Exam 3 Flashcards
a judgement made on behalf of a noncompetent patient and based on what that person would have decided had they been competent
Substituted Judgement
Substituted Judgement
a judgement made on behalf of a noncompetent patient and based on what that person would have decided had they been competent
has its origins in family law and has become the prevailing standard used to judge the adequacy of medical decision making on behalf of pediatric patients
Best interest standard
Best interest standard
has its origins in family law and has become the prevailing standard used to judge the adequacy of medical decision making on behalf of pediatric patients
incorporates the total well being of the individual rather just the medical well being
Best interest standard
a process who involves a competent individual voluntarily receiving and understanding information and then decision -making
Informed consent
what is Informed consent
a process who involves a competent individual voluntarily receiving and understanding information and then decision -making
term used to be applied when parents give permission for medical treatment on behalf of their child or adolescent
Parental Permission
Can a parent or legal guardian give legal consent for their child?
technically no, because because the person for whom the treatment is planned gives only informed consent. Parental permission is a more correct term
a broad term that covers the study of the nature of morals and the specific moral choices to be made
Ethics
type of ethics:
ethics attempts to answer the question, “Which general moral norms for the guidance and evaluation of conduct should we accept, and why?”
Normative
what type of morality?
not to kill, or harm, or cause suffering to others, not to steal, not to punish the innocent, to be truthful, to obey the law, to nurture the young and dependent, to help the suffering, and rescue those in danger
Common Morality
What type of morality?
refers to norms that bind groups because of their culture, religion, profession and include responsibilities, ideals, professional standards, and so on
Particular
what type of morality does this example represent?
the physician’s “accepted role” to provide competent and trustworthy service to their patients.
Particular
What war contributed to leading the rapid evolution of bioethics?
experimentation in concentration camps in World War II
4 principles of ethics
Beneficence
Nonmaleficence
Autonomy
Justice
which 2 principles of ethics can be traced back to the time of Hippocrates, “to help and do no harm”
Beneficence
Nonmaleficence
The other 2 evolved later
the obligation of physician to act for the benefit of the patient and supports a number of moral rules to protect and defend the right of others, prevent harm, remove conditions that will cause harm, help persons with disabilities, and rescue persons in danger.
Beneficence
The principle calls for not just avoiding harm, but also to benefit patients and to promote their welfare. While physicians’ beneficence conforms to moral rules, and is altruistic, it is also true that in many instances it can be considered a payback for the debt to society for education (often subsidized by governments), ranks and privileges, and to the patients themselves (learning and research).
Beneficence
the obligation of a physician not to harm the patient.
Nonmaleficence
This simply stated principle supports several moral rules – do not kill, do not cause pain or suffering, do not incapacitate, do not cause offense, and do not deprive others of the goods of life.
Nonmaleficence
The practical application of _________ is for the physician to weigh the benefits against burdens of all interventions and treatments, to eschew those that are inappropriately burdensome, and to choose the best course of action for the patient.
nonmaleficence
which ethical principle is particularly important and pertinent in difficult end-of-life care decisions on withholding and withdrawing life-sustaining treatment, medically administered nutrition and hydration, and in pain and other symptom control. A physician’s obligation and intention to relieve the suffering (e.g., refractory pain or dyspnea) of a patient by the use of appropriate drugs including opioids override the foreseen but unintended harmful effects or outcome (doctrine of double effect) [7, 8].
Nonmaleficence
which ethical principle?
The philosophical underpinning for ________, as interpreted by philosophers Immanuel Kant (1724–1804) and John Stuart Mill (1806–1873), and accepted as an ethical principle, is that all persons have intrinsic and unconditional worth, and therefore, should have the power to make rational decisions and moral choices, and each should be allowed to exercise his or her capacity for self-determination
Autonomy
This ethical principle was affirmed in a court decision by Justice Cardozo in 1914 with the epigrammatic dictum, “Every human being of adult years and sound mind has a right to determine what shall be done with his own body”
Autonomy
example of when would autonomy need to be weighed against another competing moral principle, being overridden?
an obvious example would be if the autonomous action of a patient causes harm to another person(s).
The principle of autonomy does not extend to
persons who lack the capacity (competence) to act autonomously; examples include infants and children and incompetence due to developmental, mental or physical disorder.
who determines incapacity to make health-care decisions?
Who determines incompetence?
Health care professionals
Incompetence is determined by a court of law
Respecting the principle of _________obliges the physician to disclose medical information and treatment options that are necessary for the patient to exercise self-determination and supports informed consent, truth-telling, and confidentiality.
autonomy
The requirements of _____ _______ for a medical or surgical procedure, or for research, are that the patient or subject (i) must be competent to understand and decide, (ii) receives a full disclosure, (iii) comprehends the disclosure, (iv) acts voluntarily, and (v) consents to the proposed action.
informed consent
what type of standard?
what the patient would wish in this circumstance and not what the surrogate would wish
substituted judgement standard
what type of standard?
what would bring the highest net benefit to the patient by weighing risks and benefits
Best interests standard
______________ is a vital component in a physician-patient relationship; without this component, the physician loses the trust of the patient.
Truth telling
The sad consequences of not telling the truth regarding a cancer include depriving the patient of an opportunity for completion of important life-tasks:
what are these tasks?
giving advice to, and taking leave of loved ones, putting financial affairs in order, including division of assets, reconciling with estranged family members and friends, attaining spiritual order by reflection, prayer, rituals, and religious sacraments
_______ is generally interpreted as fair, equitable, and appropriate treatment of persons.
Justice
refers to the fair, equitable, and appropriate distribution of health-care resources determined by justified norms that structure the terms of social cooperation
Distributive Justice
what are the principles of distributive justice?
These are distribution to each person (i) an equal share, (ii) according to need, (iii) according to effort, (iv) according to contribution, (v) according to merit, and (vi) according to free-market exchanges.
prima facie obligation
Each one of the 4 principles of ethics is to be taken as a prima facie obligation that must be fulfilled, unless it conflicts, in a specific instance, with another principle. When faced with such a conflict, the physician has to determine the actual obligation to the patient by examining the respective weights of the competing prima facie obligations based on both content and context.
Beneficence has enjoyed a historical role in the traditional practice of medicine. However, giving it primacy over patient autonomy is ________ that makes a physician-patient relationship analogous to that of a father/mother to a child.
Paternalism
the physician acts on grounds of beneficence (and, at times, nonmaleficence) when the patient is nonautonomous or substantially nonautonomous (e.g., cognitive dysfunction due to severe illness, depression, or drug addiction)
soft paternalism
action by a physician, intended to benefit a patient, but contrary to the voluntary decision of an autonomous patient who is fully informed and competent, and is ethically indefensible
Hard paternalism
a rare and extreme form of patient autonomy, that holds the view that the physician’s role is limited to providing all the medical information and the available choices for interventions and treatments while the fully informed patient selects from the available choices. n this model, the physician’s role is constrained, and does not permit the full use of his/her knowledge and skills to benefit the patient, and is tantamount to a form of patient abandonment and therefore is ethically indefensible.
Consumerism
when was the concept assent developed and for what reason
in the 1980s to address decision-making by adolescents with cancer
What is assent
Pediatric patients should participate in the decision making process commensurate with their developmental level. Their assent to medical care should be sought whenever reasonable, and parents and HCP should not exclude them without persuasive reasons.
components of assent
Helping the pediatric patient achieve developmentally appropriate awareness of the condition
Telling the pediatric patient what to expect with clinical management
Assessing understanding and factors influencing response
Soliciting expression of the pediatric patient’s willingness to accept the proposed treatment
allows patients and/or surrogates to designate desired medical interventions under applicable circumstances.
