Genetic Disorders Lecture Notes PDF

PHT2012 Orthopaedics, Traumatology & Rheumatology Lecture 12 Genetic disorders, skeletal dysplasia and malformations. Bone tumours Contents of this lecture are intended for use by BSc (Hons) students of TWC only Dr Anthony Kwok, PhD, FHKHSE, FCHSM, FAIHS, RPT Associate Professor/Clinical Co-ordina...

PHT2012 Orthopaedics, Traumatology & Rheumatology Lecture 12 Genetic disorders, skeletal dysplasia and malformations. Bone tumours Contents of this lecture are intended for use by BSc (Hons) students of TWC only Dr Anthony Kwok, PhD, FHKHSE, FCHSM, FAIHS, RPT Associate Professor/Clinical Co-ordinator (Physiotherapy) School of Medical and Health Sciences 1 Read as an adjunct: 1. Apley & Solomon’s System of Orthopeadics & Trauma: Chapter 8 and 9 (p. 157- 228) 2. Wynne-Davies R. (1975), A review of genetics in orthopaedics, Acta Orthopaedica Scandinavica, 46(3):338-349 3. Vitale, Michael, G.; Guha, Abhijit; Skaggs, David, L. (2002), Orthopaedic Manifestations of Neurofibromatosis in Children: An Update, Clinical Orthopaedics and Related Research: August 401, p 107-118 4. Journal of Orthopaedics Genetic Disorder Genetic disorders • A genetic problem caused by one or more abnormalities formed in the genome. • Most genetic disorders are quite rare and affect one person in every several thousands or millions. • Around 80% of diseases could be passed from the parents to the offspring, but whether to appear or not could be due to the environmental factors such as care and control, life style, pollutions, climate changes, diets, exercises, etc. • Genetic disorders may be hereditary or non-hereditary, as in some genetic disorders, defects may be caused by new mutations, altered phenotype, or changes to the DNA (in such cases, the defect will only be passed down if it occurs in the germline). • Genetic disorders can be monogenic, multifactoral, or chromosomal. • Some types of recessive gene disorders confer an advantage in certain environments when only one copy of the gene is present. A single-gene or monogenic disorder is the result of a single mutated gene. ***Over 6,000 human diseases are caused by single-gene defects. Note: Some of the diseases are seen in Hong Kong Chinese, e.g. Hemophilia and some are uncommon, e.g. Cystic Fibrosis (common in white people) Some are Autosomal dominant or recessive, and some are X-linked. HK is a metropolitan city, you may see different genetic diseases in HK. Pay attention to people of non-Chinese ethnic background. Huntington’s Disease (HD)/Huntington's chorea An inherited disorder that results in the death of brain cells. Epidemiology: affects about 4 -15 in 100,000 people of European descent. Rare among Japanese/Asian. Affect Men = women equally. Aetiology: caused by an autosomal dominant (a child of an affected person typically has a 50% chance of inheriting the disease) mutation in a gene called “Huntingtin”. Up to 10% of cases are due to a new mutation. Pathogenesis (the origin and development of the disease): The Huntingtin gene provides the genetic information for a protein. Expansion of CAG (cytosineadenine-guanine) triplet repeats in the gene coding for the Huntingtin protein results in an abnormal protein, which gradually damages cells in the brain. S&S: • Usually begin between 30 and 50 years of age • 8% of cases are before the age of 20 year old. Presentation symptoms: • similar to Parkinson's disease. • Earliest: poor mood/mental abilities + lack of coordination + unsteady gait. • Later: uncoordinated + jerky body movements + unable to talk + mental abilities decline into dementia. Some actor/actress has the Huntington Ds. Appear after their 40’s of age. White people pay lot of attention on this disease Diagnosis: Genetic testing. Medical ethics: Raises several ethical debates on the age at which an individual is considered mature enough to choose testing + whether parents have the right to have their children tested: need to manage confidentiality + disclosure of test results. Prognosis: No cure. Need full-time care in the later stages of the disease. Complications such as pneumonia, heart disease, and