Cancer Genetics Flashcards
sarcoma
cancers that form in the bones and soft tissues (can include muscles, bone, tendons, ligaments, lymph and blood vessels)
leukemia
cancer that begins in the blood forming tissue of the bone marrow
lymphoma
cancer that begins in the lymphocytes (usually B or T cells)
multiple myeloma
cancer that begins in plasma cells, which are immune cells; when abnormal versions of these cells build up in the marrow tumors can form throughout the body
melanoma
cancer that begins in cells that make pigment
-can occur in skin or eye
gliomas
benign tumors derived from cells of brain; pressure and size can cause problems
glioblastomas
malignant cell growth of the glioma
meningioma
- fairly common
- cancer of the meninges
astrocytoma
malignant cells derived from astrocytes
carcinoma
cancers derived from epithelial cells
germ cell tumors
tumors that arise from reproductive cells
neuroendocrine tumors (NETs)
formation of these can lead to complications related to hormone release
- most common in intestine, lung, panc, adrenal gland
- ex: pheos and paragangliomas (pheos not on adrenal gland), islet cell cancers
- can be benign or malignant
- can increase BP, sweating, anxiety
Carcinoids
Slow growing tumors often in GI; secrete substances like prostaglandins or serotonin and cause namesake syndrome
Tumor-specifics suggestive of hereditary cancer
Tumors in lateral organs or two different tumor types/primaries in the same organ
HER2+
somatic amplification is associated with poorer prognosis, but also a druggable target
atypia and breast cancer risk
- 20-25% risk in absence of family history of breast ca
- up to 40% cumulative risk with family history
DCIS
-non-invasive neoplasm of ductal origin
+currently treated, but controversial
+30% risk of becoming invasive cancer
-comedo type with higher risk of becoming invasive
LCIS
-not a pre-malignant breast cancer risk, but a marker of risk
-25-30% chance to become invasive
+often times b/l, multifocal and can invade ducts, so different place than cells are found becomes cancerous
+tx can include chemo or prophylactic mastectomy
BrCa risk factors
- aging
- early menstruation (<12y)
- late menopause (>52y)
- breast density
- nulliparity or first child later than 30y
- estrogen or progesterone use after menopause
- more than 2-3 alcoholic beverages per week
protective BrCa factors
- 4 or more hours of exercise per week
- maintaining ideal body weight to reduce body fat stores (especially after menopause)
- breastfeeding
- having children prior to 30y
ovarian cancer cells
arise from mullerian epithelium
-fallopian tube cancer and primary peritoneal cancer treated the same
sertoli-leydig cell cancer
- subset of sex-cord tumors
- occur in DICER1 and Peutz-Jehger
high grade serous tumors
associated with germline and somatic BRCA1/2 and TP53 mutations
ovarian cancer of low malignant potential
- “borderline”
- 15% of ovarian tumors
- less associated with BRCA1/2
ovarian cancer risk factors
- age
- post-menopausal HRT
- infertility
- nulliparity
- endometriosis
- increased cycles
ovarian cancer risk reduction
- OCPs
- tubal ligation
- TAH-BSO
- breast feeding
- multiple births
serous tubal intraepithelial carcinoma (STIC)
- precursor lesion, as we know high grade serous carcinomas can begin in FTs
- studies for BS with delayed oophorectomy in risk reduction
Gail Model
-breast cancer risk assessment model
+absolute lifetime risk until 90y
+5y risk
-historically used to determine chemoprevention eligibility
Gail assessment factors
- age
- 1st live birth age, menarche age
- number of first degree female relatives with breast cancer
- number of breast bx and presence of hyperplasias
- race
Gail limitations
- only incorporates breast cancer diangoses
- only uses up to second degree relatives
- paternal history excluded
- age of diagnoses excluded
Claus tables
- statistical model used to calculate breast cancer risk
- stratified by age of diagnosis in relatives and age of patient
prior probability models
