Genetic mutations Notes

NOTES NOTES GENETIC MUTATIONS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Permanent alterations of DNA sequence → clinically significant syndrome ▪ Germ cell mutations inherited ▪ Somatic cell mutations due to environmental factors (e.g. radiation) ▪ Physiologic, pathologic processes: evolution, immune system development, cancer Inheritance patterns ▪ Autosomal dominant: one genetic copy mutated ▪ Autosomal recessive: both genetic copies mutated ▪ X-linked (dominant/recessive): mutation in X chromosome; no transmission from father to son; individuals who are biologically male more frequently/severely affected ▪ Y-linked: mutation in Y chromosome; passed from father to son ▪ Codominant: two alleles affect same trait (e.g. ABO blood group) ▪ Mitochondrial: mutation in mitochondrial DNA; maternal inheritance CAUSES Error during DNA replication ▪ Point mutation within coding sequences: substitution of single base; may occur as transition (e.g. purine → purine)/ transversion (e.g. purine → pyrimidine) ▫ Silent: codes same amino acid, no phenotypic change ▫ Missense: codes different amino acid, may cause phenotypic change (e.g. sickle cell anemia) ▫ Nonsense: early stop codon, produces nonfunctional protein, may cause 162 OSMOSIS.ORG ▪ ▪ ▪ ▪ ▪ phenotypic change (e.g. adrenal gland hyperplasia) Point mutation within noncoding sequences: mutation of promoter/ enhancer sequences → reduced/abolished transcription Deletion: removal of bases Insertion: addition of bases ▫ Splice site mutation: altered splicing of mRNA ▫ Frameshift: shifted reading frame Trinucleotide-repeat mutation: ↑ trinucleotide repeats Disorders of imprinting: one gene copy silenced by methylation (e.g. Prader–Willis syndrome) TYPES Mendelian disorder ▪ Single gene mutation, large effects Chromosomal disorder ▪ Numerical: insertion/deletion of entire chromosome (e.g. trisomies, aneuploidies) ▪ Structural: change in genetic sequence Complex multigenic disorder (polymorphism) ▪ Genes increase risk of disease, no gene capable of causing disease on own (e.g. hypertension, diabetes mellitus) RISK FACTORS ▪ Parental genetic defect ▪ Exposure to radiation, carcinogens COMPLICATIONS ▪ Spontaneous abortion; severe organ defects (e.g. tetralogy of Fallot, renal dysplasia); visual/hearing disturbances;

Chapter 25 Genetic Mutations growth deficiency; intellectual disability; cancer SIGNS & SYMPTOMS ▪ Abnormal physical features ▪ Organ defect-related signs/symptoms LAB RESULTS ▪ Altered blood tests, hormones, liver enzymes OTHER DIAGNOSTICS ▪ History, physical examination ▪ Genetic tests TREATMENT DIAGNOSIS DIAGNOSTIC IMAGING X-ray, CT scan ▪ Evidence of organ defects (e.g. fibrous dysplasia, cardiac malformations) SURGERY ▪ Surgical repair of significant defects ALAGILLE SYNDROME (ALGS) osms.it/alagille-syndrome PATHOLOGY & CAUSES ▪ Autosomal dominant disorder → liver, skeletal, ocular, cardiac, renal defects ▪ AKA arteriohepatic dysplasia, Alagille– Watson syndrome ▪ Variable penetrance; severity related to size of deletion ▪ Sometimes associated with somatic/ germline mosaicism ▪ Individuals susceptible to additional mutations CAUSES ▪ Mutation/deletion related to notch signalling pathway (involved in angiogenesis, cell proliferation, differentiation) ▫ 95% involve JAG1 gene (chromosome 20p12) ▫ NOTCH2 gene (chromosome 1p.13); related to renal malformations ▪ Results in absence of intrahepatic bile ducts → ↑ risk of progressive liver disease → chronically elevated bilirubin, cholesterol COMPLICATIONS ▪ ▪ ▪ ▪ Malabsorption Pancreatic insufficiency Abnormal vertebral segmentation Vascular anomalies (e.g. basilar artery aneurysm; ↑ risk of intracranial bleeding) Liver ▪ Chronic cholestasis (95%), cirrhosis, liver failure Cardiac ▪ Peripheral pulmonary artery stenosis, tetralogy of Fallot Ocular ▪ Shallow anterior chamber, keratoconus, embryotoxon (prominent Schwalbe’s ring), Axenfeld anomaly (embryotoxon + attached iris strands), pigmentary retinopathy, cataracts Renal ▪ Dysplasia, renal tubular acidosis OSMOSIS.ORG 163

