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 a pregnancy at increased risk and preimplantation genetic testing are 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 nontruncating 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

The American Academy of Pediatrics and American College of Medical Genetics and Genomics (ACMG) have published patient management guidelines for children with NF1 [Miller et al 2019], and the ACMG has also published management guidelines for affected adults [Stewart et al 2018]. Similar recommendations have been made by other experts [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 2018]. 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 2017]. Most such tumors are asymptomatic, and they usually grow slowly or not at all over many years [Sellmer et al 2017].

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

The American Academy of Pediatrics and ACMG have published guidelines for surveillance of children with NF1 [Miller et al 2019], and the ACMG has published similar guidelines for affected adults [Stewart et al 2018]. Recommendations regarding surveillance of NF1 patients have also been made by other experts [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 EU Clinical Trials Register 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/preimplantation genetic testing 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 Testing

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 testing [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 use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

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].

Literature Cited

• Afridi SK, Leschziner GD, Ferner RE. Prevalence and clinical presentation of headache in a National Neurofibromatosis 1 Service and impact on quality of life. Am J Med Genet A. 2015;167A:2282–5. [PubMed: 26044068]
• Al Freihi SH, Edward DP, Nowilaty SR, Abouammoh MA, Morales J. Iris neovascularization and neovascular glaucoma in neurofibromatosis type 1: report of 3 cases in children. J Glaucoma. 2013;22:336–41. [PubMed: 22138687]
• Allanson JE, Upadhyaya M, Watson GH, Partington M, MacKenzie A, Lahey D, MacLeod H, Sarfarazi M, Broadhead W, Harper PS, Huson SM. Watson syndrome: is it a subtype of type 1 neurofibromatosis? J Med Genet. 1991;28:752–6. [PMC free article: PMC1017110] [PubMed: 1770531]
• Alwan S, Tredwell SJ, Friedman JM. Is osseous dysplasia a primary feature of neurofibromatosis 1 (NF1)? Clin Genet. 2005;67:378–90. [PubMed: 15811002]
• Andersson J, Sihto H, Meis-Kindblom JM, Joensuu H, Nupponen N, Kindblom LG. NF1-associated gastrointestinal stromal tumors have unique clinical, phenotypic, and genotypic characteristics. Am J Surg Pathol. 2005;29:1170–6. [PubMed: 16096406]
• Ardern-Holmes SL, North KN. Therapeutics for childhood neurofibromatosis type 1 and type 2. Curr Treat Options Neurol. 2011;13:529–43. [PubMed: 21850405]
• Armstrong L, Jett K, Birch P, Kendler DL, McKay H, Tsang E, Stevenson DA, Hanley DA, Egeli D, Burrows M, Friedman JM. The generalized bone phenotype in children with neurofibromatosis 1: a sibling matched case-control study. Am J Med Genet A. 2013;161A:1654–61. [PubMed: 23713011]
• Arrington DK, Danehy AR, Peleggi A, Proctor MR, Irons MB, Ullrich NJ. Calvarial defects and skeletal dysplasia in patients with neurofibromatosis Type 1. J Neurosurg Pediatr. 2013;11:410–6. [PubMed: 23414129]
• Ater JL, Xia C, Mazewski CM, Booth TN, Freyer DR, Packer RJ, Sposto R, Vezina G, Pollack IF. Nonrandomized comparison of neurofibromatosis type 1 and non-neurofibromatosis type 1 children who received carboplatin and vincristine for progressive low-grade glioma: a report from the Children's Oncology Group. Cancer. 2016;122:1928–36. [PMC free article: PMC4892942] [PubMed: 27061921]
• Avery RA, Katowitz JA, Fisher MJ, Heidary G, Dombi E, Packer RJ, Widemann BC, et al. Orbital/periorbital plexiform neurofibromas in children with neurofibromatosis type 1: multidisciplinary recommendations for care. Ophthalmology. 2017;124:123–32. [PMC free article: PMC5173440] [PubMed: 27817916]
• Aydin S, Kurtcan S, Alkan A, Guler S, Filiz M, Yilmaz TF, Sahin TU, Aralasmak A. Relationship between the corpus callosum and neurocognitive disabilities in children with NF-1: diffusion tensor imaging features. Clin Imaging. 2016;40:1092–5. [PubMed: 27423006]
• Babovic-Vuksanovic D, Messiaen L, Nagel C, Brems H, Scheithauer B, Denayer E, Mao R, Sciot R, Janowski KM, Schuhmann MU, Claes K, Beert E, Garrity JA, Spinner RJ, Stemmer-Rachamimov A, Gavrilova R, Van Calenbergh F, Mautner V, Legius E. Multiple orbital neurofibromas, painful peripheral nerve tumors, distinctive face and marfanoid habitus: a new syndrome. Eur J Hum Genet. 2012;20:618–25. [PMC free article: PMC3355267] [PubMed: 22258529]
• Bacci C, Sestini R, Ammannati F, Bianchini E, Palladino T, Carella M, Melchionda S, Zelante L, Papi L. Multiple spinal ganglioneuromas in a patient harboring a pathogenic NF1 mutation. Clin Genet. 2010;77:293–7. [PubMed: 19863548]
• Baujat B, Krastinova-Lolov D, Blumen M, Baglin AC, Coquille F, Chabolle F. Radiofrequency in the treatment of craniofacial plexiform neurofibromatosis: a pilot study. Plast Reconstr Surg. 2006;117:1261–8. [PubMed: 16582798]
• Bekiesińska-Figatowska M, Brągoszewska H, Duczkowski M, Romaniuk-Doroszewska A, Szkudlińska-Pawlak S, Duczkowska A, Mądzik J, Kowalska B, Pęczkowski P. Circle of Willis abnormalities in children with neurofibromatosis type 1. Neurol Neurochir Pol. 2014;48:15–20. [PubMed: 24636765]
• Ben-Shachar S, Constantini S, Hallevi H, Sach EK, Upadhyaya M, Evans GD, Huson SM. Increased rate of missense/in-frame mutations in individuals with NF1-related pulmonary stenosis: a novel genotype-phenotype correlation. Eur J Hum Genet. 2013;21:535–9. [PMC free article: PMC3641387] [PubMed: 23047742]
• Billiet T, Mädler B, D'Arco F, Peeters R, Deprez S, Plasschaert E, Leemans A, Zhang H, den Bergh BV, Vandenbulcke M, Legius E, Sunaert S, Emsell L. Characterizing the microstructural basis of "unidentified bright objects" in neurofibromatosis type 1: a combined in vivo multicomponent T2 relaxation and multi-shell diffusion MRI analysis. Neuroimage Clin. 2014;4:649–58. [PMC free article: PMC4053637] [PubMed: 24936416]
• Blakeley JO, Plotkin SR. Therapeutic advances for the tumors associated with neurofibromatosis type 1, type 2, and schwannomatosis. Neuro Oncol. 2016;18:624–38. [PMC free article: PMC4827037] [PubMed: 26851632]
• Blanchard G, Lafforgue MP, Lion-François L, Kemlin I, Rodriguez D, Castelnau P, Carneiro M, Meyer P, Rivier F, Barbarot S, Chaix Y, et al. Systematic MRI in NF1 children under six years of age for the diagnosis of optic pathway gliomas. Study and outcome of a French cohort. Eur J Paediatr Neurol. 2016;20:275–81. [PubMed: 26774135]
• Borzunov DY, Chevardin AY, Mitrofanov AI. Management of congenital pseudarthrosis of the tibia with the Ilizarov method in a paediatric population: influence of aetiological factors. Int Orthop. 2016;40:331–9. [PubMed: 26546064]
• Bottillo I, Ahlquist T, Brekke H, Danielsen SA, van den Berg E, Mertens F, Lothe RA, Dallapiccola B. Germline and somatic NF1 mutations in sporadic and NF1-associated malignant peripheral nerve sheath tumours. J Pathol. 2009;217:693–701. [PubMed: 19142971]
• Bottillo I, Torrente I, Lanari V, Pinna V, Giustini S, Divona L, De Luca A, Dallapiccola B. Germline mosaicism in neurofibromatosis type 1 due to a paternally derived multi-exon deletion. Am J Med Genet A. 2010;152A:1467–73. [PubMed: 20503322]
• Boulanger JM, Larbrisseau A. Neurofibromatosis type 1 in a pediatric population: Ste-Justine's experience. Can J Neurol Sci. 2005;32:225–31. [PubMed: 16018159]
• Brahmi M, Thiesse P, Ranchere D, Mognetti T, Pinson S, Renard C, Decouvelaere AV, Blay JY, Combemale P. Diagnostic accuracy of PET/CT-guided percutaneous biopsies for malignant peripheral nerve sheath tumors in neurofibromatosis type 1 patients. PLoS One. 2015;10:e0138386. [PMC free article: PMC4596851] [PubMed: 26445379]
• Brems H, Pasmant E, Van Minkelen R, Wimmer K, Upadhyaya M, Legius E, Messiaen L. Review and update of SPRED1 mutations causing Legius syndrome. Hum Mutat. 2012;33:1538–46. [PubMed: 22753041]
• Brunetti-Pierri N, Doty SB, Hicks J, Phan K, Mendoza-Londono R, Blazo M, Tran A, Carter S, Lewis RA, Plon SE, Phillips WA, O'Brian Smith E, Ellis KJ, Lee B. Generalized metabolic bone disease in Neurofibromatosis type I. Mol Genet Metab. 2008;94:105–11. [PMC free article: PMC2430595] [PubMed: 18289904]
• Buchanan ME, Davis RL. A distinct set of Drosophila brain neurons required for neurofibromatosis type 1-dependent learning and memory. J Neurosci. 2010;30:10135–43. [PMC free article: PMC2917756] [PubMed: 20668197]
• Burkitt Wright EM, Sach E, Sharif S, Quarrell O, Carroll T, Whitehouse RW, Upadhyaya M, Huson SM, Evans DG. 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;50:606–13. [PMC free article: PMC3756527] [PubMed: 23812910]
• Buske A, Gewies A, Lehmann R, Rüther K, Algermissen B, Nürnberg P, Tinschert S. Recurrent NF1 gene mutation in a patient with oligosymptomatic neurofibromatosis type 1 (NF1). Am J Med Genet. 1999;86:328–30. [PubMed: 10494088]
• Cai W, Kassarjian A, Bredella MA, Harris GJ, Yoshida H, Mautner VF, Wenzel R, Plotkin SR. Tumor burden in patients with neurofibromatosis types 1 and 2 and schwannomatosis: determination on whole-body MR images. Radiology. 2009;250:665–73. [PubMed: 19244040]
• Cairns AG, North KN. Cerebrovascular dysplasia in neurofibromatosis type 1. J Neurol Neurosurg Psychiatry. 2008;79:1165–70. [PubMed: 18469031]
• Calì F, Chiavetta V, Ruggeri G, Piccione M, Selicorni A, Palazzo D, Bonsignore M, Cereda A, Elia M, Failla P, Figura MG, Fiumara A, Maitz S, Luana Mandarà GM, Mattina T, Ragalmuto A, Romano C, Ruggieri M, Salluzzo R, Saporoso A, Schepis C, Sorge G, Spanò M, Tortorella G, Romano V. Mutation spectrum of NF1 gene in Italian patients with neurofibromatosis type 1 using Ion Torrent PGM™ platform. Eur J Med Genet. 2017;60:93–9. [PubMed: 27838393]
• Campos B, Balmaña J, Gardenyes J, Valenzuela I, Abad O, Fàbregas P, Volpini V, Díez O. Germline mutations in NF1 and BRCA1 in a family with neurofibromatosis type 1 and early-onset breast cancer. Breast Cancer Res Treat. 2013;139:597–602. [PubMed: 23624750]
• Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490:61–70. [PMC free article: PMC3465532] [PubMed: 23000897]
• Carcavilla A, Pinto I, Muñoz-Pacheco R, Barrio R, Martin-Frías M, Ezquieta B. LEOPARD syndrome (PTPN11, T468M) in three boys fulfilling neurofibromatosis type 1 clinical criteria. Eur J Pediatr. 2011;170:1069–74. [PubMed: 21365175]
• Chabernaud C, Sirinelli D, Barbier C, Cottier JP, Sembely C, Giraudeau B, Deseille-Turlotte G, Lorette G, Barthez MA, Castelnau P. Thalamo-striatal T2-weighted hyperintensities (unidentified bright objects) correlate with cognitive impairments in neurofibromatosis type 1 during childhood. Dev Neuropsychol. 2009;34:736–48. [PubMed: 20183730]
• Chaudhary N, Borker A. Metronomic therapy for malignant peripheral nerve sheath tumor in neurofibromatosis type 1. Pediatr Blood Cancer. 2012;59:1317–9. [PubMed: 22745048]
