Genetic and Congenital Disorders - Chapter 5

A comprehensive set of QUESTION_AND_ANSWER flashcards covering congenital and genetic disorders, inheritance patterns, specific diseases (Marfan, NF, PKU, Tay-Sachs, Fragile X, DS, Turner, Klinefelter), environmental influences, and prenatal diagnosis concepts.

What is a congenital defect and what are its typical causes and global impact?

Structural or functional anomalies that occur during intrauterine life, may be identified prenatally or at birth or later; caused by genetic or environmental factors in utero; treatable options exist; one of the main causes of global disease burden, with LMICs disproportionately affected due to fewer treatment facilities.

What are the three main categories of genetic disorders?

Single-gene disorders, chromosomal disorders, and multifactorial disorders.

What defines chromosomal disorders?

Changes in the number or structure of chromosomes; may result in extra or missing chromosomes or structural changes; most chromosomal disorders are not inheritable.

What defines single-gene disorders?

Variations (mutations) in the DNA sequence of a specific gene, affecting the gene product (usually a protein) and its function; disease features relate to the affected gene and its protein’s role.

What are the three types of single-gene disorders?

Autosomal Dominant, Autosomal Recessive, and X-Linked Recessive.

What characterizes autosomal dominant inheritance?

The gene is on a non-sex autosome; a single mutated gene copy is enough to cause the disorder; an affected child has a 50% chance of inheriting the condition from an affected parent.

In autosomal dominant disorders, what are common genotypes and their phenotypes?

Homozygous DD and Heterozygous Dd are typically affected; Homozygous dd is typically unaffected.

Which common autosomal dominant disorder affects connective tissue and often involves the heart and aorta?

Marfan syndrome.

Which gene is mutated in Marfan syndrome?

FBN1 (Fibrillin-1).

List key features of Marfan syndrome.

Tall, slender build; arachnodactyly; pectus deformities; high arched palate; crowded teeth; heart murmurs; severe nearsightedness; scoliosis; flat feet; risk of aortic dissection.

How is Marfan syndrome typically managed or treated?

Blood pressure-lowering medications; regular monitoring for progression of damage; preventive surgery to repair the aorta when needed.

What is Neurofibromatosis (NF) and how is it inherited?

A group of autosomal dominant disorders causing tumors on nerve tissue; three types exist: NF1, NF2, and Schwannomatosis.

When is NF1 usually diagnosed and what are common signs?

Usually diagnosed in childhood; signs often present by age 10; cafe-au-lait spots, axillary/inguinal freckling, Lisch nodules, neurofibromas, scoliosis, optic glioma, learning disabilities, macrocephaly.

What distinguishes NF2 and Schwannomatosis from NF1?

NF2 typically involves benign acoustic neuromas with hearing loss; Schwannomatosis involves tumors on cranial, spinal, and peripheral nerves causing chronic pain and other symptoms.

What are autosomal recessive disorders and what is the associated risk in each pregnancy if both parents are carriers?

Two mutated copies are required for the disorder to manifest; each pregnancy has a 1 in 4 (25%) chance of affected child, 2 in 4 (50%) chance of a carrier child, and 1 in 4 (25%) chance of a normal child; consanguinity increases carrier risk.

What is Phenylketonuria (PKU) and what causes it?

An autosomal recessive disorder caused by mutations in the PAH gene, leading to deficiency of the enzyme needed to break down phenylalanine, resulting in buildup that can cause severe health problems if untreated.

How is PKU detected and managed?

Newborn screening; treatment involves a diet limiting phenylalanine and, in some cases, medications allowing higher phenylalanine intake.

What is Tay-Sachs disease and its inheritance pattern?

Autosomal recessive; absence of an enzyme that breaks down fatty substances (gangliosides) leading to toxic accumulation in the brain and spinal cord; more common in Ashkenazi Jews; three types: infantile, juvenile, and late-onset.

Describe the infantile signs of Tay-Sachs disease.

Onset around 3-6 months; exaggerated startle response, cherry-red spots, loss of motor skills, seizures, vision and hearing loss, paralysis, macrocephaly.

What does X-linked recessive inheritance imply for sons and daughters?

Mutation on the X chromosome; affected sons usually come from carrier mothers; daughters have a 50% chance of being carriers if the mother is a carrier; fathers pass the mutant X to all daughters (carrier or affected) but not to sons.

What is X-linked dominant inheritance and its characteristic pattern?

Dominant gene on the X chromosome; pattern varies; all daughters of an affected father are affected, but affected sons depend on which X chromosome is passed; affected mothers may have affected both sons and daughters depending on X-chromosome inheritance.

What is Fragile X syndrome and how is it inherited?

An X-linked dominant disorder caused by a change in the FMR1 gene; most common inherited intellectual disability in males; affected females typically have milder symptoms; hallmark features include developmental delay, learning disabilities, autism spectrum features, seizures.

What are common Fragile X phenotype features after puberty?

Narrow face, large head, large ears, flexible joints, flat feet, prominent forehead; these physical signs become more evident with age.

What is multifactorial inheritance and give examples of affected conditions?

