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Last updated 9:52 PM on 8/5/26
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47 Terms

1
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Familial adenomatous polyposis (FAP)

Gene: APC

  • Adenomatous Colon Polyps

    • 100s-1000s (“carpeting”)

    • Onset 10-15yo

Inheritance

  • Autosomal Dominant

    • Inherited 70%

    • De Novo 30%

Clinical Features

  • GI

    • Adenomatous colon polyps: Colon + Duodenum

    • Onset ***10-15yo****

  • Stomach

    • Fundic gland polyps

Extra Intestinal Features

  • Eye

    • Congenital Hypertrophy of the Retinal Pigment Epithelium (CHRPE)

  • Bone

    • Osteomas: skull, mandible, long bones

    • Dental abnormities (extra/missing teeth)

  • Desmoid tumors

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FAP: Cancer Risk + Management

Cancer Risk

  • Colorectal: 100%

  • Duodenal 4-12%

  • PAPILLARY thyroid

  • Pancreatic

  • Hepatoblastoma

  • Medulloblastoma (Turcot syndrome)

Management

  • Colon

    • Colonoscopy

    • start 10-12 yo

    • every 1-2 years

  • Upper GI

    • Upper endoscopy

    • start 20-25 yo

  • Thyroid

    • Thyroid ultrasound

    • Annual

    • start Teens-early adulthood

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Attenuated FAP

Gene: APC

  • Variants near the 5′ end, 3′ end, or portions of exon 9 are more often associated with attenuated FAP

  • REDUCED PENETRANCE

  • REDUCED SEVERITY

Clinical Features

  • 20–100 adenomas (later onset)

  • CRC develops later (often 50s–60s)

  • Right-sided colon predominance is common

Management

  • Colonoscopy: begin in late teens -20s

  • Upper GI endo.: yes

  • Thyroid surveillance: Yes

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MUTYH -Polyposis

Gene: MUTYH

  • 10-100 Adenomatous colon polyps (like aFAP)

  • ****SERRATED adenomas***

Inheritance

  • Autosomal RECESSIVE

  • ***SINGLE MUTYH carriers: no MAP or polypsis, small increas in CRC risk***

Clinical Features

  • Colon polyps

    • Colorectal

    • Duodenal

Cancer Risk

  • CRC 70-90%

  • Duodenum (not as high as FAP)

  • Ovarian

  • Bladder

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MUTYH -Polyposis: Management

  • Colon

    • Colonoscopy

    • Start 25-30yo

    • every 1-2 years

  • Upper GI

    • Upper endoscopy

    • Start 30-35yo

6
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Juvenile Polyposis Syndrome

Gene: SMAD4, BMPR1A

  • HAMARTOMATOUS ( colon polpys (highly variable number

  • Clinical criteria: AT LEAST 5 juv. polyps in colon

  • juvenile = subtype of hamartomatouss

Inheritance

  • Autosomal Dominant

    • De Novo 50%

    • Inherited 50%

Clinical Features

  • Colon

    • Harmartomaus (juvenile type) polyps

    • Onset 10-20yo

    • RECTAL BLEEDING

  • *****SMAD4 Variant****

    • Hereditary Hemorgric Telangiectasia (AVMs, telangiectasias, epitaxis)

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Juvenile Polyposis Syndrome: Managment

Surveillance

  • Colon

    • Colonoscopy

    • Start 12-15 yo

    • Every 1-3 years

  • Upper Gi

    • Upper endoscoypu

    • Start 12-15 yo

    • every 1-3

  • SMAD4 variant

    • More upper GI surveillance

    • HHT screening (full body imaging looking for AVMs)

8
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Peutz-Jegher Syndrome

Gene: STK11

  • HAMARTOMATOUS ( colon polpys (highly variable number

  • Peutz-Jeghers polyp = sub type of hamartomatous p

Inheritance

  • Autosomal Dominant

    • De Novo 50%

    • Inherited 50%

Clinical Features

GI

  • DOZENS Hamartomatous polyps (peutz-jeghers subtype)

