Type 1 neurofibromatosis

Consider – surgical removal

Back

1st line –

surveillance

Subcutaneous neurofibromas are generally left alone unless they are subject to repeated trauma and/or are painful.

All types of neurofibromas typically enlarge during pregnancy. Close monitoring, preferably by an obstetrician familiar with NF1, is appropriate.

Back

Consider –

surgical removal

Additional treatment recommended for SOME patients in selected patient group

Surgical removal may cause a peripheral neuropathy distal to the surgical disruption of the involved nerve.

nodular plexiform: suitable for surgery

Consider – surgical removal or debulking

Back

1st line –

surveillance

Nodular plexiform neurofibromas may be paraspinal, arising in the dorsal root ganglion or proximal dorsal nerve root. They grow centripetally, leading to spinal cord compression and vertebral erosion, and centrifugally, causing pain and peripheral neuropathy. They are also subject to malignant degeneration (malignant peripheral nerve sheath tumour). Close monitoring, with a focus on the nervous system, is mandatory.

All types of neurofibromas typically enlarge during pregnancy. Close monitoring, preferably by an obstetrician familiar with NF1, is appropriate.

Back

Consider –

surgical removal or debulking

Additional treatment recommended for SOME patients in selected patient group

Palliative surgery may be warranted if very specific goals are delineated beforehand.

Chemotherapy or radiotherapy is not useful.

nodular plexiform: unsuitable for surgery

Consider – targeted systemic therapy

Back

1st line –

surveillance

All types of neurofibromas typically enlarge during pregnancy. Close monitoring, preferably by an obstetrician familiar with NF1, is appropriate.

Back

Consider –

targeted systemic therapy

Additional treatment recommended for SOME patients in selected patient group

Selumetinib, a mitogen-activated protein kinase 1 and 2 inhibitor, may be used for treating symptomatic and inoperable plexiform neurofibromas. However, the use of selumetinib requires specialist input and will generally be used after surveillance and condition progression.

In the UK, it is only available under a commercial arrangement agreement.[44]

It is approved for use in children ≥2 years of age in the US and children ≥3 years of age in Europe.

See local specialist protocol for dosing guidelines.

Primary options

selumetinib

diffuse plexiform: suitable for surgery

Consider – debulking surgery

Back

1st line –

surveillance

Diffuse plexiform neurofibromas may become very large, even massive, and thereby displace and/or infiltrate surrounding normal tissue. There may be serious cosmetic compromise, especially if located in and around the head and neck. Apart from cosmetic and aesthetic considerations, some patients may have impoverished or otherwise compromised social interactions.

These neurofibromas may also undergo malignant degeneration, concern for which may be one of the indications for surgery.

All types of neurofibromas typically enlarge during pregnancy. Close monitoring, preferably by an obstetrician familiar with NF1, is appropriate. Diffuse plexiform neurofibromas of the pelvis and retroperitoneal space may compromise the later stages of gestation and delivery.[Figure caption and citation for the preceding image starts]: Left anterior chest diffuse plexiform neurofibroma with overlying hyperpigmentationFrom the personal collection of Dr Vincent M. Riccardi; used with permission [Citation ends]. com.bmj.content.model.Caption@386246ed [Figure caption and citation for the preceding image starts]: Radiograph showing extensive involvement of a diffuse plexiform neurofibroma in the upper thorax (bilateral), mediastinum, retroperitoneal space, and omentumFrom the personal collection of Dr Vincent M. Riccardi; used with permission [Citation ends]. com.bmj.content.model.Caption@3c33cc51

Back

Consider –

debulking surgery

Additional treatment recommended for SOME patients in selected patient group

Debulking surgery - including amputation or joint disarticulation - may be warranted. Small-vessel haemorrhage in the operative field is frequently a limiting factor in determining the extent of the surgery.

Chemotherapy or radiotherapy is not useful.

diffuse plexiform: unsuitable for surgery

Consider – targeted systemic therapy

Back

1st line –

surveillance

These neurofibromas may also undergo malignant degeneration, concern for which may be one of the indications for surgery.

All types of neurofibromas typically enlarge during pregnancy. Close monitoring, preferably by an obstetrician familiar with NF1, is appropriate. Diffuse plexiform neurofibromas of the pelvis and retroperitoneal space may compromise the later stages of gestation and delivery.[Figure caption and citation for the preceding image starts]: Left anterior chest diffuse plexiform neurofibroma with overlying hyperpigmentationFrom the personal collection of Dr Vincent M. Riccardi; used with permission [Citation ends]. com.bmj.content.model.Caption@73c5ab01 [Figure caption and citation for the preceding image starts]: Radiograph showing extensive involvement of a diffuse plexiform neurofibroma in the upper thorax (bilateral), mediastinum, retroperitoneal space, and omentumFrom the personal collection of Dr Vincent M. Riccardi; used with permission [Citation ends]. com.bmj.content.model.Caption@57d0c151

Back

Consider –

targeted systemic therapy

Additional treatment recommended for SOME patients in selected patient group

In the UK, it is only available under a commercial arrangement agreement.[44]

It is approved for use in children ≥2 years of age in the US and children ≥3 years of age in Europe.

