RASopathies Flashcards
What are the gene, inheritance, mechanism, and clinical features of NF1?
NF1; AD; Loss of function,
“second hit”; CALMs, intertriginous freckling; neurofibromas and plexiform neurofibromas; iris Lisch nodules;
osseous dysplasia; optic glioma; no/mild cognitive impairment
What are the gene, inheritance, and clinical features of Noonan Syndrome?
PTPN11, LZTR1, SOS1,
SOS2 KRAS, NRAS,
RIT1, RAF1;
AD, AR*; Gain-of-function; Craniofacial abnormalities, short stature; undescended testicles; ophthalmologic abnormalities;
bleeding disorders; normal neurocognitive function or mild impairment; predisposition to
cancer
What are the gene, inheritance, mechanism, and clinical features of NSML (Noonan syndrome with multiple letigines)?
PTPN11, AD, Gain-of-function, Same as Noonan, but with multiple skin lentigines; unclear predisposition to cancer
What are the gene, inheritance, mechanism, and clinical features of NSLH (Noonan syndrome-like with loose anagen hair)?
SHOC2, PPP1CB; AD; Gain-of-function; Same as Noonan, but with easily pluckable, sparse, thin, slow-growing hair
What are the gene, inheritance, mechanism, and clinical features of CBL-related condition(s)?
CBL; AD; Gain-of-function; Craniofaciall like Noonan, but high risk of myeloproliferative disorders (JMML)
What are the gene, inheritance, mechanism, and clinical features of Costello syndrome?
HRAS; AD; Gain-of-function; Craniofaciall like Noonan, but more coarse; CHD; failure to thrive; short stature; eye abnormalities;
multiple skin manifestations (papillomata); no/mild cognitive impairment hypotonia;
predisposition to cancer
What are the gene, inheritance, mechanism, and clinical features of Cardiofaciocutaneous syndrome?
BRAF, MAP2K1,
MAP2K2, KRAS;
AD; Gain-of-function; Craniofacial like Noonan; CHD; failure to thrive; short stature; eye abnormalities; multiple skin
manifestations, including progressive formation of nevi; no/mild cognitive impairment;
hypotonia; unclear predisposition to cancer
What are the gene, inheritance, mechanism, and clinical features of Legius syndrome?
SPRED1; AD; Loss of function; CALMs, intertriginous freckling; macrocephaly; normal neurocognitive function or mild
impairment; no apparent predisposition to cancer
What are prenatal features of Noonan Syndrome?
Detailed pregnancy history, with
specific enquiry for exposure to
alcohol and anticonvulsants
(phenotypic overlap with some of
the dysmorphic features)
* Nuchal thickening/cystic
hygroma, pleural effusion, or
polyhydramnios.
* Birthweight usually normal or
increased because of edema.
Craniofacial features of Noonan syndrome:
Craniofacial features
* Broad forehead
* Hypertelorism
* Down-slanting
palpebral fissures
* Ptosis
* High-arched palate
* Low-set and
posteriorly rotated
ears
Other clinical features of Noonan syndrome:
- Short stature for sex and
family background - Developmental delay of
variable degree - Broad or webbed neck
- Unusual chest shape with
superior pectus carinatum
and inferior pectus
excavatum - Widely spaced nipples
- Cryptorchidism in males
- Lymphatic dysplasia of the
lungs, intestines, and/or
lower extremities - Cognitive: unaffected to
mild impairment; - Bleeding disorders
- Predisposition to cancer.
