Approach to the Child with Birth Defects

Lecture #16

November 11 (Monday), 2002


Required Reading:               Principles of Medical Genetics

Gelerhter TD, Collins FS, Ginsburg D

1998 Williams and Wilkins


Pages:  280-284 (stop at Bayes Theorem),

289-290 (Section on the Process of genetic counseling)


Understand information in this handout!


• Be able to distinguish major anomalies (such as cleft palate, congenital cardiac defects) from minor anomalies (single transverse palmar crease)


It is important to specifically look for, characterize, and precisely describe and document any major or minor anomalies that may be present in an individual when considering a genetic condition.


Major anomalies create significant medical problems for the patient or require surgical or medical management. Major anomalies generally are not considered as a variation of the ‘normal’ spectrum.


Minor anomalies are features that lie outside or on the fringes of the normal spectrum of features most commonly seen in the population but that, in and of themselves, do not cause increased morbidity, early mortality, or require intervention.


• Realize that many “normal” individuals may have a couple of minor anomalies, even they may even have a major anomaly, without having any particular syndrome or disorder. However, if several minor anomalies and/or a few major anomalies are present in one individual, a clinician must suspect an underlying syndrome or association and evaluate that individual accordingly, taking into account that individual’s ethnic background as some minor anomalies are more common in some ethnic groups.


• Recognize that major and minor anomalies may be associated with particular syndromes or, may be an isolated finding in an otherwise healthy individual. For example, a cleft lip or palate may be an isolated finding (non-syndromic) in an otherwise healthy individual, or, may be part of a syndrome in an individual with multiple birth defects.


• Understand that what appears to be the same birth defect or congenital anomaly phenotypically may have completely different etiologies in different individuals. For example a cleft lip and/or palate may be associated with a chromosome disorder, exposure to a known teratogen, amniotic bands, an autosomal dominant single gene disorder, or a combination of various genetic and environmental factors (multifactorial). It is also important to consider and remember the timing of fetal development when considering the cause of a birth defect (you will learn more about this in your embryology course). 0000


• Characterization of all major and minor anomalies in great detail as precisely as possible is essential to help arrive at the correct diagnosis. Most often, it is not just one major anomaly or one minor anomaly that makes a diagnosis but rather it is a constellation of major and minor anomalies that point to a specific syndrome diagnosis or known association.


• Understand the importance and utility of genetic counseling and genetic evaluations in the diagnostic work-up of individuals with congenital anomalies. Understand the roles of a genetic counselor in the case of stillborn infants including the importance of non-directive counseling and special issues related to infant or fetal death.


Genetic counseling at the time of fetal or of an infant’s death involves the same principles that genetic counseling does at other times. However, because of the death, it is often a very difficult time for the family to discuss and “hear” about further diagnostic evaluations and/or recurrence risks. It is usually not a good time for parents to make future reproductive choices at the time of the death of a child. Thus, it is best to have families return to clinic a few weeks or months after the loss for further counseling. It is also important that, at the time of death of the infant or birth of the stillborn infant, that the genetic counselor/geneticist works closely with other members of the health care team, including social workers, to make sure parents have a chance to see their baby, understand what happened, address issues surrounding their loss, and discuss issues relating to a burial or memorial service.


• Understand the concepts of:



Sequence or Field Defect








A syndrome is generally recognized and defined as a well-characterized constellation of major and minor anomalies that occur together in a predictable fashion presumably due to a single underlying etiology which may be monogenic, chromosomal, mitochondrial, or teratogenic in origin. For instance Down Syndrome trisomy 21, (a numeric chromosome disorder - 47 XX or XY, +21) is a syndrome associated with a predictable constellation of major and minor anomalies that create a recognizable phenotype that allowing people who have seen other individuals with trisomy 21 to immediately suspect the diagnosis when they see another individual with the same condition, even though all of the characteristic anomalies (or features) are generally not present in any one affected individual.


An association is a group of anomalies that occur more frequently together than would be expected by chance alone but that do not have a predictable pattern of recognition and/or a suspected unified underlying etiology.


A sequence is a group of related anomalies that generally stem from a single initial major anomaly that alters the development of other surrounding or related tissues or structures. Potter’s sequence is recognized by a constellation of physical findings where the outward appearance of the newborn is often characterized by flattened abnormal facial features and deformations of the hands and feet. These features along with poor lung development are secondary to decreased amounts of amniotic fluid (oligohydramnios) which is most often due to major renal (kidney) abnormalities (eg a single major anomaly) associated with decreased fetal urine output.


The term field defect is often used to describe related malformations in a particular region and sometimes is used interchangeably with sequence. The Pierre-Robin sequence is in fact sometimes referred to as a field defect where a small jaw resulting in posterior displacement of the tongue causes a cleft palate. Thus, these birth defects are related to one another in a temporal and physical sense - being limited to that field or area of the head. Spina bifida with changes to the lower extremities and disruption of bowel and bladder dysfunction would be another example of a sequence or field defect.


