility of germline mosaicism. Note: Germline mosaicism for an NF1 pathogenic variant has been demonstrated by molecular testing in a few families in which affected sibs were born to unaffected parents [Bottillo et al 2010, Trevisson et al 2014, Ejerskov et al 2016].

Offspring of a proband

• Each child of an individual with NF1 has a 50% chance of inheriting the NF1 pathogenic variant.
• Penetrance is 100%; thus, a child who inherits an NF1 pathogenic variant will develop features of NF1, but the disease may be considerably more (or less) severe in an affected child than in his or her affected parent.

Other family members. The risk to other family members depends on the status of the proband's parents: if a proband's parent is affected, other members of his or her family may be at risk.

Related Genetic Counseling Issues

Possibility of multiple de novo pathogenic variants in a single family. Upadhyaya et al [2003] reported the occurrence of three different NF1 pathogenic variants in one family and advised caution in assuming that the same pathogenic variant is present in all members of an affected family. Two different NF1 pathogenic variants have been reported in another family [Klose et al 1999].

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption may also be considered.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal or preimplantation genetic diagnosis is before pregnancy.
• Genetic counseling (including discussion of potential risks to offspring and reproductive options) should be offered to young adults who are affected or at risk.

Prenatal Testing and Preimplantation Genetic Diagnosis

Molecular genetic testing. Once the NF1 pathogenic variant has been identified in an affected family member, prenatal testing [van Minkelen et al 2014] for a pregnancy at increased risk and preimplantation genetic diagnosis [Merker et al 2015] are possible.

Ultrasound examination. Prenatal diagnosis of exceptionally severe NF1 by prenatal ultrasound examination has been reported [McEwing et al 2006], but ultrasound examination is unlikely to be informative in most cases.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Cancer and Benign Tumors

Several kinds of tumors that occur with increased frequency among persons with NF1 may exhibit somatic (but not germline) NF1 variants of one or both alleles in individuals who do not have clinical features of NF1. Examples of NF1 pathogenic variants in such sporadic NF1-associated tumors occurring in the absence of any other findings of this syndrome include malignant peripheral nerve sheath tumors [Bottillo et al 2009, Lee et al 2014], pheochromocytomas [Vicha et al 2013, King & Pacak 2014, Martins & Bugalho 2014, Crona et al 2015], juvenile myelomonocytic leukemia [Yoshimi et al 2010, Sakaguchi et al 2013, Stieglitz et al 2015], gliomas [Purow & Schiff 2009], and breast cancer [Cancer Genome Atlas Network 2012].

Somatic pathogenic variants of NF1 may also be found in liposarcomas, lung adenocarcinomas, ovarian carcinomas, colorectal carcinomas, melanomas, and adult acute myeloid leukemia, all of which are uncommon in individuals with NF1 [Laycock-van Spyk et al 2011, Patil & Chamberlain 2012, Yap et al 2014, Kanojia et al 2015].

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Suggested Reading

• Gutmann DH, Collins FS. Neurofibromatosis 1. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, eds. The Online Metabolic and Molecular Bases of Inherited Disease (Scriver's OMMBID). Chap 39. McGraw-Hill.
• Upadhyaya M. The molecular biology of neurofibromatosis type 1. San Rafael, California: Morgan & Claypool Life Sciences. Available online. 2014. Accessed 5-17-18.

Revision History

• 17 May 2018 (ma) Revision: treatment of and surveillance for NF1-related breast cancer added to Management
• 11 January 2018 (ha) Revision: to diagnostic criteria; Wimmer et al 2017 added
• 2 November 2017 (ha) Comprehensive update posted live
• 4 September 2014 (me) Comprehensive update posted live
• 3 May 2012 (me) Comprehensive update posted live
• 2 June 2009 (me) Comprehensive update posted live
• 31 January 2007 (me) Comprehensive update posted live
• 5 October 2004 (me) Comprehensive update posted live
• 30 September 2002 (me) Comprehensive update posted live
• 2 October 1998 (pb) Review posted live
• Spring 1996 (jmf) Original submission