Rasopathies

Question 1

Clinical features of NF1

Answer 1

6 OR > cafe au lait macules >5mm in diameter or greater than 15 mm in greatest diameter
Freckling and axillary or inguinal regions
Greater than equal to two neurofibromas of any type, or one plexiform neurofibroma
Optic pathway glioma
Greater than or equal to two Lish nodules identified by slitlamp exam or greater than or equal to two choroidal anomalies
Distinctive osseous lesion, such as sphenoid dysplasia anterior lateral bowing of the tibia or pseudoarthrosis of the long bone
Parent who meets diagnostic criteria
A germline NF1 pathogenic variant

Question 2

Café au lait macule

Answer 2

Pigmented, macules or patches, ranging from light to dark brown. Greater than 99% of patients have this.

Question 3

Freckling in the auxiliary/inguinal regions

Answer 3

Freckles around the armpit/groin. Usually develops after Café au laits, but not before neurofibromas. about 85% of patients have this.

Question 4

Neurofibroma

Answer 4

Peripheral nerve tumor that forms a bump under the skin. Benign finding and about 99% of patients.

Question 5

Plexiform neurofibroma

Answer 5

An uncommon variant in which neurofibromas arise from multiple nerves as bulging and deforming masses involving the connective tissue and skin folds. About 30% of patients have this.

Question 6

Optic pathway glioma

Answer 6

Low-grade astrocytic tumor that occurs in the optic nerve. blindness occurs in 5% of children. Well serious they are highly treatable. About 15 to 20% of patients will have this.

Question 7

Lisch nodules

Answer 7

One to 2 mm yellowish brown dome shaped solid lesions on the surface of the iris. Also known as iris harmartomas.

Question 8

SPHENOID dysplasia

Answer 8

Characterized by progressive exophthalmos, and facial disfiguration, secondary to herniation of the meningeal and cerebral structures 

Question 9

Breast cancer risk for NF1

Answer 9

Women are at a 20 to 40% risk for developing breast cancer. Cumulative risk for developing contralateral breast cancer is increased. Breast cancer are more likely to be her2 positive.

Question 10

De novo rate for NF1

Answer 10

50%

Question 11

Recommendations following neurofibromatosis type one diagnosis

Answer 11

Referral to NF clinic
Annual visit to dermatologist for skin exam
Annual ophthalmologic exam to identify/manage optic gliomas
Annual neurologic exam for surveillance of malignant peripheral sheath nerve tumors, possible, internal plexiform neurofibromas, seizures, pain
For females addition of early mammogram at 30 years old, alternating with breast MRI every six months

Question 12

Available treatments for NF1

Answer 12

SELUMETINIB is a MEK inhibitor and is FDA approved for inoperable plexiform neurofibromas.
For all cancers radiotherapy is contraindicated due to the risk of developing malignant peripheral sheath nerve tumors

Question 13

NF1 gene

Answer 13

In codes for neurofibromin, which activates GTPase, thereby controlling cell proliferation acting as a tumor suppressor
Most germline pathogenic variants appear to cause severe truncation of the gene product often by altering mRNA splicing. Therefore, splice variants may not be demonstrable by standard genomic DNA sequencing alone (need RNA sequencing as well).

Question 14

When is the diagnosis of tuberous sclerosis established?

Answer 14

Two Major findings, or one major with two or more minor features

Question 15

What are the major features of tuberous sclerosis?

Answer 15

Greater than or equal to three angiofibroma or fibrous cephalic plaque
Cardiac rhabdomyoma
Multiple cortical tubers, and or radial, migration lines
Lymphangioleiomyomatosis
Multiple retinal, nodular harmartomas
Greater than equal to two renal angiomyolipoma
Shagreen patch
Subpendamyl giant cell astrocytoma
Greater than equal to two Subpendamyl nodules
Greater than equal to two ungual fibromas

Question 16

What are the minor features associated with tuberous sclerosis?

