Cancer syndromes Flashcards

Question

Based on the following tumor testing results, give plausible etiologies and additional testing options for Lynch syndrome Immunohistochemistry: MLH1+, MSH2-, MSH6+, PMS2+

Answer 1

Germline MSH2/EPCAM PV sporadic cancer Germline MMR gene testing or paired germline/tumor tissue MMR gene testing If germline testing negative and paired germline/tumor tissue not done, consider tumor tissue MMR gene testing

Answer 2

Germline MSH6 PV Germline MSH2/EPCAM PV sporadic cancer with tx effect Germline MMR gene testing or paired germline/tumor tissue MMR gene testing If germline testing negative and paired germline/tumor tissue not done, consider tumor tissue MMR gene testing If applicable, consider MSI analysis or repeat IHC on nontreated tumor

Answer 3

Sporadic cancer: MLH1 promotor methylation or somatic MLH1 or PMS2 PV Germline MLH1 PV Germline PMS2 PV Targeted BRAF and/or MLH1 promoter methylation testing on tumor tissue If BRAF and MLH1 methylation normal: germline MMR gene testing or paired germline/tumor tissue MMR gene testing If germline testing negative and paired germline/tumor tissue not done, consider tumor tissue MMR gene testing

Answer 4

Germline MMR gene PV Sporadic cancer Targeted BRAF and/or MLH1 promoter methylation testing AND germline MMR gene testing or paired germline/tumor tissue MMR gene testing (often incl MLH1 methylation testing) If germline testing negative and paired germline/tumor tissue not done, consider tumor tissue MMR gene testing

Answer 5

Any (78%) CRC (44%) Endometrium (35%) Ovary (11%) Stomach (8%) Small bowel (8%) Ureter, kidney (3%) Urinary bladder (3%) Brain (2%) Breast (11%)

Answer 6

Any (64%) CRC (53%) Stomach (16%) Small bowel (16%) Ureter, kidney (4%) Urinary bladder (5%) Prostate (7%) Brain (1%)

Answer 7

Any (77%) CRC (42%) Endometrium (46%) Ovary (17%) Stomach (10%) Small bowel (10%) Ureter, kidney (13%) Urinary bladder (7%) Brain (2%) Breast (13%)

Answer 8

Any (71%) CRC (46%) Stomach (16%) Small bowel (16%) Ureter, kidney (16%) Urinary bladder (9%) Prostate (16%) Brain (4%)

Answer 9

Any (62%) CRC (20%) Endometrium (41%) Ovary (11%) Stomach (2%) Small bowel (2%) Ureter, kidney (6%) Urinary bladder (1%) Brain (1%) Breast (11%)

Answer 10

Any (28%) CRC (12%) Stomach (4%) Small bowel (4%) Ureter, kidney (2%) Urinary bladder (4%) Prostate (5%) Brain (2%)

Answer 11

Any (22%) CRC (3%) Endometrium (13%) Ovary (3%) Stomach (4%) Small bowel (4%) Prostate (5%) Breast (8%)

Answer 12

CRC: 75% Endometrium: 12%

Answer 13

CRCs with MSI tend to have better prognosis than MSS tumors, potentially reflecting active anti-tumor immune response; risk of metachronous CRC can be as high as 43% for those with MLH1/MSH2 PVs endometrial cancers with MSI show better prognosis ovarian cancer is typically of endometrioid histologic subtype gastric cancers tend to present as intestinal-type adenocarcinoma, located to the duodenum and jejunum urinary tract cancers are transitional carcinomas of the ureter, renal pelvis, and kidney brain: glioblastoma makes up more than half; then astrocytoma (22%), oligodendroglioma (9%) sebaceous neoplasm: sebaceous adenomas, sebaceous epitheliomas, sebaceous carcinomas, and keratoacanthomas (all are typically MSI high)

Answer 14

describes individuals presenting with the combination of sebaceous neoplasms of the skin and one or more visceral malignancies, commonly those seen in lynch syndrome Is an uncommon variant OF lynch syndrome

Answer 15

individuals presenting with CRC or one or more colorectal adenomas in addition to tumors of the CNS caused by PVs in one of the MMR genes or an APC PV APC PVs are more commonly associated with medulloblastoma; PVs in MMR genes are commonly associated with glioblastoma

Answer 16

rare childhood cancer predisposition syndrome caused by biallelic PVs in MLH1, MSH2, MSH6, or PMS2 have CRC or cancer of the small intestine prior to the second decade of life (colonic adenomas were the most frequent finding, cutaneous phenotype similar to NF1, nearly all with cafe au lait macules; hematologic cancers and brain tumors)

Answer 17

risk for extracolonic cancers is dependent on the size of the del. 3' EPCAM deletions have been shown to confer a lower risk for extracolonic cancers, whereas deletions that extend into MSH2 confer extracolonic cancer risks similar to intragenic MSH2 PV

Answer 18

sporadic MMR deficient tumors commonly occur in older females; show lack of MLH1 protein expression due to MLH1 promoter methylation and are strongly associated with the CpG island methylator phenotype and serrated route of carcinogenesis BRAF-related: Somatic BRAF PVs occur in 15% of all CRC and, in rare instances, may be identified in tumor tissue from individuals with Lynch. Prevalence of BRAF PVs in MSI-high CRCs also increased with age; BRAF testing is cost-inefficient for screening in those with MSI-high CRCs dx before 50yo Somatic MLH1 promoter methylation: 10-15% of CRCs are MSI high or MMR deficient due to somatic methylation of the promoter region of MLH1 that silences gene expression in the tumor tissue, rather than due to Lynch (more effective than BRAF testing); individuals in whom a Lynch syndrome associated germline PV is not identified and who have somatic MLH1 promoter methylation are likely to have sporadic cancer

Answer 19

CRC: colonoscopy beginning at 20-25yo or 2-5yrs before earliest CRC dx in family Endometrial cancer: educate females about symptoms (abnormal uterine bleeding, postmenopausal bleeding); eval of symptoms including endometrial bx q1-2yrs; screening should begin between 30-35yo Ovarian cancer: educate females about symptoms (pelvic/abdominal pain, bloating, difficulty eating, urinary frequency) Gastric and duodenal cancers: consider upper endoscopy beginning at 40yo q3-5yrs for those with FH of gastric cancer and Asian ancestry Distal small bowel: consider capsule endoscopy and small bowel enterography in symptomatic individuals Urinary tract cancers (renal pelvis, ureter, and/or bladder): consider urine cytology to identify microscopic hematuria in those with a FH beginning between 30-35yo Pancreatic cancer: consider EUS/MRCP at 50yo in those with a FH

Answer 20

adenomas of colon: complete endoscopic polypectomy w f/u colonoscopy q1-2yrs CRC: segmental or extended colonic resection; for those with rectal adenocarcinoma, proctectomy or total proctocolectomy is indicated other tumors: management as in general population prophylactic hysterectomy and bilateral salpingo-oophorectomy can be considered after childbearing is completed prophylactic colectomy is generally not recommended since screening is effective aspirin therapy has been shown to decrease the risk of CRC

Answer 21

incomplete penetrance, variable age of cancer development, cancer risk reduction from screening or prophylactic sx, or early death

Answer 22

PVs in genes involved in the MMR pathway which functions to identify and remove single-nucleotide mismatches or insertions and deletion loops germline dels with EPCAM, which is not an MMR gene, can disrupt the MMR pathway by inactivating the adjacent MMR gene, MSH2, even though MSH2 itself has not been mutated

Answer 23

EPCAM: only large dels that include the last exon of EPCAM are causative of Lynch; other EPCAM variants are NOT associated with Lynch MLH1: most instances of MLH1 promoter methylation are simplex, but a few families w inherited hypermethylation have been reported; MLH1 promoter methylation is not detectable by either sequence analysis or dup/del analysis of MLH1 PMS2: molecular analysis is more complex due to the presence of multiple pseudogenes; Long range PCR, cDNA sequencing, or specific solutions to NGS testing can help distinguish between the pseudogenes and PVs

Answer 24

proband who meets ALL THREE classic LFS criteria AND/OR has a germline PV in TP53 Classic criteria 1. proband with sarcoma before age 45 2. first degree relative with any cancer dx before 45 3. first or second degree relative with any cancer before 45yo or a sarcoma dx at any age