-determine risk to test mutation positive (mostly BRCA1/2)
-can be useful for determining who is a research v. clincal testing candidate
+many programs consider 5-10% enough risk
cancer gene connect
can evaluate PP for many cancer types
Penn II model
calculates PP for BRCA1/2 mutations
BOADICEA
cancer risk assessment and PP for several cancers
Tyrer-Cuzick
uses family history info and “epidemiological” risk factors to calculate BrCa risk and BRCA1/2 PP
HBOC cancers
br, ov, panc, prostate, melanoma
LFS cancers
br, brain, adrenocortical (ACC), sarcoma or osteosarcoma at 45 or under, leukemia, choroid plexus tumors in childhood
Cowden cancers
breast (25-50% in 30s-40s), thyroid (mainly follicular, 10% risk), trichilemommas, papillomatous papule, uterine (5-10%), kidney
PALB2 cancers
br, panc, ov-unconfirmed
HDGC cancers
lobular breast, diffuse gastric
Peutz-Jegher ca
-br, panc, colon, gastric, hamartomous polyps, mucocutaneous lesions, lung
HBOC genetics
-mutations of BRCA1/2
+effects homologous recombination DNA repair, cell cycle checkpoint control, proteolytic ubiquitylation, transcriptional regulation-DNA damage is a key activator of normal activity
-incidence of 1 in 40 in AJ pop
-incidence of 1 in 300 among Caucasian, AA, and Asian populations
PARP inhibitors
target additional enzyme in BER, causing cell already missing repair mechanism to die
-other cells with deficiencies in FA/homologous recombination repair pathway may be candidates for therapy (ex: triple negative and somatic cancers)
pancreatitis-like changes in BRCA2
pancreatitis can generally be due to infections, etc, causing inflammation
-study using endoscopic u/s found people with mutations had increased lesions, cysts and pancreatitis
FANC genes
-FANCA, FANCC, FANCG mutations account 80-90% of disease
+note: BRCA2=FANCD1
-bi-allelic PALB2/FANCN, BRIP1/FANCJ and RAD51C can also cause FA
-FANCB XL, RAD51 AD
-most patients are compound heterozygotes
-mutation of genes mostly affects the ability of the core complex to activate correction of inter-strand cross links
AJ HBOC Founder Mutations
-BRCA1 \+187delAG \+5385inC -BRCA2 \+6174delT
BRCA positive screening management
-biannual CBE, SBE and annual BrMRI at 25y
-annual mammo at 30y
+consideration of staggered MRI, mammo
-CA125 and transvaginal u/s at least 1x/yr; no proof of effectiveness of this
BRCA positive surgical management
-risk reducing or prophylactic mastectomy
+decreases BrCa risk by 90%
-risk reducing or prophylactic oophorectomy after child bearing (35-40y-BRCA1, 40-45y-BRCA2)
+TAH-BSO consideration
chemoprevention in BRCA
- tamoxifen-positive premenopausal women
- raloxifene-tamoxifen without increased uterine cancer risk
- aromatase inhibitors-only for use in post-menopausal women
LFS genetics
- mutation of TP53
- increases risk for cancer to 50% by age 35y; lifetime risk 90% for women, 70% for men
- 7-20% de novo mutation risk
- increased risk for 2nd primaries and radiation-induced tumors
sarcomas in LFS
especially concerning for female carriers in radiation field-reason to consider mastectomy over lumpectomy
LFS management
- biannual CBE by 20y or 5-10y before earliest onset in family
- annual brMRI with or w/out mammo by 20-25y; switches to both alternating 30-75y
- consideration of risk reducing mastectomy
- comprehensive PE, blood counts, neuro and skin exams
- colonoscopy every 2-3y at least by 25y
- additional surveillance based on family history with considerations of brain MRI, rapid full body MRI and u/s
hamartoma
growth of normal tissue in a place it should not
PTEN features
- cancers
- macrocephaly with or without ASD
- skin findings: trichilemmomas and papillomatous papules by late 20s near lips, nose, mouth and eyes, lipomas, fibromas
- benign brain tumors-cerebellar dysplastic gangliocytoma in LDD that can present as hydrocephalus
- esophageal glycogenic acanthosis
clinical Cowden criteria
- molecular mutation of PTEN
- 3+ major criteria one of which must be macrocephaly; can include LDD, GI hamartomas
- or 2 major and 3+ minor criteria
