41st National Conference on Pediatric Health Care March 25-28, 2020 ǀ Long Beach, Calif. Genetic Disorders Sharon Stevenson DNP, APRN, PPCNP-BC ©2020 Disclosures Sharon B. Stevenson, DNP, APRN, PPCNP-BC • Has no financial relationship with commercial interests • This presentation contains no reference to unlabeled/unapproved uses of drugs or products ©2020 Learning Objectives • Review basics of genetic principles • Identify components of family history and pedigree • List types of diagnostic studies • Discuss primary care management, monitoring and follow-up of genetic conditions • Describe common genetic disorders in children • List common diagnostic studies used when evaluating a suspected genetic disorder • Discuss presenting symptoms and diagnostic studies needed for suspected genetic disorder • List genetic disorders identified through newborn screenings ©2020 Basic Principles of Genetics Chromosomes • Each chromosome has a strand of DNA • Human cells have 23 pairs ➢22 are autosomes; are same in males/females ➢Sex chromosomes differ between males/females • Karyotype – picture of chromosomes lined up in pairs ©2020 Mutations • Mutation – variation <1% people ➢Often disease-causing • Polymorphism – in >1% people ➢Usually considered normal variation • Chromosome mutations – involve larger segments ➢Multi-organ, large effects, as in Down syndrome ©2020 Genetic Implications for Pediatric Care • Assessment ➢FH ➢Recognition of genetic red flags ➢Complete head-to-toe physical/developmental assessment ➢Comprehensive family health history ©2020 Family Health History and Pedigree • 3-generation pedigree ➢Visual record genetic links/health ➢Strength/pattern of traits or diseases ➢Insights about families, shared genes ➢Include health status of 1st, 2nd, and 3rd degree relatives ©2020 Family Health History and Pedigree (continued) • Genetic red flags from history • Physical findings indicating genetic ➢Indicate potential for genetic risk disorders ➢Rule of Too/Two ➢Physical abnormalities ➢ Too many of something ➢ Café au lait spots ➢ Two people/events occur ➢ Growth problems ➢ Multiple affected members with same ➢ Congenital anomalies disorder ➢ Earlier age at onset than expected for ➢ Neurological abnormalities disorder ➢ Hearing/vision loss ➢ Condition/disorder in less-often affected ➢ Developmental delay sex ➢ MR ➢ Appearance of disease in absence of ➢ Seizures known risk factors ➢ Malformations (birth defects) ➢ Ethnicity or ancestral background ➢ Deformities ➢ Consanguinity ➢ Dysplasia ➢ Intellectual impairment ➢ Syndrome ©2020 Diagnostic Studies • Screening • Diagnostic genetic testing ➢Used in asymptomatic populations to ➢Confirmatory identify those needing further ➢Main types: karyotype, FISH, evaluation biochemical testing, chromosomal microarray, molecular testing, next • Newborn screening generation sequencing ➢Identifies disorders benefiting from • Carrier testing early diagnosis and treatment ➢Identifies who has one copy of a gene ➢National Recommended Universal mutation Screening Panel (RUSP) – 31 core/26 ➢Family planning secondary conditions for screening • Other testing • Prenatal screening ➢Predictive/pre-symptomatic ➢Detect genetic/congenital disorders ➢Pharmacological before birth ➢forensic ©2020 Primary Care Management of Children with Genetic Disorders • Genetics referral ➢+ FH ➢Children with developmental, growth, and/or structural disorders ➢Genetics counseling a specific aspect of referral • Medical home • Age-appropriate health supervision guidelines • Specific guidelines for children with certain conditions https://www.aap.org/en-us/advocacy-and-policy/aap-health- initiatives/Pages/Genetics-in-Primary-Care-Institute.aspx ©2020 Let’s Talk Genetics ©2020 Categories of Genetic Disorders • Monogenetic ➢Occur when mutations affect a single gene • Chromosomal Abnormalities ➢Changes in number/structure ➢Mosaicism= altered changes in some cells • Multifactorial ➢Teratogens ➢Combination genetic/environmental ©2020 Monogenetic Disorders • Sickle Cell Disease • Hemophilia and von Willebrand Disease • Marfan Syndrome • Fragile X Syndrome • Duchene Muscular Dystrophy ©2020 Sickle Cell Disease (SCD) • Key Characteristics: • Includes HbAS (trait) and HbSS (anemia); HbSC; Thalassemias • Most common hemoglobinopathy in US • Auto recessive, abnormal crescent shaped RBCs • Clinical hallmarks- vaso-occlusive, and hemolysis • Recurrent acute and chronic pain ©2020 Sickle Cell Disease (continued) • SC Anemia • SC Crisis • Pain: long bones, abdomen, back, • Good health w/intermittent crisis chest • Chronic anemia (hgb 6-9) • Dehydration, hypoxia, acidosis • RBC turnover 5-10 days vs nl 120 days • Management • Folic acid 4 mg daily (SCA) • Evaluation: • Educate: Proper nutrition/hydration, • Hemoglobin electrophoresis