Neurocutaneous Disorders

Question 1

What is the prevalence and de novo rate of NF1?

Answer 1

1:30,000 newborns; 30-50% de novo

Question 2

What is the molecular mechanism of neurofibromin (NF1)?

Answer 2

Negative RAS regulator

Question 3

What are the primary manifestations of NF1?

Answer 3

Cafe au lait macules, neurofibromas

Question 4

What are other clinical features of NF1?

Answer 4

Plexiform neurofibromas, optic gliomas, intertriginous freckling (inguinal/axillary), iris lisch nodules, choroidal abnormalities

Question 5

What are the skeletal abnormalities in NF1?

Answer 5

Typical antero-lateral bowing
of tibia and fibula

pseudarthrosis of tibia and
fibula

pseudarthrosis of ulna and
bowing of radius

sphenoid bone dysplasia and orbital plexiform neurofibroma

Question 6

What cancers are NF1 carriers predisposed to?

Answer 6

Female breast cancer, brain tumors, pheochromocytomas

Question 7

What is the cardiovascular involvement of NF1?

Answer 7

Vascular involvement
* Arterial hypertension (15-20%)
* More frequent in adults
* Often primary but also secondary causes
(stenosis or pheochromocytoma)
* Pulmonary hypertension
* Associated with lung disease

Cardiac issues
* Observed 3.35x more often than general
population
* PVS and MV anomalies are the most
frequent
* Intracardiac neurofibromas can occur
* Blood pressure checks every visit and
evaluation of secondary causes

Question 8

In what other conditions besides NF1 can we see cafe au lait macules?

Answer 8

• Fanconi Anemia
• Legius syndrome
• NF2
• McCune-Albright syndrome
• Noonan
• Silver-Russel syndrome
• Constitutional mismatch repair
  deficiency syndrome
• Carney complex

Question 9

Legius Syndrome

Answer 9

• Prevalence: 1:46,000-1:75,000
• AD pattern of inheritance
• Many with affected parents,
  minority de novo
• Molecular: loss-of-function
  variants in SPRED1
• Specific diagnostic criteria
  (Legius et al, 2021) based on
  CALM and absence of NF1
  features

Question 10

What condition is like a combination between Noonan and NF1?

Answer 10

Legius syndrome

Question 11

What are the most common features of Legius syndrome?

Answer 11

Question 12

NF2

Answer 12

• NF2 not considered a
  RASopathy
• “Neurofibromatosis” is a
  misnomer, not the
  primary tumor type
• AD pattern of inheritance
• Heterozygous LoF
  variants in NF2

Question 13

What are the clinical features of NF2?

Answer 13

Question 14

What is management and differentials for NF2?

Answer 14

Management:
* Surgery for BVS,
audiology referral,
hearing aids
* Annual MRIs starting
age 12 through 4th
decade of life
* Annual hearing and
eye examinations
Differential:
Schwannomatosis due
to PVs in SMARCB1
and LZTR1 (AD)

Question 15

Schwannomatosis

Answer 15

• AD and caused by GPV in LZTR1 and
  SMARCB1 (most common)
• Predisposition to develop multiple non-
  intradermal schwannomas.
• AoO between the second and fourth
  decade of life.
• Most common presenting feature is
  localized or diffuse pain or
  asymptomatic mass.
• Schwannomas most often affect
  peripheral nerves and spinal nerves

Question 16

What other tumors can we see in schwannomatosis?

Answer 16

• Meningiomas have only been
  reported in individuals
  with SMARCB1-related
  schwannomatosis.
• Malignant transformation
  remains a risk especially in
  individuals with SMARCB1-
  related schwannomatosis

Question 17

Diagnosis and testing for schwannomatosis

Answer 17

The diagnosis of LZTR1-
or SMARCB1-related
schwannomatosis is established in
a proband with:

Characteristic clinical findings
* Two or more non-intradermal tumors
suggestive of schwannomas
* Absence of bilateral vestibular schwannomas
* A family history of AD schwannomatosis.