physical injury from falls reduce life expectancy. Suicide is the cause of death in about 9% of cases. Death occurs 15 – 20 years from onset of disease. Treatments: symptomatic relief to improve quality of life + Tetrabenazine. Current research directions: 1. determine the exact mechanism of the disease, 2. test medications to treat symptoms/slow the progression of the disease, and 3. study stem cell therapy to repair damage caused by the disease. Sickle cell anaemia (SCA) Aetiology: A blood disorders inherited from a person's parents. Results in an abnormality in the oxygen-carrying protein haemoglobin found in RBC leading to a rigid, sickle-like shape under certain circumstances. Begin around 5 to 6 months of age. Epidemiology: 2015 Data: 4.4 million people have sickle cell disease. 43 million have sickle cell trait. 80% in Sub-Saharan Africa. Frequent in India, the Arabian Peninsula, and Africans living in other parts of the world. 114,800 deaths due to the disease. Pathogenesis: Sickle cell disease occurs when a person inherits two abnormal copies of the haemoglobin gene, one from each parent, in chromosome 11. An attack can be set off by temperature changes, stress, dehydration, and high altitude. S&S: "sickle cell crisis" Attacks of pain, anemia, swelling in the hands and feet, bacterial infections and stroke. Long-term pain may develop as people get older. Prognosis: average life expectancy in the developed world is 40 - 60 years. Diagnosis: blood test in the new born or genetic screening during pregnancy. Management: vaccination and antibiotics, high fluid intake, folic acid and pain medication. Others: blood transfusion, hydroxycarbamide, hydroxyurea, Stem cell therapy . **Cured by a transplant of bone marrow cells in some people. Neurofibromatosis (NF) Tumors grow in the nervous system: 3 conditions neurofibromatosis type I (NF1), neurofibromatosis type II (NF2), and schwannomatosis. Epidemiology: 1 in 3,500 people have NF1 and 1 in 25,000 have NF2 in US. Males = Females. S&S: NF1: light brown spots on the skin, freckles in the armpit and groin, small bumps within nerves, and scoliosis. Symptoms are present at birth and before 10 years of age. Most with a normal life expectancy. NF2: hearing loss, cataracts at a young age, balance problems, fleshcolored skin flaps, and muscle wasting. symptoms become apparent from early adulthood & increases the risk of early death. Pathogenesis: Tumors are generally non-cancerous, and caused by the genetic mutation in certain genes. Inherited from a person's parents, and may develop in early stage. The tumors involve supporting cells in the nervous system rather than the neurons. NF1: Tumors are neurofibromas (tumors of the peripheral nerves). NF2 & schwannomatosis: Tumors of Schwann cells are common. Dx: based on S&S + genetic testing. Prognosis: No known prevention or cure. Management: Surgery to remove tumors that are causing problems/become cancerous +/Radiation and chemotherapy. A cochlear implant/auditory brainstem implant helps hearing loss. Multiple Hereditary Exostosis (HME), Hereditary multiple osteochondromas (HMO), Hereditary multiple Osteochondromas A disorder characterized by the development of multiple benign osteocartilaginous masses (exostoses) in relation to the ends of long bones (femur & tibia in LL; humerus, Radius, Ulnar in UL) or flat bones (in pelvic bone and scapula). Incidence: 1 in 50,000 individuals. Exostoses usually present during childhood. The distribution and number of these exostoses varies between individuals. Affected individuals become clinically manifest by the time they reach adolescence. Some exostoses may develop malignant transformation into sarcomas. malignant = spread from site S/S: A noticeable lump in the extremity. Follow by multiple deformities including coronal plane deformities around the knees, ankles, shoulders, elbows, and wrists, leading to Genu Valgum, Ankle Valgus, Ulnar Bowing and shortening, and radial head subluxation. Majority may have osteochondromas around the knee +/forearm involvement, disproportionate short stature due to the disruption of physeal growth as