Cancer Genetics Flashcards
Describe the following cancer types... Sarcoma Leukemia Lymphoma Carcinoma
Sarcoma- cancer that forms in bone and soft tissues (muscle, fat, blood and lymph vessels, tendons and ligaments)
Leukemia- cancer that begins in the blood forming tissue of the bone marrow
Lymphoma- cancer that begins in the lymphocytes (T and B cells; can be Hodgkins or Non-Hodgkins
Carcinoma- cancer that begins in the epithelial cells that line internal organs (e.g. breast, ovarian, colorectal, prostate, basal cell, renal cell)
Describe the following cancer types... Multiple Myeloma Melanoma Glioma/Glioblastoma Meningioma Astrocytoma
Multiple Myeloma- cancer that begins in the plasma cells (immune cells); abnormal plasma cells build up in the bone marrow and form tumors in bones all throughout the body
Melanoma- cancer that begins in the cells that make pigment (skin melanoma and ocular melanoma)
Glioma- form in the glial cells of the brain/spinal cord (benign); glioblastoma is the malignant form
Meningioma- form in the meninges of the brain
(benign)
Astrocytoma- form in the astrocytes of the brain/spinal cord and are malignant
Describe the following types of tumors…
Germ Cell tumors
Neuroendocrine tumors
Carcinoid tumors
Germ cell tumors- tumors that begin in the cells that give rise to sperm and eggs that can be benign or malignant (e.g. ovarian germ cell tumors vs testicular cancer)
Neuroendocrine tumors- arise in cells that release hormones into the blood; can be benign or malignant (e.g. pancreatic islet cell tumors, medullary thyroid cancer, and pheochromocytomas in adrenal gland or paraganglioma in other locations)
Carcinoid- a type of neuroendocrine tumor that is slow growing and often found in the GI tract that secretes substances like serotonin or prostaglandins which cases carcinoid syndrome
What features are suggestive of hereditary cancer syndromes?
Cancer at earlier than expected ages Cancer in paired organs Multifocal disease (multiple tumors) Rare tumors Multiple close relatives in the same lineage with same or related forms of cancer
What is DCIS?
Ductal Carcinoma in Situ
non-invasive neoplasm of ductal origin (tubes that bring milk from lobules in breast)
May or may not progress to cancer- Comedo type DCIS has a higher chance of becoming invasive- ~30% chance of invasive cancer if left untreated
Treatment options include breast conserving surgery, radiation therapy, with or without tamoxifen
What is LCIS?
Lobular Carcinoma in Situ
pre-malignant lesion that is a marker of breast cancer risk
25-35% risk of invasive breast cancer (not necessarily where you found the LCIS)
subsequent invasive cancers can be ductal (often multi-centric and frequently bilateral)
Treatment options include observation, chemoprevention, or bilateral prophylactic mastectomy
List the risk factors for breast cancer.
aging early menarche (<12 y/o) late menopause (>52) breast density/breast architecture nulliparity (not having children) first child after age 30 estrogen/progesterone use after menopause more than 2-3 alcoholic beverages per week
What are protective factors from breast cancer.
at least for or more hours a week of exercise
breastfeeding
maintaining ideal body weight (especially after menopause- because the more body fat you have the more the fat is converted to hormones via aromatase)
having children prior to the age of 30
What is Borderline Ovarian Cancer?
Ovarian cancer of Low Malignant Potential
comprise 15% of epithelial tumors of the ovary; over 90% survival
less common in BRCA1/2 carriers; BRCA positive patients are more likely to have more aggressive disease
What genes are implicated in increased risk for ovarian cancer?
HBOC- BRCA1, BRCA2, BRIP1, RAD51C, RAD51D
MMR (Lynch Syndrome)- MSH2, MLH1, MSH6, PMS2
What are the risk factors for ovarian cancer?
age post-menopausal hormone replacement therapy infertility nulliparity (not having kids) endometriosis
What factors are protective for ovarian cancer.
oral contraceptives tubal ligation hysterectomy breast feeding pariety (>2 births)
What factors are incorporated into the Gail Model?
age
age at first live birth
age at menarche
number of first degree relatives with breast cancer (MATERNAL side only)
ever had a breast biopsy/number of breast biopsies
presence of atypical hyperplasia
race
What are the limitations of the Gail Model?