    • Onset 10-20

    • Throughout GI tract (but small intestine especially)

  • *****INTUSSUSCEPTION**** (Hallmark) GI tract folds in on itself

Skin

  • ****Mucocutaneous Pigmentation **** (dark blue-brown macules) HALLMARK

    • Mouth

    • Face

    • Fingers/Toes

Other

  • ****MALES: Gynomastia****

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Peutz-Jegher Syndrome: Cancer Risk

Cancer Risk

GI

  • Colorectal:35-30%

  • Gastric 25-30%

  • Small Bowel 30-35%

  • ****PANCREATIC 30-35%****

GYN/Gonads

  • Breast: 45-55%

  • Ovary (Sex cord tumor)

  • MALES: Large-cell Calcifying Sertoli cell tumor → cause GYNOMASTIA

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Peutz-Jegher Syndrome: Managment

Surveillance

GI

  • Full colon, stomach small bowel:

    • Colonoscopy

    • Upper endoscopy

    • Small bowel evaluation (capsule endoscopy or MR enterography)

  • Start 8yo

    • polyp present: every 1-3 years

    • No polyp present: resume at 18yo (2-3yrs)

Pancreas

  • MRI or Endoscopic Ultrasound

  • Start 30-35yo

  • Annual

Breast

  • Clinical Breast exam: at 25yo, ever 6-12months

  • Annual Breast MRI: start 25yo

  • Annual mammography: start 30yo

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Lynch syndrome: Overview

Gene: MLH1, MSH2, MSH6, PMS2, EPCAM

  • Adenomous Polyps: Less than 10 (Right Sided)

Inheritance

  • Autosomal Dominant

Clinical Features

Colon

  • Adenotmous Polyps: 10 or fewer

Cancer Risk

GI

  • Colorectal (right sided):

    • MLH1, MSH2: 40-80%

    • Lower for MSH6, PMS2, EPCAM

  • Stomach

  • Small bowel

  • Pancreas

GYN/

  • ***Endometrial*** (can occur BEFORE CRC)

    • MSH6: 40-60% (highest)

  • Ovarian: 10-20%

  • Prostate

OTHER

  • Brain: Glioblastoma (Turcot)

  • Skin: Sebaceous adenomas (Muir-Torre)

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Lynch syndrome: Managment

Surveillance

Colon

  • Colonsocpy

    • MLH1/MSH2/EPCAM: start 20-25yo

    • MSH6/PMS2: Start 30-35yo

  • Repeat 1-2 years

Gastric

  • Upper endoscopy

    • especially MLH1/MSH2

  • Start 30-40yo

  • Every 2-4 years

Endometrial

  • Endometrial Biopsy

  • CONSIDERED starting at 30-35yo

    • especially MLH1, MSH2, MSH6

  • every 1-2 years

Ovarian

  • Risk Reducing Surgery

    • Total hysterectomy

    • Bilateral Salpingo-oophorectomy (BSO)

  • After childbearing (post menopause)

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Lynch syndrome: Suggestive Pathology

Immunohistochemistry of tumor

  • MLH1 and PMS2 missing → MLH1 germline

    • MODIFER: check MLH1 hypermethylation

    • MODIFER: if BRAF also missing cancer is SPORDAIC

    • Only PMS2 missing → PMS2 germline

  • MSH2 and MSH6 missing → MSH2 germline

    • Only MSH6 missing → MSH6 germline

Satellite Instability

  • High microsatellite instability → defective DNA mismatch repair

Amsterdam II Criteria

  • More than 1 Lynch syndrome cancer dx under 50yo

  • 2 Successive generations affected

  • More than 3 family members affected with lynch-related cancers

    • 1 member must be first degree with the other two

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Lynch syndrome: Murie-Torre

Muire-Torre Syndrome

  • Lynch syndrome +

    • Sebaceous adenomas

    • Keratoacanthomas

  • Usually MSH2

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Lynch syndrome: Constitutional Mismatch Repair Deficiency (CMMRD)

