Neurofibromatosis type 1: recognising and managing it in AU general practice

What NF1 is and who develops it

Neurofibromatosis type 1 (NF1) is an autosomal-dominant tumour-predisposition syndrome caused by loss-of-function variants in the NF1 gene on chromosome 17q11.2. The protein product, neurofibromin, normally inactivates Ras by accelerating GTP hydrolysis. When neurofibromin is absent, Ras signalling runs unchecked, driving uncontrolled proliferation in Schwann cells, melanocytes, and other neural-crest-derived tissues — which explains the characteristic mix of skin changes, peripheral nerve tumours, and cancer predisposition.

In Australia, NF1 affects approximately 1 in 3,000 people — around 10,000 Australians — per the RACGP genomics in general practice module. About half of all cases arise from spontaneous de novo mutations — no affected parent is identifiable, and the family history is entirely unremarkable. This matters clinically: a GP should not dismiss the diagnosis because parents appear unaffected.

NF1 is distinct from NF2-related schwannomatosis (bilateral vestibular schwannomas; 1 in 25,000–40,000 births) and non-NF2 schwannomatosis (painful peripheral schwannomas without vestibular involvement; 1 in 70,000). Both are rarer and managed at specialist centres. This article focuses on NF1, which is the condition GPs encounter in practice.

A. Core clinical — the AU general practice framework

Diagnosis — the 2021 Legius criteria

NF1 is a clinical diagnosis based on the revised 2021 Legius criteria. A person without an affected first-degree parent requires at least two of the following eight features, with at least one from categories four through seven for diagnostic confidence:

1. Six or more café-au-lait macules (CALs) greater than 5 mm in greatest diameter prepubertal, or greater than 15 mm postpubertal.
2. Axillary or inguinal freckling (Crowe’s sign).
3. Two or more neurofibromas of any type, or one plexiform neurofibroma.
4. Optic pathway glioma.
5. Two or more Lisch nodules on slit-lamp examination, or two or more choroidal abnormalities on OCT near-infrared imaging.
6. A distinctive bony lesion — sphenoid wing dysplasia, anterolateral tibial bowing, or long-bone pseudarthrosis.
7. A heterozygous pathogenic NF1 variant in normal tissue at approximately 50% variant allele frequency.
8. A first-degree relative who meets the above criteria.

A person with an affected first-degree parent needs only one additional criterion. Penetrance is virtually complete by age eight. Legius syndrome (SPRED1 gene) mimics NF1 with CALs and freckling but carries no tumour-predisposition risk — consider germline panel testing if café-au-lait macules and freckling are the only features present past age five to six.

History to take

• Pigmentary timeline — when did CALs first appear (typically within the first year of life); current count and sizes; rate of change.
• Neurofibromas — onset (cutaneous neurofibromas usually appear at puberty); any becoming painful, hard, or rapidly enlarging — the MPNST warning signs.
• Plexiform neurofibromas — soft compressible congenital masses; assess functional impact on airway, vision, spine, or limb use.
• Visual symptoms — reduced acuity, colour vision change, proptosis, squint, or RAPD in a child.
• Neurological — headache, seizure, focal weakness, new sensory change.
• Skeletal — tibial bowing in infants; scoliosis; bone pain; fractures.
• Blood pressure history — review at every visit, even infancy.
• Developmental and learning — school progress, attention, literacy, motor coordination.
• Family history — three-generation pedigree; specifically ask about CALs, learning difficulties, tumours, and premature death.
• Reproductive — breast symptoms in women; pregnancy planning (NF1 is high-risk in pregnancy).