Does NOT include... -other cancers (other than breast) -second-degree relatives -paternal history -age at diagnosis in relatives This can lead to underestimation of risk for breast cancer
What are the Claus tables?
family history based breast cancer risk model
looks at age of dx, when FHx is significant
can help determine MRI screens and usually used in insurance
does NOT consider any other risk factors outside fhx and does not always have appropriate risk for every relation (“fudges” using other tables for different relations)
List the most common, high penetrance, AD breast cancer risk conditions/genes?
Hereditary Breast Ovarian Cancer (HBOC)- BRCA1, BRCA2 Li-Fraumeni Syndrome (LFS)- TP53 Cowden Syndrome- PTEN PALB2 Associated Cancer Syndrome- PALB2 Hereditary Diffuse Gastric Cancer- CDH1 Peutz-Jegher Syndrome- STK11
Cancers involving the…
breast (multiple cases of early onset, bilateral, and/or male)
ovaries
prostate (early age, higher Gleason score, metastatic)
pancreas
Melanomas
Hereditary Breast Ovarian Cancer (HBOC)
BRCA1, BRCA2 (function: DNA repair)
High incidence in AJ population with founder mutations (187delAG; 538insC; 617delT)
Note- BRCA1 changes have increased frequency of tumors that are triple negative (ER neg, PR neg, HER2neu neg)
Note- BRCA2 incurs a higher risk of pancreatic cancer than expected (even when compared to individuals with BRCA1 genes)
Cancers involving the... *breast (as early as teens and early 20's)* brain *Adrenocortical tumors (especially in childhood)* Sarcomas (=45) Leukemia *Choroid plexus tumor* Other early onset tumors
Li Fraumeni (LFS)
TP53
7-20% de novo mutations
HIGHLY sensitive to radiation damage (typically recommend total mastectomy rather than lumpectomy + radiation therapy)
Cancers involving the…
thyroid (usually follicular, rarely papillary, NOT medullary; childhood onset/germ cell)
breast
uterine (endometrial)
Trichilemmomas (hair follicle tumors) and papillomatous papules (usually by late 20’s)
Lhermitte-Duclose disease (cerebellar dysplastic gangliocytoma -in brain- presenting typically 30-40’s); may present with hydrocephalus
Macrocephaly
Macular pigmentation of the glans penis
Esophageal glycogenic acanthosis (multiple)
Autism Spectrum Disorder
Fibromas
Lipomas
Hamartomatous intestinal polyps
AVMs or hemangiomas
Cowden Syndrome
PTEN
Cancers involving the…
breast
pancreas
ovaries (unconfirmed)
PALB2 Associated Cancer Syndrome
PALB2
Cancers involving the…
breast
ovaries
pancreas
gastric
small bowel
lung
sex-cord tumors/Sertoli cell tumors
Hamartomatous polyps (multiple - <100- usually stomach to rectum, most commonly in the small intestines/jejunum)
Adenomatous polyps
Mucocutaneous pigmentation (may fade after puberty)
Freckling on lips crossing the vermillion border
Small bowel intussusception, severe abdominal pain, GI bleeding begin at <20 y/o
Peutz-Jegher Syndrome
STK11 (LKB1)
Diagnosed on NCCN clinical criteria (2+ of the following):
-2+ Peutz-Jecher type hamartomatous polyps of the small intestine
-mucocutaneous hyperpigmentation of the mouth, lips, nose, eyes, genitalia or fingers
-family history of PJS
What is CAPS-5 and who is eligible to participate?
ongoing research study looking at different ways to screen for pancreatic cancer
Inclusion criteria (1+ of the following):
-Hereditary Pancreatitis
- Peutz-Jeghers Syndrome
- Strong family history of pancreatic cancer on one side of the family
- Confirmed germline mutation carrier (BRCA2, CDKN2A, PALB2, BRCA1, HNPCC, PRSS1/2, CTRC) and a family history of pancreatic cancer
What are the recommendations for clinical management/prophylaxes of BRCA Mutation-Positive patients?