Gene: MLH1, MSH2, MSH6, PMS2, EPCAM

  • Childhood cancer predisposition syndrome

Inheritance

  • Autosomal Recessive

Clinical Features

Skin

  • ****Cafe-au-Lait Macules**** (like NF1) HALLMARK

GI

  • Multiple adenomas - Childhood:

  • ***Polyposis can be extensive****

Childhood Cancer (100% before 18yo)

  • Brain

    • Glioblastomas

  • Hematologic

    • Leukemia

    • Lymophoma

  • “Typical” Lynch syndrome Cancers

    • Endometrial cancer

    • Ovarian cancer

    • Gastric cancer

    • Urinary tract cancers

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Constitutional Mismatch Repair Deficiency (CMMRD): Managment

Surveillance

Colon

  • Colonoscopy

  • Start at 6yo

  • repeat 6-12months

Upper GI

  • Upper endoscopy

  • Start 8-10yo

  • Annual

Brain

  • Brain MRI

  • Start infancy or early childhood

  • repeat 6-12 months

Complete Blood Count (CBC)

  • Every 6 months

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Tip for Fam Hx of colon Cancer

  • Asses age of diagnosis

    • If much later than 35yo, less likely to be FAP

  • If nobody else affected → think MUTYH (AR)

  • If no polyps found → rule out polyposis syndromes

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. Hereditary breast and ovarian cancer syndrome: BRCA2 type

Gene: BRCA2

  • Breast , less ovarian than BRCA1 + Prostate, PANCREATIC, male breast, melanoma

Inheritance

  • Autosomal Dominant

  • Biallelic = Fanconi Anemia

Clinical Features

  • Breast Cancer: 83% risk

    • ***ER + PR positive / HER 2 Negative***

    • Onset 40-50s yo

  • Ovarian Cancer: 27%

    • High-grade serous carcinoma

    • later onset than BRCA1

Other Cancers (much higher than BRCA1)

  • ****Male Breast Cancer: 9%****

  • ****Pancreatic: 7%*****

  • Melanoma

  • Prostate: 20%

19
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Hereditary breast and ovarian cancer syndrome: BRCA1 type

Gene: BRCA1

  • Breast and Ovarian Cancer: early onset, triple-negative, aggressive

Inheritance

  • Autosomal Dominant

Clinical Features

  • Breast Cancer: 87% lifetime risk (2nd primary 83%)

    • Triple Negative (ER/PR/HER2 negative)

    • Onset 30-40s yo

    • Bilateral common + contralateral risk increased

  • Ovarian Cancer: 63% lifetime risk

    • High-grade serous carcinoma

    • Onset 40-50s yo

  • Other Cancers

    • Male Breast ca: 1%

    • Prostate: 8%

    • Pancreatic

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BRCA2 Management

Surveillance

Breast (same as BRCA1)

  • Annual MRI

    • Start at 25yo

  • MRI + Mammography

    • Start at 30yo

  • Clinical Breast Exam

    • Start 25yo

    • Every 6-12 months

  • CONSIDER Prophylactic Bilateral Mastectomy (risk not 0% though)

Ovary

  • Risk reducing bilateral salpingo-oophorectomy

    • at 40-45yo (later than BRCA1)

Pancreatic

  • MRCP (Cholangiopancreatography)

and/or

  • Endoscopic Ultrasound

    • Start at 50yo OR 10 years younger than earliest Pancreatic cancer in the family

Prostate

  • Annual PSA test

    • Start at 40yo

Chemoprevention

More effective than with BRCA1 b/c Estrogen Receptor positive breast cancer

  • Tamoxifen: blocks estrogen receptor and prevents RECEPTOR PSOTIVE breast cancer