osteochondromas typically arise at the metaphyseal ends of long bones in close proximity to the physis. Other S&S: • Intra-articular osteochondromas of the hip can limit ROM, cause joint pain and acetabular dysplasia. • Joint pain at other locations + neurovascular compression. • Functional disability • Spinal deformity pain/neurological compromise (when involving the vertebrae) • Possible connection to autism/autismlike social problems. An autosomal dominant hereditary disorder: 50% chance: transmitting to their children 10% -20% chance: spontaneous mutation. Linked with mutations in 3 genes: • EXT1 maps to chromosome 8q24.1 • EXT2 maps to 11p13 • EXT3 maps to the short arm of Chromosome 19. • Resulted in synthesis of a truncated EXT protein not functioning normally in the synthesis of heparan sulfate. • Lead to the abnormal bone growth. • Affect normal chondrocyte proliferation and differentiation. Cause the congenital disorder of glycosylation (affect protein synthesis) Can be detected by preimplantation genetic testing & prenatal diagnosis. 96% penetrance (means from parent to a child: 96% manifesting, and 4% not manifesting). Symptoms are more likely to be severe if the mutation is on the ext1 gene (the most commonly affected gene) rather than ext2 or ext3. Pathophysiology: Growth of cartilage-capped benign bone tumours in the metaphysis of the long bones. Common 5 – 6 exostoses are in UL & LL. Common locations: Distal femur (70%) Proximal tibia (70%) Humerus (50%) Proximal fibula (30%) Shortening and bowing of bones leading to short stature. Exostoses can cause pain or numbness from nerve compression, vascular compromise, inequality of limb length, irritation of tendon and muscle, Madelung's deformity, limited ROM. Increased risk of developing a chondrosarcoma: Weak bones and nerve damage. Reported rate of transformation: 0.57% -8.3%. Diagnosis: Family history, P/E , Radiographic features (osteochondromas at the metaphyseal ends of long bones), & Genetic Testing of EXT1 and EXT2. Treatment: Surgical treatment includes ostechondroma excision, gradual or acute bone lengthening, corrective osteotomies, temporary hemiepiphysiodesis to correct angular joint deformities (e.g. distal radius hemiepiphysiodesis and medial distal tibial hemiepiphysiodesis). Total hip arthroplasty to remedy severe and painful hip. Genetic Disorders (A Summary) The possible carriers of genetic disorders in gene 1 to 22 and X & Y Diagnosis of the genetic disorders: Varied and dependent of the disorder. Most are diagnosed at birth or during early childhood. But some can escape detection until into adulthood, e.g. Huntington's disease. Basic approach includes genetic material examination & in-depth family history. Prenatal diagnosis include fetal development ultrasound or amniocentesis (an invasive procedures by inserting probes/needles into the uterus to collect sample). Prognosis of genetic disorder: from death to various outcomes. No known cures at present. May affect stages of development in Down syndrome to affect physical mobility in muscular dystrophy. Huntington's disease shows no signs until adulthood. Need to maintain/slow the degradation of quality of life and maintain patient autonomy. Physiotherapy, pain management, and a selection of supportive or alternative medicine programs. Treatment: gene therapy (a healthy gene is introduced to a patient to alleviate the defect caused by a faulty gene) + supportive therapy to improve patient quality of life. Skeletal Dysplasias (SD), osteochondrodysplasias and malformations • A heterogeneous group of heritable disorders characterized by abnormalities of cartilage and bone growth, resulting in abnormal shape and size of the skeleton and disproportion of the long bones, spine, and head. • Differ in natural histories, prognoses, inheritance patterns, and etiopathogenetic mechanisms. • Typified by short stature (defined as height >3SD below the mean height for age). • Accompanied by involvement of other systems, including the neurologic, respiratory, and cardiac systems. • The molecular basis for a large majority of these disorders in now known. Common