1. Neurofibromatosis Type 1
Neurofibromatosis describes a number of genetic conditions that cause the
manifestation of benign neurogenic tumours, known as neurofibromas, along the
nerves (National Health Service (NHS), 2015; Porth, 2009; Rad & Tee, 2016).
Among the forms in which this disease occurs, neurofibromatosis Type 1 (NF1) is the
most common: an autosomal dominant disorder ranging in phenotypic severity and
affecting 1 in 3000-4000 births (Pride et al, 2013; Rad & Tee, 2016; Woodrow et al,
2015). NF1 occurs equally across all genders and ethnicities and is caused by a
mutation of the Neurofibromin 1 gene (NF1), located on chromosome 17 (Pride et al,
2013; Woodrow et al, 2015). This gene expresses a tumour suppressor protein (Rad
& Tee, 2016). The disease has a variable expression in patients, even within
families, with an array of potential clinical features and the responsible mutation may
be inherited (50% of cases) but may also occur sporadically (50%) (Porth, 2009;
Pride et al, 2013; Woodrow et al, 2015). The allelic types described include many
variations of NF1, but also include Watson syndrome, familial spinal NF1, juvenile
myelomonocytic leukemia and NF Noonan syndrome (OMIM, 2016). Beyond the
formation of neurofibromas, NF1 also causes symptoms including, but not limited to,
café au lait spots, bone defects, scoliosis and Lisch nodules (NHS, 2015).
Complications may arise in the skin, bones, nervous system, eyes, respiratory
system, gastrointestinal system and cardiovascular system (Coutinho et al, 2016).
There is no cure for NF1 and patients require regular monitoring, however some
symptoms can be treated and eased with surgery or therapy (NHS, 2015). It is
usually diagnosed through the presence of common signs but can also be tested for
genetically (Ferner et al, 2007).
THE NF1 MUTATION
NF1 is a single gene disorder, meaning that it occurs due to a defective gene at a
single locus (Porth, 2009). NF1, the defective gene in NF1, is located on
chromosome 17 in the approximate area of 17q11.2 (US National Library of Medicine
(NLM), 2007). The gene is 130 kb long with 60 exons (Rad & Tee, 2016). It
expresses neurofibromin, a large protein comprising 2,818 amino acids (Rad & Tee,
2016). This protein acts as a tumour suppressor, preventing uncontrolled excessive
cell division by inhibiting the expression of Ras (NLM, 2007). Ras genes are
oncogenes involved in cell cycle progression, transcription control, cell growth,
cytoskeletal dynamics and vesicular transport, whose activation or inactivation is
controlled by the state in which they are bound (Rad & Tee, 2016). The molecules to
which Ras binds are guanosine triphosphate (GTP) and guanosine diphosphate
(GDP) (Schwab, 2012). When GTP-bound, the Ras is activated and when GDP-
bound, it is inactivated (Rad & Tee, 2016). Neurofibromin enhances the activity of
GTPases, enzymes that switch Ras from its GTP-bound state to its GDP-bound
state, by binding to a specific domain (Rad & Tee, 2016). Mutations to NF1 mean
that Ras is not inactivated and becomes hyper activated instead (Fernández-
Medarde & Santos, 2011). Unfortunately, mutations to this gene are relatively
common, occurring 1 in 10 000 gametes per generation, most likely due to the
gene’s large size (Rad & Tee, 2016). As for the nature of this mutation, many allelic
varieties have been observed occurring as insertions, transversions and deletions of
one or more base pairs resulting in frame shifts (Online Mendelian Inheritance in
Man (OMIM), 2016).
SKIN ABNORMALITIES
Hyperpigmentation caused by NF1 can manifest in the forms of freckling, café au lait
spots, Campbell de Morgan spots, also known as benign cherry angiomas or Naevus
anaemicus and xanthogranulomas, also known as benign orange papules (Ferner et

2. al. 2007). Hyperpigmentation can occur from birth in the inframammary, axillary and
inguinal areas (Trovó-Marqui & Tahara, 2006). This makes it a key diagnostic tool as
NF1 is suspected in children exhibiting 6 or more spots of 5mm across (NHS, 2015).