Examination

Key components at every GP visit:

• Blood pressure using an age-appropriate cuff — from infancy, every visit.
• Skin survey under good light — count and measure CALs; document axillary and inguinal freckling; photograph and map any changing neurofibromas annually in adults with high tumour burden.
• Eyes — examine for proptosis, lid mass, RAPD; refer to paediatric ophthalmology for slit-lamp and OCT — GPs cannot reliably detect Lisch nodules at routine examination.
• Cardiovascular — abdominal bruit (renal artery stenosis); four-limb blood pressure in young hypertensive patients; peripheral pulses.
• Musculoskeletal — scoliosis screening (forward-bend test and plumb-line) at every paediatric visit, especially around puberty; tibial inspection in infants.
• Neurological — cranial nerves; motor and sensory; document any focal deficit at each visit.
• Developmental screen in children — age-appropriate milestones; Vanderbilt or Conners parent and teacher ratings if ADHD is suspected.

Management principles

No curative treatment for NF1 currently exists. Management is multidisciplinary surveillance with symptom-directed therapy. Core GP responsibilities are:

• Annual comprehensive review from infancy: skin, neurological status, growth, blood pressure, family history update, and lifelong MPNST education.
• Ophthalmology referral: annually to age eight, then biennially to age 18.
• School and learning support coordination: formal assessment at school entry and transitions.
• Referral to state clinical genetics service at diagnosis — free for affected paediatric patients.

The eviQ NF1 risk management guideline (NSW Health, 2025) and the Children’s Tumour Foundation of Australia provide current AU-specific surveillance frameworks. GPs in areas without a specialist NF clinic can anchor care to these resources.

B. Evidence appraisal — MPNST, selumetinib, and optic pathway glioma

MPNST risk and the PAIN warning signs

Malignant peripheral nerve sheath tumour (MPNST) carries a lifetime risk of 8–13% in NF1, nearly always arising within a pre-existing plexiform or nodular neurofibroma. It is the single biggest cause of NF1-related mortality, with a median survival after diagnosis of less than two years without early detection. The ERN GENTURIS 2022 surveillance guideline and eviQ NF1 risk management both emphasise that patient education for life is the primary GP intervention.

The warning signs are captured in the acronym PAIN:

• Persistent rest pain in or around an existing lesion.
• Accelerated growth — more than 1 cm per month, or noticeable change within three months.
• Hard or firm Induration in a previously soft lesion.
• New neurological deficit in the territory of the lesion.

Any one of these signs warrants urgent contrast-enhanced MRI within two weeks and referral to a sarcoma multidisciplinary team — Peter Mac (VIC), Chris O’Brien Lifehouse (NSW), Royal Adelaide Hospital (SA), Princess Alexandra Hospital (QLD), or QEII Medical Centre (WA). FDG-PET adds metabolic data when MRI is equivocal.

Selumetinib (Koselugo) — first targeted therapy

The SPRINT trial (Gross et al. NEJM 2020) enrolled 50 children with NF1 and symptomatic inoperable plexiform neurofibromas; selumetinib 25 mg/m² twice daily in continuous 28-day cycles produced a 66% confirmed partial response rate — at least 20% tumour-volume reduction by REINS criteria — with durable responses in 56% and meaningful improvements in pain interference, motor function, and quality of life.

The PBS Authority listing from 1 August 2024 covers children aged two years and over with symptomatic, inoperable plexiform neurofibromas causing pain, disfigurement, or functional impairment. A specialist paediatrician or paediatric oncologist with NF expertise initiates the Authority application via Services Australia form PB370; the GP’s ongoing role is monitoring: ejection fraction at baseline and every three months (echocardiogram), creatine kinase, liver function tests, and vitamin E levels, and watching for characteristic adverse effects — paronychia, asymptomatic CK rise, rash, peripheral oedema, and hair colour change per the TGA product information.

Optic pathway glioma — screen with eyes, not scans

Fifteen to twenty per cent of children with NF1 develop optic pathway glioma detectable on MRI, but the majority are asymptomatic and never require treatment. Both Listernick et al. and the Children’s Tumour Foundation OPG task force conclude that routine MRI surveillance does not improve visual outcomes — treatment is indicated for visual loss or field change, not for tumour size alone. Annual ophthalmology review (visual acuity, colour vision, visual fields, slit-lamp, OCT) is the screening tool; MRI is reserved for children with documented visual change or new proptosis.