SIGNS & SYMPTOMS ▪ Intellectual disability, learning difficulties ▪ Hepatosplenomegaly Cholestasis ▪ Jaundice, pruritus, xanthomas (cholesterol deposits in skin) Facial features ▪ Triangular face, prominent forehead, hypertelorism (widely-spaced eyes), deepset eyes, upslanting eyelids, long nose with bulbous tip, large ears, prominent mandible, pointed chin; more prominent with age Growth deficiency ▪ Short stature DIAGNOSIS DIAGNOSTIC IMAGING Spinal X-ray ▪ Butterfly-shaped vertebrae, hemivertebrae, spina bifida occulta LAB RESULTS ▪ ↑ bilirubin (total, conjugated), ↑ liver enzymes, ↑ cholesterol ▪ Liver biopsy: intrahepatic bile duct paucity, portal inflammation OTHER DIAGNOSTICS ▪ History, clinical examination ▪ Genetic tests TREATMENT MEDICATIONS ▪ Choleretic agents: ursodeoxycholic acid + cholestyramine/rifampin/naltrexone SURGERY ▪ Biliary diversion/liver transplantation ▪ Heart defect surgical repair OTHER INTERVENTIONS ▪ Nutritional support Abdominal ultrasound ▪ Kidneys: small, echogenic, presence of cysts, ureteropelvic obstruction MCCUNE–ALBRIGHT SYNDROME osms.it/mccune-albright_syndrome PATHOLOGY & CAUSES ▪ Genetic disorder characterized by fibrous dysplasia (FD), endocrinopathy, unilateral café-au-lait skin spots ▪ Occurs most commonly in skull base/ proximal femur; most lesions appear < age 15 ▪ External beam radiotherapy: ↑ risk of malignant transformation ▪ More common among individuals who are biologically female 164 OSMOSIS.ORG ▪ Post zygotic mutation in GNAS1 gene (20q.13.1-13.2) ▫ Encodes Gs alpha protein → G protein/ cAMP/adenylate cyclase signaling pathway ▪ Somatic mosaicism: some somatic cells mutated COMPLICATIONS ▪ Pathologic fractures; osteosarcoma; osteomalacia; visual/hearing disturbances (due to nerve compression); severe pain; scoliosis; ovarian cysts; acromegaly,

Chapter 25 Genetic Mutations gigantism; Mazabraud syndrome (fibrous dysplasia + intra/juxtamuscular myxoma); liver disease; higher risk of thyroid, testicular, breast cancer LAB RESULTS SIGNS & SYMPTOMS GH excess ▪ ↑ GH, ↑ prolactin Clinical triad ▪ Bone fibrous dysplasia ▫ Limp, pain, dysmorphism ▪ Hyperfunctioning endocrinopathy ▫ Hyperthyroidism: change in appetite, insomnia, fatigue, palpitations ▫ Cushing’s syndrome: moon facies, plethora, hirsutism ▫ Growth hormone (GH) excess: enlarged facial/body features, excessive sweating, thickened skin ▫ Renal phosphate wasting: usually asymptomatic; weakness, pain, altered mental status ▫ Precocious puberty: early vaginal bleeding, breast development in individuals who are biologically female; early testicular/penile enlargement, scrotal rugae, body odor, pubic/axillary hair, sexual behaviour in individuals who are biologically male ▪ Café-au-lait skin spots ▫ Brown macules, irregular borders (“coast of Maine”); mostly on lower back, buttocks DIAGNOSIS DIAGNOSTIC IMAGING X-ray, radionuclide bone scan ▪ Long bones: expansile, lytic lesions; endosteal scalloping (focal resorption of cortex inner layer), cortex thinning, “ground-glass” appearance of medulla; epiphysis usually spared ▫ Proximal femur: “shepherd’s crook” malformation ▪ Skull: sclerotic lesions, “ground-glass” appearance, cyst-like lesions Hyperthyroidism ▪ ↓ thyroid stimulating hormone (TSH), ↑ triiodothyronine (T3) Cushing’s syndrome ▪ ↑ 24-hour urinary free cortisol Renal phosphate wasting ▪ ↑ urinary phosphate, ↓ serum phosphate Precocious puberty ▪ ↑ testosterone/estradiol, ↓ luteinizing hormone (LH), ↓ follicle-stimulating hormone (FSH) Bone tissue biopsy ▪ Absence of lamelation pattern, “Chinese writing” pattern, areas of unmineralized osteoid OTHER DIAGNOSTICS ▪ History, physical examination ▪ Genetic tests (e.g. polymerase chain reaction, next-generation sequencing) TREATMENT MEDICATIONS ▪ Bisphosphonate treatment for pain management (no effect on disease progression) ▪ Medication for endocrine disorders (e.g. gonadotropin releasing hormone analogues, tamoxifen, thionamides) SURGERY ▪ Surgical management of fibrous dysplasia (e.g. intramedullary devices, bone grafting) OTHER INTERVENTIONS ▪ Physical exercise (e.g. cycling, swimming) ▫ ↑ bone support → ↓ fracture risk Thyroid ultrasound ▪ Presence of cystic areas OSMOSIS.ORG 165

