RASopathies

Question 1

What are the gene, inheritance, mechanism, and clinical features of NF1?

Answer 1

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

Question 2

What are the gene, inheritance, and clinical features of Noonan Syndrome?

Answer 2

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

Question 3

What are the gene, inheritance, mechanism, and clinical features of NSML (Noonan syndrome with multiple letigines)?

Answer 3

PTPN11, AD, Gain-of-function, Same as Noonan, but with multiple skin lentigines; unclear predisposition to cancer

Question 4

What are the gene, inheritance, mechanism, and clinical features of NSLH (Noonan syndrome-like with loose anagen hair)?

Answer 4

SHOC2, PPP1CB; AD; Gain-of-function; Same as Noonan, but with easily pluckable, sparse, thin, slow-growing hair

Question 5

What are the gene, inheritance, mechanism, and clinical features of CBL-related condition(s)?

Answer 5

CBL; AD; Gain-of-function; Craniofaciall like Noonan, but high risk of myeloproliferative disorders (JMML)

Question 6

What are the gene, inheritance, mechanism, and clinical features of Costello syndrome?

Answer 6

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

Question 7

What are the gene, inheritance, mechanism, and clinical features of Cardiofaciocutaneous syndrome?

Answer 7

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

Question 8

What are the gene, inheritance, mechanism, and clinical features of Legius syndrome?

Answer 8

SPRED1; AD; Loss of function; CALMs, intertriginous freckling; macrocephaly; normal neurocognitive function or mild
impairment; no apparent predisposition to cancer

Question 9

What are prenatal features of Noonan Syndrome?

Answer 9

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.

Question 10

Craniofacial features of Noonan syndrome:

Answer 10

Craniofacial features
* Broad forehead
* Hypertelorism
* Down-slanting
palpebral fissures
* Ptosis
* High-arched palate
* Low-set and
posteriorly rotated
ears

Question 11

Other clinical features of Noonan syndrome:

Answer 11

• 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

Question 12

Other clinical manifestations of Noonan syndrome:

Answer 12

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

Question 13

Noonan syndrome evaluation and management:

Answer 13

• 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

Question 14

Clinical manifestations of NSML:

Answer 14

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

Question 15

Clinical features of Costello syndrome:

Answer 15

• 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

Question 16

Cardiac manifestations of Costello syndrome:

Answer 16

• 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.

Question 17

CFC Syndrome clinical features:

Answer 17

• 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

Question 18

Cardiac manifestations of CFC syndrome:

Answer 18

• 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

Question 19

RASopathies: misc info

Answer 19

• 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

Question 20

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

Answer 20

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

Question 21

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

Answer 21

B) Neurofibromatosis type 1

RASopathies mechanism is most often gain of function– nonsense variants don’t cause this.