Neurofibromatosis 1

Clinical characteristics.

Neurofibromatosis 1 (NF1) is a multisystem disorder characterized by multiple café au lait macules, intertriginous freckling, multiple cutaneous neurofibromas, and learning disability or behavior problems. About half of people with NF1 have plexiform neurofibromas, but most are internal and not suspected clinically. Plexiform neurofibromas can cause pain, neurologic deficits, and abnormalities of involved or adjacent structures. Less common but potentially more serious manifestations include optic nerve and other central nervous system gliomas, malignant peripheral nerve sheath tumors, scoliosis, tibial dysplasia, vasculopathy, and gastrointestinal, endocrine, or pulmonary disease.

Diagnosis/testing.

The diagnosis of NF1 is established in a proband with two or more of the characteristic clinical features or one characteristic clinical feature and a heterozygous NF1 pathogenic variant.

Management.

Treatment of manifestations: Referral to specialists for treatment of abnormalities of the eye, central or peripheral nervous system, cardiovascular system, lungs, endocrine system, spine, or long bones; surgical removal of disfiguring or uncomfortable discrete cutaneous or subcutaneous neurofibromas. Surgical treatment of diffuse or large plexiform neurofibromas is possible but may be associated with damage to involved nerves or adjacent tissues and stimulate growth of residual tumor. Complete surgical excision, when possible, of malignant peripheral nerve sheath tumors is the treatment of choice; chemotherapy may be beneficial in some individuals. 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. Individualized developmental and educational interventions may be beneficial, and methylphenidate treatment often benefits individuals with attention-deficit/hyperactivity disorder.

Surveillance: Annual physical examination by a physician familiar with the disorder; ophthalmologic examination annually in children, and regularly but less frequently in adults; developmental assessment of children; regular blood pressure monitoring; MRI for identification and follow up of clinically suspected intracranial or other tumors that are not apparent on physical examination. Begin annual mammography in women at age 30 years with consideration of annual breast MRI in women between ages 30 and 50 years. Individuals with NF1 whole-gene deletions, large or growing plexiform neurofibromas or intracranial tumors, symptomatic vascular disease, progressive osseous lesions, or other serious disease manifestations require more frequent targeted follow up.

Genetic counseling.

NF1 is inherited in an autosomal dominant manner. Approximately half of affected individuals have NF1 as the result of a de novo NF1 disease-causing variant. Each child of an individual with NF1 has a 50% chance of inheriting the disease-causing variant. Penetrance is close to 100%; thus, a child who inherits an NF1-causing variant is expected to develop features of NF1, but the features may be considerably more (or less) severe in an affected child than in his or her affected parent. Prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible if the disease-causing variant in a family is known.

Suggestive Findings

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

• Six or more café au lait macules (CALMs; Figure 1) >5 mm in greatest diameter in prepubertal individuals and >15 mm in greatest diameter in postpubertal individuals
• Freckling in the axillary or inguinal regions
• Two or more neurofibromas (Figure 2) of any type or one plexiform neurofibroma (Figure 3)
• Optic pathway glioma
• Two or more Lisch nodules identified by slit lamp examination or two or more choroidal abnormalities (bright, patchy nodules imaged by optical coherence tomography/near-infrared reflectance imaging)
• A distinctive osseous lesion such as sphenoid dysplasia, anterolateral bowing of the tibia, or pseudarthrosis of a long bone
• A parent who meets the diagnostic criteria for NF1
• A germline NF1 pathogenic variant

Establishing the Diagnosis

The diagnosis of NF1 is established in a proband with two or more of the features described in Suggestive Findings [Legius et al 2021].

Note:

1.

About half of individuals with Legius syndrome (see Differential Diagnosis) have skin pigmentary features that meet the diagnostic criteria of NF1 (i.e., ≥6 CALMs and axillary or inguinal freckling), but individuals with Legius syndrome do not have neurofibromas, optic pathway gliomas, Lisch nodules, or typical osseous lesions of NF1 [Legius et al 2021]. Moreover, Legius syndrome is much rarer than NF1, and children with Legius syndrome almost always have an affected parent with only CALMs and intertriginous freckling (see Differential Diagnosis).

