Week 12: Rare syndromes

Question 1

Bloom syndrome: gene, inheritance, carrier incidence, characteristic features

Answer 1

-AR, BLM gene
-AJ (1/3 of cases) carrier frequency 1/100
-Severe growth deficiency, wasting appearance
-Cafe au lait spots, telangiectasias, erythematous butterfly rash
-Sister chromatid exchange

Hellacancer, literally every type

Question 2

Name the most common cancers seen in Bloom syndrome

Answer 2

Leukemia (AML)
Lymphoma
CRC
Breast

Question 3

TSC genes, inheritance, major cancer types, features

Answer 3

-TSC1 and TSC2
-AD (~60% de novo)
-Brain: SEGA (subependymal giant cell astrocystomas) and cortical tubers
-Skin: angiofibromas and shagreen patches
-Kidney: renal angiomyolipoma
-Seizures, autism

Question 4

ATM associated cancer risks, features

Answer 4

-Breast: 20-30%
-Ovarian: 2-3%
-Pancreatic: 5-10%
-Carrier frequency 1/100

Question 5

NTHL1 tumor syndrome gene, inheritance, cancer risks, features

Answer 5

-NTHL1 gene, AR
-CRC, breast, basal cell carcinoma, endometrial, meningioma, bladder

Question 6

FAMMM gene, inheritance, cancer types, features

Answer 6

-CDKN2A, AD
-Melanoma, pancreatic, brain, Wilms tumor, CRC, lung

Question 7

Retinoblastoma inheritance, gene, all info

Answer 7

-AD, RB1 (MYCN somatic)
-13q deletion syndrome (includes RB and additional features), maternal imprinting
-Heritable and nonheritable forms
-80-90% penetrance, <10% of families have low penetrance or incomplete penetrance
-De novo ~32%
-Bilateral, unilateral, trilateral
-Strabismus, painful red eye, glaucoma, cataract, decreased vision, extraocular growth
-Soft tissue sarcoma, osteosarcoma, melanomas (usually occur in adulthood)

Question 8

Gorlin syndrome/NBCCS gene, inheritance, all info

Answer 8

-AD, 20-30% de novo
-PTCH1 (67-79%): complete penetrance
-SUFU (6%): incomplete penetrance
-High levels of inter and intrafamilial variable expressivity
-Symptoms vary in onset from congenital to adulthood
-Ectopic calcification of the falx (90% by 30yr)
-Macrocephaly
-Odontogenic keratocysts (PTCH1 only)
-Multiple palmar and plantar pits
-BCCs
-Congenital rib/vertebrae anomalies (wedge vertebrae, bifid ribs)
-Frontal bossing, facial milia, hypertelorism, coarse facial features, colobomas, strabismus
-Less common: DD, meningioma, medulloblastoma (more common in SUFU)

Question 9

POT1 TPDS gene, inheritance, all info

Answer 9

-Gene: POT1, regulates telomere length (error is too long telomeres)
-AD
-Multiple primaries common
-Other features: delayed greying of hair, cutaneous nevi, goiters, uterine fibroids, CHIP

“Core four”
1. cutaneous melanoma
2. CLL (B-cell chronic lymphocytic leuk)
3. Angiosarcoma (annual full body MRI)
4. Glioma (annual brain MRI)

Question 10

DICER1 TPDS gene, inheritance, all info

Answer 10

-DICER1
-AD, 20% de novo
-Pleuropulmonary blastomas (PPB)
-Thyroid gland neoplasia, multinodular goiter, ovarian sex cord-stromal tumor, cystic nephroma, pneumothorax, lung cysts, macrocephaly
-childhood management