A field defect, however can be associated with other anomalies in a syndrome such as velocardiofacial syndrome where affected individuals have often a characteristic facial appearance associated with their cleft palate and cardiac defects. This illustrates the importance of a comprehensive examination in reaching the correct diagnosis for an individual.


• When considering dysmorphic features it is also important to keep in mind the various ways in which structures and tissues may become abnormal.


For instance a structure may be visibly abnormal due to a deformation. A deformation is caused by an abnormal external physical force compressing part(s) the fetus during in utero development that results in abnormal growth or formation of the fetal structure. For example, in fetuses that grow in a uterine environment lacking sufficient amniotic fluid (oligohydramnios) as described above when discussing Potter sequence, the fetus may have flattened facial features due to compression of the face against the uterine wall with no room for significant movement and full development of the face or facial features.


Another type of abnormality is known as a disruption where a fetal structure is growing normally where growth is arrested due to something which disrupts the process. This is seen in the condition of amniotic bands where a digit or extremity may be growing normally but then growth is altered or discontinued due to the development of amniotic band at the end of that extremity. This may result in missing fingers, toes, or hands and feet. Oftentimes disruptions and deformations are relatively isolated and not associated with multiple congenital anomalies.


A malformation signifies that fetal growth and development did not proceed normally due to underlying genetic, epigenetic, or environmental factors that altered the development a particular structure.


Another type of generalized anomaly is related to an underlying tissue dysplasia where the intrinsic cellular architecture of a tissue is not normally maintained throughout growth and development. Many of the skeletal syndromes of short stature are due to dysplasia in the developing bone and cartilage.





Biochemical and Molecular Genetics III:

Clinical Correlations of Molecular Defects

Lecture 19

November 15 (Friday), 2002


Required Reading:               Principles of Medical Genetics

Gelerhter TD, Collins FS, Ginsburg D

1998 Williams and Wilkins


Pages:  137-143 (Hemophilia section)


• You will be responsible for learning about the molecular basis for disease processes through understanding the examples of hemophilia as presented in your textbook. The basic concepts that are important to know are nicely illustrated in the figures presented in the textbook and you should be sure to understand the general concepts illustrated in each of the figures.


• For hemophilia you should understand the basic concepts of the disease process especially as related to:


• Genotype - What are the basic molecular mechanisms underlying hemophilia A and B? Specifically, what kinds of mutations occur in the factor VIII gene? How do they occur? Understand the wide variety of different types of mutations that have been described in Hemophilia A and the potential mechanisms underlying the mutations – especially for any novel mechanisms of mutation (eg. the recurrent inversion, mutational hot spots) that are discussed in the book.


• Inheritance pattern – How are Hemophilia type A and B inherited? Can both women and men be affected? Why or why not? Understand that although most female carriers of hemophilia A are asymptomatic that some female may exhibit symptoms and understand why this may occur. Why are most female carriers asymptomatic?


• Phenotype – Why are there different degrees of severity in hemophilia? How do the levels of severity of disease correlate with the amount of circulating Factor VIII levels?


• Molecular diagnosis as discussed in the textbook. Understand how cloning of the gene involved in this condition has enabled accurate prenatal diagnosis by direct mutational analysis or linkage analysis and


• Other points to ponder:


• Although you will need to know the clotting cascade during your medical school career you do not need to memorize it for this class.... Really!


• Understand how cloning of the gene involved has also the way for the development of recombinant factor used for treatment and is also paving the way for development of gene transfer applications. Consider how you might design gene therapy for hemophilia. What levels of circulating Factor 8 would you need to achieve? Where might you want to express the gene? (You will have a gene therapy lecture later on in this course).


• Understand that defects at different points in the clotting cascade may cause different bleeding disorders and be familiar with Hemophilia B.


• Understand that gene expression of the Factor IX gene and the resulting clinical phenotype may change during different times of life and know one mechanism why this might happen.


• Understand why in both Hemophilia A and B that 1/3 of all mutations are thought to arise de novo (Haldane).






Biochemical and Molecular Genetics IV

Collagen Disorders

Lecture 20

November 15 (Friday), 2002


Required Reading:               Principles of Medical Genetics

Gelerhter TD, Collins FS, Ginsburg D

1998 Williams and Wilkins


Pages:  143-151


Know basic structure of collagen:

• What is the critical amino acid sequence pattern?

• Understand the process of collagen formation from the polypeptide chains through procollagen molecules to mature collagens.

• Know the triple helical structure of collagen and its precursor lesions and know that mutations at various points in collagen synthesis, processing and secretion can cause disease. Understand that there are many different types of collagen that have different levels of tissue expression and that are involved in different diseases.

• Know that some types of collagen are heterotrimers (eg Type I collagen) and others are homotrimers (eg. Type III collagen). What is the difference?


Understand that there are different types of collagen, some that are more prevalent in some tissues and less prevalent in others.

• You should understand how the expression pattern and localization of different types of collagens in different tissues is associated with different clinical manifestations of connective tissue disorders (eg. if type I collagen is not a major collagen in the vascular system, you would not anticipate major vascular problems with genetic alterations causing abnormal type I collagen).

