Genetic Disorders PDF

Gene$c disorder: - Maybe hereditary or non-hereditary Can be monogenic, mul$factorial or chromosomal Single mutated gene lead to single-gene or monogenic disorder Monogenic disorder - Involve single allele Primary gene$c defeat: usually a point/frame shiA muta$on à change the synthesis of protein...

Gene$c disorder: - Maybe hereditary or non-hereditary Can be monogenic, mul$factorial or chromosomal Single mutated gene lead to single-gene or monogenic disorder Monogenic disorder - Involve single allele Primary gene$c defeat: usually a point/frame shiA muta$on à change the synthesis of protein à in born error of metabolism Hun$ngton’s disease (HD) Background Death of brain cell Common site: Cause: Heritance: autosomal dominant muta5on in a gene – Hun5ng5n. Or new muta5on. Pathogenesis: Incidence: 4-15 in 100000 European, M=F, Rare in Asian, expansion of CAG tripletàabnormal protein Risk factor: Prognosis: No cure L Diagnosis: Gene$c tes$ng Sign *Begin 30-50 yrs old, 8% begins < 20 Similar to Parkinson’s disease Early: poor mood, lack of coordina$on, unsteady gait Later: uncoordinated, jerky body movement, unable to talk, demen$a Treatment: Tetrabenazine, symptoma$c relief Sickle cell anaermia (SCA) Background A blood disorders inherited from a person's parents, Cause: abnormality in the oxygen-carrying protein haemoglobin found in RBC leading to a rigid, sickle-like shape Pathogenesis: 4.4 m ppl, 43 m hv trait Inherit 2 abnormal haemoglobin gene, one from each parent, chromosome 11 Risk factor: Prognosis: Average life expectancy: 40-60 years Diagnosis: -blood test in the new born -gene$c screening during pregnancy Sign A]acks of pain, anemia, swelling in the hands and feet, bacterial infec$ons, stroke Long-term pain when people get older Treatment Vaccina$on and an$bio$cs, high fluid intake, folic acid and pain medica$on Others: blood transfusion, hydroxycarbamide, hydroxyurea, stem cell therapy *Cured by a transplant of bone marrow cells in some people Neurofibromatosis (NF) Background NF1, NF2, schwannomatosis Pathogenesis: Incidence NF1: 1/3500 NF2: 1/25000, M=F gene$c muta$on in certain genes inherited from patents Risk factor: Prognosis: No known preven5on or cure Diagnosis based on S&S + gene$c tes$ng Sign NF1: light brown spots on the skin, freckles in the armpit and groin, small bumps within nerves, scoliosis (normal life expectancy) Treatment Surgery to remove tumors that are causing problems/become cancerous +/- NF2: hearing loss, cataracts at a young age, balance problems, flesh-colored skin flaps, muscle was$ng (increase risk of early death) A cochlear implant/auditory brainstem implant helps hearing loss Radia5on and chemotherapy Multiple Hereditary Exostosis (HME) 多發性骨軟骨瘤, Hereditary multiple osteochondromas (HMO) Background development of mul5ple benign osteocar5laginous masses (exostoses) Common site: ends of long bones (femur & $bia in LL, humerus, Radius, Ulnar in UL) OR flat bones (in pelvic bone and scapula) Cause: Growth of car$lage-capped benign bone tumours in the metaphysis of the long bones. Common 5 – 6 exostoses are in UL & LL Pathogenesis: Incidence: 1 in 50,000 Present in childhood Clinically manifest when reach adolescence May become sarcomas 惡性肉瘤 Risk factor: Prognosis: Diagnosis Family history, P/E , Radiographic features (osteochondromas at the metaphyseal ends of long bones), & Gene$c Tes$ng of EXT1 and EXT2 Sign -no$ceable lump in the extremity -coronal plane deformi5es around the knees, ankles, shoulders, elbows, and wrists, leading to Genu Valgum, Ankle Valgus, Ulnar Bowing and shortening, and radial head subluxa$on -Intra-ar$cular osteochondromas of the hip can limit ROM, cause joint pain and acetabular dysplasia. -Joint pain at other loca$ons + neurovascular compression. -Func5onal disability -Spinal deformity pain/neurological compromise (when involving the vertebrae) -Possible connec$on to au5sm/au$sm- like social problems Treatment ostechondroma excision, gradual or acute bone lengthening, correc$ve osteotomies, temporary hemiepiphysiodesis (e.g. distal radius hemiepiphysiodesis and medial distal $bial hemiepiphysiodesis). Total hip arthroplasty àemedy severe and painful hip Mul$factorial disorder -interac$on between