• Chen PC, Yin J, Yu HW, Yuan T, Fernandez M, Yung CK, Trinh QM, Peltekova VD, Reid JG, Tworog-Dube E, Morgan MB, Muzny DM, Stein L, McPherson JD, Roberts AE, Gibbs RA, Neel BG, Kucherlapati R. Next-generation sequencing identifies rare variants associated with Noonan syndrome. Proc Natl Acad Sci U S A. 2014;111:11473–8. [PMC free article: PMC4128129] [PubMed: 25049390]
• Chetty SP, Shaffer BL, Norton ME. Management of pregnancy in women with genetic disorders: Part 2: Inborn errors of metabolism, cystic fibrosis, neurofibromatosis type 1, and turner syndrome in pregnancy. Obstet Gynecol Surv. 2011;66:765–76. [PubMed: 22192461]
• Chirindel A, Chaudhry M, Blakeley JO, Wahl R. 18F-FDG PET/CT qualitative and quantitative evaluation in neurofibromatosis type 1 patients for detection of malignant transformation: comparison of early to delayed imaging with and without liver activity normalization. J Nucl Med. 2015;56:379–85. [PubMed: 25655626]
• Chiu SL, Chen SN, Chen YT, Chen PJ (2011) Coats' disease and neovascular glaucoma in a child with neurofibromatosis. J Pediatr Ophthalmol Strabismus 48 Online: e1-3. [PubMed: 20210281]
• Clementi M, Milani S, Mammi I, Boni S, Monciotti C, Tenconi R. Neurofibromatosis type 1 growth charts. Am J Med Genet. 1999;87:317–23. [PubMed: 10588837]
• Cohen JS, Levy HP, Sloan J, Dariotis J, Biesecker BB. Depression among adults with neurofibromatosis type 1: prevalence and impact on quality of life. Clin Genet. 2015;88:425–30. [PMC free article: PMC4573679] [PubMed: 25534182]
• Colley A, Donnai D, Evans DG. Neurofibromatosis/Noonan phenotype: a variable feature of type 1 neurofibromatosis. Clin Genet. 1996;49:59–64. [PubMed: 8740913]
• Combemale P, Valeyrie-Allanore L, Giammarile F, Pinson S, Guillot B, Goulart DM, Wolkenstein P, Blay JY, Mognetti T. Utility of 18F-FDG PET with a semi-quantitative index in the detection of sarcomatous transformation in patients with neurofibromatosis type 1. PLoS One. 2014;9:e85954. [PMC free article: PMC3916322] [PubMed: 24516522]
• Consoli C, Moss C, Green S, Balderson D, Cooper DN, Upadhyaya M. Gonosomal mosaicism for a nonsense mutation (R1947X) in the NF1 gene in segmental neurofibromatosis type 1. J Invest Dermatol. 2005;125:463–6. [PubMed: 16117786]
• Crona J, Backman S, Maharjan R, Mayrhofer M, Stålberg P, Isaksson A, Hellman P, Björklund P. Spatiotemporal heterogeneity characterizes the genetic landscape of pheochromocytoma and defines early events in tumorigenesis. Clin Cancer Res. 2015;21:4451–60. [PubMed: 25991818]
• Crucis A, Richer W, Brugières L, Bergeron C, Marie-Cardine A, Stephan JL, Girard P, Corradini N, Munzer M, Lacour B, Minard-Colin V, Sarnacki S, Ranchere-Vince D, Orbach D, Bourdeaut F. Rhabdomyosarcomas in children with neurofibromatosis type I: a national historical cohort. Pediatr Blood Cancer. 2015;62:1733–8. [PubMed: 25893277]
• Curless RG, Siatkowski M, Glaser JS, Shatz NJ. MRI diagnosis of NF-1 in children without café-au-lait skin lesions. Pediatr Neurol. 1998;18:269–71. [PubMed: 9568928]
• Daly MB, Pilarski R, Berry M, Buys SS, Farmer M, Friedman S, Garber JE, Kauff ND, Khan S, Klein C, Kohlmann W, Kurian A, Litton JK, Madlensky L, Merajver SD, Offit K, Pal T, Reiser G, Shannon KM, Swisher E, Vinayak S, Voian NC, Weitzel JN, Wick MJ, Wiesner GL, Dwyer M, Darlow S. NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast and Ovarian, Version 2.2017. J Natl Compr Canc Netw. 2017;15:9–20. [PubMed: 28040716]
• D'Arco F, D'Amico A, Caranci F, Di Paolo N, Melis D, Brunetti A. Cerebrovascular stenosis in neurofibromatosis type 1 and utility of magnetic resonance angiography: our experience and literature review. Radiol Med. 2014;119:415–21. [PubMed: 24297593]
• DeBella K, Poskitt K, Szudek J, Friedman JM. Use of "unidentified bright objects" on MRI for diagnosis of neurofibromatosis 1 in children. Neurology. 2000a;54:1646–51. [PubMed: 10762507]
• DeBella K, Szudek J, Friedman JM. Use of the national institutes of health criteria for diagnosis of neurofibromatosis 1 in children. Pediatrics. 2000b;105:608–14. [PubMed: 10699117]
• De Luca A, Bottillo I, Sarkozy A, Carta C, Neri C, Bellacchio E, Schirinzi A, Conti E, Zampino G, Battaglia A, Majore S, Rinaldi MM, Carella M, Marino B, Pizzuti A, Digilio MC, Tartaglia M, Dallapiccola B. NF1 gene mutations represent the major molecular event underlying neurofibromatosis-Noonan syndrome. Am J Hum Genet. 2005;77:1092–101. [PMC free article: PMC1285166] [PubMed: 16380919]
• Deng A, Zhang HQ, Tang MX, Liu SH, Wang YX, Gao QL. Posterior-only surgical correction of dystrophic scoliosis in 31 patients with neurofibromatosis type 1 using the multiple anchor point method. J Neurosurg Pediatr. 2017;19:96–101. [PubMed: 27739946]
• De Raedt T, Brems H, Wolkenstein P, Vidaud D, Pilotti S, Perrone F, Mautner V, Frahm S, Sciot R, Legius E. Elevated risk for MPNST in NF1 microdeletion patients. Am J Hum Genet. 2003;72:1288–92. [PMC free article: PMC1180281] [PubMed: 12660952]
• Descheemaeker MJ, Plasschaert E, Frijns JP, Legius E. Neuropsychological profile in adults with neurofibromatosis type 1 compared to a control group. J Intellect Disabil Res. 2013;57:874–86. [PubMed: 23095048]
• De Schepper S, Maertens O, Callens T, Naeyaert JM, Lambert J, Messiaen L. Somatic mutation analysis in NF1 café au lait spots reveals two NF1 hits in the melanocytes. J Invest Dermatol. 2008;128:1050–3. [PubMed: 17914445]
• DiPaolo DP, Zimmerman RA, Rorke LB, Zackai EH, Bilaniuk LT, Yachnis AT. Neurofibromatosis type 1: pathologic substrate of high-signal-intensity foci in the brain. Radiology. 1995;195:721–4. [PubMed: 7754001]
• Dombi E, Baldwin A, Marcus LJ, Fisher MJ, Weiss B, Kim A, Whitcomb P, Martin S, Aschbacher-Smith LE, Rizvi TA, Wu J, Ershler R, Wolters P, Therrien J, Glod J, Belasco JB, Schorry E, Brofferio A, Starosta AJ, Gillespie A, Doyle AL, Ratner N, Widemann BC. Activity of selumetinib in neurofibromatosis type 1-related plexiform neurofibromas. N Engl J Med. 2016;375:2550–60. [PMC free article: PMC5508592] [PubMed: 28029918]
• Dombi E, Solomon J, Gillespie AJ, Fox E, Balis FM, Patronas N, Korf BR, Babovic-Vuksanovic D, Packer RJ, Belasco J, Goldman S, Jakacki R, Kieran M, Steinberg SM, Widemann BC. NF1 plexiform neurofibroma growth rate by volumetric MRI: relationship to age and body weight. Neurology. 2007;68:643–7. [PubMed: 17215493]
• Drouet A, Wolkenstein P, Lefaucheur JP, Pinson S, Combemale P, Gherardi RK, Brugières P, Salama J, Ehre P, Decq P, Créange A. Neurofibromatosis 1-associated neuropathies: a reappraisal. Brain. 2004;127:1993–2009. [PubMed: 15289270]
• Dunn GP, Spiliopoulos K, Plotkin SR, Hornicek FJ, Harmon DC, Delaney TF, Williams Z. Role of resection of malignant peripheral nerve sheath tumors in patients with neurofibromatosis type 1. J Neurosurg. 2013;118:142–8. [PubMed: 23101443]
• Dunning-Davies BM, Parker AP. Annual review of children with neurofibromatosis type 1. Arch Dis Child Educ Pract Ed. 2016;101:102–11. [PubMed: 26486853]
• Ejerskov C, Farholt S, Skovby F, Vestergaard EM, Haagerup A. Clinical presentations of 23 half-siblings from a mosaic neurofibromatosis type 1 sperm donor. Clin Genet. 2016;89:346–50. [PubMed: 25872886]
• Ekvall S, Sjörs K, Jonzon A, Vihinen M, Annerén G, Bondeson ML. Novel association of neurofibromatosis type 1-causing mutations in families with neurofibromatosis-Noonan syndrome. Am J Med Genet A. 2014;164A:579–87. [PubMed: 24357598]
• Elefteriou F, Kolanczyk M, Schindeler A, Viskochil DH, Hock JM, Schorry EK, Crawford AH, Friedman JM, Little D, Peltonen J, Carey JC, Feldman D, Yu X, Armstrong L, Birch P, Kendler DL, Mundlos S, Yang FC, Agiostratidou G, Hunter-Schaedle K, Stevenson DA. Skeletal abnormalities in neurofibromatosis type 1: approaches to therapeutic options. Am J Med Genet A. 2009;149A:2327–38. [PubMed: 19764036]
• Elgi U, Berker N, Teke MY, Simsek T, Ozdal P (2010) Unusual association of peripheral retinal ischemia-induced neovascular glaucoma and neurofibromatosis type 1. J Pediatr Ophthalmol Strabismus 47 Online:e1-3. [PubMed: 21214163]
• Emmerich D, Zemojtel T, Hecht J, Krawitz P, Spielmann M, Kühnisch J, Kobus K, Osswald M, Heinrich V, Berlien P, Müller U, Mautner VF, Wimmer K, Robinson PN, Vingron M, Tinschert S, Mundlos S, Kolanczyk M. Somatic neurofibromatosis type 1 (NF1) inactivation events in cutaneous neurofibromas of a single NF1 patient. Eur J Hum Genet. 2015;23:870–3. [PMC free article: PMC4795057] [PubMed: 25293717]
• Ennibi K, El Kassimi I, Asfalou I, Chaari J, Benyass A. Pulmonary hypertension and von Recklinghausen's disease: association and therapeutic difficulties. Pneumologia. 2015;64:55–7. [PubMed: 26738373]
• Ercolino T, Lai R, Giachè V, Melchionda S, Carella M, Delitala A, Mannelli M, Fanciulli G. Patient affected by neurofibromatosis type 1 and thyroid C-cell hyperplasia harboring pathogenic germ-line mutations in both NF1 and RET genes. Gene. 2014;536:332–5. [PubMed: 24361808]
• Ertan G, Zan E, Yousem DM, Ceritoglu C, Tekes A, Poretti A, Huisman TA. Diffusion tensor imaging of neurofibromatosis bright objects in children with neurofibromatosis type 1. Neuroradiol J. 2014;27:616–26. [PMC free article: PMC4237104] [PubMed: 25260209]
• Esposito T, Piluso G, Saracino D, Uccello R, Schettino C, Dato C, Capaldo G, Giugliano T, Varriale B, Paolisso G, Di Iorio G, Melone MA. A novel diagnostic method to detect truncated neurofibromin in neurofibromatosis 1. J Neurochem. 2015;135:1123–8. [PubMed: 26478990]
• Evans DG, Baser ME, McGaughran J, Sharif S, Howard E, Moran A. Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet. 2002;39:311–4. [PMC free article: PMC1735122] [PubMed: 12011145]
• Evans DG, Bowers N, Burkitt-Wright E, Miles E, Garg S, Scott-Kitching V, Penman-Splitt M, Dobbie A, Howard E, Ealing J, Vassalo G, Wallace AJ, Newman W, Northern UK. NF1 Research Network, Huson SM. Comprehensive RNA analysis of the NF1 gene in classically affected NF1 affected individuals meeting NIH criteria has high sensitivity and mutation negative testing is reassuring in isolated cases with pigmentary features only. EBioMedicine. 2016;7:212–20. [PMC free article: PMC4909377] [PubMed: 27322474]
• Evans DG, Howard E, Giblin C, Clancy T, Spencer H, Huson SM, Lalloo F. Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. Am J Med Genet A. 2010;152A:327–32. [PubMed: 20082463]
• Evans DG, O'Hara C, Wilding A, Ingham SL, Howard E, Dawson J, Moran A, Scott-Kitching V, Holt F, Huson SM. Mortality in neurofibromatosis 1: in North West England: an assessment of actuarial survival in a region of the UK since 1989. Eur J Hum Genet. 2011;19:1187–91. [PMC free article: PMC3198144] [PubMed: 21694737]
• Feldmann R, Schuierer G, Wessel A, Neveling N, Weglage J. Development of MRI T2 hyperintensities and cognitive functioning in patients with neurofibromatosis type 1. Acta Paediatr. 2010;99:1657–60. [PubMed: 21039823]
• Ferrari F, Masurel A, Olivier-Faivre L, Vabres P. Juvenile xanthogranuloma and nevus anemicus in the diagnosis of neurofibromatosis type 1. JAMA Dermatol. 2014;150:42–6. [PubMed: 24258576]
• Ferner RE, Gutmann DH. Neurofibromatosis type 1 (NF1): diagnosis and management. Handb Clin Neurol. 2013;115:939–55. [PubMed: 23931823]
• Ferner RE, Hughes RA, Hall SM, Upadhyaya M, Johnson MR. Neurofibromatous neuropathy in neurofibromatosis 1 (NF1). J Med Genet. 2004;41:837–41. [PMC free article: PMC1735623] [PubMed: 15520408]
• Ferner RE, Huson SM, Evans DGR. Neurofibromatoses in Clinical Practice. London, UK: Springer; 2011.