  • Aromatase inhibitors (POST-MENOPAUSE)

    • Anastrozole

    • Exemestane

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BRCA 1 Management

Surveillance

Breast

  • Annual MRI

    • Start at 25yo

  • MRI + Mammography

    • Start at 30yo

  • Clinical Breast Exam

    • Start 25yo

    • Every 6-12 months

  • CONSIDER Prophylactic Bilateral Mastectomy (risk not 0% though)

Ovary

  • Risk reducing bilateral salpingo-oophorectomy

    • at 35-40yo

Chemoprevention

Chemoprevention less effective than in BRCA2

  • Tamoxifen: blocks estrogen receproti and prevents RECEPTOR PSOTIVE breast cancer

22
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HBOC syndrome: Testing considerations

Genetic Testing

  • 10-15% of variants are due to GENOMIC REARRANGEMNTS

    • if someone says they tested negative for BRCA1/2 → MAKE SURE rearrangements were included

Ashkenazi Jewish Ancestry

  • 1/40 with AJ ancestry have founder mutations

    • 3 AJ founder mutations

    • Offer AJ ancestry screening EVEN IF they are testing for a know-familial variant

23
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Li Fraumeni Syndrome

Gene: TP53

  • Childhood Cancer Syndrome

  • Big 5: Adrenocortiol carcinoma, Breast, Leukemia, Sarcoma, Brain/CNS tumors

Inheritance

  • Autosomal dominant

    • Inherited 80%

    • De Novo 20%

Clinical Features

  • Breast Cancer

    • HER2 or ER positive

    • Onset 20-40s yo

  • Soft tissue Sarcomas

    • Leiomyosarcoma, Liposarcoma Rhabdomyosarcoma

    • Childhood onset

  • Osteosarcoma

    • Childhood-adolescence onset

  • Brain Tumors

    • Astroctoma, Glioblastoma, Medulloblastoma

  • ****Adrenocortical Carcinoma****

    • Onset before 5yo

  • Leukemia

    • Acute Leukmeia

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Li Fraumeni: Recomdneaitons

AVOID UV/Radiation exposure → very susceptible to inducing cancer

Surveillance

Breast

  • Clinical exam

    • start 20-25yo

    • Every 6-12 months

  • Annual Breast MRI

    • start 20-25yo

  • Annual Mammography

    • Start 20-25yo

Colon

  • Colonoscopy

    • Start 25yo

    • Every 2-5 years

Risk Reduction

  • Bilateral Mastectomy

  • Discuss reproductive options :

    • IVF and PGT

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Fanconi Anemia

Genes: BRCA1, BRCA2, PALB2, BRIP1

  • Birth defects + Pancytopenia + Leukemia

Inheritance

  • Autosomal Recessive

Clinical Features

Skeletal/Other

  • Bone Marrow Failure (onset 5-10yo)

  • ***Radial Ray Defects: absent thumb, absent radius (at birth) ****

  • Short Stature

  • Microcephaly

  • Cafe-Au-Lait spots

Cancer

  • ***Acute Myeloid Leukemia***

    • Onset Teenage years

  • Head and Neck Squamous Cell Carcinoma

  • Gynecologic Squamous Cell Carcinoma

  • Gene-specific cancer risk

    • ex: BRCA1 → Breas/Ovarian

Management

Testing Strategy

  • ****Chromosome Breakage Analysis****

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PTEN-hamartoma tumor syndrome

Gene: PTEN

  • Umbrella Term: cover Cowden, Bannayan-Rilet-Ruvalcaba, Proteius-like syndrome (but just focus on Cowden)

  • Big Head – Benign Growths – Breast/Thyroid/Endometrium

Inheritance

  • Autosomal Dominant

    • Inherited 80%

    • De Novo 20%

Clinical Features

Developmental

  • ****Macrocephaly****

  • ***Autism***

  • Developmental Delay

Hamartomas (benign overgrowths)