2.

CALMs, intertriginous freckling, cutaneous neurofibromas, and Lisch nodules are usually bilateral in NF1. A diagnosis of mosaic NF1 should be considered if such lesions are present only on one side or in one segment of the body.

3.

Sphenoid wing dysplasia is not a separate criterion in those with ipsilateral orbital plexiform neurofibromas.

4.

A germline NF1 pathogenic variant must be identified for genetic testing to serve as a criterion for diagnosis [Legius et al 2021]. The criterion is not met by identification of an NF1 variant only in tumor tissue or identification of a germline likely pathogenic variant or variant of uncertain significance.

5.

Negative NF1 molecular testing does not rule out a diagnosis of NF1 [Accetturo et al 2020]. Some individuals diagnosed with NF1 based on clinical criteria do not have a pathogenic variant detectable by current technology. Many clinical features of NF1 increase in frequency with age, and some individuals who have unequivocal NF1 as adults cannot be diagnosed in early childhood, before these features become apparent.

If the phenotypic findings suggest the diagnosis of NF1, single-gene testing may be considered. Sequence analysis of NF1 genomic DNA (gDNA) and/or cDNA (complementary DNA, copied from mRNA) is performed in association with gene-targeted deletion analysis. Because of the frequency of pathogenic variants that affect splicing (22%-30%, more than 1/3 of which are not detected by gDNA sequencing of protein-coding regions), methods that include cDNA sequencing have higher detection rates than methods based solely on analysis of gDNA (Table 1).

Note:

1.

If an NF1 variant is not detected, sequence analysis and deletion/duplication analysis of SPRED1 (see Differential Diagnosis) may be considered in individuals with only pigmentary features of NF1.

2.

Chromosomal microarray analysis (CMA) may be performed instead of sequence analysis to detect NF1 whole-gene deletions if the NF1 microdeletion phenotype is suspected clinically (see Genotype-Phenotype Correlations).

3.

A karyotype may be considered to look for a translocation or complex cytogenetic abnormality if a clinical diagnosis of NF1 is certain, but no pathogenic variant is found on sequence analysis of NF1 gDNA or cDNA and gene-targeted deletion analysis.

If the phenotype is indistinguishable from other disorders characterized by hyperpigmentation, tumors, and/or other overlapping features, a multigene panel that includes NF1, SPRED1, and other genes of interest (see Differential Diagnosis) may be considered. A rasopathy multigene panel is usually most appropriate. 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) Many multigene panels 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 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.

If the phenotype is nonspecific (e.g., developmental delay and hypotonia in a young child) comprehensive genomic testing (exome sequencing or genome sequencing) may be considered. Note: Identification of one or more characteristic clinical features (see Suggestive Findings) is required to establish the diagnosis in an individual with an NF1 pathogenic variant.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

Neurofibromatosis 1 (NF1) is an extremely variable multisystem disease; the progression and severity may differ throughout life in an affected individual as well as in affected family members with the same NF1 pathogenic variant [Gutmann et al 2017, Monroe et al 2017, Gianluca et al 2020]. The cardinal clinical manifestations of NF1 include multiple café au lait macules, intertriginous freckling, multiple cutaneous neurofibromas, subcutaneous or deep nodular neurofibromas, plexiform neurofibromas, and characteristic ocular signs. Problems with learning, behavior, and social adaptation are unusually common among people with NF1. Optic or non-optic gliomas occur much more often than expected, but most of these tumors exhibit a benign course. Individuals with NF1, especially those with plexiform or deep nodular neurofibromas in large numbers or of large size, are at high risk of developing malignant peripheral nerve sheath tumors, which tend to occur at a much younger age and have a worse prognosis than in the general population. Women with NF1 are at increased risk of developing breast cancer and have complications of pregnancy more often than expected. Hypertension is frequent in people with NF1, and NF1 vasculopathy may cause stroke or other cardiovascular complications in affected children and young adults. Vertebral or tibial dysplasia can cause major disability in some individuals, and NF1-associated gastrointestinal, endocrine, or pulmonary disease – although less frequent – may be quite serious.

