Genoderm - Hamartoneoplastic Syndromes

Question 1

Neurofibromatosis type 1 diagnosis

Answer 1

AD with 100% penetrance

NF1 tumour suppressor gene
Neurofibromin protein

CLINICAL FEATURES
CALMS
- first feature to appear
- Onset at birth or within 1st year of life/early childhood
- Increase in size and number throughout life

Neurofibromas

• Appear during childhood, may be present at birth
• Increase rapidly in number during puberty ? Hormonal influence
• Trunk and limbs, areola of breast in women
• May develop in relation to peripheral nerves
• Variants —> Blue red macules, pseudoatrophic macules
• Plexiform neurofibromas —> diffuse elongated fibroma along course of a nerve, frequent;y involves trigeminal nerve/upper cervical nerves, noticeable wothin 1st 2 years of life, bag of worms feeling on palpation
• Elephantiasis neurofibromatosa —> diffuse neurofibromatoses of the nerve trunks with overgrowth of subcut tissue amd skin —> wrinkled, pendulous

Freckling

• Appears by age 3 (a bit later than CALMS)
• Axillae (Crowe’s sign) pathognomonic
• Groin
• May be over an underlying plexiform neurofibroma, if extends to midline of spine —> tumour involves spinal cord

Lisch nodules

• Pigmented iris hamartomas
• Dome shaped lesions superficially around iris on slit lamp exam
• Asymptomatic
• Helps confirm Dx of NF1

Oral lesions

• Papillomatous neurofibromas of the palate, buccal mucosa, tongue, lips
• Asymmetrical macroglossia

Skeletal abnormalities

• ? D/t defect in osteoblast differentiation
• Sphenoid wing dysplasia characteristic
• Kyphoscoliosis
• Pseudoarthrosis of tibia, radius
• Osteoporosis
• Short stature
• Macrocephaly

Other organs

• Learning difficulties
• Speech impediments
• Hypertelorism
• Headaches
• Endocrine - precocious puberty, acromegaly, addison disease, hyperparathyroidism, gynaecomastia, phaeochromocytoma, renovascular HTN
• GUT - lesions lower urinary tract —> urinary symptoms
• GIT - lesions may cuse recurrent haemorrhage, obstruction
• CVS - cardiovascular abnormalities
• Resp - pulmonary HTN

Malignancy

• Optic nerve glioma (solitary intracranial tumour)
• Astrocytoma
• Schwannoma
• Sarcomatous change within deeper neurofibromas
• Malignant peripheral nerve sheath tumours (highly aggressive, enlargement or pain suggest possibility of malignant change) —> poorer prognosis if assoc with NF1 than if occurs as isolated phenomenon
• Wilms tumour
• Rhabdomyosarcoma
• Retinoblastoma
• Melanoma
• Juvenile chronic myeloid leukaemia (higher risk with concurrent NF1 and juvenile xanthogranuloma)

Pruritus

• Histamine is implicated as a cause d/t Large numbers of mast cells in skin, response to antihistamines
• Ketotifen (mast cell blocking agent) may be beneficial

DIAGNOSTIC CRITERIA (requires at at least 2 features for Dx)

1. CALMS
   - Prepubertal individuals - 6 or more CALM >5mm in greatest diameter
   - Post pubertal individuals - 6 or more CALM >15mm in greatest diameter
2. Neurofibromas
   - 2 or more of any type OR
   - 1 plexiform neurofibroma
3. Freckling
   - Axillary (Crowe’s sign) OR
   - Inguinal regions
4. Optic glioma (intracranial tumour)
5. Lisch nodules (pigmented iris hamartomas)
   - 2 or more
6. A distinctive osseus lesion i.e.
   - Sphenoid dysplasia
   - Thinning of long bone cortex
   +/- pseudoarthrosis tibia/radius
7. A first-degree relative with NF1
   - parent, sibling, offspring

IX
Molecular testing for NF1 gene
- not neccesary if diagnostic criteria clearly fulfilled (Dx established on the basis of clinical criteria)
- helpful in cases where clinical picture unclear

Question 2

NF1 course/prognosis

Answer 2

Varies considerably

Majority benign course without major complications

CALMS increase in number throughout life

Neurofibromas

• Skin lesions May increase in number during puberty, pregnancy
• Lesions in GIT, GUT, CNS poor prognosis