SD: • Achondroplasia, • Osteogenesis imperfecta, • Thanatophoric dysplasia, • Campomelic dysplasia, and • Hypochondroplasia. Infant and 2 children with achondroplasia: • relatively normal-sized trunk, a large head, rhizomelic shortening of the limbs, lumbar lordosis, and trident hands. • Radiographs: abnormal pelvis with small square iliac wings, horizontal acetabular roofs, and narrowing of the greater sciatic notch, an oval translucent area at the proximal ends of the femora, caudal narrowing of the interpedicular distances in the lumbar region, short pedicles, and lumbar lordosis. • Two infants with perinatal lethal form of osteogenesis imperfect: short-limbed skeletal dysplasia, deformed extremities, and relatively large head. • Radiographs: short, thick, ribbonlike long bones with multiple fractures and callus formation at all sites (ribs, long bones). Child with Hurler syndrome (mucopolysaccharidosis type IH): • dysplasia, scaphocephalic macrocephaly, coarse facial features, depressed nasal bridge, broad nasal tip, thick lips, short neck, protuberant abdomen, inguinal hernia, joint contractures, and claw hands. • Radiographs: hook-shaped deformity (anterior wedging) of the L1 and L2 vertebrae; abnormally short, wide, and deformed tubular bones (bullet-shaped) of the hands; and narrow base of the secondto-fifth metacarpals. The distal articular surfaces of the ulna and radius are slanted toward each other. • Infant with Larsen syndrome: the flat face with depressed nasal bridge, prominent forehead, hypertelorism, cleft palate, talipes equinovarus (TEV), and dislocations of elbows, hips, and knees. • Radiograph: dislocation at the knee. Skeletal dysplasias: inherited as autosomal dominant, autosomal recessive, X-linked, or Y-linked. i). Autosomal dominant - Fibroblast growth factor 3 ( FGFR3) disorders (achondroplasia, thanatophoric dysplasia, hypochondroplasia) and type II collagen disorders (achondrogenesis II, spondyloepiphyseal dysplasia congenita, Kniest dysplasia) ii). Autosomal recessive - Cartilage-hair hypoplasia, Ellis-van Creveld syndrome, hypophosphatasia, osteopetrosis iii). X-linked dominant - Chondrodysplasia punctata (CDP) iv). X-linked recessive - Conradi-Hunermann CDP Achondroplasia: The most common nonlethal skeletal dysplasia Occurring in 1:26,000-1:28,000 live births and affecting 250,000 individuals worldwide. The molecular mechanism for achondroplasia is a G380R mutation in the FGFR3 transmembrane domain. A gain-of-function mutation, it is present in 99% of affected individuals. Inheritance is autosomal dominant, with 80% of cases involving de novo mutations. Major characteristics: • Disproportionate short stature with rhizomelic (proximal) shortening of the arms and legs and large head with frontal bossing, • Trident hand configuration, • Average final height: 130 cm for men and 125 cm for women, • Normal intelligence and lifespan Major complications: • Craniocervical junction compression, • Middle ear infections, • Obstructive apnea, • Spinal stenosis, • Osteogenesis imperfect. Osteogenesis Imperfecta (OI): A heterogenous group of heritable connective tissue disorders. A common skeletal dysplasia. Prevalence of 1:15,000-1:20,000 births. Molecular mechanisms for OI types I-IV are mutations in type 1 collagen genes COLA1 and COLA2. Types V-XII are rarer forms. Inheritance in OI is as follows: a). Types I-IV (Sillence classification, 85% of cases): Autosomal dominant, b). Types V-XII: Autosomal recessive, except for type V (autosomal dominant) All forms are characterized by bone fragility and susceptibility to fracture from minimal trauma. OI type I - mild form with diagnosis in early childhood, is characterized as follows: Sclera may be blue, Dentinogenesis imperfecta (subtype IB), Normal stature reached, Hearing loss in 50% of patients OI type II - perinatal lethal form, is characterized as follows: • Patients may survive the neonatal period, Later mortality can occur secondary to pneumonia and respiratory insufficiency OI type III - progressive deforming form, is characterized as follows: • Moderate deformity at birth, Development of chest