C. Cognitive, behavioural, and developmental considerations

NF1 has a well-established neurocognitive profile that is distinct from intellectual disability. Thirty to sixty-five per cent of children with NF1 have a specific learning disability — most commonly in visuospatial processing, reading, and executive function — and 30–50% meet diagnostic criteria for ADHD. These proportions reflect neurofibromin’s role in neuronal signalling during development, and are not caused by medication or by a globally reduced intelligence. The intelligence distribution across the NF1 population spans the full range; the profile is uneven rather than uniformly lowered.

Formal cognitive and educational assessment at school entry (approximately age five to six) is the standard for every child with NF1 in Australia, with reassessment at significant transitions (Year 7, Year 11). Most affected children meet NDIS access criteria under permanent functional impairment with substantial functional capacity reduction — a GP letter, paediatrician or clinical psychology report, and school documentation support the Access Request. State education department disability adjustment funding (Nationally Consistent Collection of Data — NCCD) applies independently of NDIS, and the school can begin the process without requiring a GP form.

ADHD treatment in NF1 follows the same pathway as in the general population: methylphenidate, dexamfetamine, and lisdexamfetamine are all effective with similar response rates and side-effect profiles to non-NF1 ADHD. Stimulant initiation requires a paediatrician or child psychiatrist; state-based authority-prescriber rules apply (Western Australia and Queensland require a state permit).

Annual mental health screening from adolescence is appropriate: rates of anxiety and depression in NF1 are approximately two to three times the general population, driven by cosmetic burden, educational challenges, and chronic-disease load. A Mental Health Treatment Plan (MBS items 2715/2717) opens access to 10 subsidised Better Access psychology sessions.

D. Australian operations

MBS items

• Standard consultations — item 23 (Level B); item 36 (Level C, ≥20 min — appropriate for annual NF1 review); item 44 (Level D, ≥40 min) for complex initial assessment or multisystem review.
• GP Chronic Condition Management Plan (GPCCMP) — item 965 (plan preparation) and item 967 (review), replacing legacy GPMP/TCA items from 1 July 2025. NF1 with hypertension, scoliosis, learning disability, or depression routinely qualifies. Opens up to five allied-health sessions per calendar year under the item 10960 series — physiotherapy (scoliosis, post-surgical rehabilitation), psychology, occupational therapy, and dietitian.
• GP Mental Health Treatment Plan — item 2715 (20–40 min with MHST accreditation) or item 2717 (≥40 min) — opens 10 Better Access psychology sessions per calendar year.
• Breast MRI — high-risk screening — item 63464 — Medicare-rebated annual breast MRI for women at high lifetime risk; NF1 qualifies via family cancer service certification; refer from age 30.
• Preimplantation genetic testing (PGT-M) — MBS items 73306/73307/73308, available from November 2024 for monogenic conditions including NF1 — requires clinical genetics service input and applies a lifetime limit per couple.
• Consultant physician complex care — item 132 (initial ≥45 min) and item 133 (review ≥20 min) — applicable to the medically qualified clinical geneticist or paediatrician referral.

PBS

• Selumetinib (Koselugo) — Authority Required (Written); paediatric NF1 aged ≥2 years with symptomatic inoperable plexiform NF; specialist-initiated via Services Australia form PB370.
• Methylphenidate, dexamfetamine, lisdexamfetamine — PBS Authority for ADHD; paediatrician or child psychiatrist initiation (state authority-prescriber rules vary by state).
• Standard antihypertensives — ACEi (perindopril, ramipril), ARB (irbesartan, candesartan), CCB (amlodipine) — PBS general schedule; choice guided by Heart Foundation / RACGP 2024 hypertension guideline.

State clinical genetics services — free for affected paediatric patients

State genetics services accept GP referrals and provide free consultations for affected paediatric patients: Victorian Clinical Genetics Services (Royal Children’s Hospital, Melbourne); Sydney Children’s Hospital Genetics and Hunter Genetics (NSW); Genetic Health Queensland (Royal Brisbane); Genetic Services WA (King Edward Memorial and Perth Children’s Hospital); Women’s and Children’s Hospital Genetics (SA); Tasmanian Clinical Genetics Service (Royal Hobart Hospital); ACT Genetic Service (Canberra Hospital). For the Northern Territory, referral to Queensland or South Australia is the usual pathway.