Advance directive (AD)
What act requires healthcare institutions to ask anyone over the age of 18 whether they have completed an Advance Directive (AD) and if not, inform them of their right to do so.
The Federal Patient Self-Determination Act
The Federal Patient Self-Determination Act
what does this require
requires healthcare institutions to ask anyone over the age of 18 whether they have completed an Advance Directive (AD) and if not, inform them of their right to do so.
Provide care that benefits the patient
Beneficence
Avoid harming the patient
Nonmaleficence
Individuals should decide what constitutes their own best interest
Autonomy
Provides services fairly without bias from factors irrelevant to the situation
Justice
Beneficence
Provide care that benefits the patient
Nonmaleficence
Avoid harming the patient
Autonomy
Individuals should decide what constitutes their own best interest
Justice
Provides services fairly without bias from factors irrelevant to the situation
DNR is a form of _____ and has been renamed what?
Advance Directive
“Do not attempt resuscitation” or “Allow Natural Death”
why is the term “Allow Natural Death” preferred over DNR
better received, has a more positive connotation, and states what will be done rather than what will not be done for the patient
steps after refusal of care if needed to be escalated
Is this a communication problem? (Understanding)
Ethics Consult
legal counsel
medical interventions that are unlikely to produce any significant benefit to the patient is called
Inappropriate or futile care
what is the difference between withholding and withdrawing medical treatment
Withholding treatment, out of concern that withdrawing it in the future would be more difficult, risks undertreating a patient who might respond to that treatment.
a deliberate intervention undertaken with the intention of ending a life to relieve intractable suffering
Euthanasia or Physician assisted suicide
Does the American Academy of Pediatrics (AAP) support Physician assisted suicide?
no
What is the Doctrine of Double effect (DDE)
a set of ethical criteria for evaluating the permissibility of acting when one’s otherwise legitimate act will also cause a negative effect that one would normally be obliged to avoid.
The provision of adequate sedation and analgesia to a patient, even if it hastens his death is not considered euthanasia because of the Doctrine of Double Effect (DDE)
What is the Doctrine of double effect criteria?
An action having foreseen harmful effects practically inseparable from the good effect is justifiable upon satisfaction of the following: the nature of the act is itself good, or at least morally neutral
The agent intends the good effect and not the bad either as a means to the good or as an end itself
The good effect outweighs the bad effect in circumstances sufficiently grave to justify causing the bad effect and the agent exercises due diligence to minimize the harm
T/F
Nutrition and hydration is considered a form of life-sustaining treatment when administered through a feeding tube or IV. Under appropriate circumstances it is ethically defensible to forgo or withdraw this form of therapy.
True
Bolick pg 48
the HCPs obligation to prevent unauthorized access to information about a patient
Confidentiality
what are the exceptions to maintaining confidentiality
Promote public health and safety (pediatric patient neglect and abuse, communicable diseases)
Public interest demands disclosure (dangerousness to self or others, gunshot wounds)
a systematic investigation designed to develop or contribute to general knowledge.
Research
There are more restrictions placed on Research in Pediatrics patients because they cannot provide
informed consent
In general regarding research in pediatric patients, it is permissible to involve pediatric patients in research which poses _______ risk: equivalent to
minimal
risks encountered in daily life or during performance of routine physical or psychological exams or tests
requirements for pediatrics to participate in research
The pediatric patients parents (legal guardians) must give permission
Second assent of the patient should be obtained (if age appropriate) - not required and based on developmental level. The opportunity to dissent, esp for nontherapeutic research should be made available.
third, Institutional review board panel (IRB) approval must be granted for the study to be considered
what board must you gain approval from for pediatric patients to be a part of a research study
Institutional review board (IRB) panel
a person who is younger than the age of legal competence
minor
the legal age at which a person is no longer a minor
The age of majority
In Alabama and Nebraska the age of majority is
19
In Colorado and Mississippi what is the age of majority
21
Under ____ law, a parent generally retains the right to make decisions regarding their childs healthcare
State
what is Parens Patriae?
Common law doctrine that says the state may intervene against a childs natural parent or legal guardian who is in need o protection.
Parens Patriae is latin for
Parent of the nation
2 classes of minors
emancipated minor
mature minor
a minor liberated from parental control
emancipated minor
a minor who may be granted decision making authority regarding their own healthcare
Mature minor
In Texas, what are the terms for age of Emancipation
A minor may petition for emancipation if
they are a resident of Texas
17 years of age or at least 16 if living apart from guardian or parents and is self-supporting or by marriage
In Texas, what is the terms of Age to consent for medical treatment
Minors may consent to any treatment if in military or 16 years old and living apart from parents; any minor may consent to treatment for pregnancy if they are unmarried and not seeking an abortion, substance abuse, infectious diseases or if they are incarcerated
Have all states adopted the mature minor doctrine?
no
what happened in Abrahams law
15 yo with Hodkins disease
received first course of chemo
supposed to receive 2nd but parents and Abraham refused wanting to try Hoxsey method which was not well backed. Natural
Abrahams parents were charged with medical neglect and a social services agency sought to force Abraham to get the chemo and radiation
Ultimately cleared and the family was allowed to pursue Alternative treatments.
Virginia Legislature amended its child abuse statute in March 2007 “Abraham’s Law” allows parents and children between 14-17 years to refuse medical treatment for a life threatening condition. Prevents parents from being charged with medical neglect if the decision to refuse such treatment is made jointly by the parents and the child. The law requires that the child be sufficiently mature to have an informed opinion regarding the subject of his or her medical treatment. This caused many states to explore the concept of the mature minor doctrine
allows parents and children between 14-17 years to refuse medical treatment for a life threatening condition. Prevents parents from being charged with medical neglect if the decision to refuse such treatment is made jointly by the parents and the child. The law requires that the child be sufficiently mature to have an informed opinion regarding the subject of his or her medical treatment.
Abrahams law
what happened in Parker Jensen case
12 yo boy in utah (2003) was diagnosed with Ewing sarcoma. oncology recommended chemo. Parents refused and requested other options. Medical neglect filed. Court mandated chemo. Parents did not go. They left the state. Parents charged with kidnapping. Eventually dismissed.
what happened in Schmidt v mutual hosp in 2005?
Medical intervention against their faith.
7 months and was reported anonymously that there were concerns
Mom was taken to hospital against consent
Pre-eclamptic and delivered early
Never signed consents
lawsuit against the hospital and refusal to pay bills
Did not have to pay for mom
had to pay babys hospital expenses. Deemed unlawful to decline
The Schmidts must pay for the medical services provided to their daughter because “A parent has a duty to provide support for his or her minor child, which includes the provision of reasonable and necessary medical services for that child.” Scott Co. School District 1 v. Asher, 263 Ind. 47, 324 N.E.2d 496 (1975). The parent is obligated even where the parent refused in advance to pay for such services and they were rendered in spite of the refusal to pay. St. Mary’s Med. Ctr. v. Bromm, 661 N.E.2d 836 (Ind.Ct.App.1996).