- Most common is Juvenile
myelomonocytic leukemia - Neuroblastoma
- Rhabdomyosarcoma
- Acute lymphoblastic leukemia
Other clinical manifestations of Noonan syndrome:
Estimated at between 50% and
80% of affected individuals
Pulmonary valve stenosis (25%-
71%), often with dysplasia, is the
most common anomaly in NS
Hypertrophic
cardiomyopathy (10%-29%)
It usually presents early in life
- Other structural defects
- ASD
- VSD
- Aortic coarctation
- An electrocardiographic
abnormality
Noonan syndrome evaluation and management:
- Initial evaluation
- Echocardiogram & EKG To identify congenital heart defects, cardiomyopathy, &/or
cardiac conduction abnormalities - Management
- DD early intervention programs and individualized education strategies
- Bleeding depending on specific deficiency
- Growth hormone treatment
- PVS treated w/percutaneous balloon pulmonary valvuloplasty has a higher reintervention
rate vs pulmonary valve stenosis w/o NS but is still considered 1st-line treatment. 2 - HCM substantial early mortality; infants presenting before age 6 mos in congestive
heart failure have worst prognosis - Genotype-phenotype correlations:
- RAF1 –> heart
Clinical manifestations of NSML:
Clinical manifestations of
NS, but:
* Hearing loss more
common (20%)
* Lentigines (not always)
* Hypertrophic
cardiomyopathy > PV
stenosis
* Milder facial features
The lentigines are small (<5 mm) numerous dark
brown spots
Clinical features of Costello syndrome:
- Coarse facial features:
- full lips, large mouth, full nasal
tip), curly/sparse, fine hair,
macrocephaly - Perinatal:
- Increased nuchal thickness
- Polyhydramnios (>90%)
- Characteristic ulnar deviation
of the wrists - Short humeri and femurs
- Fetal tachycardia (various forms of
atrial tachycardia) - Preterm delivery
- Soft redundant skin
with deep
palmar/plantar
creases and joint laxity - Failure to thrive and GI
dysfunction - Papillomata
- # 1 cancer risk amongRASopathies:
Rhabdomyosarcoma,
neuroblastoma and
bladder cancer
Cardiac manifestations of Costello syndrome:
- Cardiac hypertrophy #1
- GH implications?
- CHD: usually PVS
- Arrhythmia
- Aortic dilatation, mild; noted in
fewer than 10% of individuals - Hypertension
- Eval by cardiologist for CHD,
HCM, arrhythmia - CHD: same management
- Aortic dilatation: care should
be individualized.
CFC Syndrome clinical features:
- Prenatally:
polyhydramnios and may
be LGA - Craniofacial like
Noonan but more coarse
(but less than CS) - In infancy: feeding
issues, DD, seizures,
ocular abnormalities - Dermatologic: severe
xerosis, hyperkeratosis
or ichthyosis, eczema,
hemangioma, CALM, hair
and nail involvement.
Improvement with age - Lymphedema and
chylothorax can occur - Malignant tumors not
reported - Other: MSK, lymphatic,
GI, endocrine,
neurologic, urogenital
Cardiac manifestations of CFC syndrome:
- Can present as PVS, ASD, VSD, HCM
- At birth or later in life (HCM)
- HCM can be progressive
- Management of cardiac structural
defects, hypertrophic cardiomyopathy,
and arrhythmias as in the general
population - Antibiotic prophylaxis
- Periodic echocardiogram (HCM), ECG
(rhythm disturbances) - Pulmonic stenosis is present in 50% of
CFC individuals with a PV in BRAF as
opposed to 37% with a PV in other genes
RASopathies: misc info
- AD pattern of inheritance (exception of LZTR1 in
Noonan) - NF1 and Legius syndrome caused by LoF
variants - PTPN11 loss of function metachondromatosis
# 156250 (not a RASopathy) - The rest are caused by missense gain-of
function (CNVs usually not implicated) - Dysmorphic features: CS > CFC > NS > NF1
- Specific diagnostic criteria for NF1 and Legius
syndrome - Buzz words:
- Short stature and pulmonary valve stenosis -> Noonan syndrome
- Papillomata and deep plantar creases -> Costello syndrome
- Eczema + heart + coarse features -> CFC
- Child with CALM and cancer + family history
of cancer on both sides –> CMMRD - Potential of MEK inhibitors as therapy for
You are called to see a 5-year-old boy with short stature, atrial septal defect and mild developmental delay. There is history of polyhydramnios and preterm delivery. Overall, phenotype is suggestive of a RASopathy. Which of
the following would be the most appropriate molecular test to order to establish a diagnosis?
A) Chromosomal microarray to look for contiguous gene deletions in
RASopathy genes
B) PTPN11 gene sequencing since it is the most common cause of Noonan
syndrome
C) Multi-gene panel for the RAS genes
D) Exome sequencing since the differential is broad
E) Molecular testing is not warranted at this point
C) Multi-gene panel for the RAS genes
Not sure exactly what RASopathy we’re looking at, so best to not go gene by gene
A pediatrician calls you because they just received a molecular test
result for a patient who was evaluated for a suspected RASopathy. They
fax you the results, but the first page is blurry and the only information
you can read is that a “PATHOGENIC nonsense variant was detected”.
What is the most likely diagnosis for this patient?
A) Noonan syndrome
B) Neurofibromatosis type 1
C) Costello syndrome
D) Cardiofaciocutanous syndrome
E) This is a somatic variant found in a tumor
B) Neurofibromatosis type 1
RASopathies mechanism is most often gain of function– nonsense variants don’t cause this.
