EXAM 3: Pathology of genetic diseases & developmental malformations Flashcards

Question

What are the 4 types of Spina Bifida? (Which is the best/worst?)

Answer 1

- Spina bifida is a LOWER neuropore does not close. - MOST common NT defect - "POSTERIOR" vertebral arches fail to fuse 1) Occulta (BEST for patients to have) - SINGLE vertebra fails to fuse - usually has a tuft of hair and dimpling on back 2) Meningocele - occipital or lumbo-sacral sac, NO NERVE roots EXPOSED - Diverticulum w/ fluid‐filled sac of meninges & CSF 3) Meningomyelocele - limbo-sacral mass of nerve roots meninges within it, DIMPLE in the center - Dura, arachnoid, and neural tissue protrude from vertebral canal forming a bulge 4) Rachischisis (WORST for patients to have) - NERVE ROOTS extend out of skin (caudal equine), NO SAC, flat against skin (w/ visible spinal cord) - Occurs when POSTERIOR neuropore of neural tube fails to close during week 4 • Moms take Folic acid to avoid NTD’s (neural tube defects)

Answer 2

1) Meningoencephalocele: • A similar diverticulum of malformed CNS tissue & flattened arachnoid extending thru a defect in POSTERIOR cranium (occiput). • The constituents of the sac are the same as for meningocele (except w/ brain tissue) * If the ventricular cistern as well as the brain & meninges protrude from the unossified gap in the skull, the condition is termed meningohydroencephalocele. * Not a spina bifida 2) Meningomyelocele: • A more severe case of Spina Bifida where dura & arachnoid, as well as neural tissue protrudes from vertebral canal, forming a bulge through opening. * A sac covered w/ skin is visible on surface, complete with trapped nerve roots, particularly those of caudal equine to be trapped in subcutaneous scar tissue. * The spinal cord appears as a flattened, ribbon-like structure. * Neurologic dysfunction is seen, related to structural abnormality of the cord itself & to superimposed infection that extends from thin, overlying skin. * The patient manifests clinical defects referable to motor & sensory function in lower extremities as well as disturbances of bowel & bladder control. * A Lumbosacral Meningocele is when meninges only protrude through opening, covered by a skin-lined sac.

Answer 3

Klinefelter's syndrome: 47 XXY Male - 2 or more X chromosomes, 1 or more Y chromosomes from non-disjunction - Rarely diagnosed before puberty b/c testicular abnormality does not develop until early teens FEATURES: lack of beard and body hair, gynecomastia, hips are FEMALE like, lack of pubic hair, testicular atrophy, INFERTILITY, long legs/arms - Eunuchoid body habitus - Elongated body - Small atrophic testes and small penis - Lack of secondary sex characteristics: deep voice, beard - Mean IQ is lower but retardation is uncommon

Answer 4

Turner’s syndrome: - Complete or partial monosomy of X-chromosome, most common = 45 XO Karyotype (Majority cases missing an entire X) - MOST common sex chromosome abnormality in females - FEATURES: short stature, amenorrhea, edema b/c of lymph stasis in hands and feet, heart shaped face, coarctation of aorta, cubits valgus, streak ovaries, infertility, broad chest & widely spaced nipples, webbing of neck b/c distended lymph channels (Cystic Hygroma), low posterior hair line, pigmented nevi of skin, - Turner’s syndrome is the single most important cause of primary AMENORRHEA - After puberty there is failure to develop secondary sex characteristics: genitalia is INFERTILE, inadequate breast development, little pubic hair, atrophic ovaries, Ribrous Strands (STREAK OVARIES) - Normal mental status, few exhibit mental retardation - 50% pts develop autoantibodies against thyroid gland - Fetal ovaries develop normally early in embryogenesis but absence of second X chromosome leads to accelerated loss of oocytes which is complete by age 2 (menopause occurs before menarche!)

Answer 5

* Short stature (rarely exceeding 150cm in height) * Pt’s present during infancy with edema (due to lymph stasis) of dorsum of hands & feet. * Webbing of neck due to distended lymphatic channels, producing the so-called CYSTIC HYGROMA. As they grow older, webbing can become a persistent looseness of skin on back of neck. * Broad-shaped chest w/ widely-spaced nipples * Pigmented nevi (sharply circumscribed & chronic lesions of skin/ mucosa) on skin of extremities & trunk * Abnormal carrying angle of the arm, called CUBITS VALGUS. * At puberty, there is a failure to develop normal secondary sex characteristics-the genetalia remains infantile, breast development is inadequate, there is little pubic hair.