Despite causing no pain or irritation, many patients find these non-threatening spots
unsightly and may choose to camouflage them with cosmetic products (Korf et al.
2005; Trovó-Marqui & Tahara, 2006).
Neurofibromas are benign tumours that have developed on nerve sheaths (Schwann
cells) and may occur as dermal or plexiform (Ferner et al 2007). Dermal
neurofibromas are further categorised into cutaneous, occurring on the skin, or
subcutaneous, beneath the skin (Rad & Tee, 2016). Of these, cutaneous are the
most common in NF1 patients and tend to cause only cosmetic distress as they are
very soft, but can become irritated if rubbed (Ferner et al. 2007; Trovó-Marqui &
Tahara, 2006). Single or multiple neurofibromas can be removed through surgical
procedures or through laser treatment (Ferner et al. 2007; Korf et al. 2005). Plexiform
tumours, on the other hand, present more of a problem as they arise from major
nerve branches and are often vascularised (Rad & Tee, 2016; Trovó-Marqui &
Tahara, 2006). These neurofibromas occur as nodular (soft) or diffused (firm) and
often cause extreme discomfort and can even be life threatening, as they have the
ability to infiltrate vital organs and bones and impact entire body sections (Rad &
Tee, 2016; Trovó-Marqui & Tahara, 2006). Diffuse plexiform neurofibromas can be
removed, although this is difficult and risky, due to the fact that they spread along the
nerves and into other tissues and relapse is likely (Ferner et al. 2007; Trovó-Marqui
& Tahara, 2006). They also have the potential to progress into malignancy, causing a
malignant peripheral nerve sheath tumour (MPNST) (NHS, 2015). These are
suspected due to the changing in texture of an existing tumour from soft to firm as
well as pain and neurological abnormalities (weakness, numbness, breathing
difficulty etc.) (NHS, 2015). Distinguishing plexiform neurofibromas from MPNSTs
can be challenging, but visualisation of metabolising cells using fluorodeoxyglucose
positron emission tomography has already been a valuable tool in diagnosis (Ferner
et al. 2007). As for treatment, adjuvant radiology or the administration of Ifosfamide
or doxorubicin has been useful in the shrinking of MPNSTs in preparation for easier
removal (Ferner et al. 2007).
EYES AND POOR SIGHT
Tumours in the optic pathways, called optic pathway gliomas (OPG), affect roughly
15% of NF1 sufferers from childhood (NHS, 2015). This leads to reduced vision and
can even cause blindness (Rad & Tee, 2016). Poor eyesight due to NF1 can be
detected early in childhood but vigilant attention from parents and regular
assessment from optometrists is necessary (NHS, 2015). This is because young
children may not complain about eyesight abnormalities, including irregular colour
vision, visual field loss, proptosis and squint (Ferner et al. 2007). Certain visual tests
are best applied at certain developmental ages. For example, visual acuity is best
tested at 3 years of age, colour vision at 5 and visual fields at 8 (Ferner et al. 2007).
Radiotherapy may be advantageous in a treatment regime to help reduce these
tumours, but this is not recommended in children as it can cause adverse impacts to
of the neuropsychological, endocrine and vascular systems (Kato et al. 1998). Due to
this, chemotherapy with cisplatin and vincristine has been favoured, which was
demonstrated in Kato’s study (et al. 1998) for children suffering with astrocytomas of
the visual pathway. In severe cases, surgery may also be warranted (Ferner et al.
2007). Lisch nodules are found in the majority of NF1 patients over 10 years old and
occur as small elevations in the iris, ranging from yellow to brown in colour (Korf et
al. 2005; Rad & Tee, 2016). These, however, are purely cosmetic and do not cause
any complications with eyesight (Trovó-Marqui & Tahara, 2006).

