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Definition: disorder derived from one's parents.
Definition: involves hereditary disorders transmitted through generations.
Definition: disorder present at birth and not all are genetic.
- Congenital disorders
- **about 20% of pediatric inpatients in university hospitals have disorders of genetic origin**
Definition: developmental abnormality referring to change in shape or form.
Definition: evolution and development of form; development of the shape of organ or other body part.
- Many errors of morphogenesis are incompatible with life and result in spontaneous abortion (miscarriage) and occur during the 1st trimester (may be due to chromosomal abnormalities).
Definition: absence of an organ or part of an organ that appears to lack the primordial tissues.
Definition: absence of an organ but a primordial or rudimentary mass of tissue is found.
Definition: congenital absence or closure of normal body opening or tubular structure; lack of hollow portion or lumen in an organ.
Definition: under development of a tissue, organ, or body.
Definition: persistence of embryonic structures that are lost during normal development.
What percentage of congenital defects in human have unknown causes?
What are teratogens?
Agents known to cause fetal malformations.
What are some examples of teratogens?
- X-rays, radiation (alpha, beta, gamma)
- Alcohol (ETOH) "preventable"- causes fetal alcohol syndrome (FAS) which is manifested as intrauterine growth retardation (small baby).
- Chemicals, illicit drugs, medications (thalidomide).
- Microbial (toxoplasmosis, other, rubella, CMV, HSV; "TORCH").
Defintion: the complete set of chromosomes.
Definition: genetic makeup/the set of instructions that may or may not be expressed (observed) in the patient.
Definition: the physical appearance of an individual/the genetic instructions that have been expressed.
Phenotype (may be effected by environment)
Definition: trait that will be expressed in phenotype.
Definition: trait that might be expressed in phenotype.
Definition: the full chromosome set in a nucleus, often is the picture of the chromosomes.
Karyotype (represents the count)
Definition: having only one member of each pair of chromosomes (23).
Definition: having a "normal" number of chromosomes.
Definition: not normal number; loss or gain of chromosomes.
Definition: chromosome number that is a multiple greater than two of the haploid number.
Definition: the loss of a chromosome; autosomal NOT compatible with life.
Monosomy (45XO compatible, 45YO not compatible)
Definition: gain of a chromosome.
Trisomy (trisomy of sex chromosomes are compatible with life; trisomy 21 (Downs) and 18 (Edwards) are most common)
What is the normal human chromosomal nomenclature for males and females?
What nomenclature is an example of an extra autosomal chromosome?
What are examples of chromosomal nomenclature that show a variation in sex chromosomes?
- 47XXY (extra sex chromosome)
- 45XO (absent sex chromosome)
What is an example of chromosomal nomenclature for missing part of a chromosome?
- 46XY del (5p) or 46XY (5p-)
- "Cri du Chat syndrome"
What is the overall incidence of Down's Syndrome (Trisomy 21) and how does maternal age affect it?
- 1 in 700-800 live births
- <20 years old (mother), 1:1550
- >45 years old (mother), 1:25
What is the pathogenesis of Down's Syndrome?
Mostly maternal origin and is a consequence of "nondisjunction" during meiotic division.
What are the characteristics manifested in someone with Down's syndrome?
- Flat face
- Epicanthal folds (eyes)
- Large protruding tongue
- Low set ears
- "Simian" crease in palm
- Congenital heart defects
- Often sub-100 IQ
- Alzheimer's very early (30-35?)
What is the incidence rate of Klinefelter's Syndrome (47XXY, male phenotype)?
1 in 700 males; increases with age of mother.
What is the pathogenesis of Klinefelter's Syndrome?
Abnormal segregation of X or Y chromosomes in the gonads (non-disjunction), not usually inherited since patients are typically infertile (testes atrophic and unable to produce sperm).
What are the clinical characteristics of Klinefelter's Syndrome (47XXY, male phenotype)?
- Small penis, small firm testes
- Diminished pubic, axillary, and facial hair
- Sexual dysfunction
- Gynecomastia (enlarged breasts)
- Tall stature
- Abnormal body proportions (long legs, short trunk)
- Learning disabilites
- Female-like hips
What is the incidence rate of Turner's Syndrome (45XO, female phenotype)?
1 in 3000 females
What is the pathogenesis of Turner's syndrome?
- Abnormal segregation of X or Y chromosomes during meiosis in the gonads (spontaneous mutation, usually with older mothers, not inherited).