Breast screening (start at age 25 y/o)- clinical breast exams (q6 months), self breast exams (q6 months), MRI screening (q12 months)
Breast screening (starting at age 30)- mammograms (q12 months)
Ovarian screening (starting at age 30-35)- CA-125 (q6-12 months), transvaginal US (q6-12 months)
*note that ovarian cancer screening has no evidence of effectiveness
Risk reducing mastectomy
Risk reducing oophorectomy (BRCA1 ideally between 35-40 y/o; BRCA2 ideally between 40-45 y/o) with/without hysterectomy- note that this can reduce breast cancer risk in pre-menopausal women (more for BRCA2 than BRCA1 carriers) but there is still a risk for primary peritoneal carcinoma
Chemoprevention for breast cancer- tamoxifen, raloxifen, aromatase inhibitors (post-menopausal women only)
How is cancer risk in Li-Fraumeni Syndrome managed in adults?
Clinical breast exams (starting at age 20 OR 5-10 years earlier than earliest onset in family) q6 months
Breast MRI with or without mammography (starting at age 20-25) q12 months
Alternating beast MRI AND mammography (starting at age 30-75) q12 months
Consider risk reducing mastectomy
Comprehensive physical exam with high index of suspicion for rare cancers, careful skin and neuro exam
Colonoscopy (starting no later than 25 y/o) q2-3 years
Can offer novel approaches including rapid whole body MRI, abdominal US, and brain MRI
Additional surveillance based on fhx
How is Cowden Syndrome managed?
Clinical breast exams (starting at age 25 or 5-10 years prior to earliest onset) q6 months
Mammogram (starting at age 25) q 12 months
Breast MRI (starting at age 25) q 12 months
Consider risk reducing mastectomy
Consider hysterectomy
Comprehensive physical exam with attention to the thyroid starting at age 18 OR 5 years earlier than earliest cancer case in family
Thyroid US (starting at age 18) q 12 months
Colonoscopy (starting at age 35) q 5-10 years OR more frequently based on symptoms or polyps
Consider dermatology exam q12 months
List examples of PTEN multiple hamartoma syndromes.
Cowden Syndrome (see other flashcard for in-depth) Bannayan-Riley-Ruvacalba- macrocephaly, hamartomatous intestinal polyposis, pigmented macules of glans penis (speckled penis) Proteus Syndrome- connective tissue nevi, asymmetric/disproportionate overgrowth (limbs, hands, feet, skull, vertebrae), lipomas or absence of fat, vascular malformations, facial phenotype/classic dysmorphisms
List the risk factors for colon cancer.
Aging Personal history of colorectal cancer or adenomas Inflammatory bowel disease (Ulcerative colitis- large intestine-, Crohn's disease- small or large intestine, NOT IBS) Family history of colorectal cancer Hereditary colon cancer syndromes Excess alcohol consumption Cigarette smoking Obesity
Multiple colonic polyps and high risk for colon cancer Risk of extracolonic tumors in the... upper GI/duodenum desmoid osteoma (in the jaw) papillary thyroid cancer medulloblastoma (and other brain tumors) hepatoblastoma *Congenital Hypertrophy of the Retinal Pigment Epithelium (CHRPE; most often bilateral and multiple lesions - >4 highly suggestive)* Supernumerary teeth, epidermoid cysts
Familial Adenomatous Polyposis (FAP) APC gene (chromosome 5q) AD up to 30% de novo most families have a unique mutation DOES have genotype-phenotype correlations
Few colonic adenomas (usually >20 but <100 polyps)
Later onset colorectal cancer (~ age 50)
+/-Upper GI lesions
NO CHRPE
Attenuated Familial Adenomatous Polyposis
APC gene (chromosome 5q)
Associated with mutation in the 5’ and 3’ ends of the gene
How is FAP managed?