environmental & gene$c factor - Polygenic in nature -environmental factors (significant role) -cluster in families -account of morbidity & mortality Gene$c disorder Prognosis: From death to various outcome Diagnosis -Varied & dependent of the disorder -Some can escape detec$on un$l adulthood ( mostly detect at birth/ early childhood) -Gene5c material examina5on & indepth family history Prenatal: fetal development US/ amniocentesis Treatment Gene$c therapy Suppor$ve therapy (improve QoL) Skeletal Dysplasias (SD), osteochondrodysplasias and malforma$ons Background -Abnormal shape and size of the skeleton , dispropor$on of the long bones, spine, and head -Typified by short nature (height<3SD of mean age height) Cause: A heterogeneous group of heritable disorders characterized by abnormali$es of car$lage and bone growth Pathogenesis: Risk factor: classifica$on Common SD: • Achondroplasia, • Osteogenesis imperfecta, • Thanatophoric dysplasia, • Campomelic dysplasia • Hypochondroplasia. Achondroplasia Background: -most common nonlethal skeletal dysplasia -1 In 26,000-28,000 Sign: -Normal-sized trunk, large head, shortening of limb, lumbar lordosis, trident hand, height :130cm (M), 125cm (F), normal lifespan& intelligent Radiograph: àabnormal pelvis with small square iliac wings à horizontal acetabular roofs à narrowing of the greater scia$c notch à an oval translucent area at the proximal ends of the femora àcaudal narrowing of the interpedicular distances in the lumbar region àshort pedicles à lumbar lordosis Major complica$ons: àCraniocervical junc$on compression à Middle ear infec$ons, à Obstruc$ve apnea, à Spinal stenosis, à Osteogenesis imperfect. Sign: Hurler syndrome (mucopolysaccharidosis type IH) - dysplasia, scaphocephalic macrocephaly, coarse facial features, depressed nasal bridge, broad nasal $p, thick lips, short neck, protuberant abdomen, inguinal hernia, joint contractures, claw hands -Radiographs: àhook-shaped deformity (anterior wedging) of the L1 and L2 vertebrae à abnormally short, wide, and deformed tubular bones (bullet-shaped) of the hands à narrow base of the secondto-fiAh metacarpals àThe distal ar$cular surfaces of the ulna and radius are slanted toward each other Osteogenesis Imperfecta (OI) - heterogeneous group of heritable connec$ve $ssue disorders - common SD -Type I-IV: muta$on in type 1 collagen gens COLA1 & COLA2 -Type V- XII: rare forms Incidence: 1in 15,000-20,000 Inheritance: a) Types I-IV (Sillence classifica$on, 85% of cases): Autosomal dominant b) Types V-XII: Autosomal recessive except for type V (autosomal dominant) *all form: bone fragility & suscep5bility to fracture from minimal trauma OI type I - mild form with diagnosis in early childhood -Sclera may be blue, Den$nogenesis imperfecta (subtype IB), Normal stature reached, Hearing loss in 50% of pa$ents OI type II - perinatal lethal form - may survive the neonatal period - later mortality: secondary to pneumonia &respiratory insufficiency OI type III - progressive deforming form -Moderate deformity at birth, -Development of chest wall deformi$es - Most pa$ents are wheelchair dependent - Very short stature, Variable sclera -Den$nogenesis imperfecta and hearing loss are common (*same with type II) Sign: Larsen syndrome Cle] palate, talipes (TEV), disloca$on of elbows, hips, knees, flat face with depressed nasal bridge, prominent forehead, hypertelorism Radiograph: disloca$on at knee OI type IV - moderately severe form -Mild to moderate bone deformity, Variable short stature, Hearing loss occurs in some families, Variable sclera Major complica$ons: i)bone fractures, ii). bone deformity iii)growth deficiency. Dx: -radiologic + gene$c evalua$ons à XR examina$on: skeletal survey including the Skull, spine: AP & lateral views Chest, tubular bones, pelvis, hands and feet: AP Cervical spine: lateral view àGene$c tes$ng: Molecular diagnos$c techniques (iden$fy the underlying gene disorders, in 2/3 of known skeletal dysplasias cases) Suppor$ve care: -To prevent neurologic & orthopedic complica$ons (e.g. long bone deformity) Surgical interven$on: Anterior and posterior fusion for progressive kyphosis à spinal cord compression and spas$c paraparesis. Extensive lumbar laminectomy(Lumbar lordosis with spinal