Answer 6

* Amenorrhea: MOST important cause of primary amenorrhea, accounting for ⅓ of the cases. * CONGENITAL HEART DEFECTS are COMMON, particularly COARCTATION of AORTA & BICUSPID VALVES. Cardiovascular abnormalities are the single most important cause of increased mortality w/ Turners. * OVARIES are reduced to atrophic, fibrous strands (streak ovaries), resulting in INFERTILITY. * MENTAL status = NORMAL, but a few may exhibit some mental retardation. * Approx. 50% develop autoantibodies directed against thyroid gland, & up to half develop clinically manifest hypothyroidism. * During normal fetal development, ovaries contain 7 million oocytes. The oocytes gradually disappear, by menarche = 400,000. * By the time menopause occurs, fewer than 10,000 oocytes remain. * Fetal ovaries develop normally early in embryogenesis, but absence of second X chromosome leads to an accelerated loss of oocytes, which is complete by age of 2 yrs. * Menopause occurs BEFORE menarche in other words.

Answer 7

- HYPOGONADISM is the most consistent finding, the plasma FSH levels are consistently HIGH & the testosterone levels are REDUCED. - The pathology relates to reduced spermatogenesis & male infertility. The testicular tubules are totally atrophied, & replaced by pink, hyaline, collagenous shells. LARGE Leydig cells may contribute to atrophy.

Answer 8

- Congenital heart defects are common, particularly Coarctation of the Aorta and Bicuspid Aortic Valves. - Cardiovascular abnormalities are the single most important cause of increased mortality in children with Turners.

Answer 9

1) Distended lymphatic channels causing a webbing of the neck. 2) Seen in Turner syndrome 3) As infants grow older, the webbing can become a persistent looseness of skin on the back of the neck.

Answer 10

1. An autosomal dominant disorder that is characterized by involuntary movements of all parts of the body, with deterioration of cognitive functions, and emotional disturbances. 2. The HD gene is located in chromosome 4, that codes for the production of an altered protein “Huntingtin”, that is widely expressed throughout the body & all regions of the nervous system, by both neurons & glial tissue • It’s function & mechanism is unknown, • HD is one of the purest examples of a true autosomal completely dominant disorder (heterozygotes do not differ clinically)

Answer 11

GENETICS: Autosomal Dominant Disorder - Dysfunction of gene on chromosome 15 that codes for Fibrillin - CT PROTEIN essential for maintenance of tissue structure of organs - Tendons & vessel walls devoid of normal FIBRILLIN become loose, weak, & cannot support normal body functions - Disorder of CT manifested by changes in skeleton, eyes, and CV system 1) SKELETAL: slender & tall, elongated head (dolichocephalic), prominent frontal bossellation, arachnodactyly (long spider fingers), frequent luxations & spinal deformities (kyphoscoliosis) 2) CV: dilatation of aorta (aortic aneurysm w/ exsanguination), fraying of tissues, floppy valves, valves malfunction, mitral valve prolapse & regurgitation leading to heart failure & death - Blood separates the layers of the weakened aorta, ultimately producing dissecting aneurysms, which are also prone to rupture. - Microscopically, there is fragmentation & loss of elastic fibers w/ abundant mutinous mucopolysaccharide deposition (CYSTIC MEDIAL NECROSIS) - Death is most often caused by heart failure secondary to valvular dysfunction or rupture of AORTIC ANEURYSM w/ exsanguination. 3) EYES: (Ocular) displaced lens (subluxations), cataracts, retinal detachments, blindness

Answer 12

- Most common autosomal recessive disease - Almost only seen in Caucasians - GENETICS: defect in gene that normally codes for protein forming CHLORIDE TRANSPORT CHANNEL in the cell membrane causing Cl transport defect across cell membrane leading to lack of NaCl in glandular secretions of all exocrine glands - Secretions have less water and are viscid leading to obstruction of lumens of organs

Answer 13

- Most important glands affected: pancreas, intestines, bronchi 1) PANCREAS: malabsorption, malnutrition, chronic pancreatitis, prevent flow of pancreatic juices 2) INTESTINE (fetal): steatorrhea, intestinal rupture and dissipation of intestinal contents throughout the abdominal cavity (meconium ileum with peritonitis) - Stool contains undigested food, bulky, greasy, foul smelling 3) BRONCHI: bronchitis, bronchiectasis, pneumonia, honeycomb lung, lung abscesses, recurrent pulmonary infection - MOST important complication is hyper viscosity of bronchial mucous making viscous plugs to prevent respiration - Other: abnormal sweat, cor pulmonale, secondary biliary cirrhosis, obstructed vas deferens (sterility), clubbing of nails

Answer 14

• Pseudomonas aeruginosa

Answer 15

* Used to screen for Cystic Fibrosis * Measures the chloride concentration that is excreted in sweat * Due to defect Chloride channels, elevated levels of chloride will be seen in a person with CF