This principle is incorporated into both federal and state healthcare laws, requires that the child be allowed to hold and express his or her own views if capable of doing so and that the childs perspective be considered when the parents deliberate on making an informed decision
Self determination
Process of self determination by which a child, having been fully informed or informed to the limits of his or her ability to understand the aspects of the decision, participates in decision making
Assent
when identifying potential live donors, a sibling is a ____% match
25% , identical twin is best match
a patient-and family centered care that optimizes quality of life by anticipating, preventing and treating suffering
Palliative care approach
when should palliative care be implemented
when medical diagnosis, intervention, and treatment cannot reasonably be expected to affect the imminence of death
elements of palliative care
pain management
expertise with feeding and nutritional issues at the end of life;
management of symptoms - minimizing nausea/vomiting, bowel obstruction, labored breathing fatigue
4 basic groups of conditions needing/could benefit from palliative care
a cure is possible, but failure is not uncommon (ie) cancer with a poor prognosis)
Long term Treatment is provided with a goal of maintaining quality of life (ie- cystic fibrosis)
Treatment that is exclusively palliative after the diagnosis of a progressive condition is made (ie trisomy 13)
Treatments are available for severe, non-progressive disability in patients who are vulnerable to health complications (severe spastic quadriparesis with difficulty in controlling symptoms)
principles of palliative care
Respect for the dignity of patients and families
Access to comprehensive and compassionate family care
Use of interdisciplinary resources
Acknowledgment and support provisions for caregivers
Commitment to quality improvement of palliative care through research and education
a treatment program for the end of life that provides the range of palliative care services by an interdisciplinary team including specialists in the bereavement and end of life process
hospice care
can children covered under Medicaid or Children’s Health Insurance Program (CHIP) have access simultaneously to hospice care and curative care
yes, in 2010 legislation was passed to allow this
the process of psychologic and spiritual accommodation to death on the part of the child and the childs family
Bereavement
the emotional response caused by a loss which may include pain, distress, and physical and emotional suffering
grief
bereavement
the process of psychologic and spiritual accommodation to death on the part of the child and the childs family
grief
the emotional response caused by a loss which may include pain, distress, and physical and emotional suffering
what type of grief is recognized as being more intense and sustained than other types of grief
parental grief
a pathologic manifestation of continued and disabling grief (rare)
Complicated grief
what circumstances make parents who lose a child more likely to resolve their grief
Parents who…
1) share their problems with others during the childs illness
2) have access to psychologic support during the last month of their childs life
3) who have had closure sessions with the attending staff
what are Piaget’s theories of cognitive development which help illustrate children’s concepts of death and disease
sensorimotor
preoperational
concrete operations
formal operations
Age of Piaget’s theories of cognitive development which help illustrate children’s concepts of death and disease:
Sensorimotor - death is seen as a separation without a specific concept of death
up to 2 years old
explain Age of Piaget’s theories of cognitive development which help illustrate children’s concepts of death and disease Sensorimotor
seen in children up to 2 years old…death is seen as a separation without a specific concept of death
Associated behaviors in grieving children of this age usually includes protesting and difficulty of attachment to other adults. The degree of difficulty depends on the availability of other nurturing people with whom the child has a good previous attachment.
Piaget
Associated behaviors in grieving children of this age usually includes protesting and difficulty of attachment to other adults. The degree of difficulty depends on the availability of other nurturing people with whom the child has a good previous attachment.
Sensorimotor
Age of Piaget’s theories of cognitive development which help illustrate children’s concepts of death and disease:
Preoperational
3-5 yrs old
Preoperational is sometimes called
the magic years
Explain Piaget’s Preoperational stage
children 3-5 yrs
have trouble grasping the meaning of the illness and the permanence of death
their language skills at this age make understanding their moods and behavior difficult
Because of developing a sense of guilt - death may be viewed as a punishment
If a child previously wished a younger sibling dead, the death may be seen psychologically as being caused by the childs wishful thinking. They can feel overwhelmed when confronted with the strong emotional reactions of their parents
Piaget
have trouble grasping the meaning of the illness and the permanence of death
Preoperational
Age of Piaget’s theories of cognitive development which help illustrate children’s concepts of death and disease:
Late preoperational to concrete operational
Ages 6-11 yrs
explain Piaget Late preoperational to concrete operational stage
The finality of death gradually comes to be understood.
Magical thinking gives way to a need for detailed information to gain a sense of control.
Older children in this range have a strong need to control their emotions by compartmentalizing and intellectualizing
The finality of death gradually comes to be understood.
Lat preoperational to concrete operational
Age of Piaget’s theories of cognitive development which help illustrate children’s concepts of death and disease:
formal operations
> =12 years of age
describe Piaget’s formal operations stage
death is a reality and is seen as universal and irreversible.
Adolescents handle death issues at the abstract or philosophical level and can be realistic.
They may also avoid emotional expression and information, instead of relying on anger or disdain.
Adolescents can discuss withholding treatments. Their wishes, hopes and fears should be attended to and respected.
Piaget
death is a reality and is seen as universal and irreversible
formal operations
Before speaking with a child about death, what should be assessed
childs :
age
experience
level of development
the childs understanding and involvement in end of life decision making
Parents:
emotional acceptance of death
coping strategies
their philosophical, spiritual and cultural views of death which can change over time
what ethical principles are involved in the care of a dying child
Autonomy
Beneficence
Nonmaleficence
plus
truth telling
confidentiality
physicians duty
The most important ethical principle is what is in the best interest of the child as determined through the process of shared decision making, informed permission/consent from the parents and assent from the child.
There is/is not a ethical or legal difference between withholding treatment and withdrawing treatment
is not
however, many parents and physicians see withdrawing treatment is more challenging
The most important ethical principle
is what is in the best interest of the child as determined through the process of shared decision making, informed permission/consent from the parents and assent from the child.
organ donation can occur one of two ways
- after fulfilling criteria for neurological (brain) death
- Through a process of donation after circulatory death (DCD)
in evaluating a child with congenital malformations, a clinical geneticist attempts to identify what?
Etiology
Mode of inheritance
Risk that a disorder might occur in the affected child’s siblings
5 categories of congenital malformations
1) single gene mutations (occurs in 6% of children with congenital anomalies)
2) Chromosomal disorders (7.5%)
3) Multifactorially inherited conditions (20%)
4) Disorders that show an unusual pattern of inheritance accounting (2-3%)
5) Conditions caused by exposure to teratogens (6%)
DNA is composed of what 4 nucleotide building blocks
Adenine
Guanine
Cytosine
Thymine
DNA molecule consists of 2 chains of nucleotides held together by ______ bonds
hydrogen
DNA molecule consists of 2 chains of nucleotides held together by ______ bonds
hydrogen
DNA molecule consists of 2 chains of nucleotides held together by ______ bonds
hydrogen
DNA molecule consists of 2 chains of nucleotides held together by ______ bonds
hydrogen
DNA molecule consists of 2 chains of nucleotides held together by ______ bonds
hydrogen
Adenine and guanine are _______ nucleotides
Purine
Thymine and cytosine are what type of nucleotides
Pyrimidines
because of cross linking in DNA, the nucleotide sequence of one strand sets the other strands sequence. What does separating the 2 strands permit
complementary nucleotides to bind to each DNA strand; this copies the DNA and replicates the sequence
DNA exists as multiple fragments that, together with a protein ____, form chromosomes
Skeleton (Chromatin)
Human cells have ___ pairs of chromosomes, with one copy of each chromosome inherited from _______
23
each parent
22 pairs of chromosomes are ______ and the remaining pair consists of ______
autosomes
sex chromosomes
What sex chromosomes do females have and what do males have
Females:
2 X chromosomes
Males have one X and one Y
Spread along the chromosomes like beads on a string, DNA sequences form _____, the basic units of heredity
genes
A typical gene contains what?
A promoter sequence
an untranslated region and a
open reading frame
In the open reading frame of a gene, every 3 nucleotides represent a single
codon
A codon codes for
a particular amino acid
The sequence of bases dictates the sequence of ___ ___ in the corresponding protein
amino acids
Some codons, rather than coding for specific amino acids act as what?