Answer 25

Identification of low-level mosaicism for TP53 in leukocytes is suggestive of a postzygotic PV due to clonal hematopoiesis of indeterminate potential related to aging, cytotoxic txs, underlying hematologic malignancy or premalignancy, or circulating tumor cells Evals include: analysis of cultured skin fibroblasts for identified TP53 PV molecular genetic testing of all offspring to determine if the TP53 PV was transmitted molecular genetic testing of other FMs to determine if the TP53 PV is segregating with cancer in the family

Answer 26

Chompret criteria; 30% will have a TP53 PV

Answer 27

lifetime cancer risk for men is 70%; women is 90% Five main types: adrenocortical carcinomas (6-13% before age 5), breast cancer (27-31%, most common cancer in women with TP53 PV, occurs prior to menopause), central nervous system tumors (9-14% of cancers typically before 40yo), osteosarcomas (3-16% by 30yo), soft-tissue sarcomas (17-27%, most common LFS cancer in children) avg onset of first cancer in men is ~17yo; for women it is ~13yo although when including breast cancer it is 28yo ~50% risk of developing a second cancer 10yo after first dx

Answer 28

Breast: triple positive; more likely to be ductal and have malignant phyllodes tumors CNS tumors: glioblastomas and astrocytomas are the most common type; medulloblastomas are typically the sonic hedgehog subtype and display chromothripsos (numerous clustered chromosome rearrangements occurring in malignant cells) Soft-tissue sarcomas: rhabdomyosarcomas and other soft-tissue sarcomas; rhabdomyosarcomas often before 5yo and are often nonalveolar tumors with diffuse anaplasia leukemias/lymphomas: in 2-4%, usually primary and secondary leukemias, especially ALL, AML, and myelodysplastic syndrome; ALL often exhibits a low hypodiploid state with 32-39 chroms

Answer 29

the pregnant mother of a fetus heterozygous for a pat inherited TP53 PV is at risk for choriocarcinoma or another gestational trophoblastic disease (occurrence of cancer in the placental tissue that can spread to other tissues)

Answer 30

individuals with LFS who carry dominant negative PVs (mutated p53 protein interferes with the function of the wild type p53 protein) TP53 founder variant p.Arg337His common in southern Brazil is associated with a high risk of childhood onset ACC, up to 55%; mat inheritance of p.Arg337His was identified in 72% of individuals, suggesting preferential selection

Answer 31

p.Arg72 polymorphism: higher levels of p53 degradation and earlier onset of first cancer MDM2 c.14+309T>G: higher levels of p53 degradation and earlier onset of first cancer microRNA R-605 variant: ten year accelerated mean age of tumor onset 16bp dup polymorphism in intron 3 (PIN3): appears to be protective, older ages of first cancer dx shortened telomere length: accelerated tumor development (anticipation) in families

Answer 32

radiation therapy is avoided if possible to reduce the risk of secondary malignancies. however, tx efficacy should be prioritized above concerns regarding risk of subsequent malignancies (radiation may be needed to provide best chance of cure) women encouraged to consider bilateral mastectomy to reduce risk of developing second primary breast cancer adults should have colonoscopies avoid sun, tobacco, other carcinogens

Answer 33

All cancers: complete physical exam (q3-4mo birth to 18yo; q6mo >18yo), whole body MRI annually for all ages ACC: u/s of abdomen and pelvis q3-4mo birth to 18yo; serum total testosterone, dehydroepiandrosterone sulfate and androstenedione if u/s is unsatisfactory Breast ca: CBE (q6-12mo from 20-25yo), Breast MRI (annually, 20-30yo); Mammogram (30-75yo) CNS tumors: neurologic exam and brain MRI annually for all ages upper endoscopy and colonoscopy q2-5yrs starting at 25yo annual dermatologic exam starting at 18yo sarcomas: whole body MRI/ u/s of abdomen and pelvis

Answer 34

YES it is recommended that predictive testing be offered to individuals at birth (via cord blood) or soon after birth special consideration should be given to education of the children and their parents prior to genetic testing and older children and adolescents should be given the option of assenting to the test

Answer 35

encodes p53 which has been termed the guardian of the genome since it is involved with DNA replication/repair, epigenetic patterning of the genome, cell cycle arrest, apoptosis, etc. PVs ultimately lead to genomic instability and malignant transformation. It is the most frequently mutated gene in human cancer TP53 missense variants are the variants most commonly identified and tumors and they present challenges in germline interpretation

Answer 36

takes into account phenotype and age at dx has been developed in adults, clinical threshold score of 10 or more leads to recommendation for referral to genetics In children, macrocephaly and one or more of the following leads to the consideration of PHTS: autism or DD dermatologic features including lipomas, trichilemmomas, oral papillomas, or penile freckling vascular features (arteriovenous malformations or hemangiomas) gastrointestinal polyps pediatric-onset thyroid cancer or germ cells

Answer 37

Adult Lhermitte-Duclos dz (presence of a cerebellar dysplastic gangliocytoma) mucocutaneus lesions: facial trichilemmomas, acral keratoses, papillomatous lesions, mucosal lesions

Answer 38

If an individual meets any ONE of the following criteria: Pathognomonic mucocutaneous lesions including one of the following: Six or more facial papules, of which three or more must be trichilemmomas Cutaneous facial papules and oral mucosal papillomatosis Oral mucosal papillomatosis and acral keratoses Six or more palmoplantar keratoses Two or more major criteria One major and three or more minor criteria Four or more minor criteria Major criteria Breast cancer Epithelial thyroid cancer (non-medullary), especially follicular thyroid cancer Macrocephaly (occipital frontal circumference ≥97th percentile) Endometrial carcinoma Minor criteria Other thyroid lesions (e.g., adenoma, multinodular goiter) Intellectual disability (IQ ≤75) Hamartomatous intestinal polyps Fibrocystic disease of the breast Lipomas Fibromas Genitourinary tumors (especially renal cell carcinoma) Genitourinary malformation Uterine fibroids

Answer 39

other relatives are considered to have a clinical diagnosis of CS if they meet any one of the following criteria: A pathognomonic criterion Any one major criterion with or without minor criteria Two minor criteria History of Bannayan-Riley-Ruvalcaba syndrome

Answer 40

sequence analysis then del dup also perform sequence analysis of the PTEN promoter region for variants that decrease PTEN gene expression (10%)

Answer 41

a multiple hamartoma syndrome with a high risk for benign and malignant tumors of the thyroid, breast, and endometrium; renal cell carcinoma and colorectal carcinoma present too

Answer 42

congenital disorder characterized by macrocephaly, intestinal polyposis, lipomas, vascular malformations, and pigmented macules of the glans penis

Answer 43

complex, highly variable disorder involving congenital malformations and overgrowth of multiple tissues

Answer 44

90% have some clinical feature by late 20s, by the 4th decade, 99% of individuals develop the mucocutaneous features as well as acral and plantar keratoses; usually have macrocephaly and dolichocephaly harmartomatous and mixed GI polyps that confer a risk for CRC high risk for breast, thyroid, renal, and endometrial cancers, risk for multifocal and bilateral cancer increased; 7-fold increase risk of developing a second primary malignant neoplasm

Answer 45

glycogenic acanthosis (in colon, small mounds of glycogen stores) have a high likelihood of finding a PTEN PV breast: 67% risk of benign breast dz; 85% lifetime risk for female breast ca with 50% penetrance by 50yo thyroid dz: benign multinodular goiter of the thyroid as well as adenomatous nodules and follicular adenomas up to 75% of individuals; lifetime risk for epithelial thyroid ca is ~35%, onset at 37yo (FOLLICULAR HISTOLOGY) endometrial: benign uterine fibroids are common; lifetime risk for endometrial cancer is ~28% starting at late 30s-40s GI neoplasias: 90% are found to have polyps (ganglioneuromatous polyps, hamartomatous, and juvenile polyps); lifetime CRC is 9% starting at late 30s RCC: estimated to be 35% by 20s w the predominant histology being papillary RCC lifetime risk for cutaneous melanoma is ~6% rare CNS tumor, cerebellar dysplastic gangliocytoma (Lhermitte-Duclos dz) may be pathognomonic

Answer 46

in addition to the features of CS, high birth weight, DD, ID, myopathic process in proximal muscles, joint hyperextensibility, pectus excavatum, scoliosis have same cancer risks of CS GI polyps may be occasionally be associated with intussusception but rectal bleeding and oozing of "serum" is more common; these polyps NOT believed to increase risk for CRC

Answer 47

progressive segmental or patchy overgrowth of diverse tissues of all germ layers affecting the skeleton, skin, adipose tissue, and CNS develops and progresses rapidly beginning in the toddler period causing severe overgrowth and disfigurement striking predisposition to DVT and pulmonary embolism