  • ****Hamartomous GI polyps****

    • usually 10-50

  • Lipomas

  • Fibromas

Skin

  • Mucocutaneus Lesions (HALLMARK)

    • ****Trichilemmomas (face)*****

    • Oral papilloma

    • Acral Keratoses

Cancer

  • Breast: 67-85% Risk

    • ER positive

  • Thyroid: 20-35% Risk

    • ***Follicular*** thyroid carcinoma

  • Endometrial: 20-30% Risk

  • Renal Cell Carcinoma: 30-35% Risk

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Cowden Sydnrome: Manamgnet

Surveillance

Breast

  • Clinical Breast Exam

    • Start 25yo

    • Every 6-12 months

  • Annual Breast MRI

    • Start 30yo

  • Annual Mammography

    • Start 30yo

Thyroid

  • Annual Thyroid Ultrasound

    • *****Start 7yo****

Kidney

  • Renal Ultrasound

    • Start 40yo

    • Repeat every 1-2 years

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Breast/Ovarian Cancer Referral Criteria (HBOC)

  • Age

    • Any Breast Ca <50yo

    • ***Triple-Negative Breast ca.<60yo***

  • Type:

    • Any Male Breast Ca.

    • Any Ovarian Ca. (especially high-grade serous)

    • Pancreatic w/ HBOC fam hx

    • Metastatic Prostate

  • Family Hx

    • One 1st degree w/ Any Breast Ca <50yo

    • Two relative (same sidE) w/ Breast Ca (ANY AGE)

    • Three HBOC assoacted Ca. on one side of the family (ANY AGE)

  • Ashkenazi Jewish Acnestry

    • One HBOC-assoacited cancer (lower threshold)

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Bloom Syndrome

Gene: BLM

  • Chromosome Breakage Syndrome: detected with sister chromatid exchange assay

  • Small Stature + Sun Sensitivity + Cancer

Inheritance

  • Autosomal Recessive

Clinical Features

Growth/Development

  • Intrauterine growth restriction

  • Proportionate Short Stature (Unlike Russell-Silver syndrome)

  • Immunodeficney (Recurrent Infections)

Fertility

  • Men infertile

  • Women early menopause

Skin

  • Photosensitive Rash

    • occurs with TELANGIECTASIAS

Cancer (extremely broad)

  • Leukemia (childhood onset)

  • Lymphoma

  • CRC: 20-30s yo

  • Breast

  • Skin

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Werner Syndrome

Gene: WRN

  • Chromosome Breakage Syndrome

Inheritance

  • Autosomal Recessive

Clinical Features

Progeria

  • Normal Childhood → failure to have puberty growth spurt

  • Premature again start 20-30s: Greying, hair loss, ****BILATERAL CATRACTS***, osteoporosis, diabetes, atherosclerosis (heart deisease)

Cancer

  • Thyroid Cancer

  • Soft tissue Sarcoma

  • Osteosarcoma

  • Melanoma

31
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Colorectal Cancer Referral: Lynch

  • Age

    • CRC <50yo

    • Endometrial <50yo

  • Type

    • Multiple Lynch Cancers in one person

      • Colon + endometrial

      • Colon + ovarian

  • Family Hx (Amsterdam II Criteria - 3-2-1)

    • 3 Relatives with a Lynch Ca

    • 2 Generations

    • 1 Diagnosed <50yo

  • Somatic testing

    • Loss of IHC in PMS2, MSH6, MLH1 w/PMS2, MSH2 w/MSH6

    • MSI-High

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Ataxia-Telangiectasia

Gene: ATM

  • Chromosome Breakage Syndrome

  • Ataxia + Tiny Blood Vessels + Infections

  • AVOID RADITION

Inheritance

  • Autosomal Recessive

Clinical Features

  • Progressive Cerebellar Ataxia

    • Onset 1-4 yo

    • Peripheral Neuropathy also develops over time

  • Telangiectasia: dilated superficial blood vessels

    • Onset 3-6yo

  • Immunodeficney

    • recurrent infections: Pneumonia, Ear, Sinus

  • Cancer Risk

    • Leukemia (childhood)