Unexplained HTN in pregnancy

Reduced life expectancy d/t development of malignancy, HTN d/t renal artery stenosis or phaeochromocytoma

Question 3

NF1 associations

Answer 3

JUVENILE XANTHOGRANULOMA

Concurrent NF1 —> higher risk for juvenile chronic myeloid leukaemia

Question 4

NF1 clinical variant - Segmental neurofibromatosis

Answer 4

CALMS
Cutaneous neurofibromas
+/- visceral neurofibromas

Limited to circumscribed body segment

Probably represents somatic mosaicism of NF1 gene

Difficult to reassure patients with apparent segmental NF that there is no risk of NF1 occuring in their offspring (risk is small)

Question 5

NF1 clinical variant - CALMS and plumonary stenosis

Answer 5

CALMS
Pulmonary stenosis
Low intelligence

+/- freckling axillae, perineum, elsewhere

Linkage with NF1 gene

Question 6

NF1 clinical variant - Neurofibromatosis-Noonan syndrome

Answer 6

Clinical Features of both NF1 and Noonan syndrome

NF1 gene mutation
No PTPN11 mutation (for Noonan sundrome)

Question 7

RASopathies

Answer 7

Group of AD disorders

Mutations affecting components of RAS/MAPK pathway —> share many phenotypic features

NF1

LEGIUS SYNDROME
SPRED1 gene mutation
Resembles NF1
Multiple CALMS
Macrocephaly
Axillary freckling
No Lisch nodules
No neurofibromas
No apparent predisposition to cancer

NOONAN SYNDROME
PTPN11
KRAS
NRAS
Craniofacial dysmorphic features - broad forehead, hypertelorism, down slanting palpebral fissures, ptosis, high arched palate, low set posteriorly rotated ears
Congenital heart defects
Short stature
Undescended testes
Eye anomalies
Bleeding disorders
Normal cognition/mild abnormality
\+ Predisposition to cancer

NOONAN SYNDROME WITH MULTIPLE LENTIGINES (LEOPARD syndrome)
PTPN11
RAF1
Same as Noonan syndrome
+ development multiple lentigines with age
Unclear predisposition to cancer

CAPILLARY MALFORMATION - AV MALFORMATION SYNDROME
RASA1
Multifocal capillary malformation —> may be assoc with AV malformation and fistulae
Unclear predisposition to cancer

CARDIO-FACIO-CUTANEOUS SYNDROME
BRAF
MAP2K1
MAP2K2
KRAS
craniofacial features similar to Noonan syndrome
Congenital heart defects
Failure to thrive
Hypotonia
Short stature
Eye anomalies
Progressive formation of naevi
Normal cognition/mild abnormality
Unclear predisposition to cancer

COSTELLO SYNDROME
HRAS
craniofacial features similar to Noonan syndrome but more coarse
Congenital heart defects
Failure to thrive
Hypotonia
Short stature
Eye anomalies
Papilloma
Normal cognition/mild abnormality
\+ predisposition to cancer

Question 8

Conditions with CALMS

Answer 8

LEGIUS SYNDROME
CALM
Axillary freckling
Macrocephaly
Developmental delay
Learning difficulties

MCCUNE-ALBRIGHT SYNDROME
One large assymmetrical CALM “coast of Maine”
Precocious puberty
Numerous hyperfunctional endocrinopathies
Polypstotic fibrous dysplasia
Pathological fractures

TUBEROUS SCLEROSIS

CHEDIAK-HIGASHI SYNDROME
CALM
Partial albinism
Solar sensitivity
Photophobia
Neuropathy
Frequent infections

BASAL CELL NAEVUS (GORLINS) SYNDROME 
CALM
Multiple jaw keratocysts
BCCs
Skeletal abnormalities
Ovarian tumours

ATAXIA TELENGIECTASIA
CALM
Cutaneous telengiectasia
Ocular telengiectasia
Neurodegenerative
Delayed puberty
Resp tract infections

BLOOM SYNDROME
CALM
Photodistributed telengiectatic rash
Telengiectasia
Micrognathia
Short stature
Recurrent resp infections
High risk cancer

FANCONI ANAEMIA
CALM
Aplastic anaemia
Intellectual impairment
Malignancies

MAFUCCI SYNDROME
CALM
Vascular tumours
Short stature
Limb length inequality

Question 9

NF1 review checklist children 16 and under

Answer 9

AT TIME OF POSSIBLE DX/DX
All confirmed patients are to be seen by
- Genetics Medicine
- Ophthalmology

