Week 12-14 Diabetes + Genetics 750 Final PDF

[Week 14 Genetic Testing: Across the Lifespan Powerpoint: ] Types of Genetic testing  - **Cytogenetic testing** - Examine chromosomes - **Linkage analysis** - Look at markers that are coinherited with a   gene that causes a genetic condition - **Direct or molecular te...

[Week 14 Genetic Testing: Across the Lifespan Powerpoint: ] Types of Genetic testing  - **Cytogenetic testing** - Examine chromosomes - **Linkage analysis** - Look at markers that are coinherited with a   gene that causes a genetic condition - **Direct or molecular testing** - Directly examine the DNA and RNA - **Biochemical testing** - Examine the protein products of genes Genetic testing is available for  - Prenatal diagnosis - Carrier testing: always test women first, because if woman is negative there's no need to test dad  - Confirmation of a genetic diagnosis - Predictive testing - Predispositional testing: ex testing for BRCA 1 or BRCA2: doesnt mean individual will develop disease, just higher risk - Presymptomatic testing: positive test for Huntingtons and live long enough, you WILL get the disease  Prenatal Testing: Includes both screening and testing - Prenatal screening - Not definitive -- Results indicate whether or not  the mother has an increased risk of carrying achild with a neural tube defect or a chromosomal abnormality - Diagnostic testing - Results indicate whether or not the fetus has a specific genetic conditions Goals of Prenatal testing:  - To lessen anxiety -- especially in couples with a strong family history of genetic conditions - To treat some   conditions   prenatally - Example: Some Neural   tube defects - To allow couples the opportunity to prepare for the birth of a child with a genetic condition - To give families the option of having their baby born in a health care facility with the resources needed to provide appropriate management - Example- having the   birth take place in a   hospital with a NICU - To make it possible for some infertile couples/couples with a family history of a genetic condition to have a child who does not have the condition - Examples: sperm and/or egg  donation preimplantation  diagnosis Non-disclosure preimplantation genetic diagnosis  - Non-disclosure testing is an option for people who are at risk of being affected by a late-onset disorder, such as Huntington's Disease (HD), SpinocerebellarAtaxia (SCA), or Early-Onset Alzheimer\'s Disease, and do not wish to learn their own genetic status but would like to ensure that their children do not inherit this disease. Two main types of prenatal testing - Noninvasive Prenatal Screening - Material serum screening - Ultrasound - Invasive diagnostic testing - Chronic villi sampling  - Performed at 11-13 wks - Risk of miscarriage approx 1:150 - Benefits: "safe" for fetus - Risks: Not definitive diagnosis  - Amniocentesis - Performed  at 15-18 wks - Risk of miscarriage approximately 1:200  - Benefit: definitive diagnosis  - Risk: Increased risk of miscarriage  Maternal Serum Screening  - Purpose: to identify pregnant women at increased risk for having a baby with certain birth defects - Blood Test -15-20  weeks - (Triple Check/Quad Test) - Alpha-fetoprotein (AFP), - Human chorionic gonadotropin (hCG) - Estriol - Inhibin A. Indications for more invasive testing  - Advanced maternal age: \>35 yrs - Previous child with a chromosome abnormality - Presence of a structural chromosome abnormality in one of the parents - Family history of a genetic disorder - Abnormal maternal serum screen or ultrasound Noninvasive prenatal genetic diagnosis (benefits and risks) - Benefits  - Can obtain a definitive diagnosis - Less risky and less expensive than invasive diagnostic testing - Risks  - Decision to terminate may become "too easy"/ access issues/ may result in - decrease in services for children with DS Carrier Screening - Test used to identify individuals   who have a gene mutation for a   genetic condition, but do not show   symptoms of the condition   because it is a condition that is   inherited in an autosomal   recessive manner Autosomal Recessive Disorders  - Both genes of a pair must be abnormal for the disorder to be expressed - Examples - PKU - Sickle Cell Anemia - Cystic Fibrosis - Tay-Sachs Disease - Spinal Muscular   Atrophy (SMA) Newborn Screening  - It is considered mandatory in every state in the USA, but currently consent is only required in a few states - Most developed nations - All states screen for PKU & hypothyroidism plus a variety of other conditions Predictive testing (2 types) - Predispositional - Genetic Testing for the BRCA1/2 Mutation - A positive result (indicating that a BRCA1 mutation is present) does not indicate a 100%risk of developing breast cancer - Presymtomatic - Mutation Analysis