Traits caused by multiple genetic and environmental factors; conditions tend to run in families and include birth defects, some cancers, hypertension, diabetes, Alzheimer’s, schizophrenia, bipolar disorder, arthritis, osteoporosis, asthma, MS.

What is Cleft Lip and Cleft Palate (CL/P) and what causes it?

A common birth defect of the Orofacial region caused by a combination of genetic and environmental factors; types include cleft lip, cleft palate, or both; identifiable prenatally by ultrasound; can be unilateral or bilateral and may occur with other anomalies.

What environmental and genetic factors contribute to CL/P?

Non-genetic environmental teratogens (smoking, alcohol, maternal diseases, stress, anticonvulsants, malnutrition) and genetic factors; syndromic (single gene) vs non-syndromic (no known cause).

What is Down syndrome and what causes it?

Most prevalent genetic disorder; trisomy 21 due to nondisjunction (or translocation in a small percentage); risk increases with maternal age; leads to intellectual disability and multiple health issues.

What prenatal diagnostic methods are used for Down syndrome and what are their risks?

Amniocentesis and Chorionic Villus Sampling (CVS); both are ultrasound-guided; amniocentesis after 15 weeks, CVS between 11-13 weeks; diagnostic tests carry miscarriage risk.

What are common health issues associated with Down syndrome?

Mental retardation, congenital heart defects, GI anomalies, hypotonia, dysmorphic facial features, hearing/vision impairment, hematopoietic issues, early-onset Alzheimer’s.

List some characteristic physical features of Down syndrome.

Palmar crease, sandal-gap toes, upslanting palpebral fissures, flat nasal bridge, small ears, protruding tongue, round/flat face, short neck, single transverse palmar crease.

What is aneuploidy?

Abnormal number of chromosomes in a cell, due to loss or duplication; includes monosomy (one copy) and polysomy (more than two copies).

What is Turner syndrome and its main features?

Monosomy X (45,X); most common in women; signs include short stature, webbed neck, low hairline, swelling of hands/feet, skeletal and kidney problems, congenital heart defects; usually not inherited.

What is Klinefelter syndrome and its typical presentation?

Male with an extra X chromosome (XXY); infertility is common; signs include abnormal body proportions, reduced facial/body hair, gynecomastia, small testes, tall stature; treated with testosterone therapy.

What is the role of testosterone therapy in Klinefelter syndrome?

Used to increase strength, muscle development, body hair, mood, energy, and concentration; helps improve quality of life and development.

What are mitochondrial gene disorders and how are they inherited?

Disorders due to mtDNA mutations; maternally inherited; commonly affect neuromuscular system; most primary mitochondrial diseases are autosomal recessive; mtDNA mutations disrupt energy production and related processes.

What are teratogenic factors and when is the embryo most susceptible?

Agents that interfere with normal in utero development; organogenesis (15-60 days post conception) is the most vulnerable period; exposure can cause birth defects.

What does TORCH stand for and why is it important?

Toxoplasmosis, Other (e.g., syphilis, HIV), Rubella, Cytomegalovirus (CMV), and Herpes simplex virus; infections can be transmitted to the fetus and cause miscarriage, birth defects, or developmental problems.

Why is folic acid important in pregnancy and what does deficiency cause?

Folate is essential for neural tube formation; folic acid is synthesized folate in fortified foods and supplements; deficiency increases risk of neural tube defects.

What is the purpose of genetic assessment in prenatal care?

Assess genetic risk and prognosis; gather detailed family and pregnancy history; inform parents' decisions, provide reassurance, and guide testing plans.

What prenatal screening and diagnostic methods are used to detect fetal genetic disorders?

Ultrasonography, maternal serum markers, amniocentesis, CVS, percutaneous umbilical cord blood sampling (PUBS), cytogenetic and DNA analyses.

What are maternal serum markers and what do AFP, hCG, uE3, and Inhibin A indicate?

A multi-marker test measuring AFP, hCG, unconjugated estriol (uE3), and Inhibin A to assess risk of chromosomal abnormalities or neural tube defects.

What is Alpha-fetoprotein (AFP) testing used for in fetal screening?

Screening for neural tube defects (e.g., spina bifida) and sometimes assessing risk for Down syndrome or Edwards syndrome when combined with other markers.

What is Chorionic Villus Sampling (CVS) and when is it performed?

A prenatal diagnostic test that samples placental villi; performed between 11-13 weeks gestation; ultrasound-guided; detects chromosomal problems.

What is Amniocentesis and when is it performed?

An invasive diagnostic test that removes amniotic fluid for karyotyping and biochemical analyses; usually performed after 15 weeks gestation; carries miscarriage risk.

What is Percutaneous Umbilical Cord Blood Sampling (PUBS) and when is it used?

Also called cordocentesis; fetal blood sampling from the umbilical cord for rapid chromosome analysis or biochemical studies; ultrasound-guided and used in high-risk pregnancies when other tests fail to provide information.

What is cytogenetic and DNA analysis in prenatal testing used for?

Examination of cells from amniocentesis, CVS, or PUBS to assess chromosome number/structure and DNA-level details for fetal diagnoses.