• Ferraz-Filho JR, da Rocha AJ, Muniz MP, Souza AS, Goloni-Bertollo EM, Pavarino-Bertelli EC. Unidentified bright objects in neurofibromatosis type 1: conventional MRI in the follow-up and correlation of microstructural lesions on diffusion tensor images. Eur J Paediatr Neurol. 2012a;16:42–7. [PubMed: 22088602]
• Ferraz-Filho JR, da Rocha AJ, Muniz MP, Souza AS, Goloni-Bertollo EM, Pavarino-Bertelli EC. Diffusion tensor MR imaging in neurofibromatosis type 1: expanding the knowledge of microstructural brain abnormalities. Pediatr Radiol. 2012b;42:449–54. [PubMed: 22033857]
• Fisher MJ, Loguidice M, Gutmann DH, Listernick R, Ferner RE, Ullrich NJ, Packer RJ, Tabori U, Hoffman RO, Ardern-Holmes SL, Hummel TR, Hargrave DR, Bouffet E, Charrow J, Bilaniuk LT, Balcer LJ, Liu GT. Visual outcomes in children with neurofibromatosis type 1-associated optic pathway glioma following chemotherapy: a multicenter retrospective analysis. Neuro Oncol. 2012;14:790–7. [PMC free article: PMC3367846] [PubMed: 22474213]
• Fossali E, Signorini E, Intermite RC, Casalini E, Lovaria A, Maninetti MM, Rossi LN. Renovascular disease and hypertension in children with neurofibromatosis. Pediatr Nephrol. 2000;14:806–10. [PubMed: 10955932]
• Friedman JM, Arbiser J, Epstein JA, Gutmann DH, Huot SJ, Lin AE, McManus B, Korf BR. Cardiovascular disease in neurofibromatosis 1: report of the NF1 Cardiovascular Task Force. Genet Med. 2002;4:105–11. [PubMed: 12180143]
• Friedrich RE, Hartmann M, Mautner VF. Malignant peripheral nerve sheath tumors (MPNST) in NF1-affected children. Anticancer Res. 2007;27:1957–60. [PubMed: 17649804]
• Friedrich RE, Nuding MA. Optic pathway glioma and cerebral focal abnormal signal intensity in patients with neurofibromatosis type 1: characteristics, treatment choices and follow-up in 134 affected individuals and a brief review of the literature. Anticancer Res. 2016;36:4095–121. [PubMed: 27466519]
• Friedrich RE, Schmelzle R, Hartmann M, Fünsterer C, Mautner VF. Resection of small plexiform neurofibromas in neurofibromatosis type 1 children. World J Surg Oncol. 2005;3:6. [PMC free article: PMC549083] [PubMed: 15683544]
• Friedrich RE, Stelljes C, Hagel C, Giese M, Scheuer HA. Dysplasia of the orbit and adjacent bone associated with plexiform neurofibroma and ocular disease in 42 NF-1 patients. Anticancer Res. 2010;30:1751–64. [PubMed: 20592374]
• Gales J, Prayson RA. Hippocampal sclerosis and associated focal cortical dysplasia-related epilepsy in neurofibromatosis type I. J Clin Neurosci. 2017;37:15–19. [PubMed: 27939253]
• García-Romero MT, Parkin P, Lara-Corrales I. Mosaic neurofibromatosis type 1: a systematic review. Pediatr Dermatol. 2016;33:9–17. [PubMed: 26338194]
• Garg S, Green J, Leadbitter K, Emsley R, Lehtonen A, Evans DG, Huson SM. Neurofibromatosis type 1 and autism spectrum disorder. Pediatrics. 2013a;132:e1642–8. [PubMed: 24190681]
• Garg S, Lehtonen A, Huson SM, Emsley R, Trump D, Evans DG, Green J. Autism and other psychiatric comorbidity in neurofibromatosis type 1: evidence from a population-based study. Dev Med Child Neurol. 2013b;55:139–45. [PubMed: 23163236]
• Goodden J, Pizer B, Pettorini B, Williams D, Blair J, Didi M, Thorp N, Mallucci C. The role of surgery in optic pathway/hypothalamic gliomas in children. J Neurosurg Pediatr. 2014;13:1–12. [PubMed: 24138145]
• Gorgel A, Cetinkaya DD, Salgur F, Demirpence M, Yilmaz H, Karaman EH, Tutuncuoglu P, Oruk G, Bahceci M, Sari AA, Altinboga AA, Paker I. Coexistence of gastrointestinal stromal tumors (GISTs) and pheochromocytoma in three cases of neurofibromatosis type 1 (NF1) with a review of the literature. Intern Med. 2014;53:1783–9. [PubMed: 25130111]
• Granström S, Friedrich RE, Langenbruch AK, Augustin M, Mautner VF. Influence of learning disabilities on the tumour predisposition syndrome NF1--survey from adult patients' perspective. Anticancer Res. 2014;34:3675–81. [PubMed: 24982386]
• Greenwood RS, Tupler LA, Whitt JK, Buu A, Dombeck CB, Harp AG, Payne ME, Eastwood JD, Krishnan KR, MacFall JR. Brain morphometry, T2-weighted hyperintensities, and IQ in children with neurofibromatosis type 1. Arch Neurol. 2005;62:1904–8. [PubMed: 16344348]
• Grisart B, Rack K, Vidrequin S, Hilbert P, Deltenre P, Verellen-Dumoulin C, Destrée A. NF1 microduplication first clinical report: association with mild mental retardation, early onset of baldness and dental enamel hypoplasia? Eur J Hum Genet. 2008;16:305–11. [PubMed: 18183042]
• Hagel C, Zils U, Peiper M, Kluwe L, Gotthard S, Friedrich RE, Zurakowski D, von Deimling A, Mautner VF. Histopathology and clinical outcome of NF1-associated vs. sporadic malignant peripheral nerve sheath tumors. J Neurooncol. 2007;82:187–92. [PubMed: 17111191]
• Han M, Criado E. Renal artery stenosis and aneurysms associated with neurofibromatosis. J Vasc Surg. 2005;41:539–43. [PubMed: 15838492]
• Harrison B, Moore AM, Calfee R, Sammer DM. The association between glomus tumors and neurofibromatosis. J Hand Surg Am. 2013;38:1571–4. [PubMed: 23849732]
• Heervä E, Huilaja L, Leinonen P, Peltonen S, Peltonen J. Follow-up of six patients with neurofibromatosis 1-related osteoporosis treated with alendronate for 23 months. Calcif Tissue Int. 2014;94:608–12. [PubMed: 24390519]
• Heervä E, Leinonen P, Kuorilehto T, Peltonen S, Pöyhönen M, Väänänen K, Peltonen J. Neurofibromatosis 1-related osteopenia often progresses to osteoporosis in 12 years. Calcif Tissue Int. 2013;92:23–7. [PubMed: 23108390]
• Heervä E, Peltonen S, Svedström E, Aro HT, Väänänen K, Peltonen J. Osteoclasts derived from patients with neurofibromatosis 1 (NF1) display insensitivity to bisphosphonates in vitro. Bone. 2012;50:798–803. [PubMed: 22226973]
• Hernández-Martín A, García-Martínez FJ, Duat A, López-Martín I, Noguera-Morel L, Torrelo A. Nevus anemicus: a distinctive cutaneous finding in neurofibromatosis type 1. Pediatr Dermatol. 2015;32:342–7. [PubMed: 25690591]
• Hirbe AC, Gutmann DH. Neurofibromatosis type 1: a multidisciplinary approach to care. Lancet Neurol. 2014;13:834–43. [PubMed: 25030515]
• Hood CT, Janku L, Lowder CY, Singh AD. Retinal vasoproliferative tumor in association with neurofibromatosis type 1. J Pediatr Ophthalmol Strabismus. 2009;25:1–3. [PubMed: 19645388]
• Howell SJ, Hockenhull K, Salih Z, Evans DG. Increased risk of breast cancer in neurofibromatosis type 1: current insights. Breast Cancer (Dove Med Press). 2017;9:531–536. [PMC free article: PMC5573065] [PubMed: 28860858]
• Hsieh HY, Fung HC, Wang CJ, Chin SC, Wu T. Epileptic seizures in neurofibromatosis type 1 are related to intracranial tumors but not to neurofibromatosis bright objects. Seizure. 2011;20:606–11. [PubMed: 21621428]
• Hu Z, Liu Z, Qiu Y, Xu L, Yan H, Zhu Z. Morphological differences in the vertebrae of scoliosis secondary to neurofibromatosis type 1 with and without paraspinal neurofibromas. Spine (Phila Pa 1976). 2016;41:598–602. [PubMed: 26780616]
• Hüffmeier U, Zenker M, Hoyer J, Fahsold R, Rauch A. A variable combination of features of Noonan syndrome and neurofibromatosis type I are caused by mutations in the NF1 gene. Am J Med Genet A. 2006;140:2749–56. [PubMed: 17103458]
• Hyman SL, Gill DS, Shores EA, Steinberg A, North KN. T2 hyperintensities in children with neurofibromatosis type 1 and their relationship to cognitive functioning. J Neurol Neurosurg Psychiatry. 2007;78:1088–91. [PMC free article: PMC2117545] [PubMed: 17299016]
• Jentarra GM, Rice SG, Olfers S, Rajan C, Saffen DM, Narayanan V. Skewed allele-specific expression of the NF1 gene in normal subjects: a possible mechanism for phenotypic variability in neurofibromatosis type 1. J Child Neurol. 2012;27:695–702. [PubMed: 22068829]
• Ji J, Shimony J, Gao F, McKinstry RC, Gutmann DH. Optic nerve tortuosity in children with neurofibromatosis type 1. Pediatr Radiol. 2013;43:1336–43. [PMC free article: PMC3904184] [PubMed: 23636538]
• Kanojia D, Nagata Y, Garg M, Lee DH, Sato A, Yoshida K, Sato Y, Sanada M, Mayakonda A, Bartenhagen C, Klein HU, Doan NB, Said JW, Mohith S, Gunasekar S, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Myklebost O, Yang H, Dugas M, Meza-Zepeda LA, Silberman AW, Forscher C, Tyner JW, Ogawa S, Koeffler HP. Genomic landscape of liposarcoma. Oncotarget. 2015;6:42429–44. [PMC free article: PMC4767443] [PubMed: 26643872]
• Kaplan L, Foster R, Shen Y, Parry DM, McMaster ML, O'Leary MC, Gusella JF. Monozygotic twins discordant for neurofibromatosis 1. Am J Med Genet A. 2010;152A:601–6. [PMC free article: PMC2830382] [PubMed: 20186797]
• Karajannis MA, Ferner RE. Neurofibromatosis-related tumors: emerging biology and therapies. Curr Opin Pediatr. 2015;27:26–33. [PMC free article: PMC4374132] [PubMed: 25490687]
• Karlsgodt KH, Rosser T, Lutkenhoff ES, Cannon TD, Silva A, Bearden CE. Alterations in white matter microstructure in neurofibromatosis-1. PLoS One. 2012;7:e47854. [PMC free article: PMC3477133] [PubMed: 23094098]
• Karvonen M, Saari A, Hannila ML, Lönnqvist T, Dunkel L, Sankilampi U. Elevated head circumference- to-height ratio is an early and frequent feature in children with neurofibromatosis type 1. Horm Res Paediatr. 2013;79:97–102. [PubMed: 23466600]
• Kawabata S, Watanabe K, Hosogane N, Ishii K, Nakamura M, Toyama Y, Matsumoto M. Surgical correction of severe cervical kyphosis in patients with neurofibromatosis Type 1. J Neurosurg Spine. 2013;18:274–9. [PubMed: 23289507]
• Kawakami I, Katsuse O, Aoki N, Togo T, Suzuki K, Isojima D, Kondo D, Iseki E, Kosaka K, Akiyama H, Hirayasu Y. Autopsy case of concurrent Huntington's disease and neurofibromatosis type 1. Psychogeriatrics. 2014;14:81–6. [PubMed: 24528652]
• Kehrer-Sawatzki H, Bengesser K, Callens T, Mikhail F, Fu C, Hillmer M, Walker ME, Saal HM, Lacassie Y, Cooper DN, Messiaen L. Identification of large NF1 duplications reciprocal to NAHR-mediated type-1 NF1 deletions. Hum Mutat. 2014;35:1469–75. [PubMed: 25205021]
• Kehrer-Sawatzki H, Cooper DN. NF1 microdeletions and their underlying mutational mechanisms. In Upadhyaya M, Cooper DN, eds. Neurofibromatosis Type 1. Berlin, Germany: Springer-Verlag; 2012:187-209.