stenosis) Surgical decompression à relieve edema of the cervico-medullary cord Bone tumours Background -neoplas$c growth of $ssue in bone -5 year survival in US, 67% bone& joint cancer Sign -Pain that gradually increases over $me (the pain increases with the growth of the tumor), fa$gue, fever, weight loss, anemia, nausea, and unexplained bone fractures. - Many pa$ents X experience any symptoms (except for a painless mass) -Some bone tumors may weaken the structure of the bone à pathologic fractures Primary bone tumor -benign & malignant tumor (cancer) -Loca$on: the distal femur & proximal 5bia -E$ology: neoplas$c, developmental, trauma$c, infec$ous, inflammatory -Some benign X true neoplasms, but hamartomas(developmental malforma$on) with focal malforma$on (resembles neoplasms) E.g. 1. Benign bone tumors 2. Malignant primary bone tumors 3. Malignant fibrous his$ocytoma (MFH) OR “Pleomorphic undifferen$ated sarcoma" - specialized studies (i.e. gene$c and immuno-histochemical tests) to classify these undifferen$ated tumors into other tumor classes (mul$ple myeloma & germ cell tumors) classifica$on 1. Primary tumors (originate in bone or from bone-derived cells and $ssues), and 2. Secondary tumors (originate in other sites and spread (metastasize) to the skeleton). * Secondary malignant bone tumors 50 100 $mes more common than primary bone cancers] Treatment All depends on the type of tumor 1. Chemotherapy and radiotherapy effec$ve in Ewing's sarcoma but less so in chondrosarcoma. A variety of chemotherapy treatment protocols exists for different types of bone tumors Secondary bone tumors -metasta$c lesions that have spread from other organs (commonly from CA Breast, Lung, or Prostate) Incidence, prevalence, and mortality of malignant bone tumors in the pa$ent > 75 y.o. are difficult to obtain due to: i). Carcinomas metasta$c to bone are rarely curable ii). Biopsies to determine the origin of the tumor are rarely done. Dx: X-rays, CT scan, MRI, PET-CT +/histopathology. An intra-arterial protocol (good in adults & children) Tumor response is tracked by serial arteriogram. When tumor response has reached >90% necrosis surgical interven$on is planned. 2. Medica5on Major concern is on bone mineral density (BMD) due to the tumour destroys the bone strength. Bisphosphonates increase bone strength and are available as once-a-week prescrip$on pills Metastron or Stron$um-89 chloride is an IV medica$on for pain relief in 3/12 intervals Denosumab (bone cancer pa$ent) 3. Surgical treatment: A) Limb amputa$on or limb sparing surgery +/- chemotherapy & radia$on therapy. The affected bone is removed and replaced by either (a) bone graA, or (b) ar$ficial limb B) Van Nes Rota$onplasty: amputa$on in which the pa$ent's foot is turned upwards in a 180 degree turn and the upturned foot is used as a knee. C) Amputa$on such as Below knee, Above knee, Symes, Hip disar$cula$on, Hemipelvectomy; Below elbow, Above elbow, Shoulder disar$cula$on, and Forequarter. D)Hemicorporectomy (translumbar or waist amputa$on): Removes the legs, the pelvis, urinary system, excretory system and the genital area (penis/testes in males and vagina/vulva in females). First stage is colostomy + urinary conduit, the second stage is the amputa$on. E) Thermal abla$on techniques (e.g. CT guided radiofrequency abla$on, RFA): Less invasive alterna$ve to surgical resec$on in the care of benign bone tumors Performed under conscious seda$on, a RF probe is introduced into the tumor nidus through a cannulated needle under CT guidance and heat is applied locally to destroy tumor cells: less bone destruc$on + safety + efficacy à 96% symptom free F) External beam radia$on therapy: A standard care for pa$ents with localized bone pain due to metasta$c disease Pain relief, but the effect is transient in >50% pa$ents. For pa$ents not respond to radia$on therapy, chemotherapy, pallia$ve surgery, bisphosphonates or analgesic medica$ons à thermal abla$on techniques (pain reduc$on) G) Cryoabla$on: A poten$ally effec$ve alterna$ve, a poten$al advantage when trea$ng tumors adjacent to cri$cal structures. Prognosis: good for benign tumors in general. For malignant bone tumors, the cure rate depends on the type of cancer, loca$on, size, and other factors.