Slide to syndrome - board study Flashcards
5 syndromes caused by inherited defects in DNA repair
Ataxia Telangiectasia, Bloom syndrome, MYH-associated polyposis, Xeroderma pigmentosa, Fanconi Anemia (all have autosomal recessive mode of inheritance)
Inheritance pattern of Lynch syndrome
also HNPCC, autosomal dominant - DNA mismatch repair gene inactivation
MEN1
AD inheritence, gene inactivated is MEN1, chromosome is 11q13 - Pituitary adenoma (or hyperplasia); parathyroid hyperplasia; Pancreateic endocrine neoplasm/islet cell tumor; duodenal gastrin producing carcinoid (causing zollinger ellison syndrome)
Combination of pituitary tumor, hyperparathyroidism, pancreatic endocrine tumor and duodenal carcinoid producing a hormonal syndrome…
MEN1, especially with gastrinoma and zollinger ellison syndrome
Birt-Hogg-Dubé syndrome (germline folliculin mutation)
Skin adnexal tumors, kidney tumors (bilateral), lung cysts with pneumothorax presentation
(fibrofolliculoma), (renal cell carcinoma)
Hereditary leiomyomatosis and RCC syndrome
(germline fumarate hydratase mutation)
autosomal dominant
characterized by the presence of cutaneous and uterine leiomyomas and RCCs. These renal tumors are now regarded as a specific subtype of RCC (i.e. HLRCC associated [or fumarate hydratase deficient] RCC)
fumarate hydratase deficient RCC is the same thing as…
HLRCC associated RCC (referring to Hereditary leiomyomatosis and RCC syndrome)
Ataxia Telangiectasia –> inheritance and diseases
Autosomal recessive, inherited defect in DNA repair , ATM is gene product (ataxia-telangiectasia mutated), chromosome 11q22-23, 100-fold risk of malignancies (ALL in children, solid tumors in adults) –> progressive ataxia, ocular and cutaneous telangectasia, thymic hypoplasia, IgA immunodeficiency –> b/c of DNA repair problem, ionizing radiation sensitive
*on list of hereditary breast cancer ddx
Bloom syndrome –> inheritance and diseases
autosomal recessive, gene product BLM helicase, chromosome 15 –> predisposition to wide range of cancers, especially leukemias (in context of developmental defects)
Fanconi anemia –> inheritance and diseases
Autosomal recessive, Several candidate genes identified (no specific chromosome) –> predisposition to leukemias and solid tumors (HCC in 10% of patients), hypoplasia of bone marrow, kidney, spleen, bone (particularly thumbs and radius)
Carney complex / carney syndrome –> inheritance and diseases
autosomal dominant, protein kinase A gene product, chromosome 17q22-24 and 2p16 –> myxoid lesions, pigmented and calcifying lesions, endocrine hyperactivity
myxoid –> cardiac myxoma, skin angiomyxoma, myxoid fibroadenoma of breast
pigmented and calcifying –> spotty skin pigmentation, epitheloid blue nevus, pigmented nodular adrenocortical hyperplasia, psammomatous melanotic schwannoma, large cell calcifying sertoli cell tumor
endocrine hyperactivity –> pituitary adenoma
*chondroid hamartoma (association)
tumors/lesions that make you think carney syndrome (not triad)
myxoid –> cardiac myxoma, skin angiomyxoma, myxoid fibroadenoma of breast
pigmented and calcifying –> spotty skin pigmentation, epitheloid blue nevus, pigmented nodular adrenocortical hyperplasia, psammomatous melanotic schwannoma, large cell calcifying sertoli cell tumor
endocrine hyperactivity –> pituitary adenoma
*chondroid hamartoma (association)
*AD inheritance, PRKAR1A gene, PKA gene product
you see myxoma with other pigmented or calcifying things and you think…
Carney complex / carney syndrome –> AD inheritance, PKA gene product, 17q22-24 and 2p16 locations
you see large cell calcifying sertoli cell tumor and you think…
look for myxoma or something else ‘pigmented’ and endocrine manifestations or a chondroid hamartoma –> CARNEY –> 17q22-24 and 2p16 (PKA), AD inheritance
*could also be Peutz-Jegher’s syndrome (intra-tubular deposits in large sertoli cells)
Retinoblastoma syndrome –> inheritance and diseases
40% are inherited in AD fashion, RB gene product on chromosome 13q14 –> bilateral retinoblastomas, pineoblastoma, osteosarcoma (and other sarcomas)
You see osteosarcoma + other sarcoma with any hint of blindness and you think…
inherited RB gene mutation, retinoblastoma syndrome, 13q14, look for pineoblastoma
you make a dx of pineoblastoma and you think….