Identification of
a heterozygous germline pathogeni
c variant in LZTR1 or SMARCB1

Question 18

Tuberous Sclerosis Complex

Answer 18

• AD, multisystem disorder
• Gene: TSC1 or TSC2
• Occurs in 1/6-10,000, no
  sex, panethnic
• Completely penetrant but
  highly variable expressivity
• Brain, heart, lungs, skin,
  eyes, kidneys are most
  commonly affected but
  other organs can be affected
• Can often also have epilepsy/seizures
• facial angiofibromas

Question 19

Genetics of TSC1/2

Answer 19

TSC1 (chromosome 9q34) and TSC2 (chromosome 16p13.3)
genes encode for the proteins hamartin and tuberin
respectively, which compose the TSC complex
TSC1 mutations are mostly nonsense or frameshift leading to
protein truncation – 10-20%
* TSC can also be found in a contiguous gene deletion
syndrome, PKD-TSC; symptoms include severe renal disease
* 2/3 are de novo
* Most de novo mutations are in TSC2

Question 20

Molecular mechanism(s) of TSC

Answer 20

TSC1 mutations are mostly nonsense or frameshift leading to protein truncation –
10-20%
* TSC2 mutations are more often missense, large deletions or rearrangements – 70-
90% (may be missed on exome testing and require deletion/duplication analysis)
* More severe phenotype (renal malignancy, intellectual disability, ASD, early
seizures)
* 10-25% have negative genetic testing; should consider somatic mosaicism or
mutations in intron or promoter regions
* Many pathogenic variants have been curated but more to come!

Question 21

What are the CNS manifestations of TSC?

Answer 21

Leading cause of
morbidity and mortality
* More that 80-90% have
seizures
* Brain lesions include:
* Subependymal nodules
(SEN’s) – 80%
* Cortical tubers – 90%
* Subependymal giant cell
astrocytomas (SEGA’s) –
80%
* Seizures – 80%

Question 22

What are the skin findings in TSC?

Answer 22

Present in almost 100% - most
often way dx is made
* Include:
* Hypomelanotic macules
(90%) ash leaf spots
* Confetti skin (3-58%)
* Facial angiofibroma (75%)
* Shagreen patch (50%)
* Fibrous cephalic plaques
* Ungual fibroma (20-80%)
* None of these findings cause
serious medical problems

• Typical hypomelanotic macule
  and shagreen patch (the
  reddish, nodular area at the
  upper lumbar area)
• Facial angiofibromas

Question 23

What are ocular findings in TSC?

Answer 23

Retinal astrocytic hamartomas
are seen in 35-50%
* Also, areas of retinal
hypopigmentation (retinal
achromic patch) seen in 40%
* Usually benign, unless
compress optic disc
Retinal astrocytic hamartoma

Question 24

What are renal findings in TSC(2)?

Answer 24

Second leading cause of morbidity and
mortality as a result of hypertension and/or
renal failure
* Single or multiple simple cysts in 45%,
usually benign
* Angiolipomas found in 70% by age 10
* Often bilateral and multiple
* Benign but may lead to life-threating
bleeding requiring embolization
* In severe cases, leads to renal failure
requiring dialysis
* Renal cell carcinoma – 1%
* With early onset and/or severe renal disease,
PKD-TSC syndrome should be considered

Question 25

What are lung and cardiac findings in TSC?

Answer 25

• Multifocal pulmonary cysts
• LAM – lymphangiomyomatosis
• progressive and ultimately results in death
• May be driven by estrogen.
• Women should be periodically screened

Cardiac rhabdomyomas
- Found in 50% of affected infants
- Can be detected prenatally
- Vast majority involute by age 3

Occasional arrythmias in adults

Question 26

What are the diagnostic criteria for TS

Answer 26

Question 27

What does management for TSC look like?

Answer 27

All TSC-related symptoms are potentially
treatable with mTOR inhibitors, including
everolimus
* Surgery is often recommended for significant
CNS tumor
* Infantile spasms – vigabitrin is choice anti-
epilepeptic; also ACTH
* However, refractory seizures are often a
problem in 60%
* Current treatment modalities are moving
toward early treatment to prevent long-term
CNS effects