Rasopathies

Question 1

Cardiofaciocutaneous syndrome

Answer 1

Inheritance: Autosomal dominant
Genes: KRAS, BRAF, MEK1, MEK2

Sparse, brittle, curly scalp hair
Skin abnormalities (dermatitis, ichthyosis,) (Cutaneous)
●	CHDs, pulmonic stenosis (Cardio)
●	Craniofacial malformations (Facio)
●	Growth delay
●	Foot abnormalities
●	Dysmorphic features
●	Severe cardiac involvement can cause shortened lifespan

Question 2

Costello syndrome

Answer 2

Inheritance: Autosomal dominant
Gene: HRAS, (proto-oncogene)

●	Intellectual disability
●	Developmental delay
●	Joint hypermobility
●	Loose folds of extra skin
●	Hypertrophic cardiomyopathy
●	Pulmonic stenosis
●	Short stature
●	Arrhythmia 
●	Rhabdomyosarcoma and neuroblastoma
●	Lifespan can be normal, but may be shortened by heart concerns

Question 3

NF1 : Genetics

Answer 3

Inheritance: Autosomal dominant w/ 50% de novo rate
Gene: NF1
● Highly phenotypically variable even w/same family
● Impossible to predict phenotype
● More features may appear with age

Question 4

NF1 Diagnositc criteria

Answer 4

●6 or more café au lait macules
oOver 5 mm diameter in prepubescent individuals
oOver 15 mm diameter in postpubescent individuals
● 2 or more neurofibromas of any type
OR
●1 plexiform neurofibroma
oCan rarely degenerate into a malignant peripheral nerve sheath tumor
●Axillary and/or inguinal freckling
●Optic pathway glioma
oVision loss when symptomatic
●2 or more Lisch nodules
●A distinctive osseous lesion such as:
oSphenoid dysplasia
oTibial pseudoarthrosis
●A first degree relative meeting the above criteria

Question 5

NF1 Minor Features

Answer 5

●Juvenile xanthogranulomas
●Learning disability (50-75%)
●Intellectual disability (~6%)
●Focal seizures
●Long-bone dysplasia
●Hypertension
●Vasculopathy
●Increased risk for breast cancer and GIST

Question 6

Legius syndrome

Answer 6

Inheritance: Autosomal dominant
Gene: SPRED1
●Often mistaken for NF1
●Almost phenotypically identical for many patients
oCafé au lait macules, optic gliomas, lD
MAJOR DISTINGUISHING FACTOR
oLegius syndrome does NOT have Lisch nodules
oNO NEUROFIBROMAS

Question 7

Noonan syndrome: Genetics

Answer 7

Inheritance: Autosomal dominant
Genes: PTPN11, KRAS, SOS1, RAF1, NRAS, HRAS, BRAF, SHOC2, MAP2K1, MAP2K2, CBL, RIT1, etc

Question 8

Noonan syndrome: Features

Answer 8

●Short stature
●Webbed neck
●Pulmonic stenosis
●Hypertrophic cardiomyopathy
●ASDs/VSDs
●GI issues
●Cryptorchidism
●Pectus deformities
●Joint contractures or hypermobility
●Scoliosis
●Hypertelorism
●Developmental delay
●Some have ID/learning disabilities
●Autism
●Clotting disorders/Factor deficiencies
●Recurrent illness
●Chronic pain
●Sensorineural hearing loss

Question 9

Leopard syndrome

Answer 9

Inheritance: Autosomal dominant 
Genes: PTPN11, RAF1, BRAF, MAP2K1
●Noonan syndrome symptoms with the addition of multiple lentigenes (liver spots) that typically appear around age 4-5
●Lentigines
●Electrocardiographic abnormalities
●Ocular hypertelorism
●Pulmonic stenosis
●Abnormal genitalia
●Retarded growth
●Deafness