Cowden management
- biannual CBE by 25y or 5-10y before earliest onset
- annual mammo and MRI by 25y
- consideration of mastectomy and hysterectomy
- comprehensive PE with focus on thyroid starting and a thyroid u/s by 18y
- colonoscopy starting at 35y every 5-10y and increased frequency for polyps or symptoms
- consider annual derm exam
Bannayan-Riley-Ruvacalba
PTEN syndrome with macrocephaly, hamartomous intestinal polyposis, pigmented macules of the glans penis
Proteus syndrome
PTEN syndrome with connective tissue nevi, disproportionate overgrowth (skull, limbs, hands, feet, vertebrae, etc), lipomas or absence of fat, vascular malformation, facial phenotype (long face, low nasal bridge, down slanting palpebral fissures, wide nostrils, open mouth expression)
standard colonic resection
- removal of tumor and portion of surrounding colon
- may be more common in non-hereditary syndrome carriers
CRC risk factors
- aging
- personal history of cancer or adenomas (polyps)
- inflammatory bowel disease (Chron’s, ulcerative colitis)
- family history and/or hereditary syndrome predisposition
- smoking and alcohol
- obesity
adenomatous polyps
associated with an increased risk to develop colon cancer; pre-malignant & typically calls for increased colonoscopy
hyperplastic polyps
more concerning if of mixed pathology, alone not considered pre-malignant
hamartomatous polyps
- tissue growing where it is not meant to in the colon
- can have very specific features
peutz-jegher polyps
type of hamartomatous polyp, has a frond-like or broccoli stalk appearance (<100)
- small intestinal/jejunal more common, though can see respiratory or urinary tract polyps, sometimes adenomatous polyps
- can require several surgeries due to obstruction, intussusception, abdominal pain, and GI pain <20y in 50% patients
sessile serrated polyps
behave like adenomatous polyps, in one syndrome development someone can develop 20+; can have mixed pathology suggestive of further genetic invesigation
FAP genetics
-AD mutations in APC (5q) \+mostly lead to truncations -30% cases de novo, many mutations also private -genotype-phenotype correlations occur *not all mutations detectable yet
attenuated FAP
- usually caused by mutations at the 5’ or 3’ end of APC
- later onset (CRC ~50y)
- fewer colonic polyps (20<100)
- common to have extracolonic features, except CHRPE
severe FAP
- causes hundreds or thousands of polyps
- seen with mutations in exon 15 of APC
desmoid tumors
-benign growths of connective tissues
+cannot typically be removed surgically as they will return
-due to centrally located mutations in exon 15 of APC-so more common in severe FAP
I1307K
- AJ APC mutation (6% pop) creates a hypermutable region
- associated with a slight increase in colon cancer risk, not polyposis
- consideration of colonoscopies every 5y starting at 40
FAP features
- colonic tumors (>100)
- risk for extra colonic tumors: upper GI/duodenal, desmoid, osteosarcoma, papillary thyroid ca, medulloblastoma, hepatoblastoma (<5y)
- CHRPE, supernumerary teeth, epidermoid cysts
osteoma
benign tumors of jaw
Turcot syndrome
- variant-FAP with medulloblastomas
- variant-Lynch with glioblastomas
CHRPE
- benign lesions, can sometimes be singular and meaningless
- when b/l or when more than 4 lesions are present it is more suggestive of FAP
FAP management
- at least annual colonoscopy, until polyposis
- colectomy with polyposis
- annual upper endoscopy
- consideration of chemoprevention
- monitoring for extracolonic features
MUTYH associated polyposis genetics
-AR mutations of MUTYH \+disruption of BER -carrier frequency of 1% \+Y165C, G382D founder mutations -monoallelic carriers still have increased cancer risks
MAP features
-increased risk for colon cancer (70%) and polyposis (15<100)
+mostly adenomatous, sometimes hyper plastic
-increased risk for duodenal polyposis and cancers
-presentation tends to be in 50s
-ovarian, bladder and skin cancer (sebaceous gland tumors) risk also increase and can mimic Lynch
MAP management
