pathoch7 genetic disorders

Chapter 7: Genetic and Congenital Disorders 1

Eina Jane & Co. 2009.

Congenital defects: birth defects; abnormalities of body structures, function, and metabolism present at birth

I. Genetic and Chromosomal Disorders A. Genetic Disorder discrete event that affects gene expression in a group of

cells related to each other by gene linkage 1. Caused by changes in (DNA) sequence that alters the synthesis of a single

gene product 2. Some caused by chromosomal rearrangements that result in deletion,

duplication of a group of closely linked genes, abnormal number of chromosomes from mistakes during meiosis or mitosis

3. Inherited as autosomal dominant disorders, in which each child has a 50% chance of inheriting the disorder, or as autosomal recessive disorders, in which each child has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected

4. Can involve a single‐gene trait, multifactorial inheritance, a chromosomal abnormality, or a mitochondrial gene disorder. The disorder may be inherited as a family trait or arise as a sporadic case due to a new mutation

B. Sex‐linked disorders almost always are associated with the X chromosome and are predominantly recessive

C. Chromosomal Abnormalities 1. Structural

a. Chromosome breakage b. Fragile sites c. Deletion d. Crossing over e. Inversion f. Duplication g. Translocation

2. Abnormal numbers a. Polyploidy b. Aneuploidy

II. Causes of Birth Defects A. Genetic factors

1. Single‐gene disorders a. Caused by a defective or mutant

allele at a single gene locus and follow mendelian patterns of inheritance

b. Obtained through a family genetic history

c. Please see “Some Disorders of Mendelian or Single‐Gene Inheritance and Their Significance” Table



2. Multifactorial Inheritance a. Caused by multiple genes and, in many cases, environmental factors b. Multifactorial traits cannot be predicted with same degree of accuracy

as mendelian single‐gene mutations B. Environmental factors (fetal development)

1. Maternal disease 2. Infections 3. Drugs taken during pregnancy ETOH, radiation, etc

C. Intrauterine factors (rare) 1. Fetal crowding 2. Positioning 3. Entanglement of fetal parts with the amnion

III. Polyploidy A. Cell has more than diploid number

1. Triploidy: zygote having 3 copies of each chromosome 69 2. Tetraploidy: four copies of each 92

B. Both triploid and tetraploid fetuses do NOT survive miscarriage IV. Aneuploidy

A. Somatic cell that does not contain a multiple of 23 chromosomes B. Trisomy: cell containing 3 copies of one chromosome C. Monosomy: cell containing one copy of any chromosome D. Trisomy 21 Down Syndrome

1. 1:800 live births 2. Mentally retarded, low nasal bridge, epicanthal folds, protruding tongue,

poor muscle tone 3. Risk increases with maternal age usually >35yo, doubles over 40



4. 5. Screening tests

a. Most commonly used are blood tests that measure maternal serum levels of α‐fetoprotein, human chorionic gonadotropin (hCG), unconjugated estriol, inhibin A, and pregnancy‐associated plasma protein A

b. Results of three or four of these tests, together with the woman's age, often are used to determine the probability of a pregnant woman having a child with Down syndrome

c. Fetal nuchal translucency (sonolucent space on the back of the fetal neck), uses ultrasonography and can be performed between 10 and 13 weeks' gestation fetus with Down syndrome tends to have a greater area of translucency compared with a chromosomally normal infant. The nuchal transparency test is usually used in combination with other screening tests

d. Only way to accurately determine the presence of Down syndrome in the fetus is through chromosome analysis using chorionic villus sampling, amniocentesis, or percutaneous umbilical blood sampling

E. Trisomy X XXX 1. Female that has three X chromosomes 2. Termed “metafemales” 3. Variable symptoms: sterility, menstrual irregularity, and/or mental

retardation 4. Symptoms worsen with each additional X more X, worse the symptoms



F. Polosomy X Klinefelter Syndrome 1. At least XXY 2. Male appearance

a. Develop female‐like breasts gynecomastia

b. Small testes c. Sparse body hair d. Long limbs e. Abnormalities will increase with each X