Answer 16

“Brittle Bone Disease” • A group of heritable disorders of connective tissue, caused by mutations in the gene for type 1 Collagen. (Autosomal Dominant) * Affects skeleton, joints, teeth, sclera, skin, ligaments, & ears * Involves MUTATIONS of COL1A1 (CHROMOSOME 17) & COL1A2 (CHROMOSOME 7) genes, which encode for chains of Type 1 pro collagen, major STRUCTURAL PROTEIN of bone. * Mutations of COL1A1 are seen in all types of OI, & affects 3/4 of the type 1 collagen molecule * Mutations of COL1A2 affects 1/2 of synthesized collagen molecule • Because of the hypoplasia of the dentine and pulp, teeth are misshapen and bluish - yellow in color *NO TREATMENT

Answer 17

1. Retrolental Fibroplasias: Long‐term, high [O2] can produce O2 radical--->toxicity in the eyes of newborn--->blindness 2. Bronchopulmonary Dysplasia (BPD): -Due to HIGH [O2} & toxicity of O2 radicals - Fibrosing condition of peribronchial & interstitial tissue---->wall thickening

Answer 18

* Patent Ductus Arteriosus (PDA) due to PREMATURITY * Mortality rate is about 50 % in infants weighing around 1000 grams. * 24-28 weeks gestation, 20-30% in infants over 30 weeks

Answer 19

* MOST common form of inherited mental retardation due to a defect on LONG ARM of X Chromosome * 2nd only to Trisomy 21 as an identifiable cause of mental retardation * A fragile site is a specific site is a specific locus on a chromosome that breaks easily. (Up to 50 fragile sites on autosomes sex chromosomes). * Locus at Xq27 is associated w/ mental retardation due to a repeat of an amino acid sequence (CGG REPEAT @ FRAGILE SITE) * Male NEWBORNS afflicted appear NORMAL, but during childhood, CHARACTERISTICS appear: - INCREASED HEAD circumference - Facial coarsening - Joint hyper extensibility - ENLARGED TESTES - ABNORMALITIES of cardiac valves * Mental retardation = (IQ 20-60) * A significant proportion of AUTISTIC MALE children carry fragile X chromosome * 80% of males who exhibit the fragile site are mentally retarded. Other 20% are clinically normal, but can transmit trait. * Females who are known to bear the fragile X chromosome (carriers), 2/3 are intellectually normal, & other 1/3 are mentally retarded * The fragile X is usually detected in cytogenetic preparations as a non-staining gap or constriction

Answer 20

a. A SEVERE X-LIKED (only MALES AFFECTED - inherited or spontaneous) RECESSIVE Disorder of muscle caused by MUTATION of the gene DMD b. The DMD gene codes for the protein Dystrophin, an important structural component w/in muscle tissue. • Provides structural stability on inner surface of muscle sarcolemma • Links subsarcolemmal cytoskeleton to exterior of cell c. The PATHOGENESIS relates to Dystrophin-deficient muscle fibers that LACK NORMAL interaction btwn sarcolemma & extracellular matrix. • A continuous effort at repair & regeneration early on in disease, where degenerative process eventually outweighs regenerative capacity of muscle * Relentless NECROSIS of muscle fibers, invasion by scavenging macrophages * Progressive fibrofatty CT d. This ABSENCE of dystrophin permits EXCESS Ca++ to penetrate sarcolemma causing oxidative stress to muscles causing NECROSIS & CELL DEATH e. The dead muscle fibers are REPLACED by ADIPOSE tissue & CT, & release Creatine Kinase (CK) into serum f. END-STAGE = characterized by an almost complete LOSS of SKELETAL MUSCLE. g. Disease characterized by progressive degeneration of muscles, particularly those of PELVIC & SHOULDER girdles h. The MOST common non-inflammatory myopathy in children i. Clinical weakness not detectable until about 4-5 yrs old - usually bed ridden by age 15 j. MOST common cause of death -> complications of respiratory insufficiency, cardiomyopathy/ cardiac arrhythmia MAIN SYMPTOMS: 1) Progressive muscle weakness 2) Muscle wasting - voluntary muscles being first affected ->hips, thigh, calf then -> arms, shoulder, neck 3) Pseudohypertrophy of calf (enlargement of a muscle due to replacement of muscle fibers by fibroadipose tissue) 4) Frequent falls, difficulty walking/running 5) Fatigue 6) express variable degrees of mental retardation 7) GI dysfunction (due to degeneration of smooth muscle) 8) Positive Gower Sign

Answer 21

- Child helps himself to get up w/ upper extremities | - Rises on arms and knees, then “walks” hands to legs to stand upright

Answer 22

* The Duchenne Muscular Dystrophy (DMD) gene codes for the protein Dystrophin, an important structural component within muscle tissue. Dystrophin provides structural stability on the inner surface of muscle sarcolemma. * Dystrophin links subsarcolemmal cytoskeleton to exterior of cell.

EXAM 3: Pathology of genetic diseases & developmental malformations Flashcards

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