for Huntington Disease - If the gene mutation for HD is present, symptoms of HD are certain to appear if the individual lives long enough Genetic Testing for Cancer - Families with a strong family history of cancer - Especially cancer at a young age - When testing is done, it is recommended to test family member(s) who has/have cancer first - Greater chance of finding the mutation - Most hereditary cancers are autosomal dominant Families with strong family history of Cancer  - High number of affected individuals - Greater than 1 generation affected - Young at age of diagnosis - Clustering of specific tumor types Genetic Fingerprint of Cancer  - Tumor expression profile - Pathogenic description of the tumor that can help predict outcome and response to therapy - Drugs based on molecular targets HER-2/neu(HER2) - HER (**^H^**uman **^E^**pidermal growth factor **^R^**eceptor) -   HER2 protein/receptor is found on the surface of breast cells - Too much HER2 protein is thought to cause cancer cells to grow and divide more quickly - 25% of women with breast cancer are HER2+  Expectation Underlying Testing - Identification of   women who are at   increased risk for   HBOC will lead to   reduced morbidity   and mortality through   targeted surveillance   and risk-reducing   strategies Management Strategies  Risk of Developing Breast Cancer  - Average Male -- 0.1% lifetime risk of developing breast cancer - Men who carry a BRCA mutation, have a much higher risk of developing breast cancer - Men with BRCA1 mutation -- 1-5% risk - Men with BRCA2 mutation- 5-10% risk - They also have a higher risk of developing prostate   cancer - Men with a BRCA mutation have a 50% chance of passing the mutation to their children. Treatment to Prognosis  - Identify patients who may benefit from genomic information - 85% of patients with stage 1-2, node neg, ER+   breast cancer, never experience distant   recurrence with tamoxifen alone (NSABP Study,   1989) - Need to figure out who are the 15% who   experience distant recurrence - Need to individualize treatment -- instead of one   size fits all Oncotype Dx Story  - Diagnostic assay that quantifies the likelihood of breast cancer recurrence in women with breast cancer who are: - Newly diagnosed - Stage I or II - Node-negative - Estrogen receptor-positive Familial adenomatous polyposis (FAP) - Mean age for polyps to develop -- 16 years (teenage years) - By age 35 years, 95% of individuals with FAP have polyps - Without colectomy, colon cancer is inevitable - Mutation in tumor suppressor gene - Annual colonoscopy or flexible sigmoidoscopy for individuals at high risk starting at age 10 or 11 - Genetic Testing can be done as early as age 10-11 - If test neg; can stop annual colonoscopy/sigmoidoscopy - Prophylactic colectomy once polyps present - Nonsteroidal anti-inflammatory may decrease size of polyps Hereditary Non-polyposis colorectal carcinoma (HNPCC)/ Lynch Syndrome  - Cancer occurs at younger age than cancers that are not hereditary -- usually before age 50 - Tumor site in proximal colon predominates - Extracolonic cancers: endometrium, ovary, stomach, urinary tract, small bowel, bile ducts,sebaceous skin tumors - Mutations in DNA Repair Genes (MSH2/MLH1) - Testing usually not   advised before the   age of 18 - At risk indiv, offer -   Prophylactic colectomy - Total Abd Hyst BSO - Indiv with Cancer - Total Colectomy Genetic Testing for Huntington Disease - Not advised before the age of 18 years - Prior to testing it is recommended they meet with a genetic expert - Psychological testing - For the results: support person - Should ideally not be someone at risk for developing HD Genetic Testing for Alzheimer's disease  - Late Onset Alzheimer's Disease (most common type) - APOE-e4 (limited role in predictive testing) - Presence of 1 or 2 copies of APOE-e4 allele increases lifetime risk of Alzheimer's in an asymptomaticindividual - *APOE* e4/e4: 40-50% chance of developing Alzheimer's by age 75 years compared - to 10-15% for general population - *APOE* e3/e4: 25-30% risk lifetime risk of developing Alzheimer's by age 80 years - Important to remember-- a person can have 1 of 2 copies of APOE-e4 allele and never developAlzheimer's - Early Onset Alzheimer's Disease (more reliable/predictive than APOE testing) - Precursor Protein (APP) - Age of onset 40s & 50's (range 30-60 years) - Presenilin 1 (PSEN1) - Age of onset 40s -- early 50's (range 30s to early 60's) rare after 65 years of age - Presenilin 2 (PSEN2) - Age of Onset 40-75 years of age - If a parent has one of these 3 rare variants, child has 50% chance of inheriting the altered gene and if the variant isinherited, the child has a strong probability of developing Alzheimer's before age 65 and sometimes earlier. Whole Genome Sequencing used to