• Kehrer-Sawatzki H, Vogt J, Mußotter T, Kluwe L, Cooper DN, Mautner VF. Dissecting the clinical phenotype associated with mosaic type-2 NF1 microdeletions. Neurogenetics. 2012;13:229–36. [PubMed: 22581253]
• Kim A, Gillespie A, Dombi E, Goodwin A, Goodspeed W, Fox E, Balis FM, Widemann BC. Characteristics of children enrolled in treatment trials for NF1-related plexiform neurofibromas. Neurology. 2009;73:1273–9. [PMC free article: PMC2764415] [PubMed: 19841379]
• King KS, Pacak K. Familial pheochromocytomas and paragangliomas. Mol Cell Endocrinol. 2014;386:92–100. [PMC free article: PMC3917973] [PubMed: 23933153]
• Kleinerman RA. Radiation-sensitive genetically susceptible pediatric sub-populations. Pediatr Radiol. 2009;39 Suppl 1:S27–31. [PMC free article: PMC2656401] [PubMed: 19083227]
• Klose A, Peters H, Hoffmeyer S, Buske A, Lüder A, Hess D, Lehmann R, Nürnberg P, Tinschert S. Two independent mutations in a family with neurofibromatosis type 1 (NF1). Am J Med Genet. 1999;83:6–12. [PubMed: 10076878]
• Kluwe L, Friedrich RE, Peiper M, Friedman J, Mautner VF. Constitutional NF1 mutations in neurofibromatosis 1 patients with malignant peripheral nerve sheath tumors. Hum Mutat. 2003;22:420. [PubMed: 14517963]
• Kluwe L, Siebert R, Gesk S, Friedrich RE, Tinschert S, Kehrer-Sawatzki H, Mautner VF. Screening 500 unselected neurofibromatosis 1 patients for deletions of the NF1 gene. Hum Mutat. 2004;23:111–6. [PubMed: 14722914]
• Kobus K, Hartl D, Ott CE, Osswald M, Huebner A, von der Hagen M, Emmerich D, Kühnisch J, Morreau H, Hes FJ, Mautner VF, Harder A, Tinschert S, Mundlos S, Kolanczyk M. Double NF1 inactivation affects adrenocortical function in NF1Prx1 mice and a human patient. PLoS One. 2015;10:e0119030. [PMC free article: PMC4361563] [PubMed: 25775093]
• Kocova M, Kochova E, Sukarova-Angelovska E. Optic glioma and precocious puberty in a girl with neurofibromatosis type 1 carrying an R681X mutation of NF1: case report and review of the literature. BMC Endocr Disord. 2015;15:82. [PMC free article: PMC4678666] [PubMed: 26666878]
• Koliou X, Fedonidis C, Kalpachidou T, Mangoura D. Nuclear import mechanism of neurofibromin for localization on the spindle and function in chromosome congression. J Neurochem. 2016;136:78–91. [PubMed: 26490262]
• Koss M, Scott RM, Irons MB, Smith ER, Ullrich NJ. Moyamoya syndrome associated with neurofibromatosis Type 1: perioperative and long-term outcome after surgical revascularization. J Neurosurg Pediatr. 2013;11:417–25. [PubMed: 23373626]
• Kriechbaumer LK, Susani M, Kircher SG, Distelmaier K, Happak W. Comparative study of CO2- and Er:YAG laser ablation of multiple cutaneous neurofibromas in von Recklinghausen's disease. Lasers Med Sci. 2014;29:1083–91. [PubMed: 24189926]
• Krishnatry R, Zhukova N, Guerreiro Stucklin AS, Pole JD, Mistry M, Fried I, Ramaswamy V, Bartels U, Huang A, Laperriere N, Dirks P, Nathan PC, Greenberg M, Malkin D, Hawkins C, Bandopadhayay P, Kieran MW, Manley PE, Bouffet E, Tabori U. Clinical and treatment factors determining long-term outcomes for adult survivors of childhood low-grade glioma: a population-based study. Cancer. 2016;122:1261–9. [PubMed: 26970559]
• Kühnisch J, Seto J, Lange C, Schrof S, Stumpp S, Kobus K, Grohmann J, Kossler N, Varga P, Osswald M, Emmerich D, Tinschert S, Thielemann F, Duda G, Seifert W, El Khassawna T, Stevenson DA, Elefteriou F, Kornak U, Raum K, Fratzl P, Mundlos S, Kolanczyk M. Multiscale, converging defects of macro-porosity, microstructure and matrix mineralization impact long bone fragility in NF1. PLoS One. 2014;9:e86115. [PMC free article: PMC3897656] [PubMed: 24465906]
• Kumar MG, Emnett RJ, Bayliss SJ, Gutmann DH. Glomus tumors in individuals with neurofibromatosis type 1. J Am Acad Dermatol. 2014;71:44–8. [PubMed: 24685357]
• Lama G, Graziano L, Calabrese E, Grassia C, Rambaldi PF, Cioce F, Tedesco MA, Di Salvo G, Esposito-Salsano M. Blood pressure and cardiovascular involvement in children with neurofibromatosis type1. Pediatr Nephrol. 2004;19:413–8. [PubMed: 14991390]
• Lammert M, Friedman JM, Kluwe L, Mautner VF. Prevalence of neurofibromatosis 1 in German children at elementary school enrollment. Arch Dermatol. 2005;141:71–4. [PubMed: 15655144]
• Lammert M, Friedman JM, Roth HJ, Friedrich RE, Kluwe L, Atkins D, Schooler T, Mautner VF. Vitamin D deficiency associated with number of neurofibromas in neurofibromatosis 1. J Med Genet. 2006;43:810–3. [PMC free article: PMC2563168] [PubMed: 16571643]
• Laycock-van Spyk S, Thomas N, Cooper DN, Upadhyaya M. Neurofibromatosis type 1-associated tumours: their somatic mutational spectrum and pathogenesis. Hum Genomics. 2011;5:623–90. [PMC free article: PMC3525246] [PubMed: 22155606]
• Lázaro C, Gaona A, Lynch M, Kruyer H, Ravella A, Estivill X. Molecular characterization of the breakpoints of a 12-kb deletion in the NF1 gene in a family showing germ-line mosaicism. Am J Hum Genet. 1995;57:1044–9. [PMC free article: PMC1801366] [PubMed: 7485153]
• Lee SM, Choi IH, Lee DY, Lee HR, Park MS, Yoo WJ, Chung CY, Cho TJ. Is double inactivation of the Nf1 gene responsible for the development of congenital pseudarthrosis of the tibia associated with NF1? J Orthop Res. 2012;30:1535–40. [PubMed: 22488919]
• Lee W, Teckie S, Wiesner T, Ran L, Prieto Granada CN, Lin M, Zhu S, Cao Z, Liang Y, Sboner A, Tap WD, Fletcher JA, Huberman KH, Qin LX, Viale A, Singer S, Zheng D, Berger MF, Chen Y, Antonescu CR, Chi P. PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors. Nat Genet. 2014;46:1227–32. [PMC free article: PMC4249650] [PubMed: 25240281]
• Legius E, Wu R, Eyssen M, Marynen P, Fryns JP, Cassiman JJ. Encephalocraniocutaneous lipomatosis with a mutation in the NF1 gene. J Med Genet. 1995;32:316–9. [PMC free article: PMC1050386] [PubMed: 7643367]
• Lehtonen A, Howie E, Trump D, Huson SM. Behaviour in children with neurofibromatosis type 1: cognition, executive function, attention, emotion, and social competence. Dev Med Child Neurol. 2013;55:111–25. [PubMed: 22934576]
• Leschziner GD, Golding JF, Ferner RE. Sleep disturbance as part of the neurofibromatosis type 1 phenotype in adults. Am J Med Genet A. 2013;161A:1319–22. [PubMed: 23636844]
• Licis AK, Vallorani A, Gao F, Chen C, Lenox J, Yamada KA, Duntley SP, Gutmann DH. Prevalence of Sleep Disturbances in Children With Neurofibromatosis Type 1. J Child Neurol. 2013;28:1400–5. [PMC free article: PMC3805763] [PubMed: 24065580]
• Lin AE, Birch PH, Korf BR, Tenconi R, Niimura M, Poyhonen M, Armfield Uhas K, Sigorini M, Virdis R, Romano C, Bonioli E, Wolkenstein P, Pivnick EK, Lawrence M, Friedman JM. Cardiovascular malformations and other cardiovascular abnormalities in neurofibromatosis 1. Am J Med Genet. 2000;95:108–17. [PubMed: 11078559]
• Lin N, Baird L, Koss M, Kopecky KE, Gone E, Ullrich NJ, Scott RM, Smith ER. Discovery of asymptomatic moyamoya arteriopathy in pediatric syndromic populations: radiographic and clinical progression. Neurosurg Focus. 2011;31:E6. [PubMed: 22133171]
• Lion-François L, Gueyffier F, Mercier C, Gérard D, Herbillon V, Kemlin I, Rodriguez D, Ginhoux T, Peyric E, Coutinho V, Bréant V, des Portes V, Pinson S, Combemale P, Kassaï B. Réseau NF1 Rhône Alpes Auvergne-France. The effect of methylphenidate on neurofibromatosis type 1: a randomised, double-blind, placebo-controlled, crossover trial. Orphanet J Rare Dis. 2014;9:142. [PMC free article: PMC4172829] [PubMed: 25205361]
• Listernick R, Ferner RE, Liu GT, Gutmann DH. Optic pathway gliomas in neurofibromatosis-1: controversies and recommendations. Ann Neurol. 2007;61:189–98. [PMC free article: PMC5908242] [PubMed: 17387725]
• Luo G, Kim J, Song K. The C-terminal domains of human neurofibromin and its budding yeast homologs Ira1 and Ira2 regulate the metaphase to anaphase transition. Cell Cycle. 2014;13:2780–9. [PMC free article: PMC4615033] [PubMed: 25486365]
• Madanikia SA, Bergner A, Ye X, Blakeley JO. Increased risk of breast cancer in women with NF1. Am J Med Genet A. 2012;158A:3056–60. [PMC free article: PMC3507419] [PubMed: 23165953]
• Madden JR, Rush SZ, Stence N, Foreman NK, Liu AK. Radiation-induced gliomas in 2 pediatric patients with neurofibromatosis type 1: case study and summary of the literature. J Pediatr Hematol Oncol. 2014;36:e105–8. [PubMed: 24136023]
• Maertens O, De Schepper S, Vandesompele J, Brems H, Heyns I, Janssens S, Speleman F, Legius E, Messiaen L. Molecular dissection of isolated disease features in mosaic neurofibromatosis type 1. Am J Hum Genet. 2007;81:243–51. [PMC free article: PMC1950809] [PubMed: 17668375]
• Mandiwanza T, Kaliaperumal C, Khalil A, Sattar M, Crimmins D, Caird J. Suprasellar pilocytic astrocytoma: one national centre's experience. Childs Nerv Syst. 2014;30:1243–8. [PubMed: 24566674]
• Maraña Pérez AI, Duat Rodríguez A, Soto Insuga V, Domínguez Carral J, Puertas Martín V, González Gutiérrez Solana L. Prevalence of sleep disorders in patients with neurofibromatosis type 1. Neurologia. 2015;30:561–5. [PubMed: 24975344]
• Margariti PN, Blekas K, Katzioti FG, Zikou AK, Tzoufi M, Argyropoulou MI. Magnetization transfer ratio and volumetric analysis of the brain in macrocephalic patients with neurofibromatosis type 1. Eur Radiol. 2007;17:433–8. [PubMed: 16733674]
• Marque M, Roubertie A, Jaussent A, Carneiro M, Meunier L, Guillot B, Pinson L, Pinson S, Bessis D. Nevus anemicus in neurofibromatosis type 1: a potential new diagnostic criterion. J Am Acad Dermatol. 2013;69:768–75. [PubMed: 23972508]
• Martin F, Kana V, Mori AC, Fischer D, Parkin N, Boltshauser E, Rushing EJ, Klein A. Neurofibromatosis type 1 (NF1) with an unusually severe phenotype due to digeny for NF1 and ryanodine receptor 1 associated myopathy. Eur J Pediatr. 2014;173:1691–4. [PubMed: 24706162]
• Martins R, Bugalho MJ. Paragangliomas/pheochromocytomas: clinically oriented genetic testing. Int J Endocrinol. 2014;2014:794187. [PMC free article: PMC4037125] [PubMed: 24899893]
• Maruoka R, Takenouchi T, Torii C, Shimizu A, Misu K, Higasa K, Matsuda F, Ota A, Tanito K, Kuramochi A, Arima Y, Otsuka F, Yoshida Y, Moriyama K, Niimura M, Saya H, Kosaki K. The use of next-generation sequencing in molecular diagnosis of neurofibromatosis type 1: a validation study. Genet Test Mol Biomarkers. 2014;18:722–35. [PMC free article: PMC4216997] [PubMed: 25325900]