3. Management a. Androgen therapy is usually initiated

when there is evidence of a testosterone deficit 12‐14yo

b. Because gynecomastia predisposes to breast cancer, breast self‐examination should be encouraged for men with Klinefelter syndrome

c. If sperm are present, cryopreservation may be useful for future family planning genetic counseling of the increased risk of autosomal and sex chromosomal abnormalities

G. Turner Syndrome 1. Females with one X 45, X/0 karyotype 2. Absence of ovaries no menstruations, no secondary sex characteristics

a. Short stature (~4’7”), normal body proportions b. Webbing of neck c. Nonpitting lymphedema of hands and feet d. Congenital heart defects coarctation of aorta, bicuspid aortic valve e. Abnormal kidney development f. Underdeveloped breasts; wide nipples g. X is usually inherited from mother



h. 3. Management

a. Starts childhood, ongoing assessment and treatment b. Growth hormone therapy is now standard treatment and can result in

a gain of 6 to 10 cm in final height c. Estrogen therapy age of puberty develop and maintain

secondary sexual characteristics d. Increased morbidity cardiovascular disease and gastrointestinal,

renal, and various endocrine disorders, reduced bone mass V. Multifactorial Inheritance Disorders

A. Caused by multiple genes and, environmental factors B. Exact # of genes contributing to multifactorial traits unknown C. Multifactorial traits cannot be predicted with same degree of accuracy as

mendelian single‐gene mutations D. Disorders can be expressed during fetal life and be present at birth, or they

may be expressed later in life E. Examples of Multifactorial Inheritance Disorders

1. Cleft lip or palate: most common birth defect



a. Require years of special treatment by medical and dental specialists, speech therapist, nurses

b. Infants with cleft palate problems sucking and feeding soft artificial nipples with large openings and a squeezable bottle

2. Clubfoot 3. Congenital dislocation of the hip 4. Congenital heart disease 5. Pyloric stenosis 6. Urinary tract malformation

F. Environmental factors are thought to play a greater role in disorders of multifactorial inheritance that develop in adult life, such as coronary artery disease, diabetes mellitus, hypertension, cancer, and common psychiatric disorders such as bipolar disorder and schizophrenia

VI. Results of Chromosomal Disorders A. Reproductive wastage early gestational miscarriage B. Congenital malformations C. Mental retardation D. Linked to more than 60 identifiable syndromes present in birth

VII. Environmental Influences Causing Disorders A. After conception, development is influenced by the environmental factors

that the embryo shares with the mother B. Physiologic status of the mother: hormone balance, her general state of

health, her nutritional status, and the drugs she takes influences the development of the unborn child

C. Period of vulnerability during organogenesis (period when differentiation and development of the organs are taking place) 15 to day 60 after conception

D. Environmental influences during the first 2 weeks after fertilization may interfere with implantation abortion

E. Teratogenic agents: chemical, physical, or biologic agents that produce abnormalities during embryonic or fetal development cause birth defects in three ways 1. Direct exposure of the pregnant woman and the embryo or fetus 2. Through exposure of the soon‐to‐be‐pregnant woman to an agent that

has a slow clearance rate such that a teratogenic dose is retained during early pregnancy

3. Result of mutagenic effects of an environmental agent that occur before pregnancy, causing permanent damage to a woman's (or a man's) reproductive cells

4. Agents a. Radiation microcephaly, skeletal malformations, and mental

retardation b. Chemicals and drugs cross placenta

i. Fetal alcohol syndrome physical, behavioral, and cognitive abnormalities resulting from maternal alcohol consumption



ii. Criteria for defining FAS o Prenatal or postnatal growth retardation weight or length

below the 10th percentile o Central nervous system involvement

Neurologic abnormalities Developmental delays Behavioral dysfunction Intellectual impairment Skull and brain malformation

o Characteristic face Short palpebral fissures (eye openings) Thin upper lip Elongate, flattened midface and philtrum