Annual colonoscopy on an annual basis (typically more often than that based on polyp findings) starting around age 10-14 y/o until polyposis develops (OR starting at 40 y/o with repeat q5 years in individuals with I1307K AJ founder mutation)
Consideration of colectomy when polyps are no longer manageable with colonoscopy
Annual upper endoscopy
Chemoprevention (Aspirin, Sulindac, others)- can slow growth of polyps/delays need for colectomy
Monitoring for desmoids and other complications
Genetic testing to identify mutation for testing of other family members
Usually at least 15 polyps (typically adenomatous, may be few hyperplastic), but fewer than 100’s of colonic polyps
Average age of presentation is in the 50’s
High risk for colon cancer
Increased risk for duodenal cancer/polyposis
Higher incidence of cancers of the…
ovaries
bladder
skin
sebaceous gland tumors
MUTYH Associated Polyposis (MAP)
MUTYH
AR (carrier frequency is ~1%)
Common mutations in European ancestry- Y165C and G382D
NOTE- carriers may have an increased colon cancer risk (and higher with additional family history)
Colon cancer that is... tumor site in proximal (right sided) colon predominately trend towards early age of onset signet ring mucinous tumor-infiltrating lymphocytes medullary pattern Extracolonic cancers... endometrial stomach ovarian pancreas ureter and renal pelvis (transitional cell ca) biliary tract brain (usually glioblastoma) sebaceous gland adenomas/carcinomas; keratoacanthomas (Muir-Torre Syndrome) carcinoma of the small bowel NOTE- Accelerated rate of progression from normal to polyp to cancer
Lynch Syndrome (Hereditary Non-Polyposis Colorectal Cancer)
Mismatch repair (MMR) genes- MLH1, MSH2, MSH6, PMS2, EPCAM (mutations in the 3’ end of the gene silence MSH2 via hypermethylation)
AD
Risk for cancer is stratified by gene
*most common genes associated (and higher risk/slightly earlier onset for cancer)
NOTE- about 10-15% of sporadic tumors are due to somatic mutations in MLH1 (promotor methylation); usually in the presence of a BRAF mutation
What is the Amsterdam criteria?
Describes individuals who are at elevated risk for colon cancer (the 3, 2, 1 rule)
3 or more relatives with verified colorectal cancer in the family
2 or more generations
1 case a first degree relative of the other two
EXCLUDES polyposis (though polyps are not an exclusion)
NOTE- this is outdated and now we are more liberal about our testing
What are the Revised Bethesda Guidelines?
Guidelines for tumors that should be tested for IHC/MSI
NOTE- increasing number of institutions have universal screening (do NOT follow Revised Bethesda) for all colon tumors and some endometrial tumors
intractable diarrhea of infancy
severe malabsorption due to intestinal epithelial dysplasia
significant mortality
Congenital Tufting Enteropathy
compound heterozygous mutations in EPCAM
AR
rare
very early onset colorectal cancer
duodenal cancer
leukemia
lymphoma
childhood brain tumors (astrocytomas, glioblastomas, Primitive Neuroectodermal Tumors)
Cafe au lait spots
high mortality rare with multiple of the above tumors
Constitutional Mismatch Repair
Homozygous MMR family gene deficiency (MSH1, MLH2, MSH6, PMS2, EPCAM
AR
rare
What is Turcot’s syndrome?
Rare hereditary syndrome of multiple colorectal adenomas and primary brain tumors
Two distinct subtypes-
APC mutations associated with medulloblastomas
MMR gene family mutations associated with glioblastomas
How is Lynch syndrome managed?
colonoscopy starting at 20-25 y/o or 2-5 years before earliest diagnosis repeated q1-2 years
monitor abnormal uterine bleeding and hysterectomy after childbearing
bilateral salpingo-oophorectomy after childbearing
some recommend upper endoscopy starting at 30 y/o repeated q3-5 years
testing for H. pylori
capsule endoscopy, enteroscopy (no data supporting these- case by case)
annual urinalysis starting at 30-35 y/o or cystoscopy
consider pancreatic screening protocols such as CAPS-5 (IF positive family history of pancreatic cancer)
NOTE- any of these may be modified by the gene affected
Consideration of prophylactic colectomy for adenomas (not generally recommended)
Total abdominal colectomy and not just resection when colon cancer is present (higher risk for secondary colon cancer)
Proctocolectomy when rectal cancer is present
Onset any time of life
hamartomatous (or mixed adenomatous), friable, juvenile polyps (that bleed significantly, potentially causing anemia) that may occur anywhere in the GI tract
Juvenile Polyposis Syndrome
BMPR1A, SMAD4
AD
Clinical diagnosis is made when >3 juvenile polyps are present
How is Juvenile Polyposis Syndrome managed?