    • Lymphoma

    • ****Breast Cancer (ONLY FOR HETEROZYGOTES)****

Laboratory Findings

  • ***Elevated Alpha-Fetoprotein**** AFTER BIRTH

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Colon Polyps Referral

# of Polyps

  • >100 Adenomas

    • FAP

  • 10-100 Adenomas

    • Attenuated FAP

    • MUTYH

  • 10-19:

    • Consider testing

  • 1-9

    • probably sporadic

Type of Polyps

  • >5 Juvenile (HAMARTOMATOUS)

    • Juvenile Polyposis

  • Any Peutz-Jeger (HAMARTOMATOUS)

    • Peutz-Jegers Syndrome

  • >20 Serrated Polyps

    • Serrated Polyposis

  • >5 LARGE serrated polyps (near anus)

    • Serrated Polyposis

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CHEK2- Associated Hereditary Cancer

Gene: CHEK2

  • Breast and Colon → NO OVARIAN

Inheritance

  • Autosomal Dominant

Clinical Features

  • Breast Cancer: 20-40% lifetime risk

    • Er-positive

    • Onset 40-60s yo

  • ****Colorectal Cancer: UPDATED****

    • CRC risk no longer elevated

  • Prostate: Modest risk increase

Surveillance

  • Breast

    • Annual Mammography

      • start at 40yo

    • Annual Breast MRI

      • start 30-35yo

    • Clinical Breast Exam

      • Every 6-12 months

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PALB2-Assoacited HBOC

Gene: PALB2

  • BRCA2 phenotype WITH OUT OVARIAN CANCER → Pancreatic the big one

  • Bialleic = Fanconi Anemia, Complementation gorup N (FANCN)

Inheritance

  • Autosomal Dominant

Clinical Features

  • Breast Cancer: 35-55% risk

    • ER-positive/ HER-2 Negative

    • Onset 40-50s yo

  • Pancreatic Cancer: 5%

Surveillance

Breast

  • Annual Breast MRI

    • Start at 30yo

  • Annual Mammography

    • Start at 30yo

Pancreatic

  • ***Need at least one 1st degree relative with Pancreatic Ca***

  • Annual MRI or EUS

    • Start at 50yo (or 10 years before ealriest Pan. Ca. in family)

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Pancreatic Screening

  • STK11, BRCA2, CDKN2A → pancreatic screening regardless of family history.

  • PALB2, BRCA1, and Lynch → pathogenic variant + family history.

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Hereditary Diffuse Gastric Cancer

Gene: CDH1, CTTNA1 (rare)

  • DIFFUSE gastric cancer: no single discrete mass

Inheritance

  • Autosomal Dominant

Clinical Features

  • Gastric Cancer

    • ****Signet Ring Cell Carcinoma**** (HALLMARK)

    • Onset 30-50s yo

  • Breast Cancer: 42% risk

    • ****LOBULAR breast Cancer ****(Hallmark)

    • ER Positive

    • ***Bilateral or multifocal***

Management

Stomach

  • Surveillance Endoscopy NOT Effective → cancer too diffuse

  • Prophylactic Total Gastrectomy

    • at 20-30yo

Breast

  • Clinical Breast Exam

    • Start 25yo

    • every 6-12 months

  • Annual Breast MRI

    • Start 30yo

  • Annual Mammography

    • Start 30yo

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Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS)

Gene: APC

  • NOT in coding region → n the PROMOTOER 1B

  • Colon usually normal or few polyps

Inheritance

  • Autosomal Dominant

Clinical Features

  • Stomach

    • 100-1000s of Fundic Gland Polps

    • *****Gastric Adenocarcinoma**** (cancer)