o iii. Cocaine babies

o Decrease in uteroplacental blood flow o Maternal hypertension o Stimulation of uterine contraction o Fetal vasoconstrction

iv. Folic acid deficiency o Development of neural tube defects anencephaly, spina

bifida, encephalocele o Increase folic acid before conception and continue during 1st

trimester of pregnancy reduced neural tube defects c. Infectious agents

i. TORCH growth retardation and abnormalities of the brain (microcephaly, hydrocephalus), eye, ear, liver, hematopoietic



system (anemia, thrombocytopenia), lungs (pneumonitis), and heart (myocarditis, congenital heart disorders o Toxoplasmosis eating raw or inadequately cooked meat or

food that has come in contact with infected meat house cat can be carrier in feces pregnant women do NOT clean out litter box

o Other o Rubella German measles major preventable cause of

hearing impairment, blindness, and adverse neurodevelopmental outcome

o Cytomegalovirus o Herpes

ii. Varicella‐zoster virus infection iii. Listeriosis iv. Leptospirosis v. Epstein‐Barr virus infection vi. Tuberculosis vii. Syphilis viii. HIV ix. Human parvovirus (B19)

5. Other Medications During Pregnancy a. Possibly cytotoxic (cell‐killing), antimetabolic, or growth‐inhibiting

activities b. Vitamin A derivatives c. Folic Acid deficiency

VIII. Prenatal Diagnosis A. Provides parents with information needed to make informed choice about

having child with an abnormality B. Provides reassurance and reduces anxiety among high‐risk groups C. Allows parents at risk to begin pregnancy with assurance that the presence

of a disorder can be confirmed with testing D. Prenatal screening cannot be used to rule out all possible fetal abnormalities.

It is limited to determining whether the fetus has (or probably has) designated conditions indicated by late maternal age, family history, or well‐defined risk factors

E. Termination of pregnancy if indicated = rare F. Can provide the information needed for prescribing prenatal treatment for

the fetus G. Methods used for Fetal Diagnosis

1. Maternal blood screening 2. Ultrasonography 3. Amniocentesis withdrawal of a sample of amniotic fluid from the

pregnant uterus using either a transabdominal or transcervical approach a. Useful in women >35yo: increased risk of giving birth to an infant

with Down syndrome; in parents who have another child with



chromosomal abnormalities; and in situations in which a parent is known to be a carrier of an inherited disease

b. Used with ultrasound to guide needle c. Performed on an outpatient basis typically at the 15th to 16th week

after the first day of the last menstrual period d. Risk of pregnancy loss

4. Chorionic villus sampling done after 10 weeks of gestation used for fetal chromosome studies, DNA analysis, and biochemical studies

5. Percutaneous umbilical fetal blood sampling transcutaneous insertion of a needle through the uterine wall and into the umbilical artery a. US guided after 16weeks gestation b. Used for prenatal diagnosis of hemoglobinopathies, coagulation

disorders, metabolic and cytogenetic disorders, and immunodeficiencies

c. Procedure carries higher risk for pregnancy loss compared to amniocentesis, reserved as last resort

6. Fetal biopsy used to detect certain genetic skin defects that cannot be diagnosed with DNA analysis fetoscope under US guidance

7. Cytogenic and biochemical analyses used for fetal karyotyping to determine the chromosomal makeup of the fetus a. Detects abnormalities of chromosome number and structure b. Karyotyping also reveals the sex of the fetus

8. IX. Autosomal Dominant Disorders

A. Marfan Syndrome 1. Connective tissue disorder manifested by changes in the skeleton, eyes,

and cardiovascular system 2. Skeletal deformities: long, thin body with exceptionally long extremities

and long, tapering fingers, sometimes called arachnodactyly or spider fingers; hyperextensible joints; and a variety of spinal deformities, including kyphosis and scoliosis



3. Chest deformities, pectus excavatum (i.e., deeply depressed sternum), or pigeon chest deformity, often are present and may require surgery