colonoscopy every 5y starting at 40
GREM1
- 40 kb duplication upstream is an AJ founder mutation
- increased polyposis risk, but evidence is not yet conclusive
Lynch or HNPCC cancers
- CRC
- endo, ov
- panc
- transitional cell
- biliary tract
- stomach and upper GI
- sebaceous tumors
Muir-Torre
- Lynch variant subtype mostly in MSH2 mutations, sometimes MLH1
- see lynch cancers with additional risk for sebaceous carcinomas/adenomas, keratocanthomas
Lynch colon cancers
- 3% of all CRC
- avg onset is 45yo with variability
- predominantly begins in proximal/right colon
- much more accelerated transition from polyp to cancer
- can see signet ring, mucinous, medullary types and tumor infiltrating lymphocytes
Lynch genetics
-AD mutation of MMR genes (MLH1, MSH2, PMS2, MSH6, EPCAM)
+causes micro satellite instability
+loss of ability to spell check errors during DNA repair and replication
MSI instability
-loss of MLH1 staining on IHC
-occurs more frequently in Lynch
-can also happen due to promoter methylation in 10-15% somatic tumors
+usually in the presence of V600E BRAF mutation
PREMM5
- web-based prediction model for risk of having a Lynch mutation
- based on logistic regression analysis
- incorporates proband history and family history
MSH6 mutation
may have an increased risk for endometrial (up to 26%) over CRC (up to 22%)
MLH1 and MSH2
-increased risk over other Lynch genes \+50-80% CRC \+25-60% end \+6-13% ov -younger ages of onset
Amsterdam criteria
*research criteria created to stratify participants
-3+ relatives with CRC in family
+one case must be a 1st degree relative of the other two
-two or more generations affected
-at least one CRC <50y
-excludes FAP
revised Bethesda criteria
- used to identify individuals that should have IHC and MSI studies, but now increasingly universal
- CRC <50y
- synchronus and metachronus CRCs
- CRC in someone with a first degree relative that had CRC <50y
- 2 or more lynch cancers in first or second degree relatives
staining co-absence
- MLH1 and PMS2
- MSH2 and MSH6
MSI and IHC in Lynch
80 & 95% respectively versus 15% in sporadic cancers
EPCAM in Lynch
3’ deletion leads to hypermethylation and inactivation of downstream MSH2 promoter
+epimutation is heritable
congenital tufting enteropathy
- due to compound heterozygous mutation of EPCAM
- presents in infancy with intractable diarrhea, severe malabsorption due to intestinal epithelial dysplasia
- causes severe mortality
congenital mismatch repair
- homozygous MMR mutation
- leads to very early onset CRC, duodenal ca
- leukemia and lymphoma risk
- brain tumors (astrocytomas, glioblastomas, primitive neuroendocrine tumors [PNET])
- CALs
- very high mortality rate and risk for NF1 misdiagnosis
Lynch management
-colonoscopy every 1-2y by 20-25y
+consideration of colectomy for certain cases (pushed when a a carrier develops CRC)
-monitoring for uterine bleeding
+consideration of TAH-BSO after childbearing
-upper endoscopy every 3-5y starting at 30y, test for H. pylori
-annual urinalysis or cystoscopy starting at 30-35y
-consideration of CAPS-5 protocol and enteroscopy or capsule endoscopy
PJS features
-caused by STK11 mutations
-see specific hamartomous polyps
-characteristic black/blue pigmentation and freckling around mouth, on fingers
+may fade after puberty and be harder to identify in older patients
-can include small bowel, ov, sex-cord tumors, panc and lung ca
PJS criteria
- 2+ certain hamartomatous polyps of small intestine
- mucocutaneous hyper pigmentation of mouth, lips, nose, eyes, genitalia or fingers
- family hx
juvenile polyposis syndrome
-AD mutations of SMAD4 and BMPR1A
-polyps can be hamartomatous polyps or mixed adenomatous etiology,
+extremely friable and can bleed easily, sometimes leading to anemia
+mixed pathology increases CRC risk
-polyps can occur anywhere in GI and 3+ should trigger thought of condition
JPS management
- with confirmed dx screening initiates by 15y
- annual colon- and endoscopy, if no polyps found reduce to every 2-3y
SMAD4 mutations
