How do Mutations Affect Health and Craniofacial Development Flashcards
Mutations are an important
cause of
poor health
The average child is born with an estimated
— to — new mutations that were not present
in the parents
100-200
– in – infants is born with a diagnosable
genetic condition that can be attributed to a
single major mutation
1 in 50
types of genetic diseases (3)
chromosome disorders
single gene disorders
multifactorial or complex
Chromosome Disorders (5)
Aneuploidy, Rearrangements/Translocations, Deletions,
Insertions, Duplications
Single Gene Disorders (3)
Dominant, Recessive, Codominant
Multifactorial or Complex (2)
Multiple genes, gene-environment
aneuploidy
An aberration in chromosome number caused
by faulty segregation of chromosomes during
mitosis or meiosis
1 in 400 infants is born with —
aneuploidy
Most cases of aneuploidy originate in female
meiosis I and the risk rises with — —
maternal age
example of aneuploidy with oral manifestations
Down syndrome
Down syndrome
1866
1959
2000
• 1866 - John Langdon Down, an English
physician, published an accurate description of
a person with Down syndrome
• 1959 - Jérôme Lejeune identified Down
syndrome as a chromosomal condition
• 2000 - an international team of scientists
successfully identified and catalogued each of
the approximately 329 genes on chromosome
21
Down syndrome (trisomy 21)
full or partial extra copy of chromosome 21
how many babies in the US are born with downs syndrome
1 in 700 babies in the US
about — per year
6000
most common chromosomal condition
Down syndrome (trisomy 21)
Nondisjunction occurs in –% of down syndrome cases
> 95%
Mosaicism occurs in ~–% of Down syndrome cases, least common form
1%
Translocation occurs in ~–% of cases
4%
translocation is
full or partial copy of chromosome 21 attaches to
another chromosome, usually chromosome 14
only factor that has been linked to an increased
chance of having a baby with Down syndrome resulting from
nondisjunction or mosaicism
Maternal age
However, due to higher birth rates in younger women, 80% of children with Down syndrome are born to women under – years of age
35
5% of the cases have been traced to the —
father
— is not a factor in trisomy 21 (nondisjunction) and mosaicism
Heredity
However, in one-third of cases of Down syndrome resulting from
translocation there is a hereditary component – accounting for
about
1% of all cases of Down syndrome
Down syndrome symptoms
• Low muscle tone,
• Small stature,
• Cognitive delay (very mild to severe), and
• Transverse palmar crease
• a single deep crease across the center of the palm
• each person with Down syndrome is a unique
individual and may possess these
characteristics to different degrees, or not at all
• 80% of adults with Down syndrome reach age
60, and many live even longer
About half the children with Down syndrome are born with some type of congenital
— —. These heart problems can be life-threatening and may require surgery in early
infancy.
heart defect
— —: Some people with Down syndrome may have a misalignment of the top two
vertebrae in the neck (atlantoaxial instability). This condition puts them at risk of serious injury to
the spinal cord from overextension of the neck
spinal problems
— —: GI abnormalities occur in some children with Down syndrome and
may include abnormalities of the intestines, esophagus, trachea and anus. The risk of developing
digestive problems, such as GI blockage, heartburn (gastroesophageal reflux) or celiac disease,
may be increased.
Gastrointestinal (GI) defects
— —. Because of abnormalities in their immune systems, people with Down
syndrome are at increased risk of developing autoimmune disorders, some forms of cancer, and
infectious diseases, such as pneumonia.
immune disorders
— —. Because of soft tissue and skeletal changes that lead to the obstruction of their
airways, children and adults with Down syndrome are at greater risk of obstructive sleep apnea.
Sleep apnea
—. People with Down syndrome have a greater tendency to be obese compared with the
general population.
Obesity
—. Young children with Down syndrome have an increased risk
Leukemia
People with Down syndrome have a greatly increased risk of —. signs and
symptoms may begin around age 50. Having Down syndrome also increases the risk of
developing Alzheimer’s disease.
dementia
Down syndrome may also be associated with other health conditions, including
(6)
endocrine problems, dental problems, seizures, ear infections, and hearing and vision problems
People with Down syndrome should always be referred to as — first
v
Instead of “a Down syndrome child,” it should be “—.” Also
avoid “Down’s child” and describing the condition as “Down’s,” as in, “He has Down’s.”
a child with Down syndrome
Down syndrome is a (2), not a disease.
condition or a syndrome
People “—” Down syndrome, they do not “suffer from” it and are not “afflicted by” it.
have
Typically developing” or “—” is preferred over “normal.”
typical
what has replaced “mental retardation” as the
appropriate term
“Intellectual disability” or “cognitive disability”
— strongly condemns the use of the word “retarded” in any derogatory context.