- Normal female organs except ovaries which don't develop normally (usually infertile).
- Do NOT naturally develop secondary sex characteristics, hormones can correct appearance but not infertility.
What are the clinical characteristics of Turner's syndrome (45XO, female phenotype)?
- Short stature
- Webbed neck
- Heart-shaped face
- Drooping eyelids
- "Shield-shaped", broad, flat chest
- Coarctation of the aorta
- Absent or delayed development of secondary sex characteristics ("streak" ovaries, amenorrhea, infertility)
What are the three patterns of inheritance for single gene disorders?
- Autosomal dominant: in heterozygous pair, the one that is expressed (Aa)
- Autosomal recessive: in a heterozygous pair (Aa)-recessive gene not expressed, dominant gene is expressed, must have homozygous pair (both recessive) to be expressed (aa).
- X-linked disorders: males can ONLY be hemizygous (XY), women are homozygous or heterozygous (XX or XX).
What are some examples of autosomal dominant disorders?
- Familial hypercholesterolemia (1 in 500)
- Marfan's syndrome (1 in 10,000)
- Polycystic kidney disease
- Huntington's disease
- Osteogenesis imperfecta
- Von Willebrand's clotting disorder
- **disorders may also develop from new mutations (egg/sperm) which presents no risk of unaffected siblings from transmitting the trait**
What is the cause and sign of familial hypercholesterolemia?
- Mutation in gene encoding low density lipoprotein cholesterol (LDL-C); less LDL is removed from blood by liver cells.
- Deposition of lipids in tissues can lead to xantholasma (deposits in skin).
What condition causes connective tissue dysfunction in fibrillin which affects tendons and connective tissue of vessels?
What is the most commonly inherited kidney disease? When does it present?
- Polycystic kidney disease
- Present at age 20-40
What are the signs and symptoms of polycystic kidney disease?
- Abdominal/flank pain (due to large kidneys)
- Painless hematuria
- Hypertension in 50-80%
- PMH of UTI and nephrolithiasis
- Large kidneys on physical exam
- Other findings include hepatic cysts, cerebral aneurysm (50% will eventually need kidney transplant).
What is Huntington's chorea and when do symptoms start?
- Premature brain cell death causing atrophy in cerebral cortex and caudate.
- Symptoms start at age 30s or 40s
What are the signs and symptoms of onset of Huntington's chorea?
- Involuntary movements (chorea)-cannot maintain tongue in protruded position
- Changes in behavior and personality (irritability)
- Cognitive impairment (dementia)
What is the life expectancy of a pt diagnosed with Huntington's chorea? What are the causes of death?
- 10-15 yrs after diagnosis
- Pneumonia, falls, suicide
What condition is a result of a defect in the production of Type I collagen which can lead to easy fractures, loose joints, scoliosis, blue sclerae and hearing loss?
Osteogenesis imperfecta (can also be due to a spontaneous mutation)
What kind of disorders make up the largest group of Mendelian (genetic) disorders, in which phenotype is seen in the homozygous state where BOTH recessive genes are present? Which children tend to get these?
- Autosomal recessive disorders
- Children from parent who are BOTH asymptomatic carriers (heterozygotes)-onset of symptoms are usually early in life
What are some examples of autosomal recessive disorders?
- Cystic fibrosis (most common)
- Sickle cell anemia
- Wilson's Disease (Kayser-Fleishcer ring=copper)
- Hemochromatosis (iron)
- Xeroderma pigmentosum
What is the incidence rate of cystic fibrosis for the general public and for those born to parents who are carriers?
- General: 1:2500 live births
- Carriers: 1:25 live births
- **it is the most common lethal autosomal recessive disorder, and occurs mostly in Caucasians**
What is the pathogenesis of cystic fibrosis?
Defect in transport of chloride across cell membrane (excess NaCl in sweat), and abnormally thick mucous secretions that block the airways and pancreatic ducts.
What are the clinical characteristics of cystic fibrosis?
- Pulmonary infections and pancreatic insufficiency (85%)
- Diagnosed by sweat chloride test in newborns
What is the incidence rate for sickle cell disease? What part of the population gets this condition?
- 1 in 500 Black/African American births
- **1 in 12 have Sickle cell trait (only one gene)**
What is the pathogenesis of sickle cell disease?
- Defect in synth of β chain of Hgb which causes sickling of Hgb at low O2 tension.
- Abnormal cells clot small vessels causing ischemia, pain, splenic infarction, skin ulcers.