Start signals
stop signals
Between the start and stop codons, genes consist of 2 major portions
Exons- regions containing the code that ultimately corresponds to a sequence of amino acids
Introns - intervening sequence which do not become part of the amino acid sequence
Between the start and stop codons, genes consist of 2 major portions
Exons- regions containing the code that ultimately corresponds to a sequence of amino acids
Introns - intervening sequence which do not become part of the amino acid sequence
what part of gene:
regions containing the code that ultimately corresponds to a sequence of amino acids
Exons
What part of gene:
intervening sequence which do not become part of the amino acid sequence
INtrons
Genes are transcribed into ______then translated into _____
RNA (mRNA)
proteins
During transcription, RNA is processed to remove _____. The mRNA serves as a template to ______
Introns
construct the protein
Through a mechanism called _____ _______, these genes may create more than 100,000 proteins. The remainder of the DNA, the portion not involved in protein formation was once termed _____ _____but a project called ENCODE found that much of this presumed junk DNA is functional and likely serves _____ functions
Alternative splicing
Junk DNA
Regulatory
Disease may be caused by _____ in the DNA sequence with the _____ ______ being the most common type
mutations
point mutation
A point mutation that changes a codon and the resulting amino acid that goes into the protein is referred to as a _____ _______
missense mutation
A point mutation that changes the codon to a stop signal so that transcription ends prematurely
nonsense mutation
A ____ _____ often stems from the loss of addition of one or more bases; this causes a shift in how the DNA is transcribed and generally leads to premature stop codons
frameshift mutation
To identify patterns of inheritance, geneticists construct and analyze
pedigrees (pictorial representations of a family history)
Pictorial representation of a family history
Pedigree
In a pedigree
what are all of the symbols
Males - squares
Females- circles
Matings - connected by solid line between each partners symbol
Children from a couple are represented below their parents (which is next generation)
Affected individuals are indicated by shading or some other technique indicated in key
Carriers of disorder are indicated by a dot in the center of their symbol
Proband (patient who is the initial contact) - arrow
Grandparents, uncles, aunts and cousins are added in similar fashion. Ages or birthdays may be written next to or under each symbol
what is the proband on a pedigree drawing
the patient who is the initial contact
To be useful, pedigrees should include representatives of at lease ______ generations of family members
3
on a pedigree
a solid line between symbols
mating
on a pedigree,
a dot in the center of their symbol indicates
they are a carrier
what type of disorder?
a single copy of a gene bearing a mutation is sufficient to cause disease and that gene is not on one of the sex chromosomes
autosomal dominant (AD) disorder
in autosomal dominant disorders, each child of an affected parent has a ____% chance of inheriting the mutated gene.
50%
Possessing one working gene and one nonworking gene is termed _______
Heterozygous
Possessing either two working genes or two nonworking genes, this is termed
Homozygous
Some people who are obligate carriers of a mutation known to cause a AD disorder do not show clinical signs of the condition, while other such individuals manifest symptoms. This phenomenon is referred to as _______
penetrance
If all individuals who carry a mutation for an Autosomal dominant disorder show signs of the disorder, the gene is said to have
complete penetrance
what type of disorder?
Neurofibromatosis
Autosomal Dominant
what type of disorder?
Huntington disease
Autosomal Dominant
What type of disorder?
Marfan syndrome
Autosomal Dominant
rules of Autosomal dominant inheritance
1) Trait appears in every generation
2) Each child of an affected parent has a one in two chance of being affected
3) Males and females are equally affected
4) Male to Male transmission occurs
5) Traits generally involve mutations in genes that code for regulatory or structural proteins (collagen)
explain variable expressivity
Often AD disorders show variability in symptoms expressed in different individuals carrying the same mutated gene
AD disorders sometimes appear in a child of unaffected parents because of a ______ _____
spontaneous mutation
Most common skeletal dysplasia in humans (Autosomal dominant disease)
Achondroplasia (ACH)
Most common skeletal dysplasia in humans (Autosomal dominant disease)
Achondroplasia (ACH)
Most common skeletal dysplasia in humans (Autosomal dominant disease)
Achondroplasia (ACH)
Most common skeletal dysplasia in humans (Autosomal dominant disease)
Achondroplasia (ACH)
Most common skeletal dysplasia in humans (Autosomal dominant disease)
Achondroplasia (ACH)
Achondroplasia (ACH) is caused by a defect in _____ which stems from a mutation in _______
Cartilage-derived bone
FGFR3
In Achondroplasia (ACH) the bony abnormalities lead to
short stature
macrocephaly
a flat midface with a prominent forehead
Rhizomelic (“root of the limb”) shortening of the limbs
Concerns as kids with Achondroplasia (ACH) grow
Hydrocephalus
Central apnea
Bowing of legs
Dental malocclusion
Obstructive apnea
hearing loss
sciatica
normal life spans and
normal intelligence
One of the most common Autosomal dominant disorders
Neurofibromatosis Type 1
Neurofibromatosis type 1 is caused by a mutation in the ____ gene, which codes for the protein ________
NF1
Neurofibromin
An Autosomal dominant disease that shows pleiotropy (a condition in which abnormalities in multiple organ systems are caused by mutation in a single gene) - mainly cardiac, ophthalmological and skeletal
mutation in FBN1
Marfan syndrome
Findings in Marfan syndrome
Dolichostenomelia (tall, thin body habitus, spider like fingers and toes (arachnodactyly)
Abnormalities of sternum (pectus excavatum or carinatum)
Scoliosis
pes planus
joint laxity
High myopia - can lead to vitreoretinal degeneration
cataracts
dilation of aortic root
aortic insufficiency followed by aortic dissection
Mutation in FBN1
Marfan Syndrome
When do disorders that are inherited in an autosomal recessive (AR) manner manifest?
only when both copies of a gene pair located on a non-sex chromosome have a mutation
Children affected with AR (autosomal recessive) disorders are usually born to
unaffected parents, each of whom carries one copy of the mutation
If both parents are heterozygotes for a mutation, each of their offspring have a ___-% chance of being affected with a Autosomal recessive disorder
25%
what type of a genetic disorder is Sickle cell disease
Autosomal recessive
What type of a genetic disorder is tay sachs disease
Autosomal Recessive
Approximately _____ genes have been identified on the X chromosome, whereas only ____ are believed to be present on the Y chromosome
2,000
200
Early in female development, one x chromosome is randomly inactivated in each cell. There are many x-linked disorders (colorblindness, Duchenne muscular dystrophy, hemophilia A) in which heterozygous (carrier) females show some manifestations of the disorder due to
skewed X chromosome inactivation.
most disorders involving the X chromosome show ______ inheritance
recessive
explain x linked recessive inheritance
whose most likely to manifest these diseases?
With only one copy of the x chromosome, males are more likely to manifest these diseases than females.
