Genetic Disorders

41st National Conference on Pediatric Health Care

March 25-28, 2020 ǀ Long Beach, Calif.

Genetic Disorders

Sharon Stevenson DNP, APRN, PPCNP-BC

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

• 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

• 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

• 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

• Assessment ➢FH ➢Recognition of genetic red flags ➢Complete head-to-toe physical/developmental assessment ➢Comprehensive family health history

• 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

• 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

• 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

• 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

• 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

• Sickle Cell Disease • Hemophilia and von Willebrand Disease • Marfan Syndrome • Fragile X Syndrome • Duchene Muscular Dystrophy

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• S/S: • Delayed motor milestones • Growth delay • Consistent pattern of weakness • Clumsiness, frequent falls • +Gowers • Calf pseudohypertrophy • Orthopedic complications • Cognitive and behavioral disorders

• 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

• Down Syndrome • Prader Willi Syndrome • Turner Syndrome

• Key Characteristics: • aka Trisomy 21 • Most common chromosomal disorder • Extra copy of genetic material on 21st chromosome • Majority of cases extra chromosome from mother • Caused by a meiotic non-junction event

• S/S and Presentation: • Short stature • Brachycephaly • Midface hypoplasia • Epicanthal folds with palpebral fissures that slant down to midline • Small mouth with protruding tongue • Myopia • Lax joints • Single palmar crease • Exaggerated space between great and 2nd toes

• Evaluation: • PC monitoring • Karyotyping pre/postnatal • No one physical characteristic is considered • Specialized growth chart diagnostic • OSA • Management: • Annual vision/hearing • Extensive interdisciplinary services • Genetic counseling • Annual thyroid screen • Prevention of secondary conditions • Caution: increased risk leukemia, • Enrollment in EIP duodenal atresia, cardiac anomalies • Associated Problems • Intellectual/Developmental delay • Hearing loss • Cardiac defects, GI anomalies, MSK, Immune system deficiency, Thyroid, Growth, Malignancies

• Key Characteristics: • Most common form of syndromic obesity • Absence of a group of genes on chromosome 15 • Majority of cases occur sporadically

• S/S: • FTT (infancy) • Evaluation: • Short stature • Methylation analysis (deletion, • Central obesity (later in childhood) uniparental disomy, or imprinting mutation) • Hypothalamic insufficiency • Major criteria: excessive wt gain, • Strabismus neonatal/infant hypotonia, feeding • Myopia/hyperopia issues, hypogonadism, DD, • Sleep apnea hyperphagia • Enamel hypoplasia • Minor criteria: decreased fetal • Scoliosis movement, behavior problems, • Hallmark- neonatal hypotonia sleep disturbance, short stature, hypopigmentation, small hands/feet, visual disturbance.

• Management: • Symptom specific • GH for growth failure • Therapy services • Clinical nutrition/weight management • Pharmacotherapy • PC Monitoring • Specialized growth chart • DD/ID • Speech • Annual vision • Behavioral problems

• Key Characteristics: • Primary hypogonadism in phenotypic females • Results from partial or complete monosomy of an X chromosome • Most common cause is absence of one X chromosome (45 X) • Less commonly, mosaicism, or deletions on the short arm of the X chromosome

• S/S: • Short stature for family • Short neck w/webbing • Posteriorly rotated ears • Ptosis • Short 4th & 5th metacarpals • Short legs • Hip dysplasia, scoliosis, &/or kyphosis • Horseshoe kidney • Cardiac disease • Delayed puberty

• Associated problems • PC monitoring • LD • Hearing loss • Specialized growth chart • Strabismus • LD • Evaluation: • BP (hypertension) • Karyotype analysis • Annual thyroid screen • Prenatal diagnostic screening (chorionic villus sampling or • Scoliosis amniocentesis) • Caution: cardiac/renal anomalies • Management: • Estrogen supplementation with • GH puberty • Estrogen therapy • Managing associated congenital anomalies, comorbidities or complications

• Neural Tube Defects (NTDs) • Cleft lip/palate

• Key Characteristics: • Malformations of the CNS • Spina bifida or myelodysplasia most common NTD • Combination of environmental and genetic factors • Autosomal recessive • No single gene • Exposure to teratogens i.e., certain medicines, hyperthermia, radiation, ETOH, lead, Infections- Rubella

• Congenital malformation of vertebrae • Spina bifida • Meningocele • Myelomeningocele • Cutaneous abnormalities • Hair tufts • Dimpling • Hemangiomas • Dermoid cysts • S/S: • LE weakness or atrophy • Foot deformities • B/B disturbances

• Evaluation: • PC • US in utero • G & D • Prenatal screening • Nutritional assessment • Postnatal: US, CT, MRI • Safety • Cardiopulmonary assessment • Immunization, AAP guidelines before surgical intervention • Condition specific screenings • Management • Assess level of involvement (CT/MRI) • NS • Multi-disciplinary team approach