Genotype-Phenotype Correlations

Several allele-phenotype correlations have been observed in NF1:

• 1.4-Mb (type 1) deletion of the entire NF1 gene are associated with larger numbers and earlier appearance of cutaneous and plexiform neurofibromas, a higher risk of developing MPNST, more frequent and more severe cognitive abnormalities, somatic overgrowth, and large hands and feet [Bettegowda et al 2021, Kehrer-Sawatzki & Cooper 2021, Pacot et al 2021, Well et al 2021]. A recurrent pattern of dysmorphic features that includes coarse facial appearance, flat forehead, ocular hypertelorism, broad nasal tip, low-set ears, and broad neck is often observed among adolescents and adults [Kehrer-Sawatzki & Cooper 2021].
• An unusually severe phenotype with frequent plexiform or spinal neurofibromas, optic pathway gliomas, malignant neoplasms, and skeletal abnormalities has been observed in adults with missense variants of one of five codons between 844 and 848 [NM_000267.3] that code for the cysteine-serine rich domain of neurofibromin [Koczkowska et al 2018, Bettegowda et al 2021].
• p.Met992del is associated with typical pigmentary features of NF1 but no cutaneous, subcutaneous, or surface plexiform neurofibromas [Bettegowda et al 2021]. One quarter of individuals with this variant lack the clinical features needed to meet NF1 diagnostic criteria, but brain tumors outside of the optic pathways, cognitive or learning disabilities, and Noonan syndrome features occur at frequencies similar to those seen in other individuals with NF1.
• p.Arg1038Gly has been associated with mild pigmentary features of NF1 but a paucity of neurofibromas and frequent NF1-Noonan syndrome features [Trevisson et al 2019].
• Missense variants affecting p.Met1149 have been associated with a mild phenotype characterized by pigmentary features, frequent learning problems, and features of NF1-Noonan syndrome [Koczkowska et al 2020]
• Missense variants affecting p.Arg1276 have been associated with a higher-than-expected frequency of cardiovascular malformations, especially pulmonic stenosis, NF1-Noonan phenotype, and symptomatic spinal neurofibromas [Koczkowska et al 2020].
• Missense variants affecting p.Lys1423 have been associated with higher-than-expected frequencies of plexiform neurofibromas, as well as of learning problems, cardiovascular malformations (especially pulmonic stenosis), and NF1-Noonan phenotype [Koczkowska et al 2020].
• Several missense variants affecting p.Arg1809 are associated with multiple CALMs but absence of cutaneous neurofibromas or clinically apparent plexiform neurofibromas, although learning disabilities, short stature, and pulmonic stenosis often occur [Pinna et al 2015, Rojnueangnit et al 2015, Bettegowda et al 2021].

Penetrance

Pedigree studies demonstrate that the penetrance of NF1 is nearly complete after childhood [Rasmussen & Friedman 2000], but molecular testing has documented incomplete penetrance of pathogenic NF1 variants in a small number of individuals [Bettegowda et al 2021].

Nomenclature

NF1 was previously referred to as peripheral neurofibromatosis, to distinguish it from NF2 (central neurofibromatosis) – although CNS 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) Legius syndrome, NF2, and schwannomatosis.

Prevalence

A Finnish register-based total population study estimated the prevalence of NF1 at 1:2,052 between ages 0 and 74 years [Kallionpää et al 2018]. The prevalence was highest in the youngest cohort and lower in older cohorts, reflecting the increased mortality (see Life Expectancy). The incidence at birth in this study was estimated at 1:1,871 [Uusitalo et al 2015], making NF1 one of the most common autosomal dominant genetic disorders. The prevalence and birth incidence were higher than previous estimates [Evans et al 2010] – likely the result of the diagnosis of more mildly affected individuals rather than differences in the actual incidence and prevalence in the populations studied.