Answer 48

germline KLLN epimutation: ~30% of individuals with CS do NOT have a PTEN PV and have a germline KLLN methylation epimutation resulting in downregulation of KLLN; have a greater prevalence of breast and RCC than do those with a germline PV susceptibility genes: individuals without PTEN PVs harbor germline variants in SDHB and SDHD in 10% of persons with CS; ~10% are found to harbor a germline PIK3CA or AKT1 PVs; ~3%-6% have germline heterozygous SEC23B PVs, which are particularly associated with thyroid carcinoma and enhanced ribosome biogenesis

Answer 49

annual comprehensive physical exam at 18yo or 5yrs before youngest age of dx breast: @18, SBE; @25, CBE q6-12mo; @30-35, annual mammogram with consideration of breast MRI; discuss mastectomy as needed thyroid u/s: starting at age of dx, annual thyroid u/s kidney: @40, consider renal u/s q1-2yrs endometrium: consider ca screening @35yo; consider endometrial bx screening q1-2yrs; transvaginal u/s in postmenopausal women as needed; discuss hysterectomy on completion of childbearing colon: @35, colonoscopy q5yrs dermatologic: annual exam developmental: consider psychomotor assessment in children, brain MRI if symptomatic, eval for early intervention

Answer 50

mucocutaneous lesions: observation, removal only if malignancy is suspected DD: support services, early intervention breast dz/neoplasia: refer to breast specialist thyroid dz: u/s, perform total thyroidectomy if suspicious for malignancy endometrial dz: multiple fibroids are tx w total abdominal hysterectomy

Answer 51

YES given the possible early dz presentation in individuals with BRRS and PTEN-related proteus syndrome

Answer 52

10-44%/ virtually all

Answer 53

downregulates the PIK3/AKT pathway nearly 40% of PVs are in exon 5 which encodes the phosphate core motif ~76% of germline PVs in PTEN predict truncated protein, haploinsufficiency, or dysfunctional protein; many missense variants are functional null and act as dominant negatives PTEN has a highly homologous pseudogene on chrom 9

Answer 54

breast (20-30%), 4% for second breast cancer w/out bilateral mastectomy (annual breast MRI @30-35, start mammo @40- insufficient evidence for risk reducing mastectomy) pancreatic (5-10%) (screen if FH) ovarian (2-3%)

Answer 55

any of the following: multiple CR adenomatous polyps (at least 10-20 cumulative) FH of the above, known APC PV, and/or extracolonic features of APC-associated polyposis conditions hepatoblastoma multifocal/bilateral congenital hypertrophy of the retinal pigment epithelium (CHRPE) desmoid tumor cribriform-morular variant of papillary thyroid cancer others: early onset CRC w few to no adenomatous polyps, dental abnormalities, osteomas, odontomas, epidermoid cysts, duodenal adenomas and cancer, gastric fundic gland polyposis, gastric cancer, pancreatic cancer, small bowel carcinoma, and/or medulloblastoma

Answer 56

heterozygous PV in APC classic FAP: > or =100 CR adenomas OR multiple but less than 100 adenomas and a relative with confirmed classic FAP attenuated FAP: relative with confirmed AFAP AND/OR <100 CR adenomas OR >100 CR adenomas at an advanced age (>40yo) GAPPS: PV in promotor 1B of APC AND: gastric polyps restricted to the body and fundus, >100 polyps in the proximal stomach or >30 polyps in a first degree relative w GAPPS; predominantly fundic gland polyps and some gastric adenomas; no evidence of CR or duodenal polyposis

Answer 57

single gene testing with del/dup; del/dup should also include the analysis of APC regulatory regions (promoter 1B) if APC PV is not identified with initial testing ~20% of simplex cases are somatic mosaic for an APC PV

Answer 58

adenomas by 2nd-3rd decade w avg age of dx at 16yo by 35yo, 95% of affected individuals have polyps which rapidly increase in number 100s-1000s typically observed 93% w CRC by 50yo inter and intrafamilial phenotypic variability common

Answer 59

Characterized by fewer CR polyps (avg ~30) but a significant risk for CRC < or = 100 CR adenomas at > or = 25yo occur more proximally in the colon than FAP avg age of CRC dx is 50yo cumulative risk for CRC by 80yo is 70%

Answer 60

small bowel, duodenal cancer (adenocarcinoma/carcinoma, 4-8%) pancreas (adenocarcinoma, ~1%) thyroid (papillary w cribriform pattern, 1-12%; female to male ratio of 80:1) CNS (usually medulloblastoma, ~1%) Liver (hepatoblastoma, ~2%; 750-7500x higher than general pop, majority before 3yo) stomach (adenocarcinoma, ~1.3% in West but higher in Asian cultures) non-malignant findings osteomas (60-80%): bony growths typically on skull and mandible dental anomalies (30-75%): unerupted teeth, congenital absence of one or more teeth, supernumerary teeth CHRPE(80%): discrete, flat, pigmented lesions of the retina; isolated ones can be seen in the general population benign cutaneous lesions desmoid tumors (10-30%): clonal proliferations of myofibroblasts but do not metastasize. 65% are in the abdomen/abdominal wall which can compress organs or complicate abdominal sx adrenal masses: 2-4x more prevalent than general pop

Answer 61

APC PV 3' of codon 1399 FH of desmoid tumors (highest magnitude of risk) female gender previous abdominal sx

Answer 62

proximal gastric fundic gastric polyps and intestinal-type gastric adenocarcinoma, typically without significant duodenal or colorectal polyps; have 13-25% lifetime risk for gastric carcinoma

Answer 63

78% of those meeting criteria for AFAP (extracolonic manifestations are rare) had a PV in: 1. the 5' end of APC, 2. the alternative spliced region of exon 9, 3. 3' codon of 1595 whole gene deletions typically associated with FAP

Answer 64

Classic FAP; Peutz-Jegher syndrome; VHL; hereditary retinoblastoma

Answer 65

CR adenomas: Colonoscopy q1-2yrs at 10-15 for classic FAP and late adolescence in attenuated; for those w total colectomy w IPPAA: endoscopy of ileal pouch q1-2yrs; for those w subtotal colectomy w ileorectal anastomosis, surveillance of remaining rectum q1-2yrs or more frequent if high polyp burden; in ppl w total colectomy w end ileostomy, ileoscopy q1-2yrs small bowel polyps/ca: EGD w complete visualization of ampulla of Vater q6mo-5yts at 20-25 depending on duodenal adenoma burden thyroid: palpation of thyroid, u/s q2-5yrs in late adolescence CNS tumors: neuro exam annually beginning at dx hepatoblastoma: liver palpation, abdominal u/s, serum AFP q3-6mo during 1st 5yrs of life gastric polyps and ca: EGD q6mo-5yrs beginning at 20-25; if neoplastic polyps, consider annual exams desmoid tumors: abdominal palpation, MRI/CT annually

Answer 66

generally offered to children at risk by 10yo some parents/pediatricians may consider hepatoblastoma screening from infancy to 5yo in affected offspring testing for AFAP can wait until late adolescence, so no testing until then

Answer 67

25% Parent w somatic and germline mosaicism for APC variant may be mildly/minimally affected. Majority (65%) of individuals with APC somatic mosaicism have between 20-100 adenomas (AFAP), 30% have FAP phenotype and 5% have no adenomas

Answer 68

dx of DGC and pathologically confirmed in situ signet ring cells and/or pagetoid spread of signet ring cells dx of DGC and a FH of 2 1st or 2nd degree relatives with DGC or LBC Dx of DGC and a personal or FH of cleft lip/palate

Answer 69

in a proband with diffuse gastric cancer confirmed on endoscopic bx AND one of the following: a FH of one or more 1st or 2nd degree relatives with gastric cancer a personal and/or FH of one individual with DGC dx before 40yo a personal and/or FH of DGC and LBC, one dx before 50yo

Answer 70

identification of a heterozygous PV in CDH1 sequence analysis of CDH1 is performed first then del/dup

Answer 71

age of onset ~38yo symptoms in the late state may include abdominal pain, nausea, vomiting, dysphagia, postprandial fullness, loss of appetite, and weight loss; tumor spread or metastasis may lead to an enlarged liver, jaundice, ascites, skin nodules, and fractures increased risk for LBC (lifetime risk 42%, avg onset @53)

Answer 72

when sporadic, 5yr survival rate can be > 90%; survival rate drops below 30% when the dx is made at a late stage bc early detection of DGC is difficult, survival of individuals with CDH1 PVs is believed to be the same as in individuals with sporadic DGC