• Masocco M, Kodra Y, Vichi M, Conti S, Kanieff M, Pace M, Frova L, Taruscio D. Mortality associated with neurofibromatosis type 1: a study based on Italian death certificates (1995-2006). Orphanet J Rare Dis. 2011;6:11. [PMC free article: PMC3079598] [PubMed: 21439034]
• Matsumine A, Kusuzaki K, Nakamura T, Nakazora S, Niimi R, Matsubara T, Uchida K, Murata T, Kudawara I, Ueda T, Naka N, Araki N, Maeda M, Uchida A. Differentiation between neurofibromas and malignant peripheral nerve sheath tumors in neurofibromatosis 1 evaluated by MRI. J Cancer Res Clin Oncol. 2009;135:891–900. [PubMed: 19101731]
• Mautner VF, Asuagbor FA, Dombi E, Fünsterer C, Kluwe L, Wenzel R, Widemann BC, Friedman JM. Assessment of benign tumor burden by whole-body MRI in patients with neurofibromatosis 1. Neuro Oncol. 2008;10:593–8. [PMC free article: PMC2666233] [PubMed: 18559970]
• Mautner VF, Kluwe L, Friedrich RE, Roehl AC, Bammert S, Högel J, Spöri H, Cooper DN, Kehrer-Sawatzki H. Clinical characterisation of 29 neurofibromatosis type-1 patients with molecularly ascertained 1.4 Mb type-1 NF1 deletions. J Med Genet. 2010;47:623–30. [PubMed: 20543202]
• McCaughan JA, Holloway SM, Davidson R, Lam WW. Further evidence of the increased risk for malignant peripheral nerve sheath tumour from a Scottish cohort of patients with neurofibromatosis type 1. J Med Genet. 2007;44:463–6. [PMC free article: PMC2598004] [PubMed: 17327286]
• McEwing RL, Joelle R, Mohlo M, Bernard JP, Hillion Y, Ville Y. Prenatal diagnosis of neurofibromatosis type 1: sonographic and MRI findings. Prenat Diagn. 2006;26:1110–4. [PubMed: 16981221]
• Méni C, Sbidian E, Moreno JC, Lafaye S, Buffard V, Goldzal S, Wolkenstein P, Valeyrie-Allanore L. Treatment of neurofibromas with a carbon dioxide laser: a retrospective cross-sectional study of 106 patients. Dermatology. 2015;230:263–8. [PubMed: 25662097]
• Merker VL, Bredella MA, Cai W, Kassarjian A, Harris GJ, Muzikansky A, Nguyen R, Mautner VF, Plotkin SR. Relationship between whole-body tumor burden, clinical phenotype, and quality of life in patients with neurofibromatosis. Am J Med Genet A. 2014;164A:1431–7. [PubMed: 24664633]
• Merker VL, Esparza S, Smith MJ, Stemmer-Rachamimov A, Plotkin SR. Clinical features of schwannomatosis: a retrospective analysis of 87 patients. Oncologist. 2012;17:1317–22. [PMC free article: PMC3481897] [PubMed: 22927469]
• Merker VL, Murphy TP, Hughes JB, Muzikansky A, Hughes MR, Souter I, Plotkin SR. Outcomes of preimplantation genetic diagnosis in neurofibromatosis type 1. Fertil Steril. 2015;103:761–8.e1. [PubMed: 25557241]
• Messiaen L, Vogt J, Bengesser K, Fu C, Mikhail F, Serra E, Garcia-Linares C, Cooper DN, Lazaro C, Kehrer-Sawatzki H. Mosaic type-1 NF1 microdeletions as a cause of both generalized and segmental neurofibromatosis type-1 (NF1). Hum Mutat. 2011;32:213–9. [PubMed: 21280148]
• Messiaen LM, Wimmer K. NF1 mutational spectrum. In: Kaufmann D, ed. Neurofibromatoses. Monographs in Human Genetics. Vol 16. Basel, Switzerland: Karger; 2008:63-77.
• Miettinen M, Fetsch JF, Sobin LH, Lasota J. Gastrointestinal stromal tumors in patients with neurofibromatosis 1: a clinicopathologic and molecular genetic study of 45 cases. Am J Surg Pathol. 2006;30:90–6. [PubMed: 16330947]
• Miller DT, Freedenberg D, Schorry E, Ullrich NJ, Viskochil D, Korf BR, et al. Health supervision for children with neurofibromatosis type 1. Pediatrics. 2019:143. [PubMed: 31010905]
• Moles KJ, Gowans GC, Gedela S, Beversdorf D, Yu A, Seaver LH, Schultz RA, Rosenfeld JA, Torchia BS, Shaffer LG. NF1 microduplications: identification of seven nonrelated individuals provides further characterization of the phenotype. Genet Med. 2012;14:508–14. [PubMed: 22241097]
• Montani D, Coulet F, Girerd B, Eyries M, Bergot E, Mal H, Biondi G, Dromer C, Hugues T, Marquette C, O'Connell C, O'Callaghan DS, Savale L, Jaïs X, Dorfmüller P, Begueret H, Bertoletti L, Sitbon O, Bellanné-Chantelot C, Zalcman G, Simonneau G, Humbert M, Soubrier F. Pulmonary hypertension in patients with neurofibromatosis type I. Medicine (Baltimore). 2011;90:201–11. [PubMed: 21512413]
• Morris SM, Acosta MT, Garg S, Green J, Huson S, Legius E, North KN, Payne JM, Plasschaert E, Frazier TW, Weiss LA, Zhang Y, Gutmann DH, Constantino JN. Disease burden and symptom structure of autism in neurofibromatosis type 1: a study of the International NF1-ASD Consortium Team (INFACT). JAMA Psychiatry. 2016;73:1276–84. [PMC free article: PMC5298203] [PubMed: 27760236]
• Murphy ES, Xie H, Merchant TE, Yu JS, Chao ST, Suh JH. Review of cranial radiotherapy-induced vasculopathy. J Neurooncol. 2015;122:421–9. [PubMed: 25670390]
• Nguyen R, Dombi E, Akshintala S, Baldwin A, Widemann BC. Characterization of spinal findings in children and adults with neurofibromatosis type 1 enrolled in a natural history study using magnetic resonance imaging. J Neurooncol. 2015;121:209–15. [PubMed: 25293439]
• Nguyen R, Dombi E, Widemann BC, Solomon J, Fuensterer C, Kluwe L, Friedman JM, Mautner VF. Growth dynamics of plexiform neurofibromas: a retrospective cohort study of 201 patients with neurofibromatosis 1. Orphanet J Rare Dis. 2012;7:75. [PMC free article: PMC3524754] [PubMed: 23035791]
• Nguyen R, Ibrahim C, Friedrich RE, Westphal M, Schuhmann M, Mautner VF. Growth behavior of plexiform neurofibromas after surgery. Genet Med. 2013a;15:691–7. [PubMed: 23598713]
• Nguyen R, Jett K, Harris GJ, Cai W, Friedman JM, Mautner VF. Benign whole body tumor volume is a risk factor for malignant peripheral nerve sheath tumors in neurofibromatosis type 1. J Neurooncol. 2014;116:307–13. [PubMed: 24166582]
• Nguyen R, Mir TS, Kluwe L, Jett K, Kentsch M, Mueller G, Kehrer-Sawatzki H, Friedman JM, Mautner VF. Cardiac characterization of 16 patients with large NF1 gene deletions. Clin Genet. 2013b;84:344–9. [PubMed: 23278345]
• Nicita F, Di Biasi C, Sollaku S, Cecchini S, Salpietro V, Pittalis A, Papetti L, Ursitti F, Ulgiati F, Zicari AM, Gualdi GF, Properzi E, Duse M, Ruggieri M, Spalice A. Evaluation of the basal ganglia in neurofibromatosis type 1. Childs Nerv Syst. 2014;30:319–25. [PubMed: 23892392]
• Nicolin G, Parkin P, Mabbott D, Hargrave D, Bartels U, Tabori U, Rutka J, Buncic JR, Bouffet E. Natural history and outcome of optic pathway gliomas in children. Pediatr Blood Cancer. 2009;53:1231–7. [PubMed: 19621457]
• NIH. National Institutes of Health Consensus Development Conference Statement: neurofibromatosis. Bethesda, Md, USA, July 13-15, 1987. Neurofibromatosis. 1988;1:172–8. [PubMed: 3152465]
• Ning X, Farschtschi S, Jones A, Kehrer-Sawatzki H, Mautner VF, Friedman JM. Growth in neurofibromatosis 1 microdeletion patients. Clin Genet. 2016;89:351–4. [PubMed: 26111455]
• Nishida T, Tsujimoto M, Takahashi T, Hirota S, Blay JY, Wataya-Kaneda M. Gastrointestinal stromal tumors in Japanese patients with neurofibromatosis type I. J Gastroenterol. 2016;51:571–8. [PMC free article: PMC4880630] [PubMed: 26511941]
• Nunley KS, Gao F, Albers AC, Bayliss SJ, Gutmann DH. Predictive value of café au lait macules at initial consultation in the diagnosis of neurofibromatosis type 1. Arch Dermatol. 2009;145:883–7. [PubMed: 19687418]
• Oguzkan S, Cinbis M, Ayter S, Anlar B, Aysun S. Familial segmental neurofibromatosis. J Child Neurol. 2004;19:392–4. [PubMed: 15224714]
• Ostendorf AP, Gutmann DH, Weisenberg JL. Epilepsy in individuals with neurofibromatosis type 1. Epilepsia. 2013;54:1810–4. [PubMed: 24032542]
• Paria N, Cho TJ, Choi IH, Kamiya N, Kayembe K, Mao R, Margraf RL, Obermosser G, Oxendine I, Sant DW, Song MH, Stevenson DA, Viskochil DH, Wise CA, Kim HK, Rios JJ. Neurofibromin deficiency-associated transcriptional dysregulation suggests a novel therapy for tibial pseudoarthrosis in NF1. J Bone Miner Res. 2014;29:2636–42. [PMC free article: PMC4268180] [PubMed: 24932921]
• Parkhurst E, Abboy S. Optic gliomas in neurofibromatosis type 1. J Pediatr Ophthalmol Strabismus. 2016;53:334–8. [PubMed: 27537249]
• Parrozzani R, Clementi M, Frizziero L, Miglionico G, Perrini P, Cavarzeran F, Kotsafti O, Comacchio F, Trevisson E, Convento E, Fusetti S, Midena E. In vivo detection of choroidal abnormalities related to NF1: feasibility and comparison with standard NIH diagnostic criteria in pediatric patients. Invest Ophthalmol Vis Sci. 2015;56:6036–42. [PubMed: 26393470]
• Pasmant E, Parfait B, Luscan A, Goussard P, Briand-Suleau A, Laurendeau I, Fouveaut C, Leroy C, Montadert A, Wolkenstein P, Vidaud M, Vidaud D. Neurofibromatosis type 1 molecular diagnosis: what can NGS do for you when you have a large gene with loss of function mutations? Eur J Hum Genet. 2015;23:596–601. [PMC free article: PMC4402624] [PubMed: 25074460]
• Pasmant E, Sabbagh A, Spurlock G, Laurendeau I, Grillo E, Hamel MJ, Martin L, Barbarot S, Leheup B, Rodriguez D, Lacombe D, Dollfus H, Pasquier L, Isidor B, Ferkal S, Soulier J, Sanson M, Dieux-Coeslier A, Bièche I, Parfait B, Vidaud M, Wolkenstein P, Upadhyaya M, Vidaud D. members of the NF France Network. NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype. Hum Mutat. 2010;31:E1506–18. [PubMed: 20513137]
• Pasmant E, Vidaud M, Vidaud D, Wolkenstein P. Neurofibromatosis type 1: from genotype to phenotype. J Med Genet. 2012;49:483–9. [PubMed: 22889851]
• Patel NB, Stacy GS. Musculoskeletal manifestations of neurofibromatosis type 1. AJR Am J Roentgenol. 2012;199:W99-106. [PubMed: 22733937]
• Patil S, Chamberlain RS. Neoplasms associated with germline and somatic NF1 gene mutations. Oncologist. 2012;17:101–16. [PMC free article: PMC3267808] [PubMed: 22240541]
• Payne JM, Pickering T, Porter M, Oates EC, Walia N, Prelog K, North KN. Longitudinal assessment of cognition and T2-hyperintensities in NF1: an 18-year study. Am J Med Genet A. 2014;164A:661–5. [PubMed: 24357578]
• Pemov A, Sung H, Hyland PL, Sloan JL, Ruppert SL, Baldwin AM, Boland JF, Bass SE, Lee HJ, Jones KM, Zhang X. NISC Comparative Sequencing Program, Mullikin JC, Widemann BC, Wilson AF, Stewart DR. Genetic modifiers of neurofibromatosis type 1-associated café-au-lait macule count identified using multi-platform analysis. PLoS Genet. 2014;10:e1004575. [PMC free article: PMC4199479] [PubMed: 25329635]
• Petramala L, Giustini S, Zinnamosca L, Marinelli C, Colangelo L, Cilenti G, Formicuccia MC, D'Erasmo E, Calvieri S, Letizia C. Bone mineral metabolism in patients with neurofibromatosis type 1 (von Recklingausen disease). Arch Dermatol Res. 2012;304:325–31. [PubMed: 22120694]