Using this word is hurtful and suggests that people with disabilities are not competent.
NDSS
Down vs. Down’s
down not downs
what causes chromosomal rearrangements
by chromosome breakage or by recombination between mispaired chromosomes during meiosis
Only chromosomal rearrangements that change the — or that break up an important gene are likely to cause disease
copy number of genes
1 in 1000 infants is born with a — chromosomal rearrangement
symptomatic
examples with oral manifestations
cri-du-chat syndrome
Cri du chat syndrome is known as
Cat’s cry
cat’s cry
infants with this condition often have a high-pitched cry that sounds like that of a cat
Cri du chat syndrome affects
1 in 20-50,000 newborns
symptoms of Cri du chat syndrome (6)
• Intellectual disability and delayed development • Small head size (microcephaly) • Low birth weight • Weak muscle tone (hypotonia) • Transverse palmar crease • Some have heart defects
Cri du chat syndrome facial features
• Widely set eyes (hypertelorism) • Low-set ears • Small jaw (micrognathia) • Rounded face (moon facies) • epicanthal folds, • broad nasal bridge, • downward-slanting palpebral fissures
single gene disorders aka
mendelian disorders
single gene disorders are mutations in a
single gene
expressed in heterozygotes, who carry
a single copy of the mutation
dominant
Severe dominant diseases are often caused by a
new
mutation
expressed only in homozygotes, who
have the mutation in both copies of the gene
recessive
multifactorial diseases aka
polygenic diseases or complex diseases
multifactorial diseases are caused not by a single major mutation but by (2)
interacting genetic and environmental risk
factors
Most of the common diseases, from (3), are
multifactorial
allergies to
diabetes and coronary heart disease
Median palatal process
(derived from medial nasal
processes and frontonasal
process) - forms the — —
primary
palate
— — - derived
from the frontonasal
prominence
Nasal Septum
— — - derived
from the maxillary process
of the first pharyngeal arch
Palatal shelves
Secondary palate separates the
nasal cavity from the oral cavity
what is the secondary palate needed for? (5)
swallowing (feeding) taste vomitting breathing speech
- – of CPO is different than that of Cleft Lip with Cleft Palate (CL/CP)
- CPO is a specific defect in palatogenesis (weeks 7-10)
- CP in CL/CP is a secondary defect for a failed lip fusion (weeks 4-7)
Etiology
Syndromic cleft palate ~ —% of cases (Cleft palate a phenotype of a known
syndrome)
30
Non-syndromic cleft palate – —% of cases (not associated with a known
syndrome)
70
identified causes of cleft palate (3)
environmental
nutritional/metabolic
genetic
Environmental
alcohol, phenytoin, retinoic acid, radiation (X-rays),
TCDD…
Nutritional / metabolic
low methionine, low folic acid, maternal DM,
hypervit. A
Genetic
350+ Mendelian disorders, chromosomal
aberrations
— is not fully understood
Pathogenesis
cleft lip and palate is not just an interesting biological problem, or just an aesthetic handicap, but also (7)
● family: shock, guilt, anxiety, depression ● babies: failure of suckling, later eating problems ● dental defects, malocclusion ● speech difficulties ● infectious complications, hearing impairment ● multiple surgery and hospital care ● psychological traumatization
Current prenatal screening does a poor job of detecting — —
facial anomalies
Cleft palate is a very early
— event, screening
occurs 18-22 weeks
intrauterine
(2) do
not exist to easily detect a cleft
palate
Technology and resources
Etiology of cleft palate is multifactorial
(and still poorly known):
(5)
•Gene - Environment interactions •Genetic susceptibility •Environmental toxins •Nutrition •Life style (smoking, alcohol etc)
A problem caused by the therapy-
defective maxillary growth
A substantial amount of knowledge about the
(2) of cleft palate has been
accumulated
developmental biology of palate and the
etiopathogenesis
Challenges:
• Lifestyle and environmental risk factors
• Gene - environment interactions (still largely an
unknown variable)
• A number of molecules expressed in the palate
during fusion is humbling
• We know many of them - however, we know
very little about their regulation and how
different signaling pathway intersect and
converge