ANNUAL REVIEW THEREAFTER
Paediatrician and GP throughout childhood
Age < 8 yrs —> At least annual review with Paeds Opthal
Age 8-15 yrs —> annual review with optician

RECORD
Height
Weight
Head circumference
BP

SKIN
Neurofibromas - can be itchy, sometimes tender, cutaneous, subcutaneous
Plexiform neurofibromas - note location, appearance, size, hardness
Monitor large areas of CALM and/or excessive hair growth for development of plexiform neurofibroma
Assess for painful lumps c/w malignant peripheral nerve sheath tumours

*Refer to SPECIALIST SARCOMA TEAM urgently if rapidly growing, painful, changing lesions

SKELETON
Scoliosis - look for this during entire growth period, esp at puberty and adolescent growth spurts
Pseudarthrosis - tibia most commonly affected, but radius and ulna may be involved

*Refer to ORTHO if any curvature or bowing

EYES
Age < 8 yrs recommend annual review with paeds Ophthal
Therafter annual review with optician/orthoptist

Look for
- Squint
- Proptosis
- Reduced visual acuity
—> optic nerve glioma, retinoblastoma

*Refer urgently to OPHTHAL if any concerns

NEUROLOGICAL
Look for - 
- Ataxia
- Headches
- LOC
- Visual disturbance
—> optic nerve glioma, astrocytoma, schwannoma

*Refer to NEURO if increase in frequency and/or severity of headches, or onset of other symptoms

DEVELOPMENT (Paeds to review)
Look for - 
- Short stature
- Macrocephaly
- Coordination difficulty
- Speech difficulty
- Precocious puberty
- Late puberty

*PAEDS

EDUCATION AND BEHAVIOUR
Increased incidence of learning and behaviour difficulties esp attention difficulties - 
- ADD
- ADHD
- ASD

*Refer to professional assessment of educational needs if identified possible special needs

CLINICAL GENETICS
Genetic counselling
- 50% of offspring likely to be affected, disease may be severe
- 1st degree relatives i.e. siblings, offspring who have no stigmata of disease unlikely to carry gene, risk to their offspring is small but not absent —> may still pass this on through gonadal mosaicism

Question 10

NF1 review checklist Adults 16+

Answer 10

ANNUAL REVIEW
GP
Age 16-18 yrs —> Clinical genetics for couselling on adult complications and genetics

SKIN
Check for -
- Symptomatic lesions —> rapidly growing, painful, changing lesions —> urgent referral to SPECIALIST SARCOMA TEAM if rapidly growing, painful, changing lesions (malignant preipheral nerve sheath tumour)
- Plexiform neurofibromas
- Lumps that require excision for non-medical reasons —> refer to PLASTICS OR DERM

PSYCHOLOGICAL BURDEN
Look for feelings of social isolation, depression

*Consider referral to a counselling service

NEURO
Look for - 
- Headaches
- Nerve pain
- Visual disturbance
- Gait disturbance
—> optic nerve glioma, astrocytoma, schwannoma

*Refer to NEURO if increase in frequency and/or severity of headaches or onset of other symptoms

BP
Check BP —> if HTN
- Renovascular lesions (ususlly <20 yrs)
- Phaeochromocytoma (any age)

*Refer to ENDOCRINE if phaeochromocytoma possibility

EYES
Look for unusual visual signs/symptoms —> needs to be investigated
—> optic nerve glioma, retinoblastoma

*Urgent referral to OPHTHAL if any concerns

WOMEN
Increased risk of Breast CA between ages 40-50 yrs

*Refer to local breast screening centre for annual mammogram from 40 yrs

PREGNANCY
Neurofibromas may increase in size and/or itchiness
Comsider phaeochromocytoma/renal artery stenosis if have particularly high BP, esp if persists post-delivery

*Women who are planning pregnancy should be referred to GENETICS

Question 11

Rx of cutaneous neurofibromas

Answer 11

Symptomatic mx

Excision

• More disfiguring lesions
• Lesions increase in size and pain suggesting possible malignant change i.e. malignant peripheral nerve sheath tumours)

Ablative 10600nm CO2 laser —> risk of hypertrophic and atrophic scars (recommended preliminary test Rx)