3. SKELETAL MALFORMATIONS
Many children with NF1 develop a physical abnormality such as curvature of the
spine (scoliosis), false joint formation (pseudarthrosis) and bowing of the legs, many
of which arise from disruptions in bone maintenance, growth & repair and depletion
of bone mineral density (Ferner et al. 2007; NHS, 2015). Many individuals with NF1
have also exhibited stunted growth or irregular puberty, which can be distressing for
adolescents who are surrounded by others growing and transitioning normally,
although hormone treatment is available to aid this (Korf et al. 2005).
Scoliosis affects more than 25% of NF1 sufferers and occurs as either dystrophic
(short, angulated, severe, segmented curve) or idiopathic (non-dystrophic), the
diagnosis for which can be achieved with X-rays and MRI scans (Ferner et al. 2007;
Woodrow et al. 2015). Management of scoliosis can be achieved depending on the
severity. In the early stages of scoliosis, both dystrophic and non-dystrophic curves
can be treated with halo traction, in an attempt to stabilise the spine and avert further
neurological damage (Woodrow et al. 2015). Depending on severity, a specified
spinal fusion surgery, catered to the nature of the scoliosis, called arthrodesis can be
carried out, in which the surgeon acquires a bone graft from either the patients own
pelvis (autogenous) or from a donors ‘bone bank’ (allogenous), which augments the
fusion of bone between the patients vertebrae (University of California San Francisco
(UCSF) Medical Center, 2003). This surgery takes from four to six hours to complete,
but can cause arising complications, including blood loss, which can be reduced with
cauterization or transfusion, and infection, combatted with sterilization and antibiotics
(UCSF Medical Center, 2003). There is also a risk of nerve injury, resulting in
numbness or even paralysis, which is reduced through the constant monitoring of
electrical activity through the nerves (UCSF Medical Center, 2003). In the unlikely
event of a relapse, pseudarthrosis occurs, which is when there is no or irregular
union of the vertebrae as intended (McMaster & James, 1976). This can manifest in
three instances: an irregular crevice is filled with fibrous tissue (definite
pseudarthrosis), a small crack is deposited with fibrocartilage (hairline
pseudarthrosis) or the bone is more adherent in some areas than adjacent areas
(doubtful pseudoarthrosis) (McMaster & James, 1976). The major surgery could
cause patients to become conflicted, knowing the potential risks, and seeing as
scoliosis may occur young in NF1 patients, parents could also become conflicted
regarding the welfare of their child. Treatment also involves a long recovery period
with limited activity for the first 6 months post and full activity not being returned until
12 months post (UCSF Medical Center, 2015). This could be a stressful concept for
both parent and child.
As well as being a potential risk factor following surgical treatment for scoliosis,
pseudarthrosis is an NF1 symptom in itself. Woodrow’s review (et al. 2015), focusing
on skeletal symptoms and treatments of NF1, revealed this abnormality often
manifests as congenital pseudarthrosis of the tibia (CPT). CPT is rare, but half of
instances are attributed to NF1. Signs of CPT, such as bowing or discontinuity of
bone, can be observed at birth using X-ray, but little can be done at this point and
prognosis tends to worsen (Woodrow et al. 2015). Treatment is complicated with
risks of further fracture and non union, and when attempts at fixation and fracture
prevention fail repeatedly, amputation of the affected limb is usually carried out
(Woodrow et al. 2015).
BEHAVIOUR AND NEUROLOGICAL PROBLEMS
A large proportion (about 60%) of NF1 patients suffer with learning difficulties,
behavioural disabilities, cognitive impairment and/or lower intelligence (Ferner et al.
2007; Korf et al. 2005; NHS, 2015). Behavioural disabilities encompass impaired
social ability, trouble interpreting social cues and low self esteem, which are

4. detrimental to a child feeling comfortable and thriving with others (Ferner et al. 2007).
NF1 has also been linked with autism spectrum disorder (ASD) and attention deficit
hyperactive disorder (30-50%) (ADHD) (Coutinho et al. 2016; NHS, 2015). ADHD
can be diagnosed using the Child Behaviours Checklist (CBCL) and the Connors’
Hyperactivity Index (Coutinho et al. 2016). Children with learning difficulties will
struggle to reach their full academic potential, which could produce feelings of
inadequacy (Ferner et al. 2007). Children may also feel misunderstood in their
learning. Therefore, managing these problems upon early onset is of paramount
importance in attempts to precede life without unnecessary stress. Special attention
and guidance can be given in education establishments to children who require it
(Korf et al. 2005).