Answer 73

loss of the E-cadherin protein causes the individual tumor cells to grow and invade neighboring structures no tumor mass is formed malignant cells have a distinctive signet ring appearance

Answer 74

total gastrectomy is recommended, cure rates ~40% prophylactic total gastrectomy (PTG) is recommended rather than endoscopic surveillance due to the observation of early gastric cancers in PTG samples; generally not recommended until individual's growth period is complete all individuals have intermediate as well as long term complications: rapid intestinal transit, diarrhea, eating habit alterations, weight loss prophylactic mastectomy may be considered in women heterozygous for CDH1 PV adjuvant therapy H pylori infection is tx in the standard manner (if present)

Answer 75

endoscopy: diffuse gastric cancer is difficult to detect at an early, treatable stage bc the lesions tend to spread in the submucosa at-risk individuals who are not ready to undergo PTG should be screened with the Cambridge protocol: detailed 30min upper endoscopy q6-12mo s multiple random bx and bx of subtle lesions; screening beginning 5-10yrs prior to the earliest ca dx in the family mo SBE @20yo; CBE q6-12mo @30; bilateral breast MRI annually @30yo colonoscopy q3-5yrs @40yo or 10yrs prior to the youngest age

Answer 76

c.7271T>G associated w high penetrance breast cancer others are associated with moderate penetrance and increased risks for other types of tumors such as pancreatic and prostate cancer

Answer 77

Breast cancer in less than or = 58%; ovarian cancer, male breast cancer, pancreatic cancer

Answer 78

Breast cancer

Answer 79

epithelial ovarian cancer, possible increased risk for breast cancer

Answer 80

Breast cancer

Answer 81

Ovarian cancer, possibly breast cancer (particularly ER/PR negative breast)

Answer 82

juvenile polyps are hamartomas that develop from an abnormal collection of tissue elements normally present at this site. proliferative characteristics of adenomas are typically not seen in juvenile

Answer 83

established in a proband with any one of the following: more than five juvenile polyps of the colon or rectum multiple juvenile polyps of the upper and lower GI tract any number of juvenile polyps and a FH of juvenile polyps identification of a heterozygous PV in BMPR1A/SMAD4

Answer 84

BMPR1A and SMAD4 concurrent testing with sequence analysis w analysis of the promoter regions and del/dup can also do serial single gene testing: sequence and del dup of SMAD4 then sequence and del dup of BMPR1A if both are negative, test for PTEN consider CMA; dels of 10q22-q23 including BMPR1A and or PTEN may be associated with additional clinical features w or wout juvenile polyposis OR with severe early onset JPS

Answer 85

predisposition to hamartomatous polyps in the GI tract (stomach, small intestine, colon, and rectum); some are sessile and others are pedunculated # of polyps in individuals varies, most have polyps by 20yo in juvenile polyposis of infancy, associated w contiguous del of BMPR1A and PTEN, polyps develop within the first few yrs and are accompanied w hypoproteinemia, protein-losing enteropathy, diarrhea, anemia, and FTT

Answer 86

most juvenile polyps are benign but malignant transformation can occur incidence of CRC by 35yo is 22%; by 60yo it approaches 68% incidence of gastric cancer is 21% in those with gastric polyps relative risk for CRC is ~34%

Answer 87

have variable findings of JPS and HTT; most individuals have one or more clinical findings of HTT epistaxis (childhood); telangiectasias (after 30yo); pulmonary AVMs (birth-50s); hepatic AVM (20s-50s); intracranial AVMs (11-18); aortopathy (~24yo); intrapulmonary shunting on echo (5-59yo)

Answer 88

individuals w SMAD4-related JPS are more likely to have a personal or FH of upper GI polyps; gastric ca almost exclusively in those w SMAD4 JPS CRC more frequently than other cancers in BMPR1A related JPS

Answer 89

colonoscopy w endoscopic polypectomy partial or total gastrectomy/colectomy in those w many polyps to alleviate symptoms iron repalcement and RBC transfusion as needed

Answer 90

assess for rectal bleeding, anemia, abdominal pain, constipation, diarrhea, or changes in stool at each visit colonoscopy/upper endoscopy q3yrs @15yo or earlier if symptomatic; w/out germline PV, recommend q5yrs

Answer 91

CBC and lower intestinal tract endoscopy

Answer 92

proband must have one of the following: 2 or > histologically confirmed PJS-type hamartomous polyps any # of PJS-polyps detected in an individual with a FH of PJS in at least one close relative mucocutaneous pigmentation in an individual who has a FH of PJS any # of PJS-type polyps in an individual who also has characteristic mucocutaneous pigmentation

Answer 93

heterozygous PV in STK11 sequence then del/dup if no STK11 PV is identified, testing of an alternative DNA source for somatic mosaicism should be considered

Answer 94

association of GI polyposis and mucocutaneous pigmentation; variable expressivity is common PJS-type hamartomatous polyps can occur anywhere in the GI tract but occur most commonly in the small intestine (greatest in jejunum, ileum, then duodenum); adenomas also appear w increased prevalence throughout the GI tract polyps can cause significant complications (bowel obstruction, rectal prolapse, severe GI bleeding with secondary anemia needing multiple emergency sx. intussusception (50% by 20yo) natural hx of polyps in a family may be a predictor of severity for offspring mucocutaneous pigmentation: melanocytic macules- dark blue/brown spots around the mouth, eyes, nostrils, perianal area, buccal mucosa; hyperpigmented MM on the fingers females are at increased risk for ovarian sex cord tumors with annular tubules and mucinous tumors of the ovaries and fallopian tubes, typically benign males occasionally develop large cell calcifying Sertoli cell tumors of the testes; may secrete estrogen and can lead to gynecomastia, advanced bone age

Answer 95

Overall: 83% by 70 CRC: 39% by 40s Stomach: 29% by 30s-40s Small bowel: 13% by late 30s Breast: 30-55% by late 30s-50s Ovarian (mostly SCTAT): 21% by 28yo Cervix (adenoma malignum): 10% by 30s-40s Uterine: 9% by 43yo Pancreas: 11-36% by 40s-50s Lung: 7-17% by 47yo

Answer 96

prophylactic polypectomy of polyps >1cm is performed to: decrease risk of bleeding, anemia, obstruction, and intussusception AND reduce the risk of cancer video capsule endoscopy for better visualization of the small-bowel polyps

Answer 97

colonoscopy and upper endoscopy at 8yrs; if neg, rpt at 18yo; if polyps detected, endoscopy q1-3yrs small bowel exam by video capsule endoscopy q1-3yrs @8yo exam for precocious puberty in females annually @8yo testicular exam, exam for feminizing changes, testicular u/s if indicated annually @10yo

Answer 98

colonoscopy and upper endoscopy at 18yo q2-3yrs small bowel exam by video capsule endoscopy @18yo q2-3yrs CBE 2x/yr @30yo; mammo/breast MRI @30yo pelvic exam and pap smear annually @18-20 pancreatic imaging w endoscopic u/s or MRI/MRCP annually @30-35yo testicular u/s if indicated annually @10yo

Answer 99

PVs are observed in 1/3 of all non-small cell lung cancers (STK is the 3rd most commonly mutated gene) appear to be frequent in male smokers of N European background and are associated w poorly differentiated tumors sporadic PVs in STK11 are observed in at least 20% of cervical cancers

Answer 100

most present in children and teenagers presenting features is usually a high total body nevi count (>50) w some having an atypical appearance resembling melanoma on the back, chest, buttocks, breasts, and scalps melanomas as early as the 2nd-3rd decade of life CDNK2A PVs (AD) have a 90% risk of developing melanoma by 80yo and 20% increased risk of developing pancreatic cancer by the age of 75yo RARELY associated w breast ca, esophageal ca, and sarcomas

Answer 101

60% dx criteria: high total body nevi count (>50), nevi w certain histologies (lentiginous pattern, nuclear atypia), melanomas in 1 or more first or second degree relative

Answer 102

screening for melanoma should begin at 10yo w total body skin eval w the use of dermoscopy clinical skin exams or self-exams should then be performed q6mos in families w a hx of pancreatic cancer or a CDNK2A PV, MRI/MRCP offered starting at 40yo