Surveillance

Stomach

  • Upper Endoscopy

    • Start late teens-early 20s

    • Every 1-2 years

  • Consider Gastrectomy if really bad

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Hereditary Paraganglioma–Pheochromocytoma Syndrome (HPPS)

Gene: SDHB, SDHD , SHD_

  • SDH-Dad: must be inherited from DAD to cause disease

  • SDH-Bad: higher metastasis and mortality

Inheritance

  • Autosomal Dominant

Clinical Features

Neuroendocrine cancers in two types

  • Paraganglioma (form within Adrenal gland - on top of kidney)

    • secrete catecholamines

    • headaches, sweating, palaipations

  • Pheochromocytoma (form OUTSIDE the adrenal gland)

    • Head & Neck, Chest, Abdomen, Pelvis

    • DO NOT secrete catecholamines

  • Onset 20-50yo

Management

Surveillance

  • MRI of neck to Pelvis

    • Start 10-15 years

    • Every 2-3 years

  • Annual Blood pressure + Blood/IUrine check

    • Detect Metanephrines

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Multiple Endocrine Neoplasia Type I (MEN1)

Gene: MEN1

  • 3 P’s: Pituitary, Parathyroid, Pancreas

Inheritance

  • Autosomal Dominant

Clinical Features

Adenomas that increase hormones

  • Pituitary

    • Prolactin (women), Growth hormone, ACTH

  • Parathyroid

    • Hyperparathyroidism

    • “"Stones, Bones, Groans, Thrones, and Psychiatric Overtones”

    • ***Hypercalcemia**

  • Pancreatic

Management

Surveillance

  • Pituitary

    • Annual Prolactin, IGF-1

    • Start at 5yo

    • MRI

    • every 3-5 years

  • Parathyroid

    • Annual Calcium, PTH

    • Start at 8yo

  • Pancreas

    • MRI or EUS

    • Start 10-20yo

    • Every 1-3 years

Treatment

  • Parathyroidectomy treats Hyperparathyroidism

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Multiple Endocrine Neoplasia Type II A (MEN2A)

Gene: RET

  • RET gain of function → uncontrolled proliferation of neuroendocrine cells

  • MEN2A = Parathyroid + Adrenal + Thyroid

Inheritance

  • Autosomal Dominant

Clinical Features

  • Thyroid

    • ***MEDULLARY Thyroid Carcinoma***: 95% risk

    • Onset: Early Adulthood

  • Adrenal

    • Pheochromocytoma (usually BENIGN ie. non-metastatic)

  • Parathyroid

    • Hyperplasia → *** PRIMARY HYPERPARATHYROIDISM ***

    • NO CANCER

Management

Adrenal

  • Annual Plasma Metanephrines

  • Start 11-16 yo

Parathyroid

  • Annual Calcium, PTH

  • Start adolescence - early adulthood

Thyroid

  • PROPHYLATIC THYROIDECTOMY (lifesaving)

  • at 5yo (Variant Dependent - could be later)

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Multiple Endocrine Neoplasia Type IIB (MEN2B)

Gene: RET

  • Marfanoid Habitus w/ Medullary and Pheochromocytoma

Inheritance

  • Autosomal Dominant

    • ****DE NOVO 50%****

Clinical Features

NO HYPERTHYROIDISM (unlike MEN2A)

  • Thyroid

    • ***Medullary Thyroid Carcinoma****

    • Onset EARLY CHILDHOOD

    • VERY AGGRESSIVE

  • Adrenal

    • Pheochromocytoma

  • Mouth

    • ***Mucosal Neuromas***(HALLMARK): Lips + Tongue

  • Marfanoid Habitus

    • But NO aortic aneurysm

Management

Thyroid

  • PROPHYLATIC THYROIDECTOMY (lifesaving)