In addition to changes in behavioural changes, neurofibromas that develop in the
brain can cause neurological changes (NHS, 2015). Difficulties with balance,
coordination, memory, attention and visual spatial ability are all examples of potential
cognitive disabilities that can arise from NF1 (Ferner et al. 2007). These kinds of
problems arise in childhood and little can be done to prevent them developing onto
adulthood (Ferner et al. 2007). Iannuzzi (et al. 2016) believed that poor motor skills
exhibited by NF1 patients is due to interference with the striatum. Unfortunately,
other than visits to clinics, there is very little management that can be applied to
cognitive disability and a major problem is that adults begin to lack understanding
and awareness of their condition (Ferner et al. 2007).
CARDIOVASCULAR PROBLEMS
A small proportion (2%) of NF1 patients develop high blood pressure due to the
narrowing of arteries and the presence specific tumours (phaeochromocytomas),
which secrete pressure-raising hormones (NHS, 2015). Narrowing of vessels
(stenosis) may occur in the renal arteries and if often caused by pressure exerted
from an adjacent tumour (Ferner et al. 2007). Surgery or medication, such as
antihypertensives, can aid this and help to reduce pressure (Ferner et al. 2007).
Because high blood pressure is a common problem in the general population, it is
relatively simple to manage in NF1 patients with medications or changes to lifestyle
(Ferner et al. 2007).
GENETIC COUNSELLING
NF1 sufferers have a 50% chance of passing the defective gene onto offspring (Korf
et al. 2005). Combing molecular techniques, such as direct sequencing, FISH and
dHPLC can provide mutation analysis at the responsible NF1 coding region (Ferner
et al. 2007). Another option for early diagnosis is prenatal sampling, including
amniocentesis and chorionic villus sampling (CVS) (NHS, 2015). Amniocentesis
should be carried out after 15 weeks of gestation and CVS after 10, to minimise the
risk of foetal loss (Alfirevic et al. 2010). It is carried out using needle insertion to
obtain a biopsy, which undergoes genetic analysis (Alfirevic et al. 2010).
Beyond the potential risk factor, some women may find these tests too invasive and
not wish to proceed. Another option for those who have a family history of NF1 is the
use of DNA markers, but neither this or foetal sampling can reveal severity (Ferner et
al. 2007).
A potential avoidance strategy is the utilisation of in vitro fertilisation. Following
genetic counselling, parents who have a family history of NF1 may wish to have
embryos tested at 3 days of age for the NF1 mutation, with the means of implanting
healthy embryos into the mother (Ferner et al. 2007). This is called preimplantation
genetic diagnosis (PGD). The genetic protocol utilises the polymerase chain reaction
(PCR) with mutation analysis (Verlinsky et al. 2002). In Verlinsky’s investigation (et
al. 2002), of 26 healthy embryos confirmed from a parenting couple with a family

5. history of NF1, eight were selected for reinsertion into the mother at two cycles,
producing two pregnancies, both confirmed to be mutation-free during the pregnancy
using CVS. However, the first of which resulted in stillbirth. It cannot be confirmed if
CVS was the cause of this, but before such procedures are carried out, parents are
made aware of the potential risks. This raises some ethical concerns, but parents
may choose this risk over the risk of producing offspring with NF1.
CONCLUSIONS
The research collected in this review suggests that the most effective means of
managing NF1 is through the tackling of individual symptoms. Due to the fact that
NF1 tends to produce a very obvious phenotype, patients may struggle to lead a
normal life, either from physical abnormalities that directly impact health, or from
insecurities related to cosmetic concerns. Ferner (et al. 2007) proposed the
establishment of specific NF1 clinics where patients could receive the variety of
clinical disciplines required in a lifetime with NF1, including specialists of neurology,
psychology, dermatology, radiology, oncology, plastic surgery and genetics. It is
agreed, due to the consideration of NF1 phenotypes to exhibit such diversity, that
this would be a valuable option for sufferers.