Answer 103

established in a proband w two or more major dx criteria: Spotty skin pigmentation with typical distribution (lips, conjunctiva and inner or outer canthi, vaginal and penile mucosa) Myxoma * (cutaneous and mucosal) Cardiac myxoma * Breast myxomatosis * or fat-suppressed MRI findings suggestive of this diagnosis Primary pigmented nodular adrenocortical disease (PPNAD) * or paradoxic positive response of urinary glucocorticosteroid excretion to dexamethasone administration during Liddle's test Acromegaly as a result of growth hormone (GH)-producing adenoma * Large cell calcifying Sertoli cell tumor (LCCSCT) * or characteristic calcification on testicular ultrasound Thyroid carcinoma * or multiple, hypoechoic nodules on thyroid ultrasound in a child younger than age 18 years Psammomatous melanotic schwannoma (PMS) * Blue nevus, epithelioid blue nevus * Breast ductal adenoma * Osteochondromyxoma * Family history of CNC consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations)

Answer 104

sequence analysis and del/dup of PRKAR1A

Answer 105

skin pigment abnormalities: pale brown to black lentigines that increase in # and appear anywhere; epithelioid-type blue nevi, combined nevi, cafe au lait macules, depigmented lesions cutaneous/mucosal myxomas: appear between birth and 40s; occur on any part of the body except the hands and feet, typically on the eyelids, external ear canal, and nipples cardiac myxomas: occur at a young age causing symptoms- intracardiac obstruction of blood flow, embolic phenomenon, heart failure, sudden death breast myxomas: bilateral, in females after puberty Primary pigmented nodular adrenocortical disease (PPNAD): overproduction of cortisol, most frequent observed endocrine tumor in the 2nd-3rd decade of life; results in Cushing syndrome w central obesity, moon facies, hirsutism, HTN, weakness, easy bruising, psychological disturbance Somatomammotrophy hyperplasia/GH-producing adenoma: clinically evident acromegaly is a relatively frequent manifestation Large cell calcifying Sertoli cell tumors (LCCSCT): in 1/3 of affected males within the first decade, almost always benign Thyroid tumors: multiple thyroid nodules; carcinomas, both papillary and follicular Psammomatous melanotic schwannoma (PMS): rare tumor of the nerve sheath, malignant degeneration in ~10%, frequently found in the nerves of the GI tract pancreatic tumors of varying histology benign breast ductal adenomas

Answer 106

most will have a normal life span complications of cardiac myxomas, metastatic or intracranial PMS, thyroid carcinoma, and metastatic pancreatic and testicular tumors

Answer 107

cardiac myxoma: sx excision before development of heart complications cutaneous/mammary myxoma: sx excision Cushing syndrome: bilateral adrenalectomy Pituitary adenoma: transsphenoidal sx thyroid adenoma: sx resection for cancerous adenomas LCCSCT: Orchiectomy for boys w aggressively growing tumors; for those whose tumors are not growing, tx w aromatase inhibitors Psammomatous melanotic schwannoma: sx to remove primary or metastatic lesions

Answer 108

cardiac myxomas: echo annually at childhood urinary free cortisol levels annually in adolescence for PPNAD serum IGF-1 annually in adolescence for pituitary tumors thyroid u/s annually beginning in adolescence testicular u/s annually in childhood to monitor for tumors

Answer 109

70% have an affected parent, 30% de novo

Answer 110

one major or two minor criteria are necessary for the dx major criteria 5 or more fibrofolliculomas/trichodiscomas with at least one confirmed histologically identification of a PV in FLCN minor criteria multiple lung cysts with or without spontaneous primary pneumothorax early onset renal cancer (<50yo) multifocal/bilateral renal cancer renal cancer of mixed chromophobe and oncocytic histology first degree relative with BHDS

Answer 111

sequence analysis then del dup of FLCN

Answer 112

cutaneous manifestations: multiple small skin-colored opaque whitish or yellowish dome shaped papules (fibrofolliculomas) between 2nd-4th decade in more than 80% of affected; increase in size, number, and distribution w age affecting the face, neck, and upper trunk; women have smaller and fewer lesions than men acrochordons (skin tags) typically on the neck, axillae, and larger skin folds; angiofibromas, oral papules, multiple epidermal cysts, cutaneous melanoma (multiple desmoplastic melanoma and choroidal melanoma) pulmonary cysts: lung cysts in more than 80% of adults; irregular shape and variable, does not exhibit signs of proliferation spontaneous recurrent pneumothorax: typically the first manifestation, overall prevalence of recurrence is ~20-35% renal cell carcinoma: tends to be bilateral and multifocal; prevalent in 19-35% of affected; most common tumor is a hybrid of oncocytoma and chromophobe but can also be clear cell carcinoma; can also have multiple nodules in the area surrounding tumors can also have: parotid tumors (Salivary glands), thyroid cancer/ goiter, colorectal polyps

Answer 113

fibrofolliculomas are benign and do not need tx other than for cosmetic purposes tx of pneumothorax is the same for the general pop; lung cysts are not tx and most show normal lung function crucial to detect renal tumors before they exceed 3.0cm bc sparing sx is the tx of choice whenever possible; if less than 3.0cm, they are monitored by periodic imaging watch for rapidly growing lesions and symptoms: pain, blood in urine, atypical presentations

Answer 114

derm exam q6-12mo for possible risk of melanoma Lung CT *only* for 1. those w suspected pneumothorax, 2. prior to scheduled flight/anesthesia abdominal/pelvic MRI annually starting @20yo consider thyroid u/s annually colonoscopy early (10yrs) if there is a FH of CRC

Answer 115

cigarette smoking (lung ca risk); high ambient pressures, which may precipitate spontaneous pneumothorax

Answer 116

based on clinical findings and/or identification of biallelic PVs in DDB2, ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, POLH, XPA, or XPC order multigene panel

Answer 117

ERCC2 (15%); POLH (23.5%); XPA (30%); XPC (27%)

Answer 118

Cutaneous findings: more than 1/2 have a hx of acute sunburn rxn on minimal UV exposure, numerous freckle-like hyperpigmented macules appear on sun-exposed skin, starts between 1-2yo, limited to sun-exposed areas, poikiloderma (constellation of hyper and hypopigmentation, atrophy, and telangiectasia), premalignant actinic keratoses, accelerated photoaging ocular abnormalities: first decade of life, findings are usually limited to the anterior, UV exposed portions of the eyes (conjunctiva, cornea, lids); dry eyes, epithelioma, SCC, melanoma are common, may be more severe in heavily pigmented individuals, benign conjunctival inflammatory masses obscure the cornea, photophobia, severe keratitis, corneal opacification, neovascularization, atrophy of the skin of the lids (can result in complete loss of the lids), lentigines, freckling on the lids, and lash loss are also common neurologic findings (30%): progressive neurologic abnormalities that worsen slowly; may be early in infancy or delayed until second decade of life; may be mild (isolated hyporeflexia) or severe (acquired microcephaly, progressive ID, SNHL, spasticity, ataxia, seizures), reduced nerve conduction velocity cutaneous neoplasms: usually in the first decade of life due to sun-induced DNA damage (50% w skin ca by 10yo); BCC >10,000 Fold risk, age of onset ~9yo; cutaneous melanoma median age of onset ~22yo other: oral cavity neoplasms (SCC of the tip of the tongue), lung cancer in those who smoke (since DNA repair system is damaged in this condition), 34-fold increase in internal neoplasms; women at risk for early menopause, may require ART for pregnancy (usually have PVs in XPC); risk for thyroid nodules/carcinoma

Answer 119

median age of death is ~29yo w neurodegeneration and ~37 w/out neurodegeneration cause of death is usually: skin cancer, neurologic deterioration, and internal cancer

Answer 120

premalignant lesions: freeze w liquid nitrogen larger area of skin damage: topical 5-FU recurrent skin cancers: best tx w Mohs sx active development of large numbers of new tumors: oral isotretinoin to prevent new neoplasms metastatic melanoma and invasive SCC: systematic chemo hematologic malignancies: standard chemo, BMT not successful internal manifestations: standard therapy, small dose X-ray if absolutely necessary thyroid nodules: bx of suspicious nodules, thyroidectomy if cancer identified neoplasms of eyelids, conjunctiva, and cornea: sx tx, topical 5-FU severe keratitis: corneal transplantation hearing loss: use of hearing aids, cochlear implants premature menopause: hormone replacement therapy

Answer 121

tx depends on early dx and IMMEDIATE aggressive avoidance of sun and other UV exposure clinical suspicion should prompt immediate sun-protective measures bc the cells of individuals with XP are hypersensitive to UVA, UVB, and UVC, it is useful to measure UV light in an individual's surroundings w a light meter so that high levels of environment UV can be identified and eliminated if possible serum vitamin D levels should be monitored and dietary supplementation w oral vitamin D is recommended for ppl w low serum concentration of vitamin D