Answer 16

Sclerotic, bone lesions
confetti, skin lesions
Greater than equal to three dental enamel pits
Greater than or equal to two intraoral fibromas
Multiple renal cysts
Non-renal hamartomas
Retinal achromic patch

Question 17

What is an angiofibroma?

Answer 17

Nine. Tumor that is made of blood vessels and fiber tissue. Usually appears as small red bumps on the face, especially on the nose and cheeks.

Question 18

What is a fibrous cephalic plaque

Answer 18

A soft skin, color or brown plaque, that typically appears on the forehead or the scalp. Seen in about 19 to 46% of patients.

Question 19

What is a cardiac rhabdomyoma?

Answer 19

A benign tumor that typically glows in clusters in the heart. Most common form of cardiac tumor in infants/children. Usually grows in the muscles of the left and right ventricles.

Question 20

What are cortical tubers?

Answer 20

Abnormal glial and neural cells that cause hamartomas legions at the gray white matter interface. 90% of patients have these.

Question 21

Lymphangioleiomyomatosis (LAMs)

Answer 21

Rare lung disease that affects women of childbearing age. Abnormal muscle like cells begin to grow out of control in the lungs and other parts of the body. Up to 80% of women with TSC will develop LAMS by 40 years old, approximately 5 to 10% of women presents symptomatically.

Question 22

Retinal, astrocytic hamartomas

Answer 22

Benign glial, tumors

Question 23

Shagreen patch

Answer 23

Irregularly shaped and thickened slightly elevated soft skin colored patch usually on the lower back made up of excess fibrous tissue. About 50% of patients have these.

Question 24

Subpendymal giant cell astrocytomas

Answer 24

Rare, low-grade glioneuronal brain tumor that occurs almost exclusively in patients with TSC. The benign can lead to serious neurological complications, including hydrocephalus, intractable seizures, and death.

Question 25

Subpendymal nodules

Answer 25

The nine tumors arise along the walls of the lateral ventricles the spaces that contains cerebral spinal fluid. Usually there is more than one.

Question 26

Ungual fibromas

Answer 26

Firm, smooth, skin, colored, or reddish papules around the fingernails and toes

Question 27

What is the leading cause of mortality and morbidity in patients with TSC

Answer 27

Central nervous system tumors

Question 28

What genetic condition is most associated with infantile spasms and seizures in patients?

Answer 28

TSC

Question 29

What is the leading cause of death in TSC?

Answer 29

Complication of severe intellectual disability

Question 30

What is TSC associated neuropsychiatric disorder?

Answer 30

Behavioral psychiatric intellectual, academic neurophysiological, and psychosocial difficulties. All patient should be evaluated since these disorders can contribute significantly poor outcomes.

Question 31

What are the surveillance recommendations for patients with TSC?

Answer 31

Central nervous system – brain MRI every one to three years in asymptomatic individuals younger than 25 years old to monitor for new SEGA occurrence. Annual TAND exam dependent on clinical needs, routine EEGS asymptomatic patients every six weeks until 12 months old and every three months up to 24 months old.

Renal- MRI of abdomen every 1 to 3 years to assess progression of angiomyolipoma and renal cystic disease

Pulmonary – screening for LAM for women older than 18 years old or those with respiratory symptoms. High resolution CT of the lungs every 5 to 7 years through menopause.

Dermatology annual skin exam

Dental: exam at least every six months

Ophthalmology: annual exam

Question 32

Treatments for TSC

Answer 32

MTOR inhibitors for SEGAS (might still need neurosurgery)
VIGABATRIN for infantile spasms. Possible MTOR inhibitor use for intractable seizures
MTOR inhibitor for growing renal angiomyoma (nephrectomy is avoided due to increased incidents of complications and increased risk for future renal insufficiency and end stage renal failure and poor, prognosis that results from chronic kidney disease)
Estrogen use is contraindicated due to possible involvement of proliferation of LAM cells, causing it to get worse