Almost half of all affected individuals have the disorder as the result of de novo variants. If the Finnish estimate of the incidence of NF1 at birth is correct and fertility in affected individuals is reduced by half [Huson et al 1989], the mutation rate for NF1 would be >1:8000, 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 evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Imaging

MRI is the method of choice for demonstrating the size and extent of plexiform neurofibromas [Ahlawat et al 2016] and for monitoring their growth over time [Nguyen et al 2012]. MRI is also useful in characterizing optic pathway gliomas, other brain tumors, structural abnormalities of the brain, and signs of cerebrovascular disease in people with NF1 [Lin et al 2011, Prada et al 2015, Blanchard et al 2016, Sellmer et al 2017, Sellmer et al 2018]. MR angiography is valuable in assessing NF1 vasculopathy [D'Arco et al 2014]. Conventional radiographic studies can demonstrate the skeletal anomalies that occur in people with NF1 [Patel & Stacy 2012], but CT imaging or three-dimensional CT reconstructions may be necessary when surgical treatment of bony lesions is being planned. PET and CT/PET can help to distinguish benign and malignant peripheral nerve sheath tumors [Chirindel et al 2015, Salamon et al 2015, Van Der Gucht et al 2016], but definitive differentiation can only be made by histologic examination of the tumor. CT/PET appears to be useful in guiding percutaneous biopsies of peripheral nerve sheath tumors suspected of being malignant [Brahmi et al 2015].

Surveillance

Surveillance recommendations for children and adults with NF1 have been published by ACMG [Stewart et al 2018, Miller et al 2019]. The evaluations summarized in Table 6a (routine surveillance of children with NF1), and Table 6b (routine surveillance of affected adults) are based on these recommendations.

Agents/Circumstances to Avoid

Activity restrictions may be required in those with tibial dysplasia or dystrophic scoliosis if recommended by orthopedic specialist.

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, Tsang et al 2017].

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 individuals with NF1 are normal, preterm delivery, delivery by cæsarean section, hypertension, and placental abruptions are more common than expected [Chetty et al 2011, Terry et al 2013, Leppävirta et al 2018]. Although many individuals with NF1 report a rapid increase in the number and size of neurofibromas during pregnancy, no ongoing difference in cutaneous or plexiform neurofibroma volume was observed on whole-body MRI between 13 persons with NF1 who had a pregnancy and 13 age-matched nulligravid persons with NF1 over an observation period that averaged 4.7 years and spanned the pregnancy [Well et al 2020].

Therapies Under Investigation

Therapy of NF1-related MPNST by interfering with various critical cell signaling pathways is under active investigation in preclinical models and early clinical trials [Brosseau et al 2020, Foiadelli et al 2020].

Many preclinical and clinical investigations of NF1-related gliomas are underway [Packer et al 2020, Packer & Vezina 2020].

Gene therapy to correct the primary disease-causing NF1 variant is also being studied in model systems [Cui et al 2020, Leier et al 2020].

Clinical studies are in progress to assess treatments for NF1-associated leukemia, cutaneous neurofibromas, pain, constipation, and hypertension, as well as for cognitive, learning, behavioral, social, and motor impairments.

See NIH ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for list of current clinical trials for NF1.