Answer 122

skin: exam q3-12mo; caregivers should look for suspicious lesions on skin q1wk eyes: exam for damage assessment q6mo neurologic: exam q12mo for symptomatic pts hearing: audiograms q6-12mo female reproduction: lab assessment for POI q12mo starting @18

Answer 123

isotretinoin and acitretin are used as skin ca chemo agents in those who are actively developing large numbers of skin ca; KNOWN TO BE TERATOGENIC may take a long time to be eliminated from the body (3yrs)

Answer 124

proband w: 2 or > endocrine tumors including parathyroid, anterior pituitary, and well-differentiated neuroendocrine tumors of the GEP tract OR one of the three endocrine tumors above AND a first degree relative w MEN1

Answer 125

Primary hyperparathyroidism: often mild, most common associated endocrinopathy and first clinical feature in 90% between 20-25yo; all w hypercalcemia by 50%, may manifest as rickets and osteomalacia in pediatric pop; pathology: multiglandular parathyroid dx w enlargement of all the parathyroid glands, rather than a single adenoma is typical; parathyroid carcinoma is RARE Anterior pituitary adenomas: first clinical manifestation in 25% of simplex cases and 10% of familial; occurs significantly more in women than men; symptoms depend on the pituitary hormone produced: PRL-secreting adenoma: amenorrhea and galactorrhea (reduction of libido or impotence) ACTH-secreting adenoma: hypercortisolism (Cushing dz) GH-secreting adenoma: giantism in children, acromegaly in adults FSH-secreting adenoma: reduced libido, erectile dysfunction

Answer 126

65-85% of pituitary adenomas are macroadenomas; significantly larger and more often invasive than sporadic pituitary tumors malignant degeneration of MEN1-associated pituitary tumors is infrequent

Answer 127

~40% have gastrinomas; > 90% occur in the duodenum; typically, multiple small gastrinomas are observed in the submucosa with diffuse hyperplastic changes of gastrin cells and multifocal microgastrinomas which are characteristic of MEN1; 70-85% are metastatic to regional lymph nodes at the time of dx; 15% show aggressive tumor growth (pancreatic ones are more aggressive than duodenal ones) Insulinoma: tumors responsible for hyperinsulinism are usually 1-4cm in diameter; single tumor in the setting of multiple islet macroadenoma, almost always benign glucagonoma: can be associated with other tumors, but are very rare; ~80% are malignant and metastasize to the liver

Answer 128

Carcinoid: thymic, bronchial, type II gastric enterochromaffin-like carcinoids in 3-10%; only tumors to exhibit male to female ratios; thymic carcinoids in females to males of 20:1 and bronchial in females to males of 1:4; tend to be multifocal and may occur synchronously or over time; thymic carcinoids are aggressive and highly lethal, most bronchial carcinoids are not aggressive; significantly increased risk of death in those with thymic carcinoids Adrenocortical tumors: involve one or both glands, usually found incidentally on CT; most are nonfunctioning but 10% demonstrating hormonal secretion leading to Cushing dz exists; rarely results in malignancy, 1% will have adrenocortical carcinoma Non-endocrine tumors: facial angiofibromas (85%), collagenomas (70%), lipomas (30%), cafe au lait macules, leiomyomas, adenomas of the thyroid, goiters, thyroid carcinomas in 25%

Answer 129

significantly increased risk for premature death malignancies account for ~30% of deaths in individuals

Answer 130

1 hyperparathyroidism: parathyroidectomy is the tx of choice; subtotal parathyroidectomy suggested as the initial tx; total parathyroidectomy w auto-transplantation may also be reserved for those w extensive dz either at first or at repeat sx; those who are asymptomatic can delay sx and have regular assessment for symptom onset Anterior pituitary adenomas: PRL-secreting adenoma: dopamine agonists, transsphenoidal sx and radiotherapy reserved for drug resistant tumors GH-secreting adenoma: transsphenoidal sx for those causing acromegaly, effective in 50-70% of cases; somatostatin analogs ACTH-secreting adenoma: excision of the adenoma, radiotherapy to reduce the production of ACTH non-functioning adenoma: sx using a transsphenoidal approach Well-Differentiated Endocrine Tumors of the GEP Tract: gastrinoma: proton pump inhibitors or H2 receptor blockers to reduce gastric acid output; tumors are usually microscopic and scattered throughout the neuroendocrine tissue, successful sx outcome rare; long term symptom free f/u after excision of a lymph node gastrinoma is the only reliable criterion for the dx of a primary lymph node tumor pancreatic tumors: sx usually indicated for insulinoma and most others; unresectable tumors or advanced metastatic ca can be treated w somatostatin analogs, chemo, inhibitors of tyrosine kinase, or inhibitors of mammalian target of rapamycin Carcinoid tumors: long-acting somatostatin analogs can control the secretory hyperfunction associated w carcinoids; risk for malignant progression of the tumor remains unchanged; tx is sx removal if possible Adrenocortical tumors: sx is suggested for adrenal tumors >4cm pheochromocytoma occurs rarely in MEN1, appropriate to measure urinary catecholamines prior to sx to dx and tx a pheochromocytoma and thus avoid dangerous and potentially lethal BP peaks during sx

Answer 131

parathyroid tumors: measure calcium and PTH annually @5yo anterior pituitary adenomas: serum concentration of prolactin, IGF-1, fasting glucose and insulin annually @5yo; Head MRI q3-5yrs @5yo well-differentiated endocrine tumors of the GEP tract: measurements for pancreatic neuroendocrine tumors annually @8yo; fasting serum gastrin concentration annually @20yo; consider abdominal CT, MRI, EUS q3-5yrs @20yo carcinoid tumors: consider chest MRI, CT, SRS octreotide scan annually @15yo non-endocrine tumors: skin exam consider annually as needed

Answer 132

parathyroid tumors: measure calcium and PTH annually @10yo anterior pituitary adenomas: serum concentration of prolactin annually @5yo well-differentiated endocrine tumors of the GEP tract: fasting serum gastrin concentration annually @20yo; EUS annually @20yo

Answer 133

~90% have an affected parent, 10% de novo

Answer 134

tissue-specific roles in DNA replication and repair; suspected to repress tumorigenesis biallelic inactivation of MEN1, by a germline heterozygous loss of function variant and an acquired somatic loss of function variant coding region of MEN1 includes exons 2-10; no PVs have been found in exon 1, and this exon is usually excluded from genetic testing

Answer 135

MEN2A: occurrence of two or more specific endocrine tumors (MTC, pheochromocytoma, parathyroid adenoma/hyperplasia) in a single individual or in close relatives FMTC: families with two or more individuals with MTC in the absence of pheochromocytoma or parathyroid adenoma/hyperplasia MEN2B: presence of early-onset MTC, mucosal neuromas of the lips and tongue, as well as medullated corneal nerve fibers, distinctive facies w enlarged lips, marfanoid body habitus

Answer 136

single gene testing (sequence and del/dup (although no del/dups have been reported) can also do select exon testing for those with suspected MEN2A/FMTC bc majority of PVs occur in exons 10,11, and 13-16 targeted analysis for RET PVs p.Met918Thr and p.Ala883Phe can be considered in those with suspected MEN2B

Answer 137

MTC typically presents at a young age and is often associated w C-cell hyperplasia (CCH) as well as multifocality or bilaterality; includes neck mass or pain prior to 35yo; plasma calcitonin concentration high and diarrhea implies poor prognosis; 70% w palpable mass have cervical lymph node metastases; 20-30% w MTC have germline RET PVs; MTC and CCH are suspected in the presence of an elevated plasma calcitonin; all individuals w an MTC-predisposing RET variant who have not undergone prophylactic thyroidectomy demonstrate biochemical evidence of MTC by 35yo; 50% w MTC who have undergone total thyroidectomy and neck nodal dissections have recurrent dz; MTC originates in calcitonin-producing cells of the thyroid gland Pheochromocytomas are often bilateral, rarely metastasize, but can be lethal bc of intractable HTN or anesthesia-induced hypertensive crises; nearly always adrenal; suspected when biochemical screening reveals elevated excretion of catecholamines and catecholamine metabolites in plasma/urine, consistently producing epinephrine or epi AND norepinephrine Parathyroid abnormalities can range from benign adenomas to clinically evident hyperparathyroidism w hypercalcemia and kidney stones; elevated serum calcium occurs simultaneously w elevated or high-normal parathyroid hormone