See local specialist protocol for dosing guidelines.

Primary options

selumetinib

cutaneous

Consider – surgical removal

Back

1st line –

surveillance

Cutaneous neurofibromas are generally left alone unless they are repeatedly subject to trauma, are a source of irritation, or are excessively itchy. Otherwise, the patient simply has to learn to live with them.

All types of neurofibromas typically enlarge during pregnancy. Close monitoring - preferably by an obstetrician familiar with NF1 - is appropriate.

Back

Consider –

surgical removal

Additional treatment recommended for SOME patients in selected patient group

Routine treatment involves surgical removal of a small number of neurofibromas in an outpatient setting.

Research approaches have used the oral mast cell blocker ketotifen.[45][46]

Glomus tumours are nail-bed vascular tumours and they can be excruciatingly painful. This makes their surgical removal a cogent consideration.

Consider – oral or topical mast cell blockers

Back

Consider –

oral or topical mast cell blockers

Additional treatment recommended for SOME patients in selected patient group

Severe crush trauma may be followed by the local development of a neurofibroma that may be intensely pruritic. Large numbers of cutaneous neurofibromas and periods of rapid growth of a diffuse plexiform neurofibroma may also be associated with excessive pruritus.

Treatment with the mast cell blocker ketotifen has shown some ameliorative effect.[45][46] However, this agent is not commonly used.

headache

1st line – ongoing surveillance + identification/treatment of underlying cause(s)

Back

1st line –

ongoing surveillance + identification/treatment of underlying cause(s)

It is critical that clinicians be intimately aware of the patient's headache history - for all age groups - updated on a regular basis.

Sudden onset of a serious headache warrants consideration of hydrocephalus, intracranial glioma, migraine, or other cerebrovascular compromise.

Headaches of one sort or another are among the most common symptoms of patients with NF1. For the vast majority, they are simply coincidental, but monitoring changes in the headache history is a very important aspect of caring for patients with NF1.

nervous system

optic pathway glioma

1st line – expectant waiting or screening cranial MRI

Back

1st line –

expectant waiting or screening cranial MRI

Without unequivocal guidelines, expectant waiting or screening cranial MRI are choices made based on the physician's aggressiveness and the concerns of the family. Although the frequency of NF1 optic pathway gliomas is 15%, routine screening with MRI is seen by some as controversial.[17][35]

Consider – surgery and/or chemotherapy

Back

Consider –

surgery and/or chemotherapy

Additional treatment recommended for SOME patients in selected patient group

Surgery, chemotherapy, or both treatments may be suitable for patients with endocrine/hypothalamic disturbances. Treatment type must be tailored to the individual patient. A common regimen for chemotherapy includes cisplatin.

Radiotherapy significantly increased the risk of intracranial tumours and moyamoya (a form of angiogenesis in response to blocked arteries in the basal ganglia) in patients with neurofibromatosis and optic pathway glioma.[53][54]

cerebral hemisphere, cerebellar, or brainstem glioma

Back

1st line –

surveillance

The frequency and nature of follow-up will depend on the associated symptoms, if any.

If a glioma is identified coincidentally by cranial MRI, neurological and/or neurosurgical evaluation should be performed.

cerebrovascular compromise

Back

Consider –

surgery

Additional treatment recommended for SOME patients in selected patient group

Surgery is a last resort because of anticipated side effects.

Consider – removal or surgical control of lesion(s)

Back

1st line –

surveillance

Respecting the confounding influences of advanced age (seventh decade and beyond) and the presence of widespread atherosclerotic vascular disease, a patient with NF1 and with cerebrovascular compromise should be at least tentatively considered to have a cerebrovascular manifestation of the disease.

Repeated neurological clinical evaluations are warranted and intervention should be considered as an option as determined by the neurological and neurosurgical consultants.

Back

Consider –

removal or surgical control of lesion(s)

Additional treatment recommended for SOME patients in selected patient group

Standard therapy for cerebrovascular compromise involves removal or surgical control of the lesion or lesions involved.

hydrocephalus

1st line – consideration of a cerebrospinal fluid shunting device and/or surgical reduction of associated glioma

Back

1st line –

consideration of a cerebrospinal fluid shunting device and/or surgical reduction of associated glioma

Neurological and neurosurgical evaluation should be performed. Shunting should be aimed at ameliorating or obviating the symptoms due to the hydrocephalus.

impaired cognitive function, including incoordination

1st line – special education resources, learning aids

Back

1st line –

special education resources, learning aids

IQ/psychological testing should be done prior to school entry. Neuropsychological evaluation, special education resources, and learning aids (e.g., laptop computer) may be appropriate.