  • ***Within 1st Year of Life****

Adrenal

  • Annual Plasma Metanephrines

  • Start EARLIER than MEN2A

Parathyroid

  • Annual Calcium, PTH

  • Start EARLIER than MEN2A

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Von Hippel-Lindau syndrome

Gene: VHL

  • Hemanioblastomas, Clear cell Renal Cell Carcinoma, Pheochromocytoma

  • Brain - Kidney - Adrenal

    • Eye→ Brain→ Kidney progression

Inheritance

  • Autosomal Dominant

    • Inherited 80%

    • De Novo 20%

Clinical Features

CNS

  • Hemangioblastomas

    • Brain / Spinal chord: onset 20-30s yo

    • ***RETINA****: onset 5-15yo, often first manifestation

Kidney

  • Clear Cell Renal Cell Carcinoma (leading cause of mortality

    • Bilateral

    • Multi Focal

    • Onset 30-50yo

  • Renal Cysts

Adrenal

  • Pheochromocytoma

    • Bilateral

    • Onset childhood

Management

Surveillance

  • Eye exam: by 1yo

  • Plasma Metanephrines: stat 5yo

  • Brain MRI: Start 11-15yo

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Familial atypical multiple mole melanoma syndrome

Gene: CDKN2A

Inheritance

  • Autosomal Dominant

Clinical Features

Skin

  • Moles (dozens, usually >50)

    • Onset childhood-adolescence

  • Melanoma

    • Onset 20-40s yo

Pancreas

  • ****Pancreatic Cancer***: 15-20% risk

Surveillance

  • Skin Exam: every 6-12months

    • Start childhood (10yo)

  • Pancreas

    • MRI or EUS

    • Start 40yo

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Gorlin Syndrome

Gene: PTCH1, SUFU

  • Nevoid Basal Cell Carcinoma

  • Cancer risk: MEDULLOBLASTOMA

Inheritance

  • Autosomal dominant

    • Inherited 80%

    • De Novo 20%

Clinical Features

Cancer

  • Basal Cell Carcinomas

    • 100s over lifetime

    • Onset before 20yo

  • ***Medulloblastoma***

    • SUFU: 20-30%, onset before 5yo

    • PTCH1: <2%

Skeletal

  • ***Jaw Cysts*** (Odontogenic Keratocysts)

    • Mandible

    • Tooth displacement

    • Onset childhood-Adolescence

  • Random Skeletal: Fused ribs, Scolosis, vertabrae anaomlies

Craniofacial

  • Macrocephaly

  • Frontal Bossing

Surveillance

  • PTCH1: no routine Brain MRI

  • SUFU: Brain MRI

    • every 3-4 months until 3yo

    • every 6 months until 5yo

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Xeroderma Pigmentosum

Gene: many genes -

  • nucleotide excision repair (NER) genes

  • Extremely susceptible to UV-induced skin cancer

Inheritance

  • Autosomal Recessive

Clinical Features

Skin

  • Extreme Photosensitivity (skin and eyes)

  • Freckling before 2yo

  • Skin Cancers before 10yo

    • BCC, SCC, Melanoma

Eye

  • Loss of eye lashes

  • Vision Loss

  • Eye cancer

CNS (30%)

  • Progressive hearing loss

  • Ataxia

  • Seizures

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Birt-Hogg-Dube Syndrome

Gene: FLCN

  • Skin, Lungs, Kidney

Inheritance

  • Autosomal Dominant

Clinical Features

Skin

  • ***Fibrofolliculomas***: benign hair follcile tumors

    • Face, Neck, Upper trunk

    • Onset 20-40s yo

  • Melanoma

Lung

  • Pulmonary Cysts

    • Bilateral

    • Onset 20-40s yo

  • Spontaneous Pneumothorax

    • Onset 20-40s yo

Kidney

  • Renal Cell Carcinoma

    • Bilateral

    • Multifocal

    • ***Slow growing***

    • Onset 40-60yo

Management

Kidney

  • MRI or CT

    • Start 20yo

    • Every 1-2 year

Lung

  • Baseline chest CT