Answer 138

MEN2A: 70-80% of individuals w MEN2; MTC is generally the first manifestation; pheochromocytomas (dx at earlier age, subtler symptoms, bilateral) usually present after or concomitantly; hyperparathyroidism is typically mild and may be due to a single adenoma or hyperplasia (most have no symptoms); small number of families have cutaneous lichen amyloidosis FMTC: 10-20%; MTC is the only clinical manifestation of FMTC; is a variant of MEN2A w decreased penetrance of pheochromocytoma and HPT MEN2B: 5%; early development of an aggressive form of MTC in all affected individuals; those who do not undergo thyroidectomy before age 1yr are likely to develop metastatic MTC at an early age; pheochromocytomas in 50%, 1/2 are multiple and often bilateral, may die from a cardiovascular hypertensive crisis perioperatively; NOT associated with an increased risk for clinically significant parathyroid dz; distinctive facies: presence of mucosal neuromas on the tongue, palate, or pharynx; lips become prominent over time, neuromas of the eyelids, thickened corneal nerves; 40% have diffuse ganglioneuromatosis of the GI tract (abdominal distention, megacolon, constipation, diarrhea); 75% have a marfanoid habitus (w kyphosis/lordosis, joint laxity, decreased subcutaneous fat)

Answer 139

prophylactic thyroidectomy is the primary preventive measure for those w a germline PV in RET; age at which sx is performed is based on the codon position: Highest risk (MEN2B, p.Met918Thr): as soon as possible in 1st yr of life High risk: less than 5yo Moderate risk: lesser gain of function variants: may delay after 5yo if criteria are met (normal calcitonin, annual neck u/s, FH of less aggressive MTC)

Answer 140

prior to any sx to avoid intraoperative catecholamine crisis: If PCC is detected, adrenalectomy before thyroidectomy to avoid intraoperative catecholamine crisis MTC: sx removal of thyroid and lymph node dissection; parathyroidectomy is not typically performed at time of thyroidectomy unless their is evidence of HPT; consider RET-selective inhibitors in those w metastatic dz Hypothyroidism following thyroidectomy: HRT PCC: tx of HTN prior to adrenalectomy often w alpha and beta adrenergic receptor blockade; resection by adrenalectomy parathyroid adenoma/hyperplasia: for those dx w HPT at time of thyroidectomy, resection of visibly enlarged parathyroid glands, subtotal parathyroidectomy, total parathyroidectomy

Answer 141

MEN2A: at risk children by age 5; finding of MTC in the thyroid of a 12mo suggests even earlier if possible FMTC: Same for MEN2A MEN2B: as soon as possible after birth If PV is not known: neck u/s and calcitonin levels for MTC; Annual albumin calcium for HPT; Annual plasma free metanephrines for pheos

Answer 142

MEN2A: 5% FMTC: None MEN2B: 50% (majority are paternal in origin)

Answer 143

GAIN of function

Answer 144

elevated metanephrine or precursor epi (adrenaline) elevated normetanephrine or precursor norepinephrine (noradrenaline) elevated dopamine and its major metabolite 3-methyoxytyramine

Answer 145

proband w a personal or FH of paraganglioma or pheochromocytoma and a germline heterozygous PV

Answer 146

multigene panel including MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD, and TMEM127 Single gene testing not often used but can be pursued based on the following: SDHB in an individual w metastatic pheo or paraganglioma SDHD in individuals w head and neck paragangliomas (account for 40-50% of HNPGLs)

Answer 147

may suggest an underlying PV any component of the mito respiratory chain complex 2 is inactivated, the entire complex becomes unstable resulting in degradation of SDHB subunit. Therefore, negative staining appears to occur when a germline PV in SDHA, SDHB, SDHC, or SDHD is accompanied by inactivation of the normal allele

Answer 148

paragangliomas head and neck paragangliomas: associated w the parasympathetic NS and do not secrete catecholamines or other hormones; most do not metastasize paragangliomas in the LOWER mediastinum, abdomen, and pelvis: associated w the sympathetic NS and usually secrete catecholamines, higher risk of metastasizing pheos are catecholamine secreting paragangliomas confined to the adrenal medulla; metastatic dz is less likely majority of GISTs are associated w SDHA/SDHC; most occur in the stomach and are multifocal pulmonary chondromas for those with PVs in SDHx genes Clear cell RCC in those with PVs in SDHB/SDHD

Answer 149

arise within the paraganglia- collections of neural crest cells distributed along the paravertebral axis from the base of the skull to the pelvis adrenal paragangliomas= pheos

Answer 150

CT MRI is a better option for those whom radiation exposure must be limited

Answer 151

bone, lung, liver, lymph nodes

Answer 152

MAX: pheos SDHA: Pheos and paragangliomas SDHFA2: HNPGLs SDHB: higher morbidity/mortality, strongly associated w extra-adrenal sympathetic paragangliomas, increased risk of metastatic dz; less frequently pheos and parasympathetic paragangliomas SDHC: HNPGLs SDHD: HNPGLs, 75% w multifocal primary paragangliomas TMEM127: pheos, HNPGLs, extra adrenal paragangliomas, CCRCC

Answer 153

SDHA: 50% by 70yo SDHB: 25-55% by 60yo

Answer 154

SDHA/SDHC/SDHD (start at 6-15yo): clinical assessment for manifestations of tumors (annually); metanephrines for secreting PGLs/PCC (q2yrs in childhood, annually in adults); whole body MRI (q2-3yrs); EGD for those w unexplained anemia and GI symptoms (as needed) SDHB (start at 6-10yo): clinical assessment for manifestations of tumors (annually); metanephrines for secreting PGLs/PCC (q2yrs in childhood, annually in adults); whole body MRI (q2-3yrs); EGD for those w unexplained anemia and GI symptoms (as needed) MAX/SDHAF2/TMEM127 (start at 6-8yo): clinical assessment for manifestations of tumors (annually); metanephrines for secreting PGLs/PCC (q2yrs in childhood, annually in adults); whole body MRI (q2-3yrs); EGD for those w unexplained anemia and GI symptoms (as needed)

Answer 155

PATERNAL EFFECT SDHD, SDHAF2, possibly MAX

Answer 156

tumor suppressor genes; somatic second-hit variants in tumors include chromosomal rearrangements, recombination, SNVs, epigenetic changes that result in allelic inactivation SDHA/SDHC/SDHD have pseudogenes

Answer 157

DUTCH positive FH: 1 VHL related tumor AND a 1st or 2nd degree relative w dx of VHL; negative FH: More than or equal to 2 VHL related manifestations clinical criteria include: retinal HB, CNS HB, RCC, Pheo, PNET, ELST *paraganglioma, multiple kidney cysts, multiple pancreatic cysts are specific to this criteria* DANISH positive FH: 1 VHL related tumor AND a 1st degree relative w dx of VHL; negative FH: More than or equal to 2 HBs OR 1 HB and 1 VHL related manifestation clinical criteria: see above

Answer 158

Hemangioblastomas: CNS hemangioblastoma is the prototypic lesion of VHL, 80% will develop in the brain, 20% in the spinal cord; increased growth was associated w male sex, symptomatic tumors, hemangioblastoma-associated cysts and germline dels remain the main cause of death brain hemangioblastomas: pituitary stalk is most common site, clinical symptoms depend on the site of the tumor; spinal: present w pain, sensory and motor loss may develop w cord compression; retinal: may be the initial manifestation and may occur in childhood in 70%, mean age of detection ~25yo, probability of these associated w vision loss increases w age renal lesions: multiple, bilateral renal cysts are common; renal cell carcinoma (clear cell), 70% of individuals affected by 60yo, leading cause of mortality (PVs in VHL are the most common cause of RCC) pheos: more likely to be identified incidentally, at a younger age; can be unilateral or bilateral and are often small and multifocal paragangliomas: often nonfunctional (non-secreting) pancreatic lesions: most are simple cysts and have no malignant potential; 6-17% have neuroendocrine tumors of the pancreas but are not typically hormonally active endolymphatic sac tumors: 10-16% of individuals, some instances unilateral or bilateral heating loss is the initial clinical manifestation, typically sudden and often severe to profound; rarely malignant epididymal and broad ligament cystadenomas: relatively common in males, if bilateral can cause infertility

Answer 159

Sequence analysis of VHL coding region, intron 1, flanking sequences, and del/dup

