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20- One Hundred Syndromes

Terms in this set (140)

Responsible gene: HBB

Protein: Hemoglobin subunit beta

Cytogenetic locus: 11p15.5

Inheritance: AR

Clinical Features and Diagnostic Criteria: severe anemia and HSM. Without Tx: severe FTT and shortened life expectancy. Thal. intermedia: present later, milder anemia, only rarely requires transfusion; at risk for iron overload due to inc intestinal absorption of iron. The clinical severity of the beta-thal syndromes depends on the extent of globin alpha chain/non-globin alpha chain imbalance. At risk pop's: Mediterranean, middle eastern, Indian, Thai, Chinese, African, African American.

Clinical Tests: microcytic hypochromic anemia, an abnl peripheral blood smear with nucleated RBCs, and reduced amounts of hemoglobin A (HbA) on hemoglobin analysis.
Carriers: reduced MCV, MCH, and RBC morphologic changes that are less severe than in affected individuals.

Molecular Tests: Mutation scanning/sequencing. In each at-risk population, 4-10 mutations account for the large majority of HBB disease. Compound heterozygosity for a mild/silent mutation and a severe mutation produces a variable phenotype, ranging from thalassemia intermedia to thalassemia major.

Disease Mechanism: Absence of globin beta chains. The non-assembled globin alpha chains that result from unbalanced globin alpha chain/non-globin alpha chain synthesis
precipitate in the form of inclusions which damage the erythroid precursors in the bone marrow and spleen, causing ineffective erythropoiesis.

Treatment/Prognosis: Treat with a regular transfusion program and chelation therapy (to reduce transfusion iron overload), allows for normal growth and development and extends life expectancy into the third to fifth decade.
Responsible gene (protein and cytogenetic locus): MLH1 (3p21.3, DNA mismatch repair protein MLH1), MSH2 (2p22-p21, DNA mismatch repair protein Msh2), MSH6 (2p16, DNA mismatch repair protein MSH6), and PMS2 (7p22, PMS1 protein homolog 2)

Inheritance: AD

Clinical Features and Diagnostic Criteria: Amsterdam II Criteria: 3 or more family members (at least one 1st degree of the other 2) with HNPCC related cancers; 2 successive affected generations; 1 or more of the HNPCC-related cancers diagnosed before age 50; exclusion of FAP. Bethesda 2004: CRC diagnosed under age 50yrs, 2 HNPCC related tumors at once, CRC with high MSI in someone <age 60yrs, CRC in one or more 1st degree relatives with and HNPCC related tumor with 1 cancer diagnosed before age 50yrs, or CRC diagnosed in 2 or more 1st or 2nd degree relatives (any age). HNPCC-related tumors: colon, endometrium, stomach, ovary, hepatobiliary tract, urinary tract, small bowel, brain/CNS.

Clinical Tests: Microsatellite instability (MSI) of tumor tissue, immuno-histochemistry of tumor tissue for the presence or absence of DNA mismatch repair proteins MLH1, Msh2, and
MSH6.

Molecular Tests: Mutation scanning MLH1 (60-69%), MSH2 (50-69%). Full sequencing MLH1 (90-95%), MSH2 (50-80%). Deletion analysis MLH1 (5-10%), MSH2 (17-50%), MSH6 (rare)

Disease Mechanism: These proteins work in a recessive manner at the cellular level- LOH leads to absence of any functional protein and dysfunctional mismatch repair.

Treatment/Prognosis: 80% lifetime risk of CRC. If CRC present, full colectomy with ileorectal anastomosis indicated. Colonoscopy every 1-2yrs by age 20-25. Consider annual
pap smear, transvaginal US, endometrial bx and CA-125 level.