• Key Characteristics: • Nonsyndromic – multifactorial • Environmental • Genetic • Syndromic • Single-gene disorders • Chromosomal abnormalities • Teratogens • sequences

• S/S and clinical presentation: • Evaluation/Diagnostic criteria: • Cleft lip: fissure of the upper lip • Obvious birth defect along the frenulum that often • Unilateral or bilateral includes bones of upper jaw and/or gum • Incomplete or complete • Cleft palate: fissure in either the • Management: hard palate and/or soft palate • Establishment of adequate feeding • Cleft palate: difficulty feeding b/c • Airway management for infants with inability to suck Pierre Robin sequence • Pierre Robin sequence: S/S of upper • Surgical reconstruction airway obstruction r/t micrognathia • Otolaryngology • Submucous cleft palate: nasal- sounding speech • Audiology and speech • Dental and orthodontic

• Key Characteristics: • Frequency 1:12,000 • Autosomal recessive • Deficiency in the enzyme phenylalanine hydroxylase • Impaired conversion of the aa phe to tyr • If undetected during the newborn period, the onset of PKU is insidious and may not cause symptoms until early infancy.

• S/S: • Management: • Appear normal at birth • Diet with low (controlled) If Untreated: phenylalanine content • Hallmark- irreversible intellectual disability, seizures, behavioral • Supplement tyrosine and other abnormalities, microcephaly and skin nutrients as needed disease • Clinical nutrition • Neonatal vomiting • Mousy odor of urine and sweat • PC monitoring • Fine, rapid, irregular tremor • G&D • Evaluation: • Diet for life • Elevated serum phenylalanine • Condition specific screening • Molecular testing • Immunizations, AAP guidelines

• Key Characteristics: • Frequency 1:2000 to 1:4000 • Most commonly congenital absence of thyroid gland • May be ectopic/hypoplastic • Preventable cause of intellectual disability

• S/S: • Evaluation: • Asymptomatic at birth • Routine screening all 50 states • Severe MR • Issues: early d/c of infants • Growth retardation • Management: • Irreversible neurologic problems • Thyroid hormone replacement after 16 days of no therapy

• Key Characteristics: • Frequency 1:60,000 • Altered metabolism of galactose • Deficiency of enzyme gal-1-PUT, most common and severe

• S/S: • Evaluation/Diagnostic: • Symptoms after galactose in diet • Newborn screening • Jaundice • Management: • Vomiting • Galactose free diet • Hepatomegaly • FTT • Poor feeding • Lethargy • Diarrhea • Sepsis

• Key Characteristics: • Frequency 1:15,000 • Inherited disorder d/t missing enzyme affecting steroid/hormone production • Three kinds • Classical/Salt Wasting CAH • Simple Virilizers • Non-Classical CAH • Most common 21-hydroxylase deficiency (21-OHD)

• Classic • Virilization • Elevated 17-OHP (hydroxyprogesterone) • Electrolyte instability • Vomiting, dehydration • FTT • Metabolic alkalosis • Adrenal crisis • Nonclassic • Female: virilization, ambiguous genitalia at birth Management: • Male: early beard growth • Glucocorticoid replacement • Both: accelerated growth, advanced • Mineralocorticoids & sodium replacement bone age, premature adrenarche • Genital surgery • Psychosocial support

• Meets all criteria for population screening • Advances: • Technology in testing (ABR/OAE) • Most common condition screened • If hearing loss detected • Before 6 months = normal speech/language • After 18 months = speech/language deficits

A. Asymptomatic B. Pleuritic chest pain, fever, cough C. Abdominal and back pain D. Fatigue, swelling of hands and feet Typical signs of a child with Sickle Cell Trait include which of the following:

Answer: Asymptomatic Question Which of the following genetic disorders would the PNP counsel about avoidance of contact sports?

A. Neurofibromatosis 1 B. Prader Willi Syndrome C. Marfan Syndrome D. Fragile X Syndrome Which of the following genetic disorders would the PNP counsel about avoidance of contact sports?

Answer: Marfan Syndrome Question Which diagnostic study would the PNP initially order in a 5 year old child with difficulty climbing stairs, running, and falls frequently.

A. Serum creatine kinase B. Molecular testing C. Karotype D. Chromosomal micro-array Which diagnostic study would the PNP initially order in a 5 year old child with difficulty climbing stairs, running, and falls frequently.

Answer: Serum creatine kinase Question

A 13-year old girl with clinical physicals on examination of short stature, webbed neck and delayed puberty. What diagnosis would the PNP suspect: A. Fragile X Syndrome B. Marfan Syndrome C. Turner Syndrome D. Prader Willi Syndrome

Answer: Turner Syndrome