Answer 160

type 1: retinal angioma, CNS hemangioblastoma, RCC, pancreatic cysts, and neuroendocrine tumors; low risk for pheos type 1B: complete or partial del that extends 5' of VHL to include BRK1 have a significantly reduced risk of RCC and pheos Type 2: pheos, retinal hemangioblastomas, CNS hemangioblastoma, high risk for pheos 2A: pheos, retinal hemangioblastomas, CNS hemangioblastoma; low risk for renal cell carcinoma 2B: pheos, retinal hemangioblastomas, CNS hemangioblastoma, pancreatic cysts, neuroendocrine tumors; high risk for RCC 2C: risk for pheos only

Answer 161

Pazopanib for advanced RCC Belzutifan for those with VHL and CCRCC, alters the biology of cells lacking the VHL protein most hemangioblastomas can be sx removed safely preoperative arterial embolization for expansive spinal hemangioblastomas, sx intervention for cysts in the spinal cord is recommended retinal hemangioblastomas are followed closely to avoid blindless, although spontaneous regression has occurred RCC should be tx w cryoablation and radiofrequency ablation instead of sx resection for small RCCs; kidney transplantation has been successful gor those that require bilateral nephrectomy pheos should be sx removed, active surveillance for pheos smaller than 2cm can be safe pancreatic neuroendocrine tumors should be sx removed if there is a high risk of metastases consider sx removal of slow growing endolymphatic sac tumors with consideration for total deafness; early intervention associated w preservation of hearing and vestibular function

Answer 162

Clinical exam annually brain and total spine MRI q2yrs @11 ophthalmology exam annually @1yr MRI of abdomen q2yrs @15 BP annually, plasma/urine metanephrines annually @5 audiology exam q2-3yrs @11yo, MRI of internal auditory canals in asymptomatic ppl 15-20yo

Answer 163

proband with retinoblastoma or retinoma and a FH of retinoblastoma MAJORITY do not have a FH of the disorder, and therefore need a heterozygous PV in RB1

Answer 164

FH: sequence analysis and del dup of RB1 no FH: same as above on blood; if tumor tissue is available, perform sequence and del dup on that sample; if PVs are identified, test DNA from blood, if no PVs are identified, methylation analysis of RB1 promoter; no hypermethylation, then DNA from tumor is tested for amplification of MYCN CMA for individuals w retinoblastoma w DD or other congenital anomalies

Answer 165

leukocorcia (white pupillary reflex), strabismus, dx before 5yo 60% have unilateral w an avg dx at 24mo, tumor is usually unifocal, in most persons without a FH, the tumor is large and it is not possible to determine if a single tumor is present 40% have bilateral w a mean age of dx of 15mo; both eyes may show multiple tumors (trilateral if bilateral retinoblastoma and a pinealoblastoma develop can also have benign retinal tumors (retinoma) pinealoblastomas: occur in the "retina-like" tissue in the pineal gland of the brain; rare and usually fatal other tumors: most common secondary neoplasms include osteosarcoma, soft tissue sarcoma, or melanoma; tumors usually in adulthood or adolescence

Answer 166

Neg FH and unilateral retinoblastoma (60%) Neg FH and bilateral retinoblastoma (30%) + FH and unilateral or bilateral retinoblastoma (~10%) chrom dels involving 13q14, often associated w DD and birth defects

Answer 167

goals are to preserve life then sight options include: enucleation, cryotherapy, laser, chemo, radiation, last resort should be external beam radiotherapy (if possible, it is avoided) included in care: ophthalmology, pediatric oncology, pathology, and radiation oncology

Answer 168

RB1 germline PV: eye exam under anesthesia, then without once they can be cooperative persons w/o a germline PV but with unilateral retinoblastoma: clinical eye exam, eye u/s persons w retinoma: retinal exams, photographic imaging to detect any change early

Answer 169

+FH, bilateral retinoblastoma= 50% -FH, bilateral retinoblastoma=2% -FH, unilateral, multifocal retinoblastoma= 1-2% -FH, unilateral and unifocal retinoblastoma= ~1%

Answer 170

If RB1+, u/s exam may be used to identify medium-sized intraocular tumors; delivery of the fetus ~36wks GA may be recommended as 30% will have tiny vision-threatening tumors if no RB1 PV has been found, can do fetal MRI but are not sensitive enough to identify small retinoblastoma tumors

Answer 171

PV in FH, sequence then del/dup CMA to detect large del/dups

Answer 172

cutaneous leiomyomas: firms skin colored papules and nodules at ~30yo, tend to increase in size and # w age; painful or sensitive to light touch and/or cold temperatures uterine leiomyomas (fibroids): have more fibroids and onset at a younger age than women in general pop; usually large and numerous and associated with irregular menses, menorrhagia, or pain; often undergo hysterectomy or myomectomy renal cancer: typically unilateral and solitary, symptoms may include lower back pain, hematuria, palpable mass although many are asymptomatic; typically type 2 papillary can have pheos and paraganglioma

Answer 173

cutaneous lesions: sx excision is considered standard; have a high rate of recurrence and meds can be used for pain relief uterine fibroids: require medical and/or sx intervention earlier, sx options include myomectomy and hysterectomy renal tumors: sx excision of renal malignancies appears to require earlier and possibly more extensive sx; due to metastatic potential, lymph node detection may be considered

Answer 174

cutaneous leiomyoma: full skin exam annually after first dx uterine leiomyoma: gynecologic consult annually @20yo or at first exam in symptomatic ppl renal tumors: MRI w contrast is preferred but can do CT annually @8yo no guidelines for pheos/paragangliomas

Answer 175

2 major findings OR 1 major and 2 minor findings MAJOR > or = 3 angiofibromas or fibrous cephalic plaques cardiac rhabdomyoma multiple cortical tuber and/or radial migration lines lymphangioleiomyomatosis (LAM)* multiple retinal nodular hamartomas > or = 2 renal angiomyolipomas* shagreen patch subependymal giant cell astrocytoma (SEGAs) > or = 2 subependymal nodules > or = 2 ungual fibromas *these two together are not dx* MINOR sclerotic bone lesions confetti skin lesions > or = 3 dental enamel pits > or = 2 intraoral fibromas multiple renal cysts nonrenal hamartomas retinal achromic patch

Answer 176

CNS tumors; angiofibromas

Answer 177

80% w seizures, KNOWN CAUSE OF INFANTILE SPASMS ~50% have ID/DD and leading cause of death is complication of severe ID Renal dz is the second leading cause of death; benign angiomyolipomas: life-threatening bleeding, ESRD; renal cysts: PKD, ESRD; Malignant angiomyolipomas and RCC: 2-5% incidence, avg age of dx 28-30yo, immunologic staining for HMB-45 for angiomyolipomas and cytokeratin for RCC recommended individuals w TSC associated LAM may present w shortness of breath or hemoptysis, some progress to death

Answer 178

TAND Behavioral, psychiatric, intellectual, academic, neuropsychological, and psychosocial difficulties all pts should be evaluated since these disorders can contribute significantly poorer outcomes

Answer 179

TSC2 produces a more severe phenotype, @ greater risk for: renal malignancy, ID, ASD, decreased IQ, infantile spasms infants w cardiac rhabdomyomas have a 75-80% chance of being affected w TSC

Answer 180

CNS: brain MRI q1-3yrs in asymptomatic individuals <25yo to monitor for new SEGA occurrence; routine EEG in asymptomatic individuals q6wks until 12mo then q3mo up to 24mo; annual TAND exam Renal: MRI of abdomen q1-3yrs to assess for progression of angiomyolipomas and renal cystic dz Pulmonary: screening for LAM for women >18yo or those w respiratory symptoms, high resolution CT of the lungs q5-7yrs through menopause Derm: annual skin exam Dental: exam @ least q6mo Ophthalmology: annual exam

Answer 181

mTOR inhibitors for SEGAs (might still need neurosx) Vigabatrin for infantile spasms. Possible mTOR inhibitor use for intractable seizures mTOR inhibitors for growing renal angiomyolipoma (nephrectomy avoided due to increased incidence of complications and increased risk for future renal insufficiency and ESRF, and poor prognosis that results from chronic kidney dz estrogen use is contraindicated due to possible involvement of proliferation of LAM cells, causing it to get worse

Answer 182

2/3 de novo rate TSC1 + TSC2 encode hamartin and tuberin respectively, which work together to regulate cell growth. Regulators of the mTOR/AKT pathway causes an abnormal gene product

Answer 183

Bethesda Amsterdam II criteria: 1+ lynch related cancer dx under 50; 2 successive generations affected, 3+ FH w lynch related cas (2 one must be a FDR or the other two)