- increased risk for CRC with JPS, but also HHT and teleangectasias or venous malformations
- signs can be frequent nose bleeds, mucocutaneous teleangectasias; congenital (especially AVM) but signs can take multiple decades to appear
HDGC
-caused by AD mutation of CDH1 (e-cadherin)
+genetic change only identified in 30-50% cases
-signet ring cell carcinoma
+can see hundreds of foci
-gastric cancer (83% F: 67% M; diffuse, not intestinal)
-lobular breast cancer risk
-age of onset typically about 40y
HDGC management
- prophylactic total gastrectomy around 20y
- endoscopy with random biopsy in younger individuals or those who decline surgery
- breast MRI, mammograms or consideration of prophylactic mastectomy
analytical validity
-laboratory has CLIA certification to stand behind tests and results
+can detect mutations they say they can
-clinical validity and clinical utility not included
clinical validity
- mutation identified, so what are the implications
- identifying what the disease risks are if any
- strength of association and confidence in the association
clinical utility
-variant has identified implications
-goal is then to understand if there are management and treatment options related to it and how the information impacts patient care
-parsing out which variants impact this and to what degree, as well as how this impact has been measured
+testing for the variant should not be offered to patients if this information is not established
ELSI issues
psychosocial implications of an identified variant
publication bias
- negative or no association study findings not often published
- oversampling for earlier ages of onset and strong family histories
- risk estimate may only be reflective of highly selected families and may not accurately reflect risk for all average risk carriers
risk modifiers
- family history
- varied risk based on specific mutation
- SNPs and modifier genes
- environmental and lifestyle risk factors
CHEK2
-moderate breast cancer risk
+recommendation of mammo starting at 40y with MRI consideration
-colon cancer risk possible
+colonoscopy every 5y, starting at 40y or 10y prior to the earliest diagnosis
ATM
- moderate breast cancer risk gene (30-60%)
- recommendation of annual mammo by 40y with MRI consideration
PALB2
- moderate breast cancer risk gene
- recommendation of annual mammo starting at 30y with consideration of MRI
- AR (FA) disease risk counseling
BODICEA model
provides risk stratification of genes in the presence of multiple factors (family history, GT results, etc)
moderate risk ovarian ca genes
-RAD51C
-RAD51D
-BRIP1
+consideration of TAH-BSO for all between 45-50y
+AR dz risk for RAD51C and BRIP1
VHL etiology
-AD mutations of VHL \+90% penetrant, but highly variable phenotype \+20% de novo \+mostly mutations with rarer deletions -incidence of 1 in 36000 -strong phenotype-genotype correlation
VHL phenotype
- diagnosis tends to occur around 25y, but can be earlier (recommended for screening)
- tumor risks: hemangioblastomas, retinal angioma, pheos (can start in teens-20s), paragangliomas, renal cysts, PNETS, epidydimal cysts, endolymphatic sac tumors
- cancers: clear cell renal carcinoma (25-45% patients)
hemangioblastoma
tumor of the cerebellum or spine
pheochromocytoma
typically benign tumor of adrenal gland
-in VHL only secretes norepi
VHL management
- annual brain and spine MRI starting at 10, with focus for ELSTs
- annual optho exam starting at age 5
- biochemical pheo screening starting at age 5y
- annual or semi-annual abdominal MRI starting at 10y-20y
MEN1 etiology
-AD MEN1 mutations
+80% familial
+60% cases with at least one clinical feature and no family history have mutation
+del/dups 1-3%
-menin protein thought to be involved in DNA rep/repair
-if tumors isolated, checking parathyroid and calcium levels biochemically may be more sensitive
MEN1 clinical criteria
