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34 Cards in this Set
- Front
- Back
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Li-‐Fraumeni syndrome: risk syndromes
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ABBLLOS
Soft tissue sarcoma Osteosarcoma Pre-‐menopausal breast cancer Brain tumors Leukemia Lung bronchoaveolar cancer Adrenocortical carcinoma |
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Li-‐Fraumeni syndrome: genetics
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• Onset is in childhood or young adulthood
– 50% of individuals with TP53 mutations had developed a malignancy by age 30, median age of diagnosis is 25 – Survivors often develop second malignancy – Have a particular sensitivity to radiotherapy • Caused by TP53 mutations – Autosomal Dominant |
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TP53
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Tumor suppressor that regulates the cell cycle by
conserving genomic stability Is able to activate DNA repair protein when DNA has sustained damage, arrest growth by holding cell cycle at the G2/S regulation point, can initiate apoptosis. |
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TP53: phenotype/genotype
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- missense mutation appear to be associated with earlier onset cancer
- deletion involving part or all of TP53 confers phenotypes more consistent with classic LFS - Brain tumor risk might be higher if the mutation lies in the DNA binding loop. May have anticipation |
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Testing Criteria for classic Li-Fraumeni
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Presence of ALL following criteria
-- A proband with a sarcoma diagnosed before age 45 years -- A first degree relative with any cancer before age 45 years -- Another first or second degree relative with any cancer before age 45 years or a sarcoma at any age. |
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Chompret Criteria
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To determine who is appropriate for testing
-- Proband with a tumor belonging to LFS tumor spectrum before age 46 yeras AND At least one first or second degree relative with a LFS tumor (except breast cancer if the proband has breast cancer) before 56 or with multiple tumors OR -- Proband with multiple tumors (except multiple breast tumors), two of which belong to the LFS tumor spectrum and the first of which occurred before age 46. OR -- Proband with adrenocortical carcinoma or choroid plexus tumor, regardless of family history |
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Cowden syndrome
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-- Multiple gastrointestinal hamartomas (95% of people with PTEN mutation)
-- Increased risk for: BERT Breast cancer; endometrial cancer; renal cancer, thyroid cancer; others. |
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Cowden syndrome: Genes
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PTEN: AD
KLLN SDHB SDHD |
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PTEN Clinical Associations
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Mutation found in 85% of Cowden syndrome (CS) when criteria met
Mutation found in 65% of Banyan Riley Ruvalcaba syndrome (BRRS) Proteus-like syndrome Macrocephaly and autism (pediatrics) |
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Proteus syndrome
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known as Wiedemann syndrome (named after the German paediatrician Hans-Rudolf Wiedemann), is a congenital disorder that causes skin overgrowth and atypical bone development, often accompanied by tumors over half the body.
– Includes malformations and hamartomatous overgrowth of multiple tissues, connective tissue and epidermal nevi and hyperostoses. – Very rarely develop malignancies |
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Riley Ruvalcaba syndrome (BRRS)
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Congenital disorder characterized by macrocephaly,
intestinal hamartomas, lipomas and pigmented macules of glans penis – 50% have intellectual disabilities |
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PTEN biology
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* Biologically is a tumor suppressor gene that encodes a dual-specificity phophotase that dephosphorylate both proteins and phospoholipids
* Names for "phosphotase and tensin homolog deleted on chromosome ten" * May surpress tumor cell growth by antagonizing protein tyrosine kinases * May regulate tumor cell invasion and metastasis through interactions at focal adhesions * Involved in multiple different processes in the body and has been associated with everything from cancer to diabetes. |