Each son born to a female carrier of an X linked recessive trait has a _____% chance of inheriting the trait. Each daughter has a _____% chance
50%
none of the daughters would be affected. Daughters would have a 50% chance to be a carrier
A affected father of an X linked recessive disorder
transmits the mutation to ____% of his daughters and _____% of his sons
all of his daughters
none of his sons
having received their fathers Y chromosome, they would not be affected (thus there is no male to male transmission)
What type of genetic disorder is Duchenne muscular dystrophy
X linked recessive
what type of genetic disorder is Hemophilia A
X linked recessive
Rules of Autosomal Recessive inheritance
1) Trait appears in siblings, not in their parents or their offspring
2) On average, 25% of siblings of the proband are affected (at the time of conception, each sibling has a 25% chance of being affected)
3) A normal sibling of an affected individual has a 2/3rds chance of being a carrier (heterozygote)
4) Males and females are likely to be affected equally
5) Rare traits are likely to be associated with parental consanguinity
6) Traits generally involve mutations in genes that code for enzymes and are associated with serious illness and shortened lifespan
Congenital Adrenal hyperplasia (CAH) is what type of genetic disorder
Autosomal recessive
PKU is what type of genetic disorder
Autosomal Recessive
Cystic fibrosis is what type of genetic disorder
Autosomal Recessive
Gender affected in X linked dominant inherited diseases
Both males and females are affected but females have less severe symptoms due to X chromosome inactivation
a disorder in which the kidneys ability to reabsorb phosphate is impaired
X linked vitamin D-resistant rickets (hypophosphatemic rickets) - X linked dominant
Phosphate levels and resulting rickets are not as severe in females as in males
Incontinentia pigmenti is caused by a mutation in the
NEMO or IKBKG gene
characteristic swirling pattern of hyperpigmentation that develops after a perinatal skin rash with blistering
Incontinentia Pigmenti
Prognosis of affected males in Incontinentia Pigmenti
death occurs before birth
Affected mothers can have affected or normal daughters but only normal sons. All affected sons die before birth
Females affected by Incontinentia Pigmenti have variable involvement of
the CNS,
Hair
nails
teeth
eyes
Rett syndrome is caused by mutations in what gene
MECP2
Rett syndrome is what type of genetic disorder
X linked dominant
in this genetic disorder, females are normal at birth but later in the first year of life develop microcephaly, developmental regression and often a seizure disorder
Rett syndrome
Signs/symptoms of Rett syndrome
females are normal at birth but later in the first year of life develop microcephaly, developmental regression and often a seizure disorder
Girls are often diagnosed with autism, and by 2 yrs of age, adopt a handwashing posture that causes them to lose all purposeful hand movements
Girls are often diagnosed with autism, and by 2 yrs of age, adopt a handwashing posture that causes them to lose all purposeful hand movements
Rett syndrome
multifactorially inherited disorders result from the interplay of genetic and environmental factors
polygenic inheritance
Rules of X linked recessive inheritance
1) Incidence of the trait is higher in males than in females
2) Trait is passed from carrier females, who may show mild expression of the gene, to half of their sons, who are more severely affected
3) Each son of a carrier female has a one in 2 chance of being affected
4) Trait is transmitted from affected males to all of their daughters, it is never transmitted father to son
5) Because the trait can be passed through multiple carrier females, it may skip generations
hypertrophic pyloric stenosis (HPS) is five times more likely to occur in ____ than _____
males
females
does an affected male in Hypertrophic Pyloric stenosis in adulthood have an increased chance of having an affected child
yes, markedly increased over the general population
The occurrence of neural tube defects in the United States are more likely to be born during what season?
During late fall and early winter, suggesting an environmental component or a folate responsive gene effect
Periconceptual supplementation with folic acid has significantly lowered the risk of having an infant with an Neural tube defect. This nutritional influence suggests an _____ component.
Parents who have one child with an Neural tube defect are 20-40xs more likely to have a second affected child, this provides further evidence of a ______ component
environmental
genetic
A woman with a mutation in her mtDNA passes this mutation to ____% of her children
100
More than one population of mitochondria may be present in the oocyte which is a phenomenon called ______
heteroplasmy
The mtDNA mutation may be present in a few or many mitochondria. When the fertilized egg divides, mitochondria or distributed randomly. The presence of symptoms in the offspring and their severity depends on what factors
The ratio of mutant to wild-type mrDNA present in a particular tissue.
If an abundant of mutant mitochondria exists in tissue that has high energy requirements (brain, muscle, liver), clinical symptoms occur
normal in early childhood, individuals with ________ develop episodic vomiting
seizures
recurrent cerebral insults that resembles strokes between 5-10 yrs of age
Mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes (MELAS)
in 80%of MELAS cases, what gene mutation
(A3242G) in MTTL1
in families which MELAS occurs, a range of symptoms is seen in 1st degree relatives including
progressive external ophthalmoplegia
hearing loss
cardiomyopathy
diabetes mellitus
evaluation of a child with uniparental disomy (UPD) reveals a _______ karyotype
normal
However, chromosomal markers for one particular chromosome are identical to the markers found of the patients mother or father (but not both which would be normal)
what happens in uniparental disomy (UPD)
the individual inherits 2 copies of one parents chromosome and no copy from the other parent. The most common cause is from a spontaneous rescue mechanism. At the time of conception, through nondisjunction, the fertilized egg is trisomic for a particular chromosome, with 2 copies of one parents chromosome and one copy of the other parents; conceptuses with trisomy often miscarry early in development. Fetuses with UPD survive bc they spontaneously lose one of 3 copies of the affected chromosome. If the single chromosome from one parent is lost the patient has UPD.
Can also involve monosomy for a chromosome rather than trisomy. Had the conceptus, at the time of conception, inherited only a single copy of a chromosome, spontaneous duplication of the single chromosome would lead to UPD.
characterized by neonatal hypotonia, postnatal growth delay and a characteristic appearance
-almond-shaped eyes
-small hands and feet
-developmental disability
-hypogonadotropic hypogonadism
-obesity after infancy
Early in life, affected infants are so hypotonic that they cannot consume enough calories to maintain their weight needing NG feedings
Prader-Willi syndrome (PWS)
In Prader-Willi Syndrome (PWS) during the first year of life what happens to the muscle tone
improves and children develop a voracious appetite resultant in obesity
what syndrome do you see a child go from FTT to obesity
Prader-Willi Syndrome (PWS)
Between 60% to 70% of individuals with Prader-Willi syndrome have what chromosomal abnormality
a small deletion of chromosome 15(15q11)
in individuals without a deletion, 20% have UPD of chromosome 15
a condition with moderate to severe intellectual disability
absence of speech
ataxic movements of arms and legs
characteristic craniofacial appearance
seizure disorder that is characterized by inappropriate laughter
Angelman syndrome
what genetic syndrome has a seizure disorder that is characterized by inappropriate laughter
Angelman syndrome (AS)
Angelman syndrome (AS) is characterized by a deletion in the ______ region in 70% of affected individuals; UPD for chromosome _____ in approx 10% of patients
15q11
15
If the deletion occurs in paternal chromosome 15, the affected individual will/will not develop PWS, whereas Angelman syndrome results from a deletion occurring
Will
only in the maternal chromosome 15
nelson pg 176
When UPD is responsible, _______ UPD results in PWS, whereas _____ UPD results in Angelman syndrome
Maternal -> PWS
Paternal -> AS
If a copy of paternal chromosome _____ is lacking, PWS occurs; if maternal chromosome _____ is lacking, AS occurs
15q11.2
an epigenetic phenomenon, a nonheritable change in the DNA that causes an alteration in gene expression based on parental origin of the gene
Genomic imprinting
PWS(Prader-willi) is caused by deficiency of the protein product of the gene _____
SNRPN (small nuclear ribonucleoprotein)
SNRPN (expressed only in paternal derived chromosome) is associated with
Prader-Willi Syndrome
UBE3A (expressed only in maternally derived chromosome 15) is associated with
Angelman syndrome
Fragile X syndrome (FRAX)
Huntington Disease
Myotonic dystrophy
Friedreich ataxia
Spinocerebellar ataxias
These disorders are caused by?
expansion of trinucleotide repeats
the most common cause of inherited intellectual disability
Fragile X Syndrome (FRAX)
Fragile X features
craniofacial findings (large head, prominent forehead, jaw and ears)
macroorchidism with testicular volume twice normal in adulthood
mild connective tissue disorder
-joint laxity
-patulous eustachian tubes
-mitral valve prolapse
Neurobehavioral profile
-intellectual disability (ranging from mild to profound)
-autism spectrum disorders
In Fragile X
what is the difference in carriers (Unaffected individuals), premutation carriers and affected considered to have full mutation
Unaffected who have no fam history
Have 0-45 CGG repeats (most have 25-35)
premutation carriers
have 56-200 repeats - these have typical development
Full mutation
number of repeats is >200
Fragile X
Positional cloning in the _____ region identified a triplet repeat region composed of what?