• Pessis R, Lantieri L, Britto JA, Leguerinel C, Wolkenstein P, Hivelin M. Surgical care burden in orbito-temporal neurofibromatosis: multiple procedures and surgical care duration analysis in 47 consecutive adult patients. J Craniomaxillofac Surg. 2015;43:1684–93. [PubMed: 26210305]
• Pinho RS, Fusão EF, Paschoal JK, Caran EM, Minett TS, Vilanova LC, Masruha MR. Migraine is frequent in children and adolescents with neurofibromatosis type 1. Pediatr Int. 2014;56:865–7. [PubMed: 24832054]
• Pinna V, Lanari V, Daniele P, Consoli F, Agolini E, Margiotti K, Bottillo I, Torrente I, Bruselles A, Fusilli C, Ficcadenti A, Bargiacchi S, Trevisson E, Forzan M, Giustini S, Leoni C, Zampino G, Digilio MC, Dallapiccola B, Clementi M, Tartaglia M, De Luca A. p. Arg1809Cys substitution in neurofibromin is associated with a distinctive NF1 phenotype without neurofibromas. Eur J Hum Genet. 2015;23:1068–71. [PMC free article: PMC4795103] [PubMed: 25370043]
• Pizzuti A, Bottillo I, Inzana F, Lanari V, Buttarelli F, Torrente I, Giallonardo AT, De Luca A, Dallapiccola B. Familial spinal neurofibromatosis due to a multiexonic NF1 gene deletion. Neurogenetics. 2011;12:233–40. [PubMed: 21365283]
• Plasschaert E, Descheemaeker MJ, Van Eylen L, Noens I, Steyaert J, Legius E. Prevalence of autism spectrum disorder symptoms in children with neurofibromatosis type 1. Am J Med Genet B Neuropsychiatr Genet. 2015;168B:72–80. [PubMed: 25388972]
• Plotkin SR, Bredella MA, Cai W, Kassarjian A, Harris GJ, Esparza S, Merker VL, Munn LL, Muzikansky A, Askenazi M, Nguyen R, Wenzel R, Mautner VF. Quantitative assessment of whole-body tumor burden in adult patients with neurofibromatosis. PLoS One. 2012;7:e35711. [PMC free article: PMC3338705] [PubMed: 22558206]
• Prada CE, Hufnagel RB, Hummel TR, Lovell AM, Hopkin RJ, Saal HM, Schorry EK. The use of magnetic resonance imaging screening for optic pathway gliomas in children with neurofibromatosis type 1. J Pediatr. 2015;167:851–6.e1. [PubMed: 26233602]
• Prada CE, Rangwala FA, Martin LJ, Lovell AM, Saal HM, Schorry EK, Hopkin RJ. Pediatric plexiform neurofibromas: impact on morbidity and mortality in neurofibromatosis type 1. J Pediatr. 2012;160:461–7. [PubMed: 21996156]
• Prada CE, Zarate YA, Hagenbuch S, Lovell A, Schorry EK, Hopkin RJ. Lethal presentation of neurofibromatosis and Noonan syndrome. Am J Med Genet A. 2011;155A:1360–6. [PubMed: 21567923]
• Pride NA, Crawford H, Payne JM, North KN. Social functioning in adults with neurofibromatosis type 1. Res Dev Disabil. 2013;34:3393–9. [PubMed: 23911645]
• Pride NA, North KN. The cognitive profile of NF1 children: therapeutic implications. In: Upadhyaya M, Cooper DN, eds. Neurofibromatosis Type 1. Berlin, Germany: Springer-Verlag; 2012:55-69.
• Pride N, Payne JM, Webster R, Shores EA, Rae C, North KN. Corpus callosum morphology and its relationship to cognitive function in neurofibromatosis type 1. J Child Neurol. 2010;25:834–41. [PubMed: 20142468]
• Purow B, Schiff D. Advances in the genetics of glioblastoma: are we reaching critical mass? Nat Rev Neurol. 2009;5:419–26. [PMC free article: PMC3387541] [PubMed: 19597514]
• Quintáns B, Pardo J, Campos B, Barros F, Volpini V, Carracedo A, Sobrido MJ. Neurofibromatosis without neurofibromas: confirmation of a genotype-phenotype correlation and implications for genetic testing. Case Rep Neurol. 2011;3:86–90. [PMC free article: PMC3084038] [PubMed: 21532985]
• Rad E, Tee AR. Neurofibromatosis type 1: fundamental insights into cell signalling and cancer. Semin Cell Dev Biol. 2016;52:39–46. [PubMed: 26860753]
• Ragge NK, Falk RE, Cohen WE, Murphree AL. Images of Lisch nodules across the spectrum. Eye (Lond). 1993;7:95–101. [PubMed: 8325432]
• Rasmussen SA, Yang Q, Friedman JM. Mortality in neurofibromatosis 1: an analysis using U.S. death certificates. Am J Hum Genet. 2001;68:1110–8. [PMC free article: PMC1226092] [PubMed: 11283797]
• Ratner N, Miller SJ. A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor. Nat Rev Cancer. 2015;15:290–301. [PMC free article: PMC4822336] [PubMed: 25877329]
• Rea D, Brandsema JF, Armstrong D, Parkin PC, deVeber G, MacGregor D, Logan WJ, Askalan R. Cerebral arteriopathy in children with neurofibromatosis type 1. Pediatrics. 2009;124:e476–83. [PubMed: 19706560]
• Rodrigues AC Jr, Ferraz-Filho JR, Torres US, da Rocha AJ, Muniz MP, Souza AS, Goloni-Bertollo EM, Pavarino ÉC. Is magnetic resonance spectroscopy capable of detecting metabolic abnormalities in neurofibromatosis type 1 that are not revealed in brain parenchyma of normal appearance? Pediatr Neurol. 2015;52:314–9. [PubMed: 25585912]
• Rojnueangnit K, Xie J, Gomes A, Sharp A, Callens T, Chen Y, Liu Y, Cochran M, Abbott MA, Atkin J, Babovic-Vuksanovic D, Barnett CP, Crenshaw M, Bartholomew DW, Basel L, Bellus G, Ben-Shachar S, Bialer MG, Bick D, Blumberg B, Cortes F, David KL, Destree A, Duat-Rodriguez A, Earl D, Escobar L, Eswara M, Ezquieta B, Frayling IM, Frydman M, Gardner K, Gripp KW, Hernández-Chico C, Heyrman K, Ibrahim J, Janssens S, Keena BA, Llano-Rivas I, Leppig K, McDonald M, Misra VK, Mulbury J, Narayanan V, Orenstein N, Galvin-Parton P, Pedro H, Pivnick EK, Powell CM, Randolph L, Raskin S, Rosell J, Rubin K, Seashore M, Schaaf CP, Scheuerle A, Schultz M, Schorry E, Schnur R, Siqveland E, Tkachuk A, Tonsgard J, Upadhyaya M, Verma IC, Wallace S, Williams C, Zackai E, Zonana J, Lazaro C, Claes K, Korf B, Martin Y, Legius E, Messiaen L. High incidence of Noonan syndrome features including short stature and pulmonic stenosis in patients carrying NF1 missense mutations affecting p.Arg1809: genotype-phenotype correlation. Hum Mutat. 2015;36:1052–63. [PMC free article: PMC5049609] [PubMed: 26178382]
• Rosenbaum T, Wimmer K. Neurofibromatosis type 1 (NF1) and associated tumors. Klin Padiatr. 2014;226:309–15. [PubMed: 25062113]
• Rosenfeld A, Listernick R, Charrow J, Goldman S. Neurofibromatosis type 1 and high-grade tumors of the central nervous system. Childs Nerv Syst. 2010;26:663–7. [PubMed: 19937438]
• Rosser TL, Vezina G, Packer RJ. Cerebrovascular abnormalities in a population of children with neurofibromatosis type 1. Neurology. 2005;64:553–5. [PubMed: 15699396]
• Roth TM, Petty EM, Barald KF. The role of steroid hormones in the NF1 phenotype: focus on pregnancy. Am J Med Genet A. 2008;146A:1624–33. [PubMed: 18481270]
• Roy A, Barbarot S, Charbonnier V, Gayet-Delacroix M, Stalder JF, Roulin JL, Le Gall D. Examining the frontal subcortical brain vulnerability hypothesis in children with neurofibromatosis type 1: Are T2-weighted hyperintensities related to executive dysfunction? Neuropsychology. 2015;29:473–84. [PubMed: 25365565]
• Ruggieri M, Polizzi A, Spalice A, Salpietro V, Caltabiano R, D'Orazi V, Pavone P, Pirrone C, Magro G, Platania N, Cavallaro S, Muglia M, Nicita F. The natural history of spinal neurofibromatosis: a critical review of clinical and genetic features. Clin Genet. 2015;87:401–10. [PubMed: 25211147]
• Sabbagh A, Pasmant E, Imbard A, Luscan A, Soares M, Blanché H, Laurendeau I, Ferkal S, Vidaud M, Pinson S, Bellanné-Chantelot C, Vidaud D, Parfait B, Wolkenstein P. NF1 molecular characterization and neurofibromatosis type I genotype-phenotype correlation: the French experience. Hum Mutat. 2013;34:1510–8. [PubMed: 23913538]
• Sabbagh A, Pasmant E, Laurendeau I, Parfait B, Barbarot S, Guillot B, Combemale P, Ferkal S, Vidaud M, Aubourg P, Vidaud D, Wolkenstein P, et al. Unravelling the genetic basis of variable clinical expression in neurofibromatosis 1. Hum Mol Genet. 2009;18:2768–78. [PMC free article: PMC2722187] [PubMed: 19417008]
• Sabol Z, Resić B, Gjergja Juraski R, Sabol F, Kovac Sizgorić M, Orsolić K, Ozretić D, Sepić-Grahovac D. Clinical sensitivity and specificity of multiple T2-hyperintensities on brain magnetic resonance imaging in diagnosis of neurofibromatosis type 1 in children: diagnostic accuracy study. Croat Med J. 2011;52:488–96. [PMC free article: PMC3160695] [PubMed: 21853543]
• Safaee MM, Lyon R, Barbaro NM, Chou D, Mummaneni PV, Weinstein PR, Chin CT, Tihan T, Ames CP. Neurological outcomes and surgical complications in 221 spinal nerve sheath tumors. J Neurosurg Spine. 2017;26:103–11. [PubMed: 27472744]
• Safaee M, Parsa AT, Barbaro NM, Chou D, Mummaneni PV, Weinstein PR, Tihan T, Ames CP. Association of tumor location, extent of resection, and neurofibromatosis status with clinical outcomes for 221 spinal nerve sheath tumors. Neurosurg Focus. 2015;39:E5. [PubMed: 26235022]
• Sakaguchi H, Okuno Y, Muramatsu H, Yoshida K, Shiraishi Y, Takahashi M, Kon A, Sanada M, Chiba K, Tanaka H, Makishima H, Wang X, Xu Y, Doisaki S, Hama A, Nakanishi K, Takahashi Y, Yoshida N, Maciejewski JP, Miyano S, Ogawa S, Kojima S (2013) Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia 45:937-41. [PubMed: 23832011]
• Salamon J, Papp L, Tóth Z, Laqmani A, Apostolova I, Adam G, Mautner VF, Derlin T. Nerve sheath tumors in neurofibromatosis type 1: assessment of whole-body metabolic tumor burden using F-18-FDG PET/CT. PLoS One. 2015;10:e0143305. [PMC free article: PMC4666520] [PubMed: 26625155]
• Salamon J, Veldhoen S, Apostolova I, Bannas P, Yamamura J, Herrmann J, Friedrich RE, Adam G, Mautner VF, Derlin T. 18F-FDG PET/CT for detection of malignant peripheral nerve sheath tumours in neurofibromatosis type 1: tumour-to-liver ratio is superior to an SUVmax cut-off. Eur Radiol. 2014;24:405–12. [PubMed: 24097302]
• Sant DW, Margraf RL, Stevenson DA, Grossmann AH, Viskochil DH, Hanson H, Everitt MD, Rios JJ, Elefteriou F, Hennessey T, Mao R. Evaluation of somatic mutations in tibial pseudarthrosis samples in neurofibromatosis type 1. J Med Genet. 2015;52:256–61. [PubMed: 25612910]
• Santoro C, Malan V, Bertoli M, Boddaert N, Vidaud D, Lyonnet S. Sporadic NF1 mutation associated with a de-novo 20q11.3 deletion explains the association of unusual facies, Moyamoya vasculopathy, and developmental delay, reported by Bertoli et al in 2009. Clin Dysmorphol. 2013;22:42–3. [PubMed: 23207425]
• Sarkozy A, Schirinzi A, Lepri F, Bottillo I, De Luca A, Pizzuti A, Tartaglia M, Digilio MC, Dallapiccola B. Clinical lumping and molecular splitting of LEOPARD and NF1/NF1-Noonan syndromes. Am J Med Genet A. 2007;143A:1009–11. [PubMed: 17366582]
• Satgé D, Sasco AJ, Goldgar D, Vekemans M, Réthoré MO. A. 23-year-old woman with Down syndrome, type 1 neurofibromatosis, and breast carcinoma. Am J Med Genet A. 2004;125A:94–6. [PubMed: 14755474]