colonoscopy beginning at about age 15 and repeated annually if polyps are found and every 2-3 years if polyps are found
upper endoscopy starting at 15 y/o and repeating annually if polyps are found and every 2-3 years if no polyps are found
individuals with SMAD4 mutations should be screened for vascular lesions associated with HHT within the first 6 months of life
no recommendations at this time for screening for small intestine or pancreas
GI, brain, spine, and pulmonary arteriovenous malformations (usually congenital)
mucocutaneous, face, hand, GI tract telangiectasias (may not present until second or third decade)
recurrent epistaxis (may not appear until second or third decade)
Hereditary Hemorrhagic Telangiectasia
SMAD4 (this means that it can present +/- Juvenile Polyposis syndrome)
diffuse (signet ring cell) gastric cancer that may have hundreds of foci; unassociated with intestinal gastric cancer
high risk for lobular breast cancer (in women)
mean age at diagnosis is 40 y/o
Hereditary Diffuse Gastric Cancer/Lobular Breast Cancer
CDH1 gene
AD
How is Hereditary Diffuse Gastric Cancer managed?
prophylactic total gastrectomy (usually not until 20 y/o unless very early onset family)- this is because screening is ineffective
endoscopic screening with random biopsy for those who are too young or who decline surgery
high risk options for breast cancer risk management (high risk breast screening such as mammograms and breast MRI; prophylactic surgery)
Average age at diagnosis 25 y/o (can be as early as 5)
Hemangioblastoma (cerebellum or spine)
Retinal angioma (eye hemangioblastoma)- can lead to vision loss
Pheochromocytoma (adrenal gland tumor that secretes norepinephrine)
Paraganglioma
Clear cell renal carcinoma (multifocal, bilateral)
Multiple renal cyst
Pancreatic neuroendocrine tumors and cysts
Epidydimal cysts/cystadenomas
Cystadenomas of the broad ligament
Endolymphatic sac tumors; can lead to hearing loss
von Hippel Lindau Disease
VHL
AD (90% penetrance but variable expressivity)
Good genotype-phenotype correlation
How is VHL managed?
Annual MRI of brain and full spine starting age 10
Ophthalmological exam annually by a retinal specialist starting in early childhood (by age 5 y/o)
Annual/semi-annual abdominal MRI/CT starting at age 20 and annual renal US starting at age 10 (renal cell cancers are watched until 3m carcinomas)
Biochemical screening for pheochromocytomas starting at age 5
Hyperparathyroidism
Hypercalcinemia
Parathyroid tumors
Pituitary tumors
Gastro-enteropancreatic neuroendocrine tumors (GI carcinoid tumors, pancreatic islet cell tumors)
Meningiomas and ependymomas
Facial angiofibromas, collagenomas, lipomas, leiomyomas
Bronchial and thymic carcinoids
Zollinger-Ellison Syndrome (gastrinomas, pancreatic islet tumors, and/or atypical peptic ulcers)
Multiple Endocrine Neoplasia Type 1
MEN1
AD
Most sensitive test is checking parathyroid hormone and calcium level (rather than genetic testing IF presents with isolated tumor and no fhx)
How is MEN1 managed?
MRI every 1-3 years
Annual biochemical analysis for PTH and calcium
List the syndromes that are associated with Non-medullary/differentiated thyroid cancer.