PRIMARY CILIARY DYSKINESIA osms.it/primary-ciliary-dyskinesia PATHOLOGY & CAUSES ▪ Congenital disease; defect in cilia motility → impaired mucociliary clearance, decreased fertility ▪ AKA immotile-cilia syndrome ▪ Affects cilia of respiratory tract, fallopian tubes, sperm flagella ▪ Inheritance pattern: autosomal recessive CAUSES ▪ Defect in proteins of cilia structure → absent/altered motion (e.g. clockwise rotation) ▪ Genetic mutations ▫ DNAH5, DNAI1: encode axonemal outer dynein arms ▫ RSPH4A, RSPH9: encode radial spokes COMPLICATIONS ▪ Chronic sinusitis; Kartagener’s syndrome (situs inversus, chronic sinusitis, and bronchiectasis); hydrocephalus; transposition of great vessels; epispadias; pectus excavatum; chronic secretory otitis media; conductive hearing loss SIGNS & SYMPTOMS ▪ Recurrent upper/lower respiratory tract infections: chronic cough, mucopurulent sputum; symptoms increase during course of day ▪ Newborns: present with mild respiratory distress (tachypnea, mild hypoxemia) ▪ Bronchiectasis: crackles, wheezes ▫ Exacerbation: dark sputum, dyspnea, pleuritic pain ▪ Rhinosinusitis: runny nose, constant congestion, nasal polyps, altered sense of smell ▪ Fatigue, headaches 166 OSMOSIS.ORG ▪ Infertility ▪ ↓ aerobic fitness DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray, CT scan ▪ Pulmonary hyperinflation, peribronchial thickening, atelectasis, bronchiectasis; situs inversus LAB RESULTS ▪ Reduced/absent nasal nitric oxide (also present in some cases of cystic fibrosis) Cell culture ▪ Inferior concha epithelium: tissue culture → cilia shed → emergence of new, immotile cilia → diagnosis confirmation OTHER DIAGNOSTICS ▪ Spirometry: obstructive pattern ▪ Genetic tests Ciliary motion, ultrastructure ▪ High speed video microscopy analysis (HSVA): live examination of respiratory epithelial cells; after air-liquid interface/ cooling → assessment of motion pattern, beat frequency ▪ Transmission electron microscopy (TEM): observation of ciliary ultrastructure defects TREATMENT MEDICATIONS ▪ Bronchiectasis ▪ Antibiotics, airway hydration (e.g. nebulized hypertonic saline), mucolytic agents Chronic rhinitis ▪ Nasal saline lavage + intranasal glucocorticoids

Chapter 25 Genetic Mutations SURGERY Chronic rhinitis ▪ Polyp removal OTHER INTERVENTIONS ▪ Smoking cessation ▪ Pneumococcus, influenza vaccination Bronchiectasis ▪ Daily chest physiotherapy TREACHER COLLINS SYNDROME osms.it/treacher-collins-syndrome PATHOLOGY & CAUSES ▪ Severe genetic disorder of craniofacial development ▪ AKA mandibulofacial dysostosis, Franceschetti–Zwahlen–Klein syndrome ▪ Inheritance pattern: autosomal dominant, variable penetrance; 60% spontaneous CAUSES ▪ TCOF1 gene mutation (chromosome 5q32) → treacle protein (ribosome biogenesis regulator) insufficiency → neuroepithelial cell apoptosis → ↓ neural crest cells → first, second branchial arch anomalies → cranioskeletal hypoplasia ▪ Other genetic mutations: POLR1C (6q21.2), POLR1D (13q12.2); involved in ribosome biogenesis COMPLICATIONS ▪ Perinatal death; bilateral conductive hearing loss; speech problems; airway compromise; feeding difficulties; visual loss; brachycephaly; choanal atresia; congenital heart defects; intellectual disability; renal malformation SIGNS & SYMPTOMS ▪ Facial bone hypoplasia (esp. mandible, zygomatic bone): retrognathia, sunken cheeks ▪ Facial asymmetry ▪ Projection of scalp hair to lateral cheek ▪ Dental: high/arched/cleft palate; malocclusion, tooth agenesis, enamel opacities ▪ Ocular: downslanting eyelids, lower eyelid coloboma, paucity of eyelashes medial to notch, hypertelorism (widely spaced eyes) ▪ Malformation of external ear, external auditory canals, middle ear ossicles DIAGNOSIS DIAGNOSTIC IMAGING Cranial X-ray, orthopantomogram, CT scan ▪ Facial bone hypoplasia, altered middle ear ossicles, external auditory canal stenosis OTHER DIAGNOSTICS ▪ History, clinical examination ▪ Prenatal: amniocentesis, chorionic villus sampling OSMOSIS.ORG 167

TREATMENT SURGERY ▪ Reconstructive surgery ▪ Tracheostomy (severe airway obstruction at birth) ▪ Glossopexy (tongue-lip adhesion) ▪ Corrective surgery for cleft lip/palate/ choanal atresia ▪ Gastrostomy tube placement OTHER INTERVENTIONS ▪ Supportive treatments (e.g. hearing aid, speech therapy) 168 OSMOSIS.ORG Figure 25.1 The face of a female child with Treacher Collins syndrome.