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Cowden Diagnostic Criteria
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Pathognomonic mucocuteneous lesions combined with one of the following:
-- >= 6 facial papules, of whihc >=3 must be trichilemmoma -- Cutaneous facial papules and oral mucosal papillomatosis -- Oral mucosal papillomatosis and acral keratoses -- >=6 palmo-plantar keratoses OR Two or more major criteria OR One major and three or more minor criteria OR Four or more minor criteria |
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Cowden Diagnostic major Criteria
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– Breast cancer
– Follicular thyroid cancer – Macrocephaly – Endometrial carcinoma – Multiple GI hamartomas or ganglioneuromas – Macular pigmentation of glans penis |
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Peutz-‐Jeghers Syndrome (PJS)
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Syndrome involving multiple GI tumors
– Esophagus, stomach, small bowel, colon and pancreas – Other cancers may also be increased: Lung, Testes, Breast, Gynecological (uterine, ovarian, cervical, sex chord) – Pathognomonic feature is mucocutaneous pigmentation (blue spots) • Also appear on finger tips |
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Peutz-‐Jeghers Syndrome (PJS)
Genetics and pathology |
Pathology of polyps is key
– Peutz-‐Jegher type hamartomatous polyps – Most common in small intestine (prevalence: jejunum, ileum and duodenum) • May cause intussusceptions • Also found in stomach, large bowel, renal pelvis, bronchus, gallbladder, nasal passages, urinary bladder and ureters Caused by STK11 mutations – Autosomal Dominant |
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STK11
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Serine/threonine kinase 11
– Previously known as LKB1 – Regulates cell polarity inhibiting inappropriate expansion of tumor cells 80-‐94% of individuals have detectable mutation – 55% of mutations detected with sequencing, 45% detected with deletion/duplication analysis • 65% of mutations stop protein function. • ~45% of individuals with a known mutation have no family history known of the disorder |
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Lifetime cancer risk with PJS
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Breast, pancreas, GI and Genitourinary
Breast Cancer 45~50% Colon 39% Stomach 29% Pancreas 11~36% Small intestine 13% Lung 15~17% Uterus 9% Cervix 10% Ovary 18~21% Testes 9% |
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Multiple Endocrine Neoplasia Type 2 (MEN2)
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• Typically associated with medullary thyroid
carcinoma – Genetic testing of people with MTC considered standard of care • Caused by the RET gene • Prevalence 1/35,000 • Separated into three sub-‐types: – Type 2A – Familial Medullary Thyroid Carcinoma (FMTC) – Type 2B |
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Medullary Thyroid Carcinoma
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• Originates in calcitonin-‐producing cells (C-‐cells) of thyroid
• Histologically diagnosed when C-‐cell nests extend beyond basement membrane and destroy thyroid follicles. – IHC for calcitonin can be done pathologically. • Biochemical analysis can be used to screen for the presence of elevated plasma calcitonin concentration. – A calcitonin level of ≥100 pg/ml is indication for surgery • May be preceded by appearance of puritic cutaneous lichen amylodosis (PCLA/CLA) on upper portion of back |
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Amyloidosis
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A generic term that signifies the abnormal extracellular tissue deposition of one of a family of biochemically unrelated proteins that share certain characteristic staining properties, including apple-green birefringence of Congo red–stained preparations viewed under polarizing light. Under electron microscopy (EM), amyloid deposits are composed of linear, nonbranching, aggregated fibrils, 7.5-10 nm thick of indefinite length arranged in a loose meshwork.
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Lichen amyloidosis
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Associated with multiple endocrine neoplasia type 2A (MEN 2A), also known as Sipple syndrome. The cardinal triad of this autosomal dominant syndrome is medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism. Many cases of familial lichen amyloidosis were reported in families with MEN 2A. The lichen amyloidosis in this syndrome is usually localized to the interscapular region consisting of lichenoid papules, with hyperpigmentation and fine scaling. The histopathologic and immunohistochemistry findings are similar to those in isolated lichen amyloidosis, pointing to keratin-derived amyloidosis.