Carney Complex 1 (PRKAR1A)
Cowden Disease (PTEN)
Familial adenomatous polyposis (FAP)
Multinodular goiter (14q, Xp22, 3p26)
Medullary thyroid carcinoma (risk almost 100%); may also see differentiated thyroid cancer
Pheochromocytoma (metanephrine predominant)
Hyperparathyroidism
GI ganglioneuromas
Marfanoid appearance
Skeletal abnormalities
Neuromas of the mucosa and eyelids
Multiple Endocrine Neoplasia Type 2 RET AD low de novo rate Genotype-phenotype correlation- -MEN2A: risks for medullary thyroid cancer, pheochromocytoma, etc -MEN2B: risks similar to 2A plus other features -FMTC: medullary thyroid cancer only
How is MEN2 managed?
Prophylactic thyroidectomy recommended at time of diagnosis/early childhood
Annual screening of plasma metanephrines (starting age depends on mutation)
Pheochromocytoma Paragangliomas Renal Cell carcinoma GI stromal tumors \+/- thyroid cancer
Hereditary Paraganglioma-Pheochromocytoma Syndrome
SDHB, SDHC, SDHD, SDHA, SDHAF2, MAX, TMEEM127
AD (tumor risks if inherited paternally)
How is Hereditary Paraganglioma-Pheochromocytoma Syndrome managed?
Begin at age 10-
Annual physical exams, including vital signs, BP, and heart rate
Annual non-sedated neck to pelvis MRI without contrast
Annual neck/thoracic US
Annual serum metanephrines and catecholamines
Appropriate evaluation of symptoms suggestive of PGL, PCC, or GIST
Renal cell carcinoma (average age of onset 50) typically multiple tumors of many types (chromophobe, oncocytoma/mixed oncocytic, hybrid chromophobe/oncocytoma, clear cell) that are less aggressive
Pneumothorax; lung bebs
Multiple fibrofolliculomas
Angiofibromas, perifollicular fibromas, acrochordons
+/-Colon polyps
Birt Hogg Dube
FLCN
AD- ~85% penetrance
How is Birt Hogg Dube managed?
Renal MRI every 1-2 years starting at age 20
Renal cell carcinoma papillary type II ("fried egg" appearance of nuclei)
*Cutaneous leiomyomas* (dozens to hundreds); may be hot or painful to the touch (not normally on the face)
Uterine fibromas (may be large or have distinctive pathology); uterine leiomyosarcomas are reported but rareHereditary Leiomyomatosis- Renal Cell Cancer Syndrome FH AD thought to be highly penetrant Some genotype-phenotype correlation
How is Hereditary Leiomyomatosis-Renal Cell Carcinoma Syndrome managed?
Annual renal US starting by age 10
Annual abdominal CT or MRI starting at age 20
Uterine fibromas may be so large or difficult that hysterectomy at a young age is needed
Renal cell carcinoma papillary type 1 diagnosed on average 50’s-70’s (may also occur at young age); multiple or bilateral that are slow-growing
No other features
Hereditary Papillary Renal Carcinoma Syndrome
MET
Highly penetrant (~90%)
Rare
How is Hereditary Papillary Renal Carcinoma Syndrome managed?
Annual abdominal CT or MRI starting at age 30 y/o
Malignant melanoma (often multiple cases)
High total body nevi count (>50) including clinically atypical nevi (architectural disorder, subepidermal fibroplasia, lentiginous melanocytic hyperplasia, dermal lymphocyte infiltration)
Pancreatic cancer
Brain tumors (acoustic neuroma, astrocytoma, ependymoma, glioblastoma, medulloblastoma, neurofibroma, neurolemma)
Familial Atypical Mole Melanoma
CDKN2A (>90% of mutations), CDK4 (2-3% of mutations)
AD
High penetrance
How is Familial Atypical Mole Melanoma managed?