REFERENCES
Alfirevic, Z., Walkinshaw , S.A., Kilby, M.D. (2010). Amniocentesis and Chorionic
Villus Sampling. 4th ed. UK: Royal College of Obstetricians and Gynaecologists. pp.
1-13.
Coutinho, V., Kemlin, I., Dorison, N., et al. 2016). Neuropsychological evaluation and
parental assessment of behavioral and motor difficulties in children with
neurofibromatosis type 1. Research in Developmental Disabilities. 48. pp. 220–230.
Fernández-Medarde, A., Santos, E.. (2011). Ras in Cancer and Developmental
Diseases. Genes and Cancer. 2 (3), pp. 344–358.
Ferner, R.E., Huson, S.M., Thomas, N., et al. (2007). Guidelines for the diagnosis
and management of individuals with neurofibromatosis 1. Journal of Medical
Genetics. 44 (2), pp. 81–88.
Iannuzzi, S., Albert, J., Chignon, C., et al. (2016). Motor impairment in children with
Neurofibromatosis type 1: Effect of the comorbidity with language disorders. Brain
and Development. 38 (16), pp. 181–187.
Kato T., Sawamura, Y., Tada, M., et al. (1998). Cisplatin/vincristine chemotherapy for
hypothalamic/visual pathway astrocytomas in young children.. Journal of
Neurooncology. 37 (3), pp. 263-270.
Korf, B.R., Schneider, G., Frenkel, D.P. (2005). Facing Neurofibromatosis: A Guide
for Teens. New York: Children Tumour Foundation (CTF). Pp. 1-10.
McMaster, M.J., James, J.I.P. . (1976). Pseudarthrosis after spinal fusion for
scoliosis. The Journal of Bone and Joint Surgery. 58 (3), pp. 305-312.
National Health Service (NHS). (2015). Neurofibromatosis type 1. Available:
http://www.nhs.uk/conditions/Neurofibromatosis/pages/introduction.aspx. Last
accessed 22nd Feb 2016.

6. Online Mendelian Inheritance in Man (OMIM). (2016). NEUROFIBROMIN1; NF1.
Available: http://www.omim.org/allelicVariant/613113. Last accessed 9th Mar 2016.
Porth C.M.. (2009). Genetic and Congenital Disorders. In: Porth, C.M., Maftin, G
Pathophysiology: Concepts of Altered Health States. China: Wolters Kluwer Health &
Lippincott Williams & Wilkins. pp. 134-137.
Pride, N.A., Crawford, H., Payne, J.M., North, K.N., . (2013). Social functioning in
adults with neurofibromatosis type 1. Research in Developmental Disabilities. 34
(10), pp. 3393–3399.
Rad, E., Tee, A.R.. (2016). Neurofibromatosis Type 1: fundamental insights into cell
signalling and cancer. Seminars in Cell & Developmental Biology. (In Press)
Schwab, M. (2012). Encyclopedia of Cancer. 3rd ed. Germany: Springer-Verlag
Berlin Heidelberg. pp. 1516-1609.
Trovó-Marqui, A.B., Tajara, E.H.. (2006). Neurofibromin: a general outlook. Clinical
Genetics. 70 (1), pp. 1–13.
Verlinsky, Y., Rechitsky, S., Verlinsky, O., et al. (2002). Preimplantation diagnosis for
neurofibromatosis.. Reproductive Biomedicine Online. 4 (3), pp. 218-22
Woodrow, C., Clarke, A., Amirfeyz, R.. (2015). Neurofibromatosis. Orthopaedics and
Trauma. 29 (3), pp. 206–210.
University of California San Francisco Medical Center. (2003). Spinal Fusion Surgery
for Scoliosis. Available:
https://www.ucsfhealth.org/treatments/spinal_fusion_surgery_for_scoliosis/. Last
accessed 11th Mar 2016.
US National Library of Medicine (NLM). (2007). NF1 - neurofibromin 1. Available:
http://ghr.nlm.nih.gov/gene/NF1. Last accessed 22nd Feb 2015.