4. Most common eye disorder is bilateral dislocation of the lens due to weakness of the suspensory ligament

5. Most life‐threatening aspects of the disorder cardiovascular defects mitral valve prolapse, progressive dilation of the aortic valve ring, and weakness of the aorta and other arteries dissection and rupture of the aorta may lead to premature death in women, the risk of aortic dissection is increased in pregnancy

6. Some go undiagnosed drop dead from aortic dissection or rupture

7. B. Neurofibromatosis (NF)

1. Condition involving benign neurogenic tumors that arise from Schwann cells and other elements of the peripheral nervous system

2. At least two genetically and clinically distinct forms of the disorder result from a genetic defect in a tumor suppressor gene that regulates cell differentiation and growth a. Type 1 NF (NF‐1) von Recklinghausen disease chromosome 17

i. Common disorder, 1 in 3500



ii. Neurofibromas o Cutaneous from a few to many hundreds, manifest as soft,

pedunculated lesions that project from the skin not apparent until puberty, and are present in greatest density over the trunk

o Subcutaneous lesions grow just below the skin; they are firm and round, and may be painful

o Plexiform neurofibromas involve the larger peripheral nerves form large tumors that cause severe disfigurement of the face, overgrowth of an extremity, or skeletal deformities such as scoliosis

o iii. Children with NF‐1 susceptible to neurologic complications

learning disabilities, attention deficit disorders, abnormalities of speech among affected children

b. Type 2 bilateral acoustic NF (NF‐2) chromosome 22 i. Characterized by tumors of the acoustic nerve ii. Asymptomatic through the first 15 years of life most frequent

symptoms are headaches, hearing loss, tinnitus (ringing in ears), intracranial and spinal meningiomas

iii. Persons with the disorder should be warned that severe disorientation may occur during diving or swimming underwater, and drowning may result

X. Autosomal‐Recessive Disorders A. Manifested only when both members of the gene pair are affected both

parents may be unaffected but are carriers of the defective gene B. Occurrence risks in each pregnancy are one in four for an affected child, two

in four for a carrier child, and one in four for a normal (noncarrier, unaffected), homozygous child

C. Phenylketonuria (PKU)



1. Rare metabolic disorder that affects approximately 1 in every 15,000 infants in the United States and Canada

2. Inherited as a recessive trait, is caused by a deficiency of the liver enzyme phenylalanine hydroxylase toxic levels of the amino acid phenylalanine accumulate in the blood and other tissues if untreated, results in mental retardation, microcephaly, delayed speech, and other signs of impaired neurologic development

3. Symptoms of untreated PKU develop gradually and would often go undetected until irreversible mental retardation had occurred, newborn infants are routinely screened for abnormal levels of serum phenylalanine blood samples for PKU screening be obtained at least 12 hours after birth to ensure accuracy

4. Infants with the disorder are treated with a special diet that restricts phenylalanine intake started early in neonatal life to prevent brain damage

5. Women with PKU who wish to have children require careful attention to their diet, both before conception and during pregnancy, as a means of controlling their phenylalanine levels

D. Tay‐Sachs Disease 1. Variant of a class of lysosomal storage diseases, known as the

gangliosidoses failure to break down the GM2 gangliosides of cell membranes

2. Predominantly Eastern European (Ashkenazi) Jews 1 in 30 3. The GM2 ganglioside accumulates in the lysosomes of all organs, mostly

brain neurons and retina neurons ballooned with cytoplasmic vacuoles distended lysosome filled with gangliosides a. Progressive destruction of neurons within the brain substance,

including the cerebellum, basal ganglia, brain stem, spinal cord, and autonomic nervous system

b. Involvement of the retina is detected by ophthalmoscopy as a cherry‐red spot on the macula

4. Infants with Tay‐Sachs disease appear normal at birth but begin to manifest progressive weakness, muscle flaccidity, and decreased attentiveness at approximately 6 to 10 months of age rapid deterioration of motor and mental function, often development of generalized seizures retinal problems leads to blindness

5. No cure death usually occurs before 4 to 5 years of age 6. Accurate ID for carrier = deficient of lysosomal enzyme hexosaminidase A

pathoch7 genetic disorders

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