These repeats occur in the promoter region of the gene _____
Xq27
one Cytosine and two guanine (CGG)
FMR1
FRAX (fragile x) results from a failure to express
FMRP - the protein product of the FMR1 gene which is expressed primarily in the CNS and testes during early embryonic development
explain FMRP in pt affected by Fragile x
FMRP is produced in unaffected and premutation carriers
in those with the full mutation -> FMRP transcription of the protein is blocked because the large number of CGG repeats become methylated (epigenetic phenomenon) and FRAX occurs as a consequence of loss-of-function mutation (the failure of expression of FMRP because of methylation of the promoter sequence)
In fragile X -
In female premutation carriers, an expansion in the number of repeats from the premutation to the full mutation range may occur during
gametogenesis
The cause of this expansion is not understood
In fragile x
Although premutation carriers do not show symptoms and signs of Fragile X,
women may manifest what?
men and women may manifest
primary ovarian insufficiency and early menopause
men and women may develop a movement disorder known as fragile x tremor/ataxia syndrome later in life
chemical, physical or biologic agents that have the potential to damage embryonic tissue and result in congenital malformations
Teratogens
agents known to be teratogenic
drugs (prescription and nonprescription)
Intrauterine infections (Rubella)
maternal diseases such as Diabetes mellitus
environmental like alcohol and heavy metals
first maternal infection known to cause a pattern of malformations in fetuses affected in utero
Rubella
Maternal infections known to cause a pattern of malformations in fetuses affected in utero
Rubella
cytomegalovirus
Toxoplasma gondii
Herpes simplex
zika virus
varicella
maternal disease that can be teratogenic
Diabetes mellitus
maternal phenylketonuria (PKU)
strict control of these diseases during pregnancy protects the developing child
most common teratogenic syndrome
fetal alcohol spectrum disorder
features of fetal alcohol spectrum disorder
prenatal and postnatal growth deficiency
developmental disabilities
microcephaly
skeletal abnormalities
cardiac abnormalities
characteristic facial appearance
To cause the full blown fetal alcohol syndrome, pregnant women must drink
throughout the pregnancy
lesser consumption during all or part of the gestation will lead to milder symptoms
Medications mentioned in Nelson that are Teratogenic agents
Warfarin
Retinoic acid
Phenytoin
High dose radiation exposure during pregnancy in Hiroshima and Nagasaki Japan was shown to increase the rate of
spontaneous abortion and result in children born with microcephaly, mental retardation and skeletal malformations
individuals who are referred to a geneticist bc of suspicion of a genetic disorder are called
probands
Individuals who come for genetic counseling are called
consultants
increases the likelihood that offspring may be born with a rare autosomal recessive condition
consanguinity- both parents may be carriers of the same mutated gene
generally the closer the relation between the partners, the greater the chance
Consanguinity increases risk of ______ disorder
Autosomal recessive disorder
The risk of first cousins having a child with an AR disorder is 1 in ___
64
It is common for couples to be ______ for disorders that may occur more commonly in their particular ethnic group
screened
People of _____ ethnic background may wish to be screened for cystic fibrosis
Ashkenazi Jewish background
People whose ancestors originated in _________ may be screened for thalassemia
Mediterranean basin
People of what ethnic group may wish to be screened for SCD
African ancestry
elevated maternal serum alpha-fetoprotein (MS AFP) is used to identify pregnancies in which the fetus was affected with?
neural tube defects
omphalocele
gastroschisis
low levels of maternal serum alpha-fetoprotein (MS AFP) is used to identify pregnancies in which the fetus was affected with?
Approx 50% of fetuses with autosomal trisomies (down syndrome, trisomy 18, trisomy 13) can be detected by low levels of MS AFP
quad screen
each associated with varying degrees of fetal aneuploidy. Used to detect autosomal trisomies (down syndrome, trisomy 18, trisomy 13)
using this biochemical profile - detect 80%
MS AFP
Unconjugated estriol (uE3)
inhibin A
Human chorionic gonadotropin (HCG)
when is the quad screen performed
during the second trimester
during the first trimester, what is used as a marker for aneuploidy
measurement of the fetal nuchal fold by sonogram
increase in nuchal thickness is a marker for fetal chromosomal anomalies but for certain genetic and structural abnormalities as well
aneuploidy
the condition of having an abnormal number of chromosomes in a haploid set.
what serum testing is done in the first trimester
Free B-HCG and PAPP-A (pregnancy associated plasma protein) -the addition of these screenings has enhanced first trimester screening to a detection rate of almost 90%
do screening tests during first and second trimester diagnose problems?
no, they are used to identify individuals at increased risk.