inherited RB gene mutation, retinoblastoma syndrome, 13q14, look for osteosarcoma /other sarcoma and bilateral retinoblastomas
Carney triad vs. Carney complex/syndrome
Triad: paraganglioma, pulmonary chondroma (chondroid hamartoma), GIST (gastric epitheloikd) —> classically young female
syndrome/complex: PKA gene product, 17q22-24 and 2p16, myxoid, pigmented/calcifying, endocrine (pituitary adenoma)
what is the other name for hereditary hemorrhagic telangiectasia
Rendu-osler-weber syndrome, AD, ACVRL1 + ENG gene products (both in TGFbeta pathway) —> aneurysmal telangiectasias in multiple organs (bleeding)
Rendu-osler-weber syndrome…
(AKA: hereditary hemorrhagic telangiectasia)
AD inheritance, ACVRL1 + ENG gene products (both in TGFbeta pathway) —> aneurysmal telangiectasias in multiple organs (bleeding)
Li-Fraumeni syndrome —> inheritance and diseases
Autosomal dominant (AD), p53 gene product, chromosome 17p13 —> multiple primary tumors at a young age
sarcoma, carcinoma (breast, colon, pancreas, adrenal cortex), leukemia, melanoma, glioma
*on list of ‘hereditary breast cancer’ ddx
A young person has multiple primary tumors of different organs and you think…
Li-fraumeni? Inherited AD, problem with p53, sarcoma, carcinoma (breast, colon, pancreas, adrenal cortex), leukemia, melanoma, glioma
Hereditary breast and ovarian cancer….
BRCA1 and 2 (AD inheritance pattern)
BRCA1 - 40-50% of hereditary breast carcinoma –> 17q21 –> >70% of these patients get breast cancer (especially medullary breast ca) —> 30-60% of these patients get ovarian cancer (serous carcinoma and STICs therefore look at entire tube and section the fimbriae)
BRCA2 - 20-30% of hereditary breast carcinoma –> >60% of patients with this mutation get breast cancer, increased risk for ovarian (though less than BRCA1) —> also prostate cancer and pancreas cancer associations
male breast cancer hereditary association
BRCA2 >BRCA1
*after this, some other inherited solid tumor predisposition
Breast cancer and prostate cancer have what in common?
BRCA2 mutation
Chromosomal location of BRCA1
17q21 —> breast and ovarian cancer
Chromosomal location of BRCA2
13q —> breast and ovarian (less than BRCA1) and prostate and pancreas, male breast cancer
Cowden’s disease / syndrome —> inheritance and manifestation
Autosomal Dominant (AD), PTEN gene product, chromosome 10q
*multiple neoplasms and HAMARTOMAS (all cell origins)
*breast cancer, skin changes and trichilemmomas, GI polyps, soft tissue benign tumors (hemagiomas, lymphangiomas, lipomas, neurofibromas, leiomyomas)
*thyroid, RCC, merkel cell, lymphoma, melanoma, meningioma
Chromosomal location and gene product mutated in Cowden’s disease/syndrome
PTEN, 10q (AD inheritance)
HAMARTOMAS ‘plus’
*thyroid (follicular>ptc), RCC, merkel cell, lymphoma, melanoma, meningioma
Cowden’s disease/syndrome and breasts…
Increased likeliehood of breast cancer (>50% lifetime risk, like 5 fold elevated risk from baseline)
*PTEN, 10q, AD
*thyroid, RCC, merkel cell, lymphoma, melanoma, meningioma
HAMARTOMAS
A patient has a ton of HAMARTOMAS, and now another cancer…
Cowden’s disease/syndrome
*multiple neoplasms and HAMARTOMAS (all cell origins)
*breast cancer, skin changes and trichilemmomas, GI polyps, soft tissue benign tumors (hemagiomas, lymphangiomas, lipomas, neurofibromas, leomyomas)
*medullary (thyroid), RCC, merkel cell, lymphoma, melanoma, meningioma
*HAMMMMARTOMMMMAS (mmmmmooooooo) - cowdens
DDX of anything ‘hereditary breast cancer’
Start with BRCA1 and BRCA2
*then cowden’s syndrome/disease
*then Ataxia-telangiectasia (AT), Li-fraumeni
Familial atypical multiple mole melanoma syndrome (FAMMM) or B-K Mole syndrome) —> inheritance and diseases
Autosomal dominant (AD), p16 is gene product, chromosome 9p21 —> TONS (more than 100) nevi
*will present with atypical/dysplastic nevi and/or melanoma
*ALSO pancreatic adenocarcinoma (10-20 fold increased relative risk)
Gorlins syndrome and FAMMM / B-K Mole syndrome have something in common…
chromosome 9
*FAMMM has 9p21 location with p16 gene product mutation (CDKN2A gene)
*Gorlins syndrome has 9q22.3-q31 location with PTCH gene product mutation
Gorlin’s syndrome —> inheritance and diseases
PTCH gene product, location 9q22.3-q31, inherited AD
*two or mor basal cell carcinomas before 20 years old
*odontogenic keratocyst of jaw
*ovarian fibroma (particularly bilateral, multinodular, calcified)
*medulloblastoma
(ALSO skeletal abnormalities particularly macrocephaly)
What does STK11 have to do with breast cancer?