• Schaffer R, Goss L, Romer MM, Kalamchi S. Down syndrome and neurofibromatosis: a case report. Spec Care Dentist. 2014;34:313–8. [PubMed: 24320743]
• Schievink WI, Riedinger M, Maya MM. Frequency of incidental intracranial aneurysms in neurofibromatosis type 1. Am J Med Genet A. 2005;134A:45–8. [PubMed: 15690406]
• Seitz S, Schnabel C, Busse B, Schmidt HU, Beil FT, Friedrich RE, Schinke T, Mautner VF, Amling M. High bone turnover and accumulation of osteoid in patients with neurofibromatosis 1. Osteoporos Int. 2010;21:119–27. [PubMed: 19415373]
• Sellmer L, Farschtschi S, Marangoni M, Heran MK, Birch P, Wenzel R, Friedman JM, Mautner VF. Non-optic glioma in adults and children with neurofibromatosis 1. Orphanet J Rare Dis. 2017;12:34. [PMC free article: PMC5312522] [PubMed: 28202035]
• Sellmer L, Marangoni M, Farschtschi S, Heran MK, Birch P, Wenzel R, Mautner VF, Friedman JM. Serial MRIs provide novel insight into natural history of optic pathway gliomas in patients with neurofibromatosis 1. Orphanet J Rare Dis. 2018;13:62. [PMC free article: PMC5913802] [PubMed: 29685181]
• Seminog OO, Goldacre MJ. Age-specific risk of breast cancer in women with neurofibromatosis type 1. Br J Cancer. 2015;112:1546–8. [PMC free article: PMC4453683] [PubMed: 25742481]
• Seminog OO, Goldacre MJ. Risk of benign tumours of nervous system, and of malignant neoplasms, in people with neurofibromatosis: population-based record-linkage study. Br J Cancer. 2013;108:193–8. [PMC free article: PMC3553528] [PubMed: 23257896]
• Shamji MF, Benoit BG. Syndromic and sporadic pediatric optic pathway gliomas: review of clinical and histopathological differences and treatment implications. Neurosurg Focus. 2007;23:E3. [PubMed: 18004965]
• Sharif S, Ferner R, Birch JM, Gillespie JE, Gattamaneni HR, Baser ME, Evans DG. Second primary tumors in neurofibromatosis 1 patients treated for optic glioma: substantial risks after radiotherapy. J Clin Oncol. 2006;24:2570–5. [PubMed: 16735710]
• Shields JA, Pellegrini M, Kaliki S, Mashayekhi A, Shields CL. Retinal vasoproliferative tumors in 6 patients with neurofibromatosis type 1. JAMA Ophthalmol. 2014;132:190–6. [PubMed: 24357334]
• Shofty B, Constantini S, Ben-Shachar S. Advances in molecular diagnosis of neurofibromatosis type 1. Semin Pediatr Neurol. 2015;22:234–9. [PubMed: 26706011]
• Soucy EA, van Oppen D, Nejedly NL, Gao F, Gutmann DH, Hollander AS. Height assessments in children with neurofibromatosis type 1. J Child Neurol. 2013;28:303–7. [PMC free article: PMC3947790] [PubMed: 22752476]
• Stansfield BK, Ingram DA, Conway SJ, Friedman JM. Molecular basis of cardiovascular abnormalities in NF1. In: Upadhyaya M, Cooper DN, eds. Neurofibromatosis Type 1. Berlin: Springer-Verlag; 2012: 353-66.
• Stemmer-Rachamimov A, Nielsen GP. Pathologic and molecular diagnostic features of peripheral nerve sheath tumors in NF1. In: Upadhyaya M, Cooper DN, eds. Neurofibromatosis Type 1. Berlin, Germany: Springer-Verlag; 2012:429-43.
• Stevens CA, Chiang PW, Messiaen LM. Café-au-lait macules and intertriginous freckling in piebaldism: clinical overlap with neurofibromatosis type 1 and Legius syndrome. Am J Med Genet A. 2012;158A:1195–9. [PubMed: 22438235]
• Stevenson DA, Little D, Armstrong L, Crawford AH, Eastwood D, Friedman JM, Greggi T, Gutierrez G, Hunter-Schaedle K, Kendler DL, Kolanczyk M, Monsell F, Oetgen M, Richards BS, Schindeler A, Schorry EK, Wilkes D, Viskochil DH, Yang FC, Elefteriou F. Approaches to treating NF1 tibial pseudarthrosis: consensus from the Children's Tumor Foundation NF1 Bone Abnormalities Consortium. J Pediatr Orthop. 2013;33:269–75. [PubMed: 23482262]
• Stevenson DA, Schwarz EL, Viskochil DH, Moyer-Mileur LJ, Murray M, Firth SD, D'Astous JL, Carey JC, Pasquali M. Evidence of increased bone resorption in neurofibromatosis type 1 using urinary pyridinium crosslink analysis. Pediatr Res. 2008;63:697–701. [PMC free article: PMC3235045] [PubMed: 18317233]
• Stevenson DA, Viskochil DH, Carey JC, Sheng X, Murray M, Moyer-Mileur L, Shelton J, Roberts WL, Bunker AM, Hanson H, Bauer S, D'Astous JL. Pediatric 25-hydroxyvitamin D concentrations in neurofibromatosis type 1. J Pediatr Endocrinol Metab. 2011;24:169–74. [PMC free article: PMC3246508] [PubMed: 21648285]
• Stevenson DA, Viskochil DH, Rope AF, Carey JC. Clinical and molecular aspects of an informative family with neurofibromatosis type 1 and Noonan phenotype. Clin Genet. 2006;69:246–53. [PMC free article: PMC3243644] [PubMed: 16542390]
• Stevenson DA, Viskochil DH, Schorry EK, Crawford AH, D'Astous J, Murray KA, Friedman JM, Armstrong L, Carey JC. The use of anterolateral bowing of the lower leg in the diagnostic criteria for neurofibromatosis type 1. Genet Med. 2007;9:409–12. [PMC free article: PMC3244139] [PubMed: 17666887]
• Stewart DR, Cogan JD, Kramer MR, Miller WT Jr, Christiansen LE, Pauciulo MW, Messiaen LM, Tu GS, Thompson WH, Pyeritz RE, Ryu JH, Nichols WC, Kodama M, Meyrick BO, Ross DJ. Is pulmonary arterial hypertension in neurofibromatosis type 1 secondary to a plexogenic arteriopathy? Chest. 2007;132:798–808. [PubMed: 17573495]
• Stewart DR, Korf BR, Nathanson KL, Stevenson DA, Yohay K. Care of adults with neurofibromatosis type 1: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2018;20:671–82. [PubMed: 30006586]
• Stieglitz E, Taylor-Weiner AN, Chang TY, Gelston LC, Wang YD, Mazor T, Esquivel E, Yu A, Seepo S, Olsen SR, Rosenberg M, Archambeault SL, Abusin G, Beckman K, Brown PA, Briones M, Carcamo B, Cooper T, Dahl GV, Emanuel PD, Fluchel MN, Goyal RK, Hayashi RJ, Hitzler J, Hugge C, Liu YL, Messinger YH, Mahoney DH Jr, Monteleone P, Nemecek ER, Roehrs PA, Schore RJ, Stine KC, Takemoto CM, Toretsky JA, Costello JF, Olshen AB, Stewart C, Li Y, Ma J, Gerbing RB, Alonzo TA, Getz G, Gruber TA, Golub TR, Stegmaier K, Loh ML. The genomic landscape of juvenile myelomonocytic leukemia. Nat Genet. 2015;47:1326–33. [PMC free article: PMC4626387] [PubMed: 26457647]
• Stoker GE, Lenke LG, Dorward IG. Posterior vertebral column resection for the treatment of dystrophic kyphosis associated with type-1 neurofibromatosis: a case report and review of the literature. Spine (Phila Pa 1976). 2012;37:E1659–64. [PubMed: 23044623]
• Stokland T, Liu JF, Ironside JW, Ellison DW, Taylor R, Robinson KJ, Picton SV, Walker DA. A multivariate analysis of factors determining tumor progression in childhood low-grade glioma: a population-based cohort study (CCLG CNS9702). Neuro Oncol. 2010;12:1257–68. [PMC free article: PMC3018938] [PubMed: 20861086]
• Summers MA, Quinlan KG, Payne JM, Little DG, North KN, Schindeler A. Skeletal muscle and motor deficits in neurofibromatosis type 1. J Musculoskelet Neuronal Interact. 2015;15:161–70. [PMC free article: PMC5133719] [PubMed: 26032208]
• Szudek J, Birch P, Friedman JM. Growth charts for young children with neurofibromatosis 1 (NF1). Am J Med Genet. 2000a;92:224–8. [PubMed: 10817659]
• Szudek J, Birch P, Friedman JM. Growth in North American white children with neurofibromatosis 1 (NF1). J Med Genet. 2000b;37:933–8. [PMC free article: PMC1734506] [PubMed: 11106357]
• Tadini G, Milani D, Menni F, Pezzani L, Sabatini C, Esposito S. Is it time to change the neurofibromatosis 1 diagnostic criteria? Eur J Intern Med. 2014;25:506–10. [PubMed: 24784952]
• Takazawa Y, Sakurai S, Sakuma Y, Ikeda T, Yamaguchi J, Hashizume Y, Yokoyama S, Motegi A, Fukayama M. Gastrointestinal stromal tumors of neurofibromatosis type I (von Recklinghausen's disease). Am J Surg Pathol. 2005;29:755–63. [PubMed: 15897742]
• Tassabehji M, Strachan T, Sharland M, Colley A, Donnai D, Harris R, Thakker N. Tandem duplication within a neurofibromatosis type 1 (NF1) gene exon in a family with features of Watson syndrome and Noonan syndrome. Am J Hum Genet. 1993;53:90–5. [PMC free article: PMC1682238] [PubMed: 8317503]
• Terry AR, Barker FG 2nd, Leffert L, Bateman BT, Souter I, Plotkin SR. Neurofibromatosis type 1 and pregnancy complications: a population-based study. Am J Obstet Gynecol. 2013;209:46.e1–8. [PubMed: 23535241]
• Terry AR, Jordan JT, Schwamm L, Plotkin SR. Increased risk of cerebrovascular disease among patients with neurofibromatosis type 1: population-based approach. Stroke. 2016;47:60–5. [PubMed: 26645253]
• Thiel C, Wilken M, Zenker M, Sticht H, Fahsold R, Gusek-Schneider GC, Rauch A. Independent NF1 and PTPN11 mutations in a family with neurofibromatosis-Noonan syndrome. Am J Med Genet A. 2009;149A:1263–7. [PubMed: 19449407]
• Tomson SN, Schreiner MJ, Narayan M, Rosser T, Enrique N, Silva AJ, Allen GI, Bookheimer SY, Bearden CE. Resting state functional MRI reveals abnormal network connectivity in neurofibromatosis 1. Hum Brain Mapp. 2015;36:4566–81. [PMC free article: PMC4619152] [PubMed: 26304096]
• Tonsgard JH, Kwak SM, Short MP, Dachman AH. CT imaging in adults with neurofibromatosis-1: frequent asymptomatic plexiform lesions. Neurology. 1998;50:1755–60. [PubMed: 9633723]
• Trevisson E, Forzan M, Salviati L, Clementi M. Neurofibromatosis type 1 in two siblings due to maternal germline mosaicism. Clin Genet. 2014;85:386–9. [PubMed: 23621909]
• Tucker T, Friedman JM, Friedrich RE, Wenzel R, Fünsterer C, Mautner VF. Longitudinal study of neurofibromatosis 1 associated plexiform neurofibromas. J Med Genet. 2009a;46:81–5. [PubMed: 18930997]
• Tucker T, Schnabel C, Hartmann M, Friedrich RE, Frieling I, Kruse HP, Mautner VF, Friedman JM. Bone health and fracture rate in individuals with neurofibromatosis 1 (NF1). J Med Genet. 2009b;46:259–65. [PubMed: 19066167]
• Tucker T, Wolkenstein P, Revuz J, Zeller J, Friedman JM. Association between benign and malignant peripheral nerve sheath tumors in NF1. Neurology. 2005;65:205–11. [PubMed: 16043787]
• Ullrich NJ, Raja AI, Irons MB, Kieran MW, Goumnerova L. Brainstem lesions in neurofibromatosis type 1. Neurosurgery. 2007a;61:762–6. [PubMed: 17986937]
• Ullrich NJ, Robertson R, Kinnamon DD, Scott RM, Kieran MW, Turner CD, Chi SN, Goumnerova L, Proctor M, Tarbell NJ, Marcus KJ, Pomeroy SL. Moyamoya following cranial irradiation for primary brain tumors in children. Neurology. 2007b;68:932–8. [PubMed: 17372129]
• Upadhyaya M, Chuzhanova N, Cooper DN. The somatic mutational spectrum of the NF1 gene. In: Upadhyaya M, Cooper DN, eds. Neurofibromatosis Type 1. Berlin: Springer-Verlag; 2012: 211-33.