-at least 2 of the following: parathyroid, pituitary, or gastroenteropancreatic NETs (GI carcinoid tumors or panc islet cell tumor) \+combos of >20 endo and non-endo tumors \+GEP-NETs more suggestive of dx -hyperparathyroidism and hypercalcinemia -facial angiofibromas -meningiomas and ependyomas -bronchial and thymic carcinoids -Zollinger-Ellison syndrome
MEN1 management
- MRIs every 1-3y
- biochemical screenings annually
- all begins at young age in cases of known familial diagnosis
MEN2 genetics
-AD mutation of RET proto-oncogene
+low de novo rate
-genotype-phenotype correlations seen (A-MTC, differentiated TC, metanephrine secreting pheos; B-A+other features; FMTC-only MTC)
MEN2 management
- prophylactic thyroidectomy recommended in early childhood or when mutation identified (may see c-cell hyperplasia or cancer formation at excision)
- annual metanephrine biochemical screening
p.Met918Thr
mutation in 98% MEN2B patients; usually de novo
MEN2B phenotype
- marfanoid habitus and skeletal anomalies
- GI ganglioneuromas
- 100% MTC risk, 50% pheo risk
- mucosa and eyelid neuromas
hereditary paraganglioma-pheochromocytoma syndrome
-AD mutations of the SDHX genes, MAX and TMEM127
+paternal inheritance of SDHD confers tumor risk due to imprinting
-50% lifetime risk of tumor with mutation
+may be higher with SDHB
+presence of malignant tumors and multiple tumors increase likelihood of mutation
HPGL-Pheo risks
-pheochromocytomas
-paragangliomas
+sympathetic: usually secretory, present in abdomen, thorax or retroperitoneum
+para: usually non-secretory present in head, neck (glomus, carotid body, nonchromaffic)
-RCC and GIST, possibly thyroid ca
HPGL-pheo management
monitoring begins at least by age 10y
- annual PE
- annual non-contrast neck to pelvis MRI
- annual neck and thoracic ultrasounds
- annual metanephrine and catecholamine bloodwork
- monitoring for other necessary screening
kidney cancer formation
- only about 1.6% in general population
- more commonly begins in collecting ducts/renal pelvis
Birt-Hogg-Dube genetics
-AD FLCN mutations
+affects tumor suppressor functions
+85% penetrance
-incidence of 1 in 200000
BHD phenotype
- tumors: RCC (15-45% patients; often several and mixed types)
- pneumothorax and/or lung blebs
- fibrofolliculomas (multiple are pathognomonic)
BHD management
- renal imaging every 1-2y
- annual abdominal MRI by 20y
hereditary leiomyomatosis-RCC syndrome genetics
- AD FH gene mutations
- high penetrance
- some genotype-phenotype correlations
HLRCC phenotype
-RCC-papillary type II with fried egg appearance
-cutaneous leiomyomas (dozens to hundreds; pathognomonic)
+typically non-malignant but painful
-uterine fibroids
+can be large or have specific pathology and also have a risk for cancer conversion
HLRCC management
- annual kidney imaging by age 8-10y
- hysterectomy considerations
- leiomyoma removal if bothersome for patients
- annual abdominal CT or MRI by 20y
hereditary papillary renal carcinoma syndrome (HRPC) genetics
- mutation of MET porto-oncogene
- incidence of 1 in 10M
- penetrance of 90%
HPRC phenotype and management
-onset 50s-70s, but limited info
-high risk RCC, papillary type 1
+can be multiple or bilateral, slow-growing tumors
-annual abdominal CT or MRI by 30y
familial atypical multiple mole melanoma (FAMMM) genetics
-AD mutations with high penetrance \+debate over utility of GT -CKN2A tumor suppressor \+90% mutations \+2 separate proteins encoded -CDK4 Rb phosphorylating protein \+2-3%
FAMMM clinical criteria and risks
- at least one FDR or SDR with malignant melanoma
- greater than 50 nevi on body; some clinically atypical
- risk for pancreatic cancer (up to 17% by 75y)
- brain tumors: acoustic neuromas, ependymoma, glioblastoma, medulloblastoma, meningioma, neuroblastoma, neurofibroma, neurolemma
FAMMM management
- skin exam at least biannually starting at 10y
- avoidance of excessive sun exposure
Gorlin/nevoid bcc syndrome genetics (NBCCS)
-AD mutations of PTCH1
+100% penetrant
+variable expressivity
NBCCS criteria
-2 major and one minor or 3 minor and one major
-major:
+lamellar calcification of Falx
+jaw keratocyst
+palmar/plantar pits