STK11 (serine/threonine kinase 11) is mutated in the autosomal dominant condition Peutz-Jeghers syndrome. Patients with this syndrome have a 30% to 50% risk of developing breast cancer.
*also have: specific GI polyps and some risk of GI cancer but not from those polyps
What does PTEN have to do with breast cancer?
Germline mutations in PTEN (phosphatase and tensin homolog) can lead to a rare autosomal dominant inherited cancer syndrome, Cowden syndrome, which is characterized by a high risk of breast cancer.
What does CDH1 have to do with breast cancer?
Mutations in the CDH1 gene cause familial diffuse gastric cancer, an autosomal dominant cancer syndrome. Patients with a familial diffuse gastric cancer have a risk of about 50% of getting breast cancer.
Male breast cancer….what genes should you think about?
*BRCA2 primarily
*Other mutations associated with male breast cancer include androgen receptor, CHEK2 mutations (associated with Li-Fraumeni syndrome), PTEN (Cowden syndrome), HNPCC (Lynch syndrome), and CYP17 polymorphism.
Tumors associated with von Hippel Lindau Syndrome (VHL gene)
Clear cell renal cell carcinoma
Along with Hemangioblastomas, pheochromocytoma, pancreatic serous cystadenomas, and endolymphatic sac tumor
Germline DICER mutations…
(DICER1-PPB familial tumor predisposition syndrome)
Think, in a pediatric patient, pleuropulmonary blastoma
PPBs are characterized by DICER1 mutations, and about two-thirds of children with PPB have heterozygous germline DICER1 mutations
Children with germline mutations are at risk for other tumors:
cystic nephroma of the kidney,
nasal chondromesenchymal hamartoma,
Sertoli-Leydig tumor of the ovary,
embryonal rhabdomyosarcoma of the cervix (and other sites),
pituitary blastoma pineoblastoma.
You see these together….
cystic nephroma of the kidney,
nasal chondromesenchymal hamartoma,
Sertoli-Leydig tumor of the ovary,
embryonal rhabdomyosarcoma of the cervix (and other sites),
pituitary blastoma pineoblastoma.
(DICER1-PPB familial tumor predisposition syndrome)
Think, in a pediatric patient, pleuropulmonary blastoma
(DICER1-PPB familial tumor predisposition syndrome)
Think, in a pediatric patient, pleuropulmonary blastoma
also:
cystic nephroma of the kidney,
nasal chondromesenchymal hamartoma,
Sertoli-Leydig tumor of the ovary,
embryonal rhabdomyosarcoma of the cervix (and other sites),
pituitary blastoma pineoblastoma.
Peutz-Jegher polyp in the stomach…
Peutz-Jegher’s syndrom
*sex cord tumor with annular tubules
*breast cancer
*skin mucocutaneous melanin pigmentation
*lots of GI polyps (which should NOT be dysplastic)
*autosomal dominant
*young patient
*STK11/LKB1 genes
*arborizing vessels
*gastric type adenocarcinoma in the cervix
*sertoli cell tumor
Gastric type adenocarcinoma in the cervix
Peutz Jeger’s syndrome
*deeply penetrating glands that look like foveolar cells with tons of mucin
*p16 negative , ER/PR negative (not HPV associated
*poor prognosis
Do PJS patients have increased risk of GI cancer?
PGJ = Peutz Jeger’s syndrome
*yes, they do have increased risk
*tends to NOT come from PJ polyps
*gastric, small intestinal, colonic
*also breast and pancreas
hamartomatous polyposis syndrome characterized by macrocephaly, lipomatosis, hemangiomas, and hamartomatous polyps in the gastrointestinal tract.
Bannayan-Ruvalcaba-Riley syndrome is a hamartomatous polyposis syndrome characterized by macrocephaly, lipomatosis, hemangiomas, and hamartomatous polyps in the gastrointestinal tract.
Bannayan-Ruvalcaba-Riley syndrome
hamartomatous polyposis syndrome characterized by macrocephaly, lipomatosis, hemangiomas, and hamartomatous polyps in the gastrointestinal tract.
Most common hamartomatous polyp syndrome
The most common of the hamartomatous syndromes is familial juvenile polyposis, which has an estimated incidence of 1 per 100,000 births
JPS in the world of syndromes
juvenile polyposis syndrome
*The most common of the hamartomatous syndromes is familial juvenile polyposis, which has an estimated incidence of 1 per 100,000 births. This disorder shows an autosomal dominant pattern of inheritance, and patients show germline mutations in the SMAD4 gene or in the BMPR1A gene.
*cystically dilated glands
*AD inheritance