Therapists, educators, and primary care providers need to communicate regularly regarding progress (both developmental and educational) and update any recommendations.[47]

Consider – central nervous system stimulants

Back

Consider –

central nervous system stimulants

Additional treatment recommended for SOME patients in selected patient group

Use of stimulants (e.g., methylphenidate) may be appropriate for some patients, particularly those with attention deficit compromise. These should only be prescribed through expert centres.

seizures

1st line – anticonvulsants

Back

1st line –

anticonvulsants

Neurology referral should be provided for evaluation and anticonvulsant regimen. The evaluation will almost certainly include neuroimaging, whether or not it has already been done.

spinal cord compression with remediable symptoms or functional losses

Back

1st line –

surgery

MRI and neurological/neurosurgical evaluation should be provided in the presence of dystrophic scoliosis or paraspinal nodular plexiform neurofibromas or a diffuse plexiform neurofibroma extending to or beyond the midline.

Surgery should be considered only with remediable symptoms or functional losses. Non-surgical accommodation and supportive treatment of the established motor and sensory compromise (e.g., physiotherapy) is always appropriate.

peripheral neuropathy

Consider – pain management

Back

1st line –

surveillance

Concern should be heightened in the presence of subcutaneous and nodular plexiform neurofibromas.

Neuroimaging can assess spinal cord involvement and vertebral erosion.

Back

Consider –

pain management

Additional treatment recommended for SOME patients in selected patient group

Pain management is an important adjunctive therapy.

Morphine, including a morphine pump, may be necessary. Advice from a pain management consultant may be helpful.

1st line – goniotomy or trabeculotomy

Back

Consider –

surgery

Additional treatment recommended for SOME patients in selected patient group

Surgery most often becomes an option when there is intractable pain or vertebral collapse.

Surgery risks significant motor and sensory compromise. Non-surgical accommodation and supportive treatment of the established motor and sensory compromise (e.g., physiotherapy) are always appropriate.

eye

congenital glaucoma

Back

1st line –

goniotomy or trabeculotomy

Unexplained crying and/or irritability in a newborn should raise concern about this manifestation of NF1.

Consider – medical therapy to lower intraocular pressure

Back

Consider –

medical therapy to lower intraocular pressure

Additional treatment recommended for SOME patients in selected patient group

Can be used to lower intraocular pressure before and/or after surgery.

Medicines determined by the ophthalmologist.

ptosis

symptomatic oropharyngeal neurofibromas

Back

1st line –

surgery

Periorbital neurofibromas causing upper or lower lid ptosis will probably require surgery to remove the associated lesion(s).

oral

excess caries and other dental problems

Back

1st line –

surgery

Labial, buccal, oral, palatal, pharyngeal, and/or laryngeal neurofibromas may require surgery for removal or debulking.

1st line – surveillance and counselling

Back

1st line –

surveillance and counselling

Patients with NF1 appear to be at higher risk for dental caries. Counselling to enhance dental hygiene plus close dental follow-up are required to minimise premature and excessive tooth loss.

Consider – restoration

Back

Consider –

restoration

Additional treatment recommended for SOME patients in selected patient group

Restoration when needed.

skeletal

sphenoid wing dysplasia

Back

1st line –

surveillance

Regular radiographic studies are key elements of the monitoring schema.

1st line – avoidance of weight-bearing

Back

Consider –

surgery

Additional treatment recommended for SOME patients in selected patient group

The development of ocular proptosis, which may be pulsatile, may warrant urgent surgery to correct herniation of the frontal lobe into the orbit.

Corrective surgery may be warranted for worsening of this progressive lesion in the absence of acute problems.

tibial pseudarthrosis

Back

1st line –

avoidance of weight-bearing

Avoidance of weight-bearing until surgery becomes appropriate.

Consider – bracing

Back

Consider –

bracing

Additional treatment recommended for SOME patients in selected patient group

Bracing may assist in the avoidance of weight-bearing.

Back

2nd line –

surgery

Surgery is a strong consideration if severe bowing or a fracture results.

vertebral dysplasia

Consider – surgery, including internal fixation

Back

1st line –

surveillance

The presymptomatic presence of vertebral dysplasia can be appreciated by an abnormal hair whorl over the spinal column, warranting plain radiographs of the spine and close follow-up throughout the first decade of life.