in prenatal genetic testing - Fetal cells are usually tested for
chromosomal abnormalities by cytogenic techniques but the use of chromosomal microarray is becoming more common
Biochemical testing is used for known family history of
an inherited metabolic disorder
Molecular screening is used for known
familial mutations
advantage of testing cell free fetal DNA in maternal blood
its noninvasive as opposed to an amniocentesis or CVS (chorionic villus sampling)
TORCH is to help remember
chronic conditions may expose fetus to teratogenic effects
Toxoplasmosis
Other including syphilis, varicella and zika virus, mumps,
parvovirus and HIV
Rubella
Cytomegalovirus
HSV
what does a pedigree hep visualize
various inheritance patterns
When evaluating an affected child from genetics….if parents are unaffected, the childs condition is most likely the result of a new mutation, in which case, the risk of recurrence is
extremely low
When evaluating an affected child in genetics, when one parent is affected, the recurrence risk rises to ____% for each subsequent pregnancy
50%
With x linked disorders, genetic history is focused on the paternal or maternal side
maternal to determine if there is a significant enough risk to warrant testing
Questions about the couples age are important to ascertain the risk related to maternal age for ________ abnormalities and paternal age for __________
chromosomal
new mutations leading to AD and X-linked disorders
A history of more than 2 spontaneous abortions increases the risk that one of the parents carries a
balanced translocation and the spontaneous abortions are due to chromosomal abnormalities in the fetus
children with______ disorders may have a normal period followed by increasing weakness or ataxia
neuromuscular
Children with lysosomal storage diseases, such as mucopolysacharidoses often have recurrent _____ and can develop ___-
ear infections
sleep apnea
Children with inborn error of metabolism who have intermittent symptoms often have a history of
multiple hospitalizations for dehydration or vomiting
many inborn errors of metabolism, including storage disorders cause ________ manifestations after a period of normal development
developmental
In pediatrics, what can be used for chromosome analysis
lymphocytes from peripheral blood
cells from bone marrow aspiration
skin biopsy cells (fibroblasts)
or prenatally from amniotic fluid or chorionic villi
process to prep cells for chromosome analysis
cells placed in culture medium
stimulated to grow using a mitogen
their division is arrested in either metaphase or prophase using a spindle poison
slides are made
chromosomes are stained with Giemsa or other dyes
Chromosomes are examined and analyzed under microscope
What phase are chromosomes short, squat and easy to count
Metaphase
Metaphase chromosome analysis should be ordered in children whose features suggest
a known aneuploidy syndrome such as trisomy or monosomy
Chromosomes analyzed in ______ are long, thin and drawn out, giving far more details than are seen in ______ preparations
Prophase
metaphase
_______chromosomal analysis is ordered in individuals with multiple congenital anomalies without an obvious disorder
Prophase
allows the identification of the presence or absence of a specific region of DNA
Fluorescent In Situ Hybridization (FISH)
what lab eval is helpful in Prader-Willi syndrome and Angelman syndrome and Williams and DiGeorge syndrome bc it allows the number of copies of DNA segment in question to be counted…looking for deletions of segments or duplications
Fluorescent In Situ Hybridization (FISH)
has essentially replaced prophase analysis in cases in which a subtle copy number variant (chromosomal deletion or duplication) is suspected
Microarray comparative genomic hybridization (array CGH)
DNA from the individual being studied and a normal control are labeled with fluorescent markers and hybridized to thousands of FISH like probes for sequences spread around the genome. The probes are derived from known genes and noncoding regions. By analyzing the ratio of density of the fluorescent marker at each site, it is possible to determine whether the individual has any difference in copy number compared with control number
Microarray comparative Genomic hybridization
This analysis allows identification of mutations in a growing number of genetic disorders. Using polymerase chain reactions, the specific gene in question can be amplified and analyzed
Direct DNA analysis
This lab evaluation permits examination of all 20,000 -21,000 genes that compose the genome by isolating DNA from an individual, looking for variations in the exomes or coding sequences of the genes and compares identified variation with the DNA from the individuals parents
whole exome sequencing
In whole exome sequencing, variation found in the subject that is not present in either parent suggests
a spontaneous mutation
In whole exome sequencing, 2 copies of a mutation in an individual whose parents are each found to be carriers of the mutation suggests that
the subject is affected with an autosomal recessively inherited disorder
what are the shortcomings in whole exome sequencing
expensive
interpretation is complicated as thousands of variations are often identified -> vast majority of which are benign
how often does the American Academy of Pediatrics recommends routine office visits
first week of life
at 2 weeks
1 mth
2 mth
4 mths
6 months
9 months
12 months
15 months
18 months
2 yrs
2 1/2 yrs
3 years
and then annually through adolescence/young adulthood
when caloric intake is inadequate, what percentile drops first on charts
weight percentiles fall first, then height, head circumference is last
caloric intake may also be inadequate due to
increased caloric needs such as chronic illness
rules of thumb for weight
wight loss in first few days of life
5-10% of birthweight
rules of thumb for weight
return to birthweight
7-10 days of age
rules of thumb for weight
double birthweight
4-5 months
rules of thumb for weight
triple birthweight
1 year
rules of thumb for weight
daily weight gain
20-30g for the first 3-4 months
15-20g for the rest of the first year
rules of thumb for height
average length: 20in at birth, 30 in at 1 year
at age 4 yrs, the average child is double birth length or 40 in
rules of thumb for head circumference
Average HC: 35 cm at birth (13.5in)
HC increases: 1 cm per month for the first yr (2cm per month for the first 3 months, then slower)
a increasing weight percentile in the face of a falling height percentile suggests
hypothyroidism
when may head circumference be disproportionately large
familial megalocephaly
hydrocephalus
merely catch-up growth in a neurologically normal premature infant
A child is considered microcephalic if the head circumference is <
3rd percentile - even if length and wt measurements are proportionately low
Serial measurements of head circumference are crucial during infancy and should be plotted regularly until ______
2 yrs
errors that occur in meiosis during the production of gametes can lead to abnormalities of chromosome ______ or ______
structure or number
Syndromes caused by chromosomal abnormalities
Trisomy 21
Trisomy 13
Trisomy 18
Turner syndrome
Klinefelter syndrome
as well as other rarer chromosomal duplications, deletions or inversions
most common chromosomal abnormality that causes spontaneous abortions
45,X (TS)
general features that suggest an chromosome anomaly
low birth weight (small for gestational age)
failure to thrive
developmental disability
presence of 3 or more congenital malformations
During meiosis or mitosis, failure of a chromosomal pair to separate properly results in ___________
nondisjunction
a change in the number of chromosomes that results in nondisjunction
Aneuploidy
A cell that has one copy of a particular chromosome
monosomy
A cell that has 3 copies of a particular chromosome
trisomy
most common abnormality of chromosomal number in liveborn infants
Down syndrome (trisomy 21)
what is the cytogenic nomenclature for trisomy 21
47, XX, +21
47, XY, +21
The most common robertsonian translocation leading to DS involves chromosomes
14 and 21
46, XX, t(14q21q)
46, XY, t(14q21q)
Robertsonian Translocation leading to DS
The parents of infants with DS who have translocations should have a
karyotype to exclude a balanced translocation
These individuals have 2 populations of cells, one with trisomy 21 with a normal chromosome complement
Mosaicism
Mosaicism DS results from either
nondisjunctional event after fertilization or
Trisomic rescue
47,XX, +21/46XX
47, XY,+21/46/XY
Mosaic DS
Characteristics of DS features at birth
normal birth weight and length
Hypotonic - may cause feeding problems and decreased activity
characteristic facial appearance
-Brachycephaly
-flattened occiput
-hypoplastic midface
-flattened nasal bridge
-upslanting palpebral fissures
-epicanthal folds
-large protruding tongue
short broad hands often with a single transverse palmar crease
Wide gap between first and second toes
Problems associated with DS
Almost all have intellectual disability discovered as they get older
Half have congenital heart disease
-AV canal
Ventriculoseptal or atrioseptal defects
Valvular disease
3-5% with Gastrointestinal tract anomalies
most common are
Duodenal atresia
annular pancreas
imperforate anus
4-18% congenital hypothyroidism (part of newborn screen)
(Acquired hypothyroidism later in life is more common)
Polycythemia at birth (HCT >70%) is common and may require treatment
Some infants at birth may show a leukemoid reaction - markedly increased WBC - self resolves over the first month
but they also have increased risk of leukemia
Children with DS < 2yrs are at increased risk for what type of leukemia
Acute megakaryoblastic leukemia
Children with DS older than 3 yrs what type of leukemia are they at highest risk for
Acute lymphoblastic leukemia (ALL)
heart defects common in DS
congenital heart disease
AV canal
VSD
ASD
Valvular disease
3 most common GI anomalies seen in DS
Duodenal atresia
annular pancreas
imperforate anus
Kids with DS are more susceptible to
infection
more likely to develop cataracts
5-10% have atlantoaxial instability -> increased distance between first and second cervical vertebrae that may predispose to spinal cord injury
Many >35 years develop Alzheimer like features
Virtually all cases of Trisomy 18 are due to
nondisjunction
More than 95% of conceptuses with trisomy ___ are lost as spontaneous abortuses in the first trimester
95%
In Trisomy 18, _____ are more likely to survive to term than ____
females
males
Outcomes of Trisomy 18
most end in spontaneous abortion
Females more likely to survive to term 4:1 ratio
infants rarely survive
<10% will reach their first birthdays
Clinical features of Trisomy 18
hypertonia
prominent occiput
micrognathia
low set and malformed ears
short sternum
rocker bottom feet
hypoplastic nails
characteristic clenching of fists: the second and fifth digits overlap the third and 4 th digits
(47, XX, +18)
(47, XY, +18)
Trisomy 18
(47, XX, +13)
(47, XX, +13)
Trisomy 13
Prognosis of Trisomy 13
usually fatal in first year of life with only 8.6% of infants surviving beyond 1st bday
Trisomy 13 can be caused from
nondisjunction (75%)
robertsonian translocation with most common involving chromosome 13 and 14
characteristics of Trisomy 13
small for gestational age
microcephalic
midline facial defects such as cyclopia (single orbit)
cebocephaly (single nostril)
cleft lip and palate
midline central nervous system anomalies
-alobar holopresencephaly
forehead sloping
ears are often small and malformed
microphthalmia or anophthalmia
Postaxial polydactyly of hands is common
clubfeet or rocker bottom feet
hypospadias
cryptorchidism common in boys
girl have hypoplasia of labia minora
most infants have congenital heart desease
most have a punched out scalp lesion over the occiput called aplasia cutis congenita
characteristics that are pathopneumonic for trisomy 13
punched out scalp lesion over the occiput called aplasia cutis congenita
polydactyly
and some or all of the facial features
midline facial defects such as cyclopia (single orbit)
cebocephaly (single nostril)
cleft lip and palate
most common cause of hypogonadism and infertility iin men
Klinefelter Syndrome
why does Klinefelter syndrome sometimes go undetected until adolescence
phenotypically indistinguishable from rest of population before puberty
under androgenation, in the presence of testes that remain infantile in volume should alert the physician
Characteristics of Klinefelter syndrome
testes that remain infantile in adolescence
tend to be tall with long limbs
During adolescence or adulthood may develop gynecomastia
because of growth failure of testes, hypergonadotropic hypogonadism and failure to produce viable sperm
low production of testicular testosterone results in failure to develop later secondary sexual characteristics such as facial hair, deepening of voice and libido.