+multiple BCC (greater than 5 or occurred under 30y)
-minor:
+childhood medulloblastoma
+lymph or pleural cysts
+macrocephaly
+vertebral or rib anomalies
+cardiac or ovarian fibromas
+polydactly
+ocular anomalies
XP genetics and management
- several XP genes (account for 50% cases)
- AR inheritance
- defective NER
- best diagnostic test involves studying cellular reaction to UV damage
- recommended for patients to have frequent derm exams and avoid sun exposure
XP phenotype
-extreme photosensitivity related to cellular hypersensitivity to DNA damage and pyrimidine dimer formation
-predisposition to BCC, squamous carcinoma and melanoma
+cancer can occur on tongue, mucosal tissues and skin
-many cancers possible with first usually in early childhood
+eye cancers, tumors, corneal clouding
+brain ca
+lung ca if smoke
-neurological issues (30%)-sz, balance coordination problems
-premature skin aging
NF1 etiology
-AD NF1 mutations
+98% patients with mutation or deletion
+50% with de novo changes
NF1 additional features
- increased risk breast ca
- vascular dz (HTN, renal artery stenosis-can be secondary to a pheo)
- skeletal anomalies: scoliosis, short stature, macrocephaly
- variable phenotype except spinal involvement only families
- variable LD, ADHD
NF2 genetics
-AD NF2 mutations
+identifiable in 60% simplex cases, 90% familial
+50% de novo
+30% mosaic cases
-truncating mutations can lead to more severe phenotype
NF2 criteria
-major criteria:
+b/l vestibular schwannomas
+family history with u/l VS or (2+) meningiomas, gliomas, neurofibromas, schwannomas, posterior sub capsular lenticular opacities
-or u/l VS with 2+ other features
NF2 phenotype
-“adult onset” between 17-21y, but variable
-near 100% likelihood to develop b/l VS by 30yo
-neurofibromas atypical
-neuropathy
+mono: facial palsy, squint/third nerve palsy/foot drop in childhood)
+poly: systemic in 40% patients
-cataracts, subcapsular lenticular opacities that rarely progress to full cataracts
-skin schwannomas, sometimes CALMs
NF2 management
- annual optho, neuro audio exam from infancy
- annual cranial MRI starting 10-12yo
- spinal MRI every 1-3y starting 10-12yo
- consideration of surgical resections, stereotactic radio surgery (for brain tumors), VEGF inhibitor
Tuberous sclerosis genetics
-AD mutations of TSC1 (hamartin) or TSC2 (tuberin)
+80-85% identifiable mutations with clinical phenotype
-de novo TSC2 mutations cause a more severe phenotype
-sometimes contiguous deletion of TSC2 can also include PKD1 and cause AD PKD
Legius syndrome
- rare mutations of SPRED1
- causes an NF1 phenotype of freckling, CALMs, macrocephaly, without tumor risks
- short stature, Noonan-like dysmorphism, pectus, lipomas, hypopigmented macules, and vascular lesions can occur
TSC phenotype
-brain \+cortical tubers, subependymal nodules, more rarely giant cell astrocytomas \+seizures, including infantile spasms \+sometimes ID, increased anxiety and ASDs -skin \+hypomelanotic macules, shagreen patches \+facial angiofibromas \+ungual fibromas -retinal hamartomas -rhabdomyomas -kidney \+angiomyolipomas \+renal cancer, cysts -lymphangiomyomatosis (LAMs) in women
TSC managment
-Chest CT in adult women every 5-10y with ablation procedure if LAMS larger than 3mm
-baseline EEG with contrast brain MRI every 1-3y starting at 25y
-renal MRIs every 1-3y
+embo of AMLs larger than 3mm and mTOR inhibitors
-echo, EKG until rhabdo resolves
-annual optho and derm exam
+consideration of topical mTor inhibitor
familial pleuropulmonary blastoma
- AD DICER1 mutations
- unknown incidence and de novo rate due to rarity
- children with PPBs or cystic nephromas have a high likelihood of harboring mutation
DICER1 syndrome phenotype
-20% lifetime risk, with highest risk for children under 7 at present
+potentially 40% risk for females
-tumors/cancers: PPB, sertoli-leydig ovarian stromal cell cancers, cystic nephromas, anaplastic sarcomas of the kidney, Wilms tumor, differentiated thyroid ca, cervical and bladder (etc) rhabdomyosarcoma, nasal chondromesenchymal hamartomas, pineoblastomas