S/S of infection • CBC w/indices • Vaccinate • Screen in pregnancy (African, • Diagnose and treat infections Mediterranean, Middle Eastern) promptly; tx crisis promptly • • Routine labs ie., CBC, Cr, LFTs, urine Common complications culture, iron and ferritin • Pulmonary, UTI osteomyelitis, jaundice, cardiomegaly, LVH, CVA ©2020 Hemophilia and von Willebrand Disease • Key Characteristics: • Von Willebrand (vascular • Hemophilia A hemophilia) • Factor VIII deficiency or absence • Caused by abnormality of vWF protein • Prolonged bleeding (spontaneous or trauma) • Affects both sexes • X-linked recessive • Most common inherited bleeding disorder • Hemophilia B • Factor IX deficiency • Males primarily affected ©2020 Hemophilia and von Willebrand Disease • S/S: Hemophilia A & B • S/S: Von Willebrand • +FH • Excessive bruising • Hx of ecchymosis • Prolonged bleeding (minor lacerations, • Prolonged/excessive bleeding immunizations, circumcision) (menses, epistaxis, trauma) • Hemarthrosis • Evaluation • Evaluation • Factor VIII clotting activity, • Prolonged aPTT vWF antigen and vWF • Factor VIII or IX specific assay decreased • Management • Management • Prevention of trauma • Plasma replacement therapy • DDAVP • Cold and pressure to hemarthrosis • Factor VIII or vWF areas concentrate • Ø ASA or NSAIDS ©2020 Marfan Syndrome • Key Characteristics: • Variable systemic connective tissue inherited disorder, autosomal dominate • Mutation in the fibrillin gene • Fibrillin important component of microfibrils in Elastin • Affects skeleton, eyes, and CVS ©2020 Marfan Syndrome (continued) • S/S: • Tall stature • Long fingers • Pigeon breast deformity • Hyper-extensible joints • High arched palate • BL subluxation of lens • Floppy mitral valve • Aortic aneurysm and dissection • Defects in skin, lungs • Spontaneous pneumothorax ©2020 Marfan Syndrome (continued) • Evaluation: • PC monitoring • Clinical attributes: long bone • Specialized growth chart overgrowth, dislocated lenses of the • Orthopedic problems, including eye, aortic root aneurysm scoliosis, pes planus • Fibrillin-1 genetic test • B/P (hypertension) • Management: • Annual ophthalmology screen • Echo • Avoid contact sports • Pharmacotherapy for cardiac • Caution: spontaneous symptoms pneumothorax, aortic root • Specialty care team dilatation, MVP ©2020 Fragile X Syndrome • Key Characteristics: • Most common inherited cause of intellectual disability • Caused by mutation in fragile X mental retardation 1 gene (FMR1) • Fragile or break at the X chromosome (Xq27.3) • Males = Females ©2020 Fragile X Syndrome (continued) • S/S Males: • S/S Females: • Mild to severe MR & LD • Mild cognitive deficits to MR • Delayed language • Delayed language • Long or narrow face • Shy, social anxiety • Prominent or cupped ears • Prominent ears • Enlarged testicles • Long, narrow face or high-arched • Hyperextensible finger joints, pes palate planux • Hyperextensible finger joints, pes • Hyperactivity or ADHD planus • Inattention but < hyperactivity ©2020 Fragile X Syndrome (continued) • Evaluation: • PC monitoring • Molecular genetic testing • Developmental/behavior problems • 1 or more typical features: prominent ears, hyperextensible finger joints, poor • OM/sinus eye contact, in combination with DD or • OSA MR • Obesity • Management: • Vision • Medications for hyperactivity • Caution: hypertension, MVP • Medications for aggression or severe mood lability • Special education support w/therapy services • Genetic counseling ©2020 Duchene Muscular Dystrophy • Key Characteristics: • Most common neuromuscular disease of childhood • Early age onset • Primarily affects skeletal and heart muscle • X-linked, majority males affected • Mutation in the dystrophin gene Xp21 • Chronic, degenerative, fatal disorder ©2020 Duchene Muscular Dystrophy (continued) • S/S: • Delayed motor milestones • Growth delay • Consistent pattern of weakness • Clumsiness, frequent falls • +Gowers • Calf pseudohypertrophy • Orthopedic complications • Cognitive and behavioral disorders ©2020 Duchene Muscular Dystrophy (continued) • Evaluation: • Management: • Elevated CK • No cure for DMD • Genetic analysis (deletions/duplications) • Plan should be individualized • Muscle biopsy • Therapies (PT, OT, St, recreational, • EMG aqua) • Associated problems • Immunizations, AAP guidelines • Pulmonary effects • PC monitoring • Cardiac dysfunction • Dental care • Cognitive impairments • Feeding/swallowing difficulties • Growth, development, safety • Obesity • Constipation ©2020 Chromosomal Defects • Down Syndrome • Prader Willi Syndrome • Turner Syndrome ©2020 Down Syndrome • Key Characteristics: • aka Trisomy 21 • Most common chromosomal disorder • Extra copy of genetic material on 21st chromosome • Majority of cases extra chromosome