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RET gene
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• RET -‐ “rearranged during transfection”
• This gene is the only gene associated with MEN2 • Oncogene that is receptor for members of the glial cell line-‐derived neurotrophic factor (GDNF) family of extracellular signaling molecules or ligands (GFLs). • Only gain of function mutations are associated with MEN2 – Gain of function mutations are associated with Hirschprung’s disease – Genotype/Phenotype correlations • MEN2A majority exon 10/11 • MEN2B 95% have Met918Thr in exon 16 |
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MEN2A
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• 70-‐80% cases of MEN2
• 5% de novo, 95% have affected family member • Cancer Risk – 95% risk to develop MTC – 50% risk to develop pheochromocytoma – 20-‐30% of patients develop hyperparathyroidism |
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FMTC
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• 10-‐20% of cases of MEN2
• MTC is the only clinical manifestation – Age of onset is older and penetrance is lower than MEN2A/B – Typically viewed as a variant of MEN2A, rather than distinct subtype – General clinical criteria • >10 members with RET mutation • Multiple mutation positive members >50 years old • All members with absence of pheochromocytoma or hyperparathyroidism |
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MEN2B
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• 5% of cases of MEN2
• 50% de novo • Characterized by aggressive form of MTC • 50% develop pheochromocytomas • Significant parathyroid disease is rare • 40% have diffuse ganglioneuromatosis of GI tract • 75% of affected individuals have marfanoid habitus, joint laxity and decreased subcutaneous fat • Early identification may be made through mucosal neuromas • May have developmental disabilities |
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Bloom Syndrome
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• Recessive disorder associated with mutations in
BLM – Causes high rate of chromosomal instability • Clinical features – Prenatal and postnatal growth delay, short stature, hypo and hyperpigmentation, facial telangiectatic erythema (bulerfly midface), photosensitivity, microcephaly, immunoglobulin deficiency |
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Bloom Syndrome associated malignancies
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– High rate of cancer, acute leukemia/lymphoma
– solid tumors in childhood including Medulloblastoma, Wilms tumor and osteosarcoma – solid tumors in adulthood in tongue, esophagus, colon and breast especially |
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Fanconi Anemia
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Characterized by physical abnormalities, bone marrow failure and increased risk of malignancy.
– Short stature, abnormal skin pigmentation, malformations of the thumbs, forearms, skeletal system, eyes, kidneys and urinary tract, hearing, heart, GI system, CNS system, hypogonadism and developmental delay – Progressive bone marrow failure usually present in the first decade – Hematologic malignancies (primarily AML) 10-‐30% and solid tumors of head, neck, skin and GI and genital tract 25-‐30%. |
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Ataxia Telangectasia
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progressive cerebellar ataxia beginning between
ages one and four years – Presents as gait and truncal ataxia – Head tilting – Slurred speech – Oculomotor apraxia (interrupted tracking across a visual field) – Typically wheelchair bound by age 10 Choreoathetosis, telangiectasias of the conjunctivae, immunodeficiency, with frequent infections, premature aging |
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Choreoathetosis
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the occurrence of involuntary movements in a combination of chorea (irregular migrating contractions) and athetosis (twisting and writhing).
It is caused by many different diseases and agents. It is a symptom of several diseases, including Lesch-Nyhan Syndrome, Phenylketonuria, and Huntington disease. |
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Telangiectasias
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Telangiectasias /tɛlˌæn.dʒiː.ɛkˈteɪ.zi.ə/ or angioectasias (also known as spider veins) are small dilated blood vessels near the surface of the skin or mucous membranes, measuring between 0.5 and 1 millimeter in diameter. They can develop anywhere on the body but are commonly seen on the face around the nose, cheeks, and chin. They can also develop on the legs, specifically on the upper thigh, below the knee joint, and around the ankles. Many patients who suffer with spider veins seek the assistance of physicians who specialize in vein care or peripheral vascular disease. These physicians are called phlebologists or interventional radiologists.
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Conjunctivae
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lines the inside of the eyelids and covers the sclera (white part of the eye). It is composed of non-keratinized, stratified columnar epithelium with goblet cells.
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Ataxia Telangectasia: risk for malignancies
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leukemia and lymphoma.
– Sensitive to ionizing radiation • Life span is typically until sometime after age 25 • Carrier women at an increased risk for breast cancer. |