DICER1 syndrome management
- baseline chest CT at 3-6mo, if normal repeat at 2.5y
- CXR every 6mo oil 8y
- biannual renal u/s until age 8, then annual
- (bi)annual pelvic/uterine u/s starting in early childhood
- thyroid u/s starting at 8y, if nL repeat every 3y
Chompret criteria
- pt with LFS tumor <46y and an FDR or SDR with LFS <56y (unless pt and relative both have BrCa) or with multiple cancers
- pt with multiple non-BrCa tumors if 2+ are LFS tumors and first was dx <46y
- pt with adrenocortical carcinoma (ACC) or choroid plexus carcinoma
childhood LFS management
-annual PE and neurological eval
-abdominal and pelvic u/s every 2-4mo
-annual brain MRI
+1st with contrast, can go without in future if first is normal and no new sx
-annual full body MRI
hereditary retinoblastoma genetics
-AD mutation of RB1 tumor suppressor \+80% de novo \+90% penetrance -chance to uncover mutation \+fam hx and dx ~100% \+b/l dx ~100% \+u/l, unifocal ~14% \+u/l, multifocal ~15-95% -incidence of 1 in 15000-1 in 20000
13q deletion syndrome
contiguous gene deletion that includes RB1 so patients at risk for Rb, ID/DD and other sx
Rb signs and tx
- extremely curable, but focus is on preserving vision
- can visualize leukocoria, strabismus, glaucoma, orbital cellulitis, uveitis, hyphen, vitreous hemorrhage prior to dx
- mostly dx prior to 5y
Rb cancer risks
- Rb
- second ca risk high (20-50%) related to high dose external beam RT
- pineal blastomas, osteosarcomas, soft tissue sarcomas, melanoma, brain, PNET and epithelial cancers may also occur
nephroblastoma
-also Wilms tumor
-incidence of 1 in 8000-1 in 10000
-mostly u/l and sporadic
+ ~10% genetic
familial Wilms tumor genetics
-several, main is AD mutation of WT1
+affects normal formation of kidney and gonad development due to zinc-finger protein loss
-found in other syndromes: BWS, WAGR, isolated hem-hypertrophy
Denys Drash syndrome
- due to point mutations in WT1
- nephropathy leading to liver failure in early childhood
- ambiguous genitalia in 46, XY males
- 90% risk Wilms tumor
WT1 mutation effects
embryonal kidney cancer of childhood; bilateral more likely
Frasier syndrome
- due to splice site WT1 mutations
- glomurosclerosis or scarring of renal blood vessels, increased Wilms tumor risk
- ambiguous genitalia in 46, XY male; risks for gonadoblastomas
- neuropathy
WAGR
- microdeletion syndrome that includes PAX6 and WT1 genes
- risk of Wilms tumor is 40-50%
- signs: wilms tumor, aniridia, GU anomalies, growth delay or ID
hypoplastic anemia
hypo cellular bone marrow (<25% normal cells)
Bloom syndrome genetics
-AR mutation of BLM
+mutation causes genomic instability
-incidence of 1 in 50000
+increased rate in AJ
Bloom phenotype
- extreme sun sensitivity and cancer risk
- short stature, low weight
- dilation of blood vessels with reddening of skin and both hyper and hypo pigmentation
- facies: long, narrow face with prominent ears and nose and “butterfly” teleangectasia
- immunodeficiency with recurrent infection and increased risk for diabetes
- male infertility
- LD
- anemia
Bloom management
- avoidance of sun exposure
- immunoglobulin replacement therapy for severe anemia
- increased risk of chemo-induced toxicity
FA dx
-induce chromosomal breakage with DEB
+best to use peripheral blood lymphocytes and can confirm in fibroblasts
-GT
schwachman diamond genetics
-AR mutation of SBDS
+detectable in 75% of affected kids
-incidence of 1 in 75000
-no current genotype/phenotype correlations
-mutation causes defective ribosome activity and occurs due to abnormal recombination event with nearby pseudogene
Schwachman diamond phenotype
-neutropenia and hypo cellular bone marrow
+leads to recurrent infection
-exocrine pancreatic insufficiency
+second most common cause after CF; due to lack of acinar cells
-growth delay (at least 50% below 3rd percentile for height)
-skeletal anomalies-thumb, limb, rib cage abnormalities and small HC
-cancer risks: AML, myelodysplastic syndrome
Schwachen diamond management
BMT