• Upadhyaya M, Cooper DN, eds. Neurofibromatosis Type 1. Berlin: Springer-Verlag; 2012.
• Upadhyaya M, Huson SM, Davies M, Thomas N, Chuzhanova N, Giovannini S, Evans DG, Howard E, Kerr B, Griffiths S, Consoli C, Side L, Adams D, Pierpont M, Hachen R, Barnicoat A, Li H, Wallace P, Van Biervliet JP, Stevenson D, Viskochil D, Baralle D, Haan E, Riccardi V, Turnpenny P, Lazaro C, Messiaen L. An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in exon 17 of the NF1 gene (c.2970-2972 delAAT): evidence of a clinically significant NF1 genotype-phenotype correlation. Am J Hum Genet. 2007;80:140–51. [PMC free article: PMC1785321] [PubMed: 17160901]
• Upadhyaya M, Majounie E, Thompson P, Han S, Consoli C, Krawczak M, Cordeiro I, Cooper DN. Three different pathological lesions in the NF1 gene originating de novo in a family with neurofibromatosis type 1. Hum Genet. 2003;112:12–7. [PubMed: 12483293]
• Upadhyaya M, Spurlock G, Kluwe L, Chuzhanova N, Bennett E, Thomas N, Guha A, Mautner V. The spectrum of somatic and germline NF1 mutations in NF1 patients with spinal neurofibromas. Neurogenetics. 2009;10:251–63. [PubMed: 19221814]
• Vaassen P, Rosenbaum T. Nevus anemicus as an additional diagnostic marker of neurofibromatosis type 1 in childhood. Neuropediatrics. 2016;47:190–3. [PubMed: 27019377]
• Vagge A, Nelson LB, Capris P, Traverso CE. Choroidal freckling in pediatric patients affected by neurofibromatosis type 1. J Pediatr Ophthalmol Strabismus. 2016;53:271–4. [PubMed: 27637020]
• Valentin T, Le Cesne A, Ray-Coquard I, Italiano A, Decanter G, Bompas E, Isambert N, Thariat J, Linassier C, Bertucci F, Bay JO, Bellesoeur A, Penel N, Le Guellec S, Filleron T, Chevreau C. Management and prognosis of malignant peripheral nerve sheath tumors: the experience of the French Sarcoma Group (GSF-GETO). Eur J Cancer. 2016;56:77–84. [PubMed: 26824706]
• Valero MC, Martín Y, Hernández-Imaz E, Marina Hernández A, Meleán G, Valero AM, Javier Rodríguez-Álvarez F, Tellería D, Hernández-Chico C. A highly sensitive genetic protocol to detect NF1 mutations. J Mol Diagn. 2011;13:113–22. [PMC free article: PMC3128626] [PubMed: 21354044]
• Valeyrie-Allanore L, Ismaïli N, Bastuji-Garin S, Zeller J, Wechsler J, Revuz J, Wolkenstein P. Symptoms associated with malignancy of peripheral nerve sheath tumours: a retrospective study of 69 patients with neurofibromatosis 1. Br J Dermatol. 2005;153:79–82. [PubMed: 16029330]
• Van Der Gucht A, Zehou O, Djelbani-Ahmed S, Valeyrie-Allanore L, Ortonne N, Brugières P, Wolkenstein P, Luciani A, Rahmouni A, Sbidian E, Itti E. Metabolic tumour burden measured by 18F-FDG PET/CT predicts malignant transformation in patients with neurofibromatosis Type-1. PLoS One. 2016;11:e0151809. [PMC free article: PMC4795780] [PubMed: 26987124]
• van der Vaart T, Rietman AB, Plasschaert E, Legius E, Elgersma Y, Moll HA, et al. Behavioral and cognitive outcomes for clinical trials in children with neurofibromatosis type 1. Neurology. 2016;86:154–60. [PMC free article: PMC4731686] [PubMed: 26519538]
• van Leeuwen RL, Berretty PJ, Knots E, Tan-Go I. Triad of juvenile xanthogranuloma, von Recklinghausen's neurofibromatosis and trisomy 21 in a young girl. Clin Exp Dermatol. 1996;21:248–9. [PubMed: 8914381]
• Van Meerbeeck SF, Verstraete KL, Janssens S, Mortier G. Whole body MR imaging in neurofibromatosis type 1. Eur J Radiol. 2009;69:236–42. [PubMed: 19091504]
• van Minkelen R, van Bever Y, Kromosoeto JN, Withagen-Hermans CJ, Nieuwlaat A, Halley DJ, van den Ouweland AM. A clinical and genetic overview of 18 years neurofibromatosis type 1 molecular diagnostics in the Netherlands. Clin Genet. 2014;85:318–27. [PubMed: 23656349]
• Varan A, Şen H, Aydın B, Yalçın B, Kutluk T, Akyüz C. Neurofibromatosis type 1 and malignancy in childhood. Clin Genet. 2016;89:341–5. [PubMed: 26073032]
• Vicha A, Musil Z, Pacak K. Genetics of pheochromocytoma and paraganglioma syndromes: new advances and future treatment options. Curr Opin Endocrinol Diabetes Obes. 2013;20:186–91. [PMC free article: PMC4711348] [PubMed: 23481210]
• Virdis R, Sigorini M, Laiolo A, Lorenzetti E, Street ME, Villani AR, Donadio A, Pisani F, Terzi C, Garavelli L. Neurofibromatosis type 1 and precocious puberty. J Pediatr Endocrinol Metab. 2000;13 Suppl 1:841–4. [PubMed: 10969931]
• Virdis R, Street ME, Bandello MA, Tripodi C, Donadio A, Villani AR, Cagozzi L, Garavelli L, Bernasconi S. Growth and pubertal disorders in neurofibromatosis type 1. J Pediatr Endocrinol Metab. 2003;16 Suppl 2:289–92. [PubMed: 12729406]
• Vogt J, Kohlhase J, Morlot S, Kluwe L, Mautner VF, Cooper DN, Kehrer-Sawatzki H. Monozygotic twins discordant for neurofibromatosis type 1 due to a postzygotic NF1 gene mutation. Hum Mutat. 2011;32:E2134–47. [PubMed: 21618341]
• Vranceanu AM, Merker VL, Park E, Plotkin SR. Quality of life among adult patients with neurofibromatosis 1, neurofibromatosis 2 and schwannomatosis: a systematic review of the literature. J Neurooncol. 2013;114:257–62. [PubMed: 23817811]
• Vranceanu AM, Merker VL, Park ER, Plotkin SR. Quality of life among children and adolescents with neurofibromatosis 1: a systematic review of the literature. J Neurooncol. 2015;122:219–28. [PubMed: 25663248]
• Walker L, Thompson D, Easton D, Ponder B, Ponder M, Frayling I, Baralle D. A prospective study of neurofibromatosis type 1 cancer incidence in the UK. Br J Cancer. 2006;95:233–8. [PMC free article: PMC2360616] [PubMed: 16786042]
• Walsh KS, Vélez JI, Kardel PG, Imas DM, Muenke M, Packer RJ, Castellanos FX, Acosta MT. Symptomatology of autism spectrum disorder in a population with neurofibromatosis type 1. Dev Med Child Neurol. 2013;55:131–8. [PubMed: 23163951]
• Wang X, Levin AM, Smolinski SE, Vigneau FD, Levin NK, Tainsky MA. Breast cancer and other neoplasms in women with neurofibromatosis type 1: a retrospective review of cases in the Detroit metropolitan area. Am J Med Genet A. 2012;158A:3061–4. [PMC free article: PMC3505236] [PubMed: 22965642]
• Wilding A, Ingham SL, Lalloo F, Clancy T, Huson SM, Moran A, Evans DG. Life expectancy in hereditary cancer predisposing diseases: an observational study. J Med Genet. 2012;49:264–9. [PubMed: 22362873]
• Williams VC, Lucas J, Babcock MA, Gutmann DH, Korf B, Maria BL. Neurofibromatosis type 1 revisited. Pediatrics. 2009;123:124–33. [PubMed: 19117870]
• Wimmer K, Rosenbaum T, Messiaen L. Connections between constitutional mismatch repair deficiency syndrome and neurofibromatosis type 1. Clin Genet. 2017;91:507–19. [PubMed: 27779754]
• Wimmer K, Yao S, Claes K, Kehrer-Sawatzki H, Tinschert S, De Raedt T, Legius E, Callens T, Beiglböck H, Maertens O, Messiaen L. Spectrum of single- and multiexon NF1 copy number changes in a cohort of 1,100 unselected NF1 patients. Genes Chromosomes Cancer. 2006;45:265–76. [PubMed: 16283621]
• Wu R, Legius E, Robberecht W, Dumoulin M, Cassiman JJ, Fryns JP. Neurofibromatosis type I gene mutation in a patient with features of LEOPARD syndrome. Hum Mutat. 1996;8:51–6. [PubMed: 8807336]
• Yap YS, McPherson JR, Ong CK, Rozen SG, Teh BT, Lee AS, Callen DF. The NF1 gene revisited - from bench to bedside. Oncotarget. 2014;5:5873–92. [PMC free article: PMC4171599] [PubMed: 25026295]
• Yoshida Y, Sato N, Furumura M, Nakayama J. Treatment of pigmented lesions of neurofibromatosis 1 with intense pulsed-radio frequency in combination with topical application of vitamin D3 ointment. J Dermatol. 2007;34:227–30. [PubMed: 17352718]
• Yoshimi A, Kojima S, Hirano N. Juvenile myelomonocytic leukemia: epidemiology, etiopathogenesis, diagnosis, and management considerations. Paediatr Drugs. 2010;12:11–21. [PubMed: 20034338]
• Zamora AC, Collard HR, Wolters PJ, Webb WR, King TE. Neurofibromatosis-associated lung disease: a case series and literature review. Eur Respir J. 2007;29:210–4. [PubMed: 16870664]
• Zehou O, Fabre E, Zelek L, Sbidian E, Ortonne N, Banu E, Wolkenstein P, Valeyrie-Allanore L. Chemotherapy for the treatment of malignant peripheral nerve sheath tumors in neurofibromatosis 1: a 10-year institutional review. Orphanet J Rare Dis. 2013;8:127. [PMC free article: PMC3766199] [PubMed: 23972085]
• Zhang J, Tong H, Fu X, Zhang Y, Liu J, Cheng R, Liang J, Peng J, Sun Z, Liu H, Zhang F, Lu W, Li M, Yao Z. Molecular characterization of NF1 and neurofibromatosis type 1 genotype-phenotype correlations in a Chinese population. Sci Rep. 2015;5:11291. [PMC free article: PMC4460887] [PubMed: 26056819]
• Zobor D, Kaufmann DH, Weckerle P, Sauer A, Wissinger B, Wilhelm H, Kohl S. Cone-rod dystrophy associated with amelogenesis imperfecta in a child with neurofibromatosis type 1. Ophthalmic Genet. 2012;33:34–8. [PubMed: 21728811]
• Zöller M, Rembeck B, Akesson HO, Angervall L. Life expectancy, mortality and prognostic factors in neurofibromatosis type 1. A twelve-year follow-up of an epidemiological study in Göteborg, Sweden. Acta Derm Venereol. 1995;75:136–40. [PubMed: 7604643]

Revision History

• 6 June 2019 (ha) Revision: ACMG patient management guidelines for children with NF1 [Miller et al 2019] and for affected adults [Stewart et al 2018] added
• 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