wall deformities, Most patients are wheelchair dependent, Very short stature, Variable sclera, Dentinogenesis imperfecta and hearing loss are common. OI type IV - moderately severe form, characteristics as follows: • Mild to moderate bone deformity, Variable short stature, Hearing loss occurs in some families, Variable sclera Major complications: i). bone fractures, ii). bone deformity, and iii). growth deficiency. Dx: radiologic + genetic evaluations, for diagnosis + determination of the best treatment options + counseling on outcomes and risk of recurrence. • XR examination: skeletal survey including the skull: AP & lateral views + Chest: AP + spine: AP & lateral views + dedicated lateral view of the cervical spine + Pelvis: AP + Tubular bones: AP, and/or hands and feet: AP. • Genetic testing: Molecular diagnostic techniques led to identify the underlying gene disorders (in 2/3 of known skeletal dysplasias cases). Supportive care: To prevent neurologic & orthopedic complications (e.g. spinal cord compression, joint instability, and long bone deformity). Surgical intervention: Anterior and posterior fusion for progressive kyphosis that may lead to spinal cord compression and spastic paraparesis. Extensive lumbar laminectomy for Lumbar lordosis with spinal stenosis. Surgical decompression to relieve edema of the cervico-medullary cord secondary to bony compression. Bone tumours • A bone tumor is a neoplastic growth of tissue in bone. Abnormal growths found in the bone can be either benign (noncancerous) or malignant (cancerous). • Average five-year survival in the United States after being diagnosed with bone and joint cancer is 67%. Primary Bone Tumour Secondary Bone Tumour S&S: • Pain that gradually increases over time (the pain increases with the growth of the tumor), fatigue, fever, weight loss, anemia, nausea, and unexplained bone fractures. • Many patients will not experience any symptoms, except for a painless mass. • Some bone tumors may weaken the structure of the bone, causing pathologic fractures. 2 types 1. Primary tumors (originate in bone or from bone-derived cells and tissues), and 2. Secondary tumors (originate in other sites and spread (metastasize) to the skeleton). Note: i). Carcinomas of the prostate, breasts, lungs, thyroid, and kidneys are the carcinomas that most commonly metastasize to bone. ii). Secondary malignant bone tumors are 50 -100 times as common as primary bone cancers]. 1. Primary bone tumors: • Divide into benign tumors + malignant tumors (cancers). Etiology: neoplastic, developmental, traumatic, infectious, or inflammatory. Some benign tumors (e.g. osteochondroma) are not true neoplasms, but hamartomas that is a mostly benign, focal malformation that resembles a neoplasm in the tissue of its origin. Traditionally, hamartoma is considered as a developmental malformation. Many hamartomas have clonal chromosomal aberrations that are acquired through somatic mutations, and is considered to be neoplastic. Locations for many primary tumors (both benign & malignant): the distal femur and proximal tibia. Examples: Benign bone tumors: osteoma, osteoid osteoma, osteochondroma, osteoblastoma, enchondroma, giant cell tumor of bone and aneurysmal bone cyst. Malignant primary bone tumors: common types are osteosarcoma, chondrosarcoma, Ewing's sarcoma and fibrosarcoma. The other types need special study to differentiate. Malignant fibrous histiocytoma (MFH) or “Pleomorphic undifferentiated sarcoma" needs specialized studies (i.e. genetic and immuno-histochemical tests) to classify these undifferentiated tumors into other tumor classes. • Multiple myeloma (originating in the bone marrow) is a hematologic cancer that frequently presents as one or more bone lesions. • Germ cell tumors (e.g. teratoma) often present and originate in the midline of the sacrum, coccyx, or both. 2. Secondary bone tumors: Are metastatic lesions that have spread from other organs (commonly from CA Breast, Lung, or Prostate). Incidence, prevalence, and mortality of malignant bone tumors in the patient > 75 y.o. age are difficult to obtain due to: i). Carcinomas metastatic to bone are rarely curable. ii). Biopsies to determine the origin of the tumor are rarely done. Diagnosis: X-rays, CT scan, MRI, PET-CT +/- histopathology. postron electron for cancer Treatment of bone tumors: All depends on the type of tumor. 