Back

Consider –

surgery, including internal fixation

Additional treatment recommended for SOME patients in selected patient group

Between 5 and 10 years of age, serious angular deformity of the spine is a consequence of NF1 vertebral dysplasia. The angulation may be forwards and/or lateral. As soon as serious angular deformity is identified, corrective surgery, including internal fixation, must be considered.

Bracing is generally not helpful.

dystrophic scoliosis

Consider – surgery, including internal fixation

Back

1st line –

surveillance

Between 5 and 10 years of age, serious angular deformity of the spine is a consequence of NF1 vertebral dysplasia. The angulation may be forwards and/or lateral.

Back

Consider –

surgery, including internal fixation

Additional treatment recommended for SOME patients in selected patient group

As soon as serious angular deformity of the spine is identified, corrective surgery, including internal fixation, must be considered.

Bracing is generally not helpful.

pectus excavatum/carinatum

Back

1st line –

surveillance

Chest radiographs may be useful for initial assessment for mediastinal involvement.

Back

Consider –

surgery

Additional treatment recommended for SOME patients in selected patient group

Ordinarily, at the end of the second decade, NF1 pectus deformity may become sufficiently severe to warrant corrective surgery, particularly if mediastinal/intrathoracic respiratory and/or cardiac compromise is present.

genu valgum/varum

1st line – orthotics

Back

1st line –

orthotics

Orthotics may be of some use in childhood and adolescence.

ankle valgus and pes planus

Back

2nd line –

surgery

By the end of the first decade or within the second decade, surgery may become the preferred treatment.

1st line – orthotics

Back

1st line –

orthotics

Orthotics may be of some use in childhood and adolescence.

In adults, this manifestation of NF1 may require the long-term use of orthotics, including corrective shoes.

vascular

renovascular hypertension

1st line – antihypertensive medicine

Back

1st line –

antihypertensive medicine

Any person with NF1 and hypertension (infant to adult, transient or stable) must be evaluated for renovascular pathogenesis if a phaeochromocytoma has been ruled out. Every patient with NF1 - infant, child, or adult - must have a blood pressure measurement at every clinical engagement.

Documentation of renovascular hypertension warrants consideration of surgery as the definitive treatment, although antihypertensive medicines are likely to have an interim and/or long-term role.

1st line – surveillance and/or surgery

Back

2nd line –

surgery

Patients inadequately responsive to oral medicines become surgical candidates. Surgery is likely to involve stenting or shunting around afferent obstructions.

gastrointestinal

bleeding

Back

1st line –

surveillance and/or surgery

Gastrointestinal haemorrhage in NF1 warrants consideration that bleeding is due to vascular abnormalities or an NF1-related tumour, including both neurofibromas and gastrointestinal stromal tumours. Arteriography for localisation and surgical extirpation become reasonable considerations.

gastrointestinal stromal tumours (GISTs): localised or potentially resectable

Consider – targeted systemic therapy

Back

1st line –

surgery

Severe and/or recurrent abdominal pain and/or gastrointestinal bleeding should raise consideration of GISTs and the need for surgical treatment. As more than one of these tumours may be present, surgical decision-making may be difficult.

Multiple GISTs should initiate a search for other features of NF1.[55][56]

Back

Consider –

targeted systemic therapy

Additional treatment recommended for SOME patients in selected patient group

Imatinib, a tyrosine kinase inhibitor, is useful in treating tumours that cannot be entirely surgically removed, that have spread, or where there is thought to be a high risk of recurrence. However, the use of imatinib for GIST in NF1 is not as effective as for sporadic GIST.[49][50] It is approved for the treatment of KIT (CD117)-positive GIST.

Sunitinib, a multitargeted tyrosine kinase inhibitor, may be considered if there is disease progression on, or an intolerance to, imatinib.[49][51]

See local specialist protocol for dosing guidelines.

Primary options

imatinib

Secondary options

sunitinib

gastrointestinal stromal tumours (GISTs): unresectable or metastatic

1st line – targeted systemic therapy

Back

1st line –

targeted systemic therapy

Imatinib, a tyrosine kinase inhibitor, is useful in treating tumours that cannot be surgically removed or that have spread, although the use of imatinib for GIST in NF1 is not as effective as for sporadic GIST.[49][50] It is approved for the treatment of KIT (CD117)-positive GIST.

Sunitinib, a multitargeted tyrosine kinase inhibitor, may be considered if there is disease progression on, or an intolerance to, imatinib.[49][51]

See local specialist protocol for dosing guidelines.

Primary options

imatinib

Secondary options

sunitinib

colon hyperganglionosis

1st line – oral mineral oil

Back

1st line –

oral mineral oil

Any infant, child, or adult with severe constipation or obstipation should be considered to be symptomatic of colon hyperganglionosis.

Depending on the severity, treatment with daily oral mineral oil may suffice.