- Abnormal cells then hemolyze, causing anemia and jaundice.
What are the clinical characteristics of sickle cell disease?
- Homozygotes have symptoms starting at age 1-2.
- Triggers for crisis include fever, respiratory disease, physical exertion, and pregnancy, mountain climbing (later in life).
What is the pathogenesis for phenylketonuria (PKU)?
- Enzyme PAH normally metabolizes phenylalanine to tyrosine.
- Deficiency of PAH does not allow metabolism of phenylalanine causing it to accumulate in tissue and blood.
- Affects developing CNS (mental retardation, seizures, etc), inhibits melanin synthesis (blond hair/blue eyes), "musty" urine (excreted phenylketones).
- Identified by PKU test in neonates.
How can CNS effects be prevented in someone with PKU?
- Diet low in phenylalanine.
- AVOID meat, chicken, fish, nuts, legumes, dairy products, diet foods with aspartame.
What are some examples of X-linked recessive diseases?
- G6PD deficiency
- Duchenne's Muscular Dystrophy
- Fragile X Syndrome
What is the incidence rate of G6PD deficiency?
- More common in Africa, Asia, Mediterranean.
- 10% of African-American men.
What is the pathogenesis of G6PD deficiency?
- Defect in enzyme G6PD in RBCs which offers no protection from reactive O2 species, increasing rate of hemolysis.
- Crisis triggered by drugs (anti-malarial, sulphas, aspirin), infection and fava beans.
- Deficiency may actually protect against getting malaria since the intra-cellular environment of the RBCs is unfavorable for the parasites.
What is the incidence rate of Hemophilia A and B?
- Hemophilia A (1:5000)
- Hemophilia B (less common than A)
What is the pathogenesis of Hemophilia A and B?
Defect in genes for coagulation factors VIII (Hemophilia A) or IX (Hemophilia B) (half inherited on X chromosome, half are spontaneous mutation).
What is the is clinical presentation for Hemophilia A and B?
- Hem A: mild to severe
- Hem B: usually severe
- Bleeding joints (hemarthrosis), bleeding from minor trauma.
How is Hemophilia A or B treated?
- With recombinant clotting factors.
- This avoids having to get plasma from several donors which increases risk of blood-borne disease (hepatitis and HIV).
What is the incidence rate for Duchenne's muscular dystrophy? How is it inherited?
- 1:3000 males
- 2/3 inherited on X chromosome
- 1/3 spontaneous mutation
What is the pathogenesis for Duchenne's muscular dystrophy?
- Defect in gene for dystrophin which normally maintains cell shape and response to stress.
- Defect affects mostly skeletal muscle.
- Weak muscles and deformity are present from early childhood.
What is the incidence rate for Fragile X Syndrome?
- Second in frequency only to Down's syndrome.
- Most common hereditary mental deficiency in males.
- Familial mental retardation (moderate to severe)-lesser degree in females.
- 1:1250 males, 1:2500 females
- 1:250 females & 1:700 males carry premutation.
What is the pathogenesis for Fragile X Syndrome?
CGG amplification along long arm of the X chromosome.
What are the clinical characteristics of Fragile X Syndrome?
- Macro-orchidism in 90% or prepubertal males.
- Full carrier males have mental retardation.
- Physical manifestations are not always present.
What are the physical manifestations possible with Fragile X Syndrome?
- Normal structure
- Broad forehead
- Elongated face
- Large prominent ears
- Strabismus (cross eyed)
- Highly arched palate
- Hyperextensible joints
- Hand calluses (from self abuse)
- Pectus excavatum (indentation of chest)
- Mitral valve prolapse (benign heart condition)
- Enlarged testicles
- Hypotonia (low muscle tone)
- Soft, fleshy skin
- Flat feet
- Seizures (in about 10%)
What are some examples of multifactorial inheritance of various disorders?
- Anencephaly: more common in Rio Grande valley; may be folic acid deficiency
- Diabetes: variable penetrance, some have mild symptoms, other have more severe symptoms
How are genetic disorders tested for pre-natally in high-risk pregnancy when the mother is older than 35 or has a family history of genetic disorders?
- Ultrasound: detects anatomic abnormalities, development, placement of placenta
- Chorionic villus biopsy: early pregnancy (fetal cells for chromosomal analysis, biochemical testing for enzyme deficiencies)
- Amniotic fluid analysis: needle aspiration
- Maternal blood AFP: increased in brain/spinal abnormalities, decreased in Down's syndrome