Careful skin exam at least 2 times a year beginning at age 10
Avoid excessive sun exposure and radiation
Lamellar calcification of the Falx Jaw keratocyst, odontogenic keratocyst Palmar/plantar pits (>2) Multiple basal cell carcinomas (>5 in lifetime or first onset before 30 y/o) Medulloblastoma in childhood
Nevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome)
PTCH1
AD
~100% penetrant with variable expressivity
Extreme photosensitivity
Cellular hypersensitivity to UV induced DNA damage (pyrimidine dimers)
Very high risk of basal cell cancer, squamous cell cancer, and melanoma (can be on skin, mucosal tissue, or tongue)- usually multiple cancers with first occurring in early childhood
Eye cancers, benign eye tumors, cloudy cornea
Brain tumors
Lung cancer
Premature skin aging
+/- neurological issues (e.g. hearing loss, coordination problems, seizures)
Xeroderma Pigmentosum
XP
AR
How is Xeroderma Pigmentosum managed?
Avoidance of all sun exposure
Frequent dermatologic exams
> 6 cafe au lait macules (over 5 mm in diameter in prepubertal pts; over 15 mm in diameter in post pubertal pts)
2+ neurofibromas (or 1 plexiform neurofibroma)
Axillary/inguinal freckling
2+ Lisch nodules (hamartomas)
Distinctive osseous lesion (e.g. sphenoid dysplasia or thinning of long bone cortex with or without pseudoarthrosis)
Increased risk of breast cancer
Vascular disease (hypertension, renal artery stenosis) secondary to pheochromocytomas
Skeletal features (scoliosis, macrocephaly, short stature)
Learning disabilities (variable)
Neurofibromatosis Type 1 NF1 AD ~50% de novo phenotypic variability even within families
Symptoms first noted average around 17-21 y/o
Bilateral vestibular schwannomas
unilateral vestibular schwannomas
Meningiomas, glioma, neurofibroma, schwannoma, posterior subcapsular lenticular opacities
Neuropathy (mononeuropathy- facial palsy, squint/third nerve palsy, hand/foot drop can present in childhood; polyneuropathy- systemic)
Cataracts, juvenile posterior subcapsular lenticular opacities
Cafe au lait macules (usually only a few)
Neurofibromatosis Type 2
NF2
AD
~50% de novo (~30% mosaic)
List the main cancer syndromes linked to brain tumors.
von Hippel Lindau (hemangioblastoma; endolymphatic sac tumors)
Tuberous Sclerosis Complex (SEGA)
Cowden disease (Lhemitte-Duclos)
Li Fraumeni Syndrome (brain tumors)
Turcot’s syndrome (Medulloblastoma; Glioblastoma)
Gorlin Syndrome (Medulloblastoma)
Cortical tubers, subependymal nodules, giant cell astrocytomas
+/- cognitive impairment
Seizures
Autism, anxiety
Hypomelanotic macules, facial angiofibromas, shagreen patches/collengenomas, ungual fibromas
Retinal hamartomas
Cardiac rhabdomyomas
Angiomyolipomas in the kidney, renal cancer, renal cysts
Lymphangiomyomatosis (LAM)
Tuberous Sclerosis
TSC1, TSC2
AD
NOTE- some are due to contiguous gene deletions of TSC2 and PKD1 (which also means that these individuals have ADPKD as well)
How is TSC managed?
Brain MRI with contrast every 1-3 years until age 25
Baseline EEG
Renal MRI with contrast and functional studies every 1-3 years; mTOR inhibitors for widespread renal disease
Chest CT in adult women every 5-10 years
ECHO and EKG until rhabdos resolve
Annual ophthalmology and skin exam
Consider topical mTOR inhibitors
Cancer risk highest for children <7 y/o
Pleuropulmonary blastoma (can be bilateral; earliest case 6 mo)
Cystic nephromas
Anaplastic sarcoma of the kidney
Wilms’ tumor
Thyroid cancer (differentiated), multinodular goiters, thyroid nodules
Rhabdomyosarcoma of the bladder, cervix, and other organs
Nasal chondromesenchymal hamartomas
Pineoblastoma (“trilateral retinoblastoma”)
Medulloepithelioma
Pituitary adenoma/blastoma
Higher cancer risk for females (Sertoli-Leydig cell/ovarian stromal tumor, gynandroblastoma, and sarcomas of the ovaries)
DICER1 Syndrome (Familial Pleuropulmonary Blastoma)
DICER1
AD
How is DICER 1 managed?