in adulthood osteopenia and osteoporosis develop
Klinefelter syndrome will need ______ supplmentation
Testosterone
future of having children in Klinefelter syndrome
with microdissection testicular sperm extraction and in vitro they can father children. Offspring have a normal chromosome complement
only condition where a monosomic conceptus survives to term
Turner syndrome
however, 99% of embryos with 45,X are spontaneously aborted
Women affected with Turner syndrome….what is their intelligence and life expectancy
typical intelligence
normal life expectancy
features of Females with Turner syndrome
short stature
low set mildly malformed ears
triangular face
flattened nasal bridge and epicanthal folds
webbing of the neck
+/- cystic hygroma
shield like chest with widened internipple distance
puffiness of hands and feet
internal malformations of Turner syndrome
congenital heart
-coarctation of aorta is most common
-bicuspid aortic valve
later in life poststenotic aortic dilation with aneurysm may develop
Renal anomalies
horseshoe kidney
streak gonads (gonadal dysgenesis) instead of well developed ovaries leads to estrogen deficiency which prevents from secondary sex characteristics results in amenorrhea
10% have normal pubertal development and are even fertile
most women will need estrogen replacement to complete secondary development
women with turner syndrome are at high risk for
congenital hypothyroidism
fertility in turner syndrome for women
assisted reproductive technology using donor ova with close follow up bc poststenotic dilation of aorta leading to dissecting aneurysms may occur
late detection in Turner syndrome in girls
in subtle phenotypes
sometimes diagnosed during workup for short stature for which they may receive growth hormone
sometimes dx during adolescence or adulthood when they fail to develop secondary sexual characteristics or during infertility workup
although monosomy x in Turner syndrome is caused by nondisjunction, TS is not associated with advanced maternal age, Rather it is believed that
the 45, X karyotype results from a loss of either an X or Y chromosome after conception so a postconceptual mitotic (rather than meiotic) nondissjunctional event
A deletion in the short arm of chromosome 5 is responsible for
Cri du chat syndrome
characteristic catlike dry during infancy
Cri du chat syndrome
Clinical features of Cri du chat syndrome
catlike dry during infancy
low birth weight
postnatal failure to thrive
hypotonia
developmental disability
microcephaly
craniofacial dysmorphism
-ocular hypertelorism
-epicanthal folds
-downward obliquity of the palpebral fissures
-low set malformed ears
-cleft lip/palate
-congenital heart disease
Caused by a 1.55 megabase deletion in chromosome 7q11.2 that contains at least 28 genes
Williams Syndrome
Features of Williams syndrome
congenital heart disease (80%)
-supravalvular aortic and pulmonic stenosis most common
-growth delay with short stature
-Distinctive facial appearance
-median flare of eyebrows
-fullness of perioral and periorbital region
-blue irides with stellate pattern of pigment
-depressed nasal bridge
-anteversion of nares
-moderate intellectual disability (ave IQ 57)
-Strong personal social skills
-“Cocktail party personality”
-Loquacious and gregarious
-Deficiency in cognitive skills
-Autism spectrum
-occasionally have unusual musical ability
-hypercalcemia
Inheritance in Williams
most have a de novo deletion
rare cases- inherited from a parent in a Autosomal Dominant pattern
deletion of 11p13
WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation)
What does WAGR stand for
Wilms tumor
Aniridia - is an eye disorder characterized by a complete or partial absence of the colored part of the eye (the iris).
Genitourinary anomalies (cryptorchidism and hypospadias)
mental retardation
Deletions of chromosome 22q11.2 are responsible for a group of findings that have been called by several names, including
Velocardiofacial syndrome
Conotruncal anomaly face syndrome
Shprintzen syndrome
DiGeorge syndrome
22q11.2D can be inherited in an _____ _______ fashion, most cases arise _______
Autosomal dominant
de novo
Features of 22q11.2 deletion
cleft palate with velopharyngeal insufficiency
conotruncal cardiac defects (truncus arteriosus, VSD, TOF and Right sided aortic arch)
characteristic facial
-prominent nose
broad nasal root
can also have
cleft palate
micrognathia
Speech and language difficulties are common
mild ID
70% with immunodeficiency s/t T-cell dysfunction
psychiatric problems (wide range to include schizophrenia, bipolar)
abnormalities in
thymus gland
parathyroid gland
What tests need to be ordered if pt is confirmed 22q11DS
Either fluorescence in situ hybridization (FISH) or
chromosomal microarray analysis
The region, composed of about 3 million bases contains between 30-40 genes
Many of these deleted genes probably contribute to the phenotype, special attention has been focused on TBX1 and COMT which are believed to be responsible for many of the features related to this condition
In 22q11DS, what genes are thought to be responsible for many of the features related to the condition
The region, composed of about 3 million bases contains between 30-40 genes
Many of these deleted genes probably contribute to the phenotype, special attention has been focused on TBX1 and COMT which are believed to be responsible for many of the features related to this condition
Duplications and deletions occur secondary to
misalignment and unequal crossing over during meiosis
Chromosome ___is the most common of all marker chromosomes (small extra chromosomes)
15
its inverted duplication accounts for almost 40% of this group of chromosomal abnormalities
Inverted Duplication chromosome 15 features
Developmental disability
autism
seizures
behavioral disorders
sloping forehead
short and downward slanting palpebral fissures
prominent nose with a broad nasal bridge
long and well defined philtrum
a midline crease in lower lip
micrognathia
named for iris coloboma that gives patients a catlike appearance
Cat eye syndrome
caused by presence of a small extra chromosome composed of an inversion duplication of 22q11
cat eye syndrome
clinical features of cat eye syndrome
iris coloboma that gives pt a catlike appearance
mild ID
behavioral disturbances
ocular hypertelorism
downward slanting palpebral fissures
micrognathia
auricular pits and/or tags
anal atresia with rectovestibular fistula
renal agenesis