1. Chemotherapy and radiotherapy: effective in Ewing's sarcoma but less so in chondrosarcoma. A variety of chemotherapy treatment protocols exists for different types of bone tumors. An intra-arterial protocol seems to be satisfactory in both adults & children. Tumor response is tracked by serial arteriogram. When tumor response has reached >90% necrosis surgical intervention is planned. 2. Medication: Major concern is on BMD due to the tumour destroys the bone strength. Bisphosphonates increase bone strength and are available as once-a-week prescription pills. Metastron or Strontium-89 chloride is an IV medication for pain relief in 3/12 intervals. Denosumab also is used in bone cancer patient. Surgical treatment: 1. Limb amputation or limb sparing surgery +/chemotherapy & radiation therapy. Limb sparing surgery/limb salvage surgery means the limb is spared from amputation. The affected bone is removed and replaced by either (a) bone graft, or (b) artificial limb/limb salvage prostheses. 2. Van Nes Rotationplasty: amputation in which the patient's foot is turned upwards in a 180 degree turn and the upturned foot is used as a knee. 3. Amputation such as Below knee, Above knee, Symes, Hip disarticulation, Hemipelvectomy; Below elbow, Above elbow, Shoulder disarticulation, and Forequarter. 4. Hemicorporectomy (translumbar or waist amputation): 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 amputation. 5. Thermal ablation techniques (e.g. CT guided radiofrequency ablation, RFA): A less invasive alternative to surgical resection in the care of benign bone tumors, most notably osteoid osteomas. Performed under conscious sedation, 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 destruction + safety + efficacy (up to 96% reporting free from symptoms), but with some reported symptom recurrence. Used in the palliative treatment of painful metastatic bone disease. 6. External beam radiation therapy: A standard care for patients with localized bone pain due to metastatic disease. Good for pain relief, but the effect is transient in >50% patients. For patients not respond to radiation therapy, chemotherapy, palliative surgery, bisphosphonates or analgesic medications: thermal ablation techniques have been explored as alternatives for pain reduction. 7. Cryoablation: A potentially effective alternative, a potential advantage when treating tumors adjacent to critical structures. Prognosis: good for benign tumors in general. For malignant bone tumors, the cure rate depends on the type of cancer, location, size, and other factors. Q & A Time References 1. Blom, A., Warwick, DJ, & Whitehouse, M.. (2018). Apley & Solomon’s System Of Orthopaedics And Trauma. (10th ed.). Florida, CRC Press. 2. Frontera, W. R., Silver, J. K., & Rizzo, T. D. (2018). Essentials of Physical Medicine and Rehabilitation: Musculoskeletal Disorders, Pain and Rehabilitation. (4th ed.). Philadelphia: W.B. Saaunders Company. 3. Jiang G, Eastel R, Barrington NA, Ferrar L. Comparison of methods for the visual identification of prevalent vertebral fracture in osteoporosis. Osteoporosis International 2004; 15:887–896. 4. Journal of Genetic Disorders 5. Lentle B, Brown J, Khan A, Leslie W D, Levesque J, Lyons D J et al. Guidelines for the Recognition and Reporting of Vertebral Fractures: A Powerful Tool to Reduce the Risk of Future Fractures. The Canadian Association of Radiologists 6. Porter, S. (2013), Tidy's Physiotherapy, 15e (Physiotherapy Essentials). 7. Porter, R. (2018), The Merck Manual of Diagnosis & Therapy (20th edition), Weiley 8. Photos from Google web pages. 9. Wynne-Davies R. (1975), A review of genetics in orthopaedics, Acta Orthopaedica Scandinavica, 46(3):338-349 10. Vitale, Michael, G.; Guha, Abhijit; Skaggs, David, L. (2002), Orthopaedic Manifestations of Neurofibromatosis in Children: An Update, Clinical Orthopaedics and Related Research: August 401, p 107-118