Baseline chest CT at 3 to 6 months (or when mutation is found); if normal, then second chest CT at 2.5 to 3 y/o
Chest XR every 6 months until age 8
Biannual abdominal US until age 8, then annual US
Annual or biannual pelvic US starting in early childhood
Thyroid US starting at 8 y/o; if normal, repeat every 3 years
How is Li-Fraumeni Syndrome managed in children?
Annual general assessment including complete physical exam and neurological exam
US of abdomen and pelvis every 3-4 months
Annual brain MRI (with first with contrast, others without if prior was normal and no new symptoms)
Annual whole body MRI (for soft tissue and bone sarcomas)
*Bilateral retinoblastoma* (can also be unilateral); keukocoria "cat's eye reflex", strabismus, glaucoma, orbital cellulitis, uveitis, hyphema, vitreous hemorrhage Pineoblastoma Osteosarcomas and soft tissue sarcomas Melanoma Possibly lung, brain, epithelial cancers
Hereditary Retinoblastoma
RB1
AD
~80% de novo; 90% penetrance (though small subset with significantly reduced penetrance)
Wilms’ Tumor
Nephropathy leading to renal failure in early childhood
Glomerulosclerosis, nephropathy
Gonadoblastoma
Ambiguous or female genitalia in 46,XY individuals
Familial Wilms’ Tumor (spectrum of conditions that include Denys-Drash Syndrome, Frasier Syndrome, or WAGR)
WT1 gene (WAGR can also be associated with a microdeletion including both WT1 and PAX6)
AD
What conditions should be considered when a Familial Wilms’ Tumor is identified?
WT1 associated Familial Wilms’ Tumor
Beckwith-Weidmann Syndrome
Isolated hemi-hypertrophy
WAGR
Extreme sensitivity to sun exposure
Short adult stature; low weight
Dilated blood vessels and reddening of the skin; skin hypopigmentation and hyperpigmentation; distinctive “butterfly” pattern of telangiectasia on face
Long, narrow face; prominent nose and ears
Mild to moderate immunodeficiency with recurrent infections
Infertility (in males)
Learning disabilities
Higher risk for diabetes and generally higher risk for cancers
Bloom Syndrome
BLM
AR
Rare (more frequent in the AJ population)
How is Bloom Syndrome managed?
Avoid sun exposure
IGG replacement if anemia becomes severe
Increased risk of chemo-induced toxicity (when treating malignant tumors)
Hypersensitivity to DNA damaging agents
Children often present with leukopenia or thrombocytopenia (typically by 8 y/o)
Short stature
Pigmentation abnormalities (hyper/hypo-pigmentation), cafe au lait macules
Radial malformations (absent/hypoplastic); absent/hypoplastic/bifid/duplicated/rudimentary /proximally placed thumbs; clinodactyly/polydactyly; flat thenar eminence; dysplastic/short ulnae
Progressive bone marrow failure (onset typically by age 10 y/o)
Narrow chin, hypertelorism
Microcephaly
Structural renal abnormalities
Increased risk of cancer (myelodysplastic syndrome, acute myelogenous leukemia, SCC head/neck, SCC of vagina, SCC of skin, liver tumors, medulloblastoma, neuroblastoma, Wilms’ tumor) and infections
Fanconi Anemia
FANC genes (FANCA most common- 60-70%) as well as some other genes associated with AD breast cancer (PALB2, BRIP1, RAD51C)
AR (some are XL)
Diagnosed by chromosomal breakage analysis in peripheral blood lymphocytes (of skin fibroblasts to confirm if ambiguous) OR genetic testing
How is Fanconi Anemia managed?
HSCT
Neutropenia* with other decreased immune cells, thrombocytopenia, anemia, and recurrent infections
Exocrine pancreatic insufficiency*
Growth delay*
Metaphyseal dystosis (thumb/limb abnormalities), thoracic dystrophy (rib cage abnormalities, smaller occipitofrontal head circumference
Myelodysplastic syndrome, Acute myelogenous leukemia
Schwachman Diamond Syndrome
SBDS
AR
NO phenotype-genotype correlations
How is Schwachman Diamond managed?
HSCT