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 both 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; and
  • Ophthalmologic examination (including slit lamp examination and infrared reflectance imaging or optical coherence tomography) to look for Lisch nodules, choroidal freckling, or other ophthalmologic signs of NF1.
• If neither parent of an individual with NF1 has features that meet the clinical diagnostic criteria for NF1 [Legius et al 2021] after detailed medical history, physical examination, and ophthalmologic examination, the proband most likely has NF1 as the result of a de novo pathogenic variant. Alternatively, the proband may have NF1 as the result of a disease-causing variant inherited from a parent who is mosaic or, rarely, from a heterozygous parent with incomplete penetrance. If the disease-causing variant has been identified in a child with NF1, targeted molecular testing of the parents can be performed to look for mosaicism and determine if a parent is heterozygous (but apparently unaffected due to incomplete penetrance).
  Note: Parental somatic and germline mosaicism may be present even if there are no clinical signs of NF1 and no evidence of the proband’s disease-causing NF1 variant on standard molecular testing of either parent’s leukocyte DNA [Lázaro et al 1995, Bottillo et al 2010, Trevisson et al 2014, Yang et al 2020].
• 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. Therefore, an apparently negative family history cannot be confirmed unless both parents have undergone detailed clinical examination for signs of NF1.
• 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 manifestations of NF1 [Messiaen et al 2011, García-Romero et al 2016, Kluwe et al 2020]. The risk of a parent with mosaicism for an NF1 pathogenic variant transmitting the disorder to his or her child is less than 50%, but if the pathogenic variant is transmitted, it will be present in every cell in the child's body and the child 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 features may be considerably more (or less) severe in an affected sib than in the proband.
• If a parent of a proband has mosaicism for a disease-causing NF1 variant, the risk to sibs of having typical (usually more severe) NF1 is less than 50% and probably depends on the frequency of the NF1 variant in parental germ cells. The frequency of the NF1 variant in parental germ cells cannot be predicted from the frequency of the variant in parental blood or other somatic tissues.
• 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 parental germline mosaicism. 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 [Lázaro et al 1995, Bottillo et al 2010, Trevisson et al 2014, Yang et al 2020].

Offspring of a proband

• Each child of an individual with NF1 has a 50% chance of inheriting the NF1 pathogenic variant.
• Penetrance is close to 100%; thus, a child who inherits an NF1 pathogenic variant is expected to develop features of NF1, but the features may be considerably more (or less) severe in an affected child than in the child's 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 other families [Klose et al 1999, Pacot et al 2019].

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 for a pregnancy at increased risk and preimplantation genetic testing 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 instances.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

NF1 encodes neurofibromin, which activates ras GTPase, thereby controlling cellular proliferation and acting as a tumor suppressor [Rad & Tee 2016, Bergoug et al 2020]. Neurofibromin has other functions as well, including involvement in somatic cell division and regulation of adenylyl-cyclase activity and intracellular cyclic-AMP generation [Mo et al 2022].

NF1 is large, and more than 3000 different disease-causing variants have been described [Bettegowda et al 2021]. Many pathogenic variants have been observed repeatedly, but none has been found in more than a very small proportion of families studied. Most disease-causing variants are novel, and about half are de novo. Most of the germline NF1 pathogenic variants described appear to cause severe truncation of the gene product, often by altering mRNA splicing.

Mechanism of disease causation. Loss of function

NF1-specific laboratory technical considerations. Splice variants may not be demonstrable by standard gDNA sequencing alone.

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 [D'Angelo et al 2019, Eoli et al 2019, Dunnett-Kane et al 2020, Fisher et al 2021]. Examples of sporadic tumors with NF1 somatic variants include malignant peripheral nerve sheath tumors, pheochromocytomas, juvenile myelomonocytic leukemia, gliomas, and breast cancer. Somatic NF1 pathogenic variants may also be found in liposarcomas, lung adenocarcinomas, ovarian carcinomas, colorectal carcinomas, bladder transitional cell carcinoma, neuroblastomas, melanomas, and adult acute myeloid leukemia, all of which are uncommon in individuals with NF1 [Philpott et al 2017, Dunnett-Kane et al 2020]. Cancers associated with somatic NF1 variants often have different mutational spectra than those seen in individuals with germline NF1 variants.

Revision History

• 21 April 2022 (sw) Comprehensive update posted live
• 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

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