E. Special populations

Children 0–5. Establish baseline ophthalmology at diagnosis — paediatric slit-lamp and OCT. Measure blood pressure at every consultation using an age-appropriate cuff. In infants, inspect and palpate the tibiae: anterolateral tibial bowing is pre-fracture pseudarthrosis and requires same-week paediatric orthopaedic referral and a clamshell AFO brace. Review frequency is three-monthly in infancy, six-monthly from one to five years.

Children 6–18. Annual GP review including scoliosis screening at every visit — forward-bend test plus plumb-line, especially around puberty when dystrophic scoliosis (a short angular curve) can progress rapidly and requires early surgical planning. Formal cognitive and educational assessment at school entry and again at secondary school transition.

Women aged 30–50. Breast cancer risk in women with NF1 under 50 is approximately five times the general population, driven predominantly by hormone-receptor-negative cancers. Refer all women with NF1 to a family cancer service from age 30 for annual breast MRI under MBS item 63464. A mammography decision is made jointly by the family cancer service.

Pregnancy. NF1 pregnancy carries increased risk of pre-eclampsia, renal-artery-stenosis-related hypertension, plexiform neurofibroma growth, and MPNST, and should be co-managed with fetomaternal medicine. Fifty per cent of offspring will inherit NF1; preimplantation genetic testing (PGT-M) is available via Genea, Monash IVF, and Virtus Health. Genetic counselling before conception is strongly recommended and provided free via state clinical genetics services.

When to escalate

Escalate urgently when any of the following arise:

• Same day / emergency — rapidly growing painful neurofibroma with new neurological deficit; acute visual loss; severe hypertension with headache and sweating (phaeochromocytoma crisis); infant tibial fracture.
• Within 1–2 weeks — any single PAIN criterion present (suspected MPNST); new hypertension in a child, adolescent, or pregnant patient; proptosis or documented visual field change.
• Within 6–12 weeks — new NF1 diagnosis for state genetics service referral; preconception counselling; cosmetically or functionally limiting plexiform neurofibroma; learning or behavioural concerns requiring educational psychology assessment.

Safety-net language to provide at every annual review: “If a lump becomes painful, grows quickly, feels hard, or causes new tingling, weakness, or vision change — contact me the same day.”

What this article is and is not

This is general health information drawn from current Australian guidelines and major clinical trials — RACGP Genomics in General Practice, eviQ NF1 risk management (NSW Health 2025), TGA, PBS, Children’s Tumour Foundation of Australia, SPRINT trial (NEJM 2020), and ERN GENTURIS 2022. It is not personal medical advice and does not create a doctor–patient relationship. Specific management decisions, including surveillance schedules and medication initiation, are made with each individual’s GP and treating specialists.

For Australian consumer information: Children’s Tumour Foundation of Australia, HealthDirect — Neurofibromatosis, Better Health Channel.

For acute or urgent concerns: emergency services 000 | Lifeline 13 11 14.

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Sources cited

1. RACGP — Genomics in general practice: NF1
2. eviQ — NF1 risk management (NSW Health, 2025)
3. PBS — Koselugo (selumetinib) medicine status
4. TGA — Koselugo (selumetinib) AusPAR
5. Children’s Tumour Foundation of Australia
6. HealthDirect — Neurofibromatosis
7. Better Health Channel — Neurofibromatosis
8. Legius et al. — Revised NF1 diagnostic criteria (Genetics in Medicine 2021)
9. Gross et al. — SPRINT trial: selumetinib in NF1 (NEJM 2020)
10. ERN GENTURIS 2022 — NF1 tumour surveillance guideline
11. Lin et al. — NF1 Cardiovascular Task Force (Genetics in Medicine 2022)
12. Listernick et al. — Optic pathway gliomas in NF1