hunt for diagnosis in rare diseases  - Collect information from family - Phone, Email, Video - Obtain past medical records - An extensive literature review is conducted - Data gathered entered into database - Additional testing or imaging is done if necessary - If hospital visit is required, team works with family to arrange the visit **[Family Hx and Clinical Features Associated W/ Genetic Conditions Pptx]** Purpose of a Pedigree  - Facilitates the identification of genetic syndromes - Assists the provider in establishing a presymptomatic diagnosis of a genetic disease - Helps identify at risk individuals - Helps to establish patterns of inheritance. - Illuminates social and biological relationships  Prenatal History  - Multiple gestation (increased risk for birth defects) - Onset and amount of fetal movement - Maternal disease (diabetes -- increases risk by 2-3x) - Maternal medicines, drug, alcohol use - Maternal serum screening - Ultrasound examinations - Adverse reproductive outcomes Perinatal history  - Presentation - APGAR score - Birth weight, length, head circumference - Initial physical exam - Neonatal adaptation Postnatal History  - Growth parameters - Body proportions - Development - Intellectual - (smiling, talking etc) - Physical - (sitting, walking etc) - Serious illnesses (Meningitis) Genetic Physical Assessment  - Examination to detect physical clues (some are subtle) - Measurements - Photographs  Anomalies Classified as:  - Major - Require medical and/or   surgical intervention - Isolated congenital   anomaly - Multiple congenital   anomalies - 2nd only to childhood   accidents as leading cau   of morbidity and health   cost in US - Minor - Do not require cosmetic   or functional correction - May be clues in the   diagnosis of a genetic   condition - May be associated with   an underlying major  malformation - The presence of a minor malformation should alert the clinician to look for a major malformationsuch as a heart defect, kidney problems, etc - If one minor malformation is present,   the probability of a major   malformation is 3%. - If three or more malformations are   present, the risk of a major   malformation is 90%. Deformation - Underlying tissue structurally normal - Usually occurs late in gestation (intrauterine constraint) - Most involve cartilage, bone, & joints - Many correct spontaneously Disruption - Destruction of previously normal tissue - Can be caused by mechanical forces, ischemia, hemorrhage - Usually affects different tissue types in a distinct anatomic area Dysplasia  - Often abnormal cellular biochemistry; gene typically cause this  - Lethal prenatally - Major mutant gene is often the cause - Changes as the child grows -- clinical effects continue as long as tissue grows or functions - Lethal prenatally Malformation - Failure of completion of one or more embryonic processes - Usually occurs early in gestation - Chromosomal abnormalities, mutant genes, teratogens - Hereditary or environmental  Prenatal Development - Implantation stage (first 3 weeks) - Period when 15% of all conceptions are lost - Rapid cell proliferation/Early cell differentiation - Embryonic stage (4^th^ to end of 7^th^ wk) - Critical Period- formation of definitive organs - Abnormal development results in structural anomalies - Fetal stage (8^th^ week to 40^th^ week) - Primarily period of growth - Deformations and  disruptions occur  Hypotonia  - One of the most common reasons for considering a genetic diagnosis in a newborn. - On physical exam -- newborn with hypotonia has: - Limited voluntary movement - Reduced strength - Joints that have increased range of movement and diminished resistance when manipulated Importance of Figuring out cause of hypotonia  - Accurate diagnosis can: - Inform prognosis - Guide management to maximize development and   prevent secondary complications - Great variations in disease with hypotonia - Zellweger syndrome -- lethal (usually before age 1) - Prader Will -- compatible with long term survival, but life long   challenges/disability - Congenital Myasthenia Gravis -- life threating, but some types   can resolve in first through years of life - Different conditions/Different types of testing Clinical features of Turner Syndrome - Short neck with webbed appearance - Low hairline --back of neck - Low-set ears - Lymphedema - Puffy hands and feet at birth - Soft nails that turn upward - Small size Head to Toe Assessment  - Looking for features commonly seen in people with genetic conditions - Head: - Fontanelles too large or too small - Overlapping sutures due to premature closure of sutures - Low set or posteriorly rotated ears - Malformed ears - Ear tags or pits Macrocephaly   Microcephaly  Cri-du Chat - Microcephaly - High pitched cry - Low birth weight - Poor muscle tone - Significant intellectual difficulties - Feeding difficulty - Self-abusive behavior PKU Phenylketonuria  - Signs and symptoms when PKU is untreated - Microcephaly - Lighter skin, hair and eye color (phenylalanine can't transform into melanin) - Intellectual disability - Skin rashes - Musty odor in the breath - Hyperactivity - Behavioral, emotional and social problems Severe Microcephaly: Seen in infants w/ congenital Zika  - Zika virus -- single stranded ribonucleic acid (RNA) flavivirus  Craniosynostosis  - A condition in which one or more sutures on an infant's skull close/fuse early (before 2-3 years) turning into bone (ossification) - Skull can not expand perpendicular to the fused suture -- it grows in a parallel direction - Types - Sagittal (Scaphocephaly) - Most common - Front-back - top of head - Coronal - Suture from ear to ear - Brachycephaly - Plagiocephaly - Metopic (Trigoncephaly) - Suture close to forehead Crouzon Syndrome - Fused coronal sutures cause the skull to grow sideways and upward, causing a flattened forehead andincreased height and width of the head.  Apert Syndrome - Unlike Crouzan, Apert Syndrome also has involvement of the hands and feet. - Prematurely fused cranial   sutures - Fused fingers - Fused toes Eyes - Hypertelorism - widely spaced - Hypotelorism - closely spaced  ***Blue Sclera -- often seen in people with Osteogenesis Imperfecta*** Wardenburg Syndrome - Poliosis (white forelock) - Iris pigmentary abnormality (different colors of iris in two eyes/ very pale or brilliantly blue) - Sensory hearing loss - Lateral displacement of inner canthi  Albinism:  - Pale skin - Hair that is very light blonde, brown, or reddish. - Eyes that are pink, light blue, green, gray, or light brown. - Eyes that are sensitive to light. - Strabismus "lazy eye" - Nystagmus (back and forth movement of the eyes) - Vision problems. Trisomy 13 - Small, close set eyes - Coloboma (iris defect) - Cleft Lip and Palate - Low set ears - Microcephaly - Single transverse crease on the palm - Extra fingers and toes (polydactyly) - Hyperconvex, narrow fingernails are common - 80% Congenital heart defects (VSD, ASD, PDA) - 66% holoprosencephaly (failure of forebrain to divide properly) Hurler Syndrome MPSI- primarily affects males  - Clouded cornea - Coarse facial features - Large face - Thick eyebrow - Wide nasal bridge - Widely spaced teeth - Short neck - Protruding belly - Abundant, coarse hair on body Neurofibromatosis  - **Lisch nodules on the irises (nodular aggregate of dendrite melanocytes) -- do not affect vision** → Ear abnormalities: increased frequency of renal problems   Boy with fragile X Syndrome  - Long face - Large ears - Mental impairment - Attention deficit - Hyperactivity - Anxiety and unstable mood - Autistic-like behaviors → Synophrys: unibrow (can be seen in Cornelia de Lange and Wardenburg Syndrome) Child w/ Cornelia de Lange Syndrome - Synophrys - eyebrows extend midline and meet above nose - Anteverted nares - upturned nose - Down turned lips Velo-Cardo-Facial Syndrome 22q Microdeletion  - Cleft palate - Underdeveloped thymus/absent thymus - Cardiac Anomalies - Dysmorphic features - Small, short palpebral fissures - Prominent nose - Small mouth - Thin Lips - Learning Difficulties - Psychiatric Problems Micrognathia- lower jaw (much shorter or smaller) - Cri-du-chat syndrome - Pierre Robin syndrome - Progeria - Treacher Collins - Trisomy 13 - Trisomy 18 Treacher Collins  - Down slanting palpebral fissures - Receding chin - Depressed cheek bones - Malformed ears Child with Williams Syndrome (autosomal dominant 1 in 10,00 to 50,000) - Long philtrum - (upper lip length) - Wide mouth Full lips Small chin - Puffiness around eyes - Excessively social - - "cocktail child" Alagille's Syndrome: bile builds up in liver d/t too few bile ducts (mutation in JAG1 gene) - Prominent forehead - Deep set eyes - Pointed chin - Bulbous tip of nose - Heart Defects - Butterfly vertebrae - Jaundice - Itchy skin Extremities - Brachydactyly - short fingers or toes - Clinodactyly - curved fingers or toes - Arachnodactyly - long fingers &/or toes - Hypoplastic/absent nails - Single transverse palmar crease - Abnormally positioned feet Trisomy 18 - Clenched hand- overlapping fingers - Rocker bottom feet - Small mouth and unusually small jaw - Microcephaly (small head) - Low set malformed ears - Cleft lip/palate are common - Underdeveloped nails - Feeding difficulties - Congenital heart defects Marfan Syndrome - Aorta can be easily stressed, dilated, and progressively enlarged   Huntington Disease  Achondroplasia  - Prominent Forehead - Short limbs relative to trunk length - Redundant skin folds in the arms and legs  Skin - Café-au-lait spots - - Axillary freckling - Hypopigmented macules - Facial Angiofibromas Neurofibromatosis