• Where is type I collagen predominantly located? Type III?

• What disorders are associated with type I collagen defects?

• Why might one type of mutation affecting type I collagen result in a relatively mild form of OI while a different type of alteration may cause a severe, neonatal lethal form of OI?

• Why are defects in type III collagen associated with such significant morbidity d mortality? What disease is caused by defects in type III collagen and what are features of this condition?


Know the different kinds of mutations that may occur to cause disease and be able to describe the predicted consequences of certain kinds of mutations:

• Understand how different types of mutations in genes encoding structural collagen proteins may cause different kinds or severity of disease.

• Be able to recognize and understand the concept of “protein suicide” and also understand why a ‘null’ allele for an autosomal dominant disorder may have less of a devastating phenotypic effect than a point mutation that causes protein suicide. Understand the differences between mutations that cause qualitative defects in the collagen produced versus those that cause quantitative defects.


Know the general types of and wide variety of symptoms that are seen in the Ehlers-Danlos and Osteogenesis Imperfecta syndromes.

• What are the cardinal clinical manifestations of OI?

Brittle bones with osteopenia

Blue sclerae +/-

Dentinogenesis imperfecta +/-

May also have some joint laxity, short stature, and multiple deformities, easy bruising

• What are the cardinal clinical manifestations of classic EDS?

Joint hyperextensibility and dislocations

Abnormal “tissue paper” scars

Easy bruising

Increased elasticity of skin

• You do not (yet) need to know all of the specific details about each of the symptoms of the various subtypes of each of these syndromes, but as noted above, you should know classic features of OI and EDS and should realize that there are different types of OI and different types of EDS. You should also know the general features of the specific type of OI (OI type II) and the specific type of EDS (EDS type IV also known as the “vascular type” of EDS) that are associated with significantly increased morbidity and mortality.

• You should know when to suspect one of these conditions based on physical findings. You should have some sense about the general approach to further evaluation of these individuals.

• You should be able to distinguish classic OI phenotypes from EDS phenotypes. Specifically, you should be able to compare and contrast the classic features and pathophysiology of OI and EDS. How are the disorders the same? Is there overlap? How are they different?

• Understand that the inheritance pattern of many connective tissue disorders is autosomal dominant, but other inheritance patterns have also been described.

• Understand genetic counseling issues in connective tissue disorders especially regarding recurrence risks. Know that if a severely affected child is born to healthy, unaffected parents, one must consider the possibility of a new mutation, autosomal recessive inheritance AND gonadal or germline mosaicism of an autosomal dominant disorder. This means that a certain percentage of either the mother’s eggs or father’s sperm contains this mutation. This has been described in several cases of severe Osteogenesis Imperfecta (OI type II). Thus, a couple would be at an increased risk of having another child with the same autosomal dominant disorder even though they themselves do not have the disorder. This is an important concept in genetics that was not discussed in the textbook, but will be discussed in lecture.





Clinical Genetics IV: The Practice of Prenatal Diagnosis

Lecture 29

December 2 (Monday), 2002


Required Reading:               Principles of Medical Genetics

Gelerhter TD, Collins FS, Ginsburg D

1998 Williams and Wilkins


Pages:  297-307 (Prenatal diagnosis of genetic disease)




• Know that all couples face a nearly 3% risk that their child will be born with a medical problem or birth defect that will require intervention.


• Understand that prenatal tests are used specifically and selectively. There is no 100% guarantee of a healthy baby even if when prenatal tests are done (such as cytogenetic analysis and ultrasounds) and are completely normal.


• The use of non-directive genetic counseling in prenatal diagnoses, selective terminations, and assisted reproductive technologies is extremely important.


• Understand and respect the ethnocultural, moral, and/or religious backgrounds that may strongly influence an individual’s or couple’s choice surrounding prenatal diagnosis, selective termination of a pregnancy, and the use of reproductive technologies. Appreciate the difficult decisions that individuals, couples and families must face when encountering situations where pregnancy termination is being considered or presented as an option.


• Examine your own moral/religious/cultural beliefs regarding challenging and complex issues surrounding prenatal diagnosis and available options. Make an effort to understand the potential biases you may bring to a genetic counseling session where these issues are discussed. Find ways to address your feelings and concerns regarding these issues prior to meeting with your patients to avoid introducing personal biases.


• Understand the grief process associated with unanticipated pregnancy loss due to genetic causes or due to pregnancy termination that couples might face. Be aware of the important role a physician or other health care worker can play in helping individuals/couples/families cope with that grief. Specifically, understand the importance of providing individuals with education information about their fetus and the disorder, address why this may have happened without implying blame, provide for “remembrances” of their fetus (photographs, clips of hair, a chance to hold their fetus), access to support groups/counseling, and general information about recurrence risk. An autopsy and further genetic studies may be needed to understand the cause of fetal demise and the parents should understand the need for these studies and plans for follow-up counseling should be made. It is important to raise the issue of burial of the fetus and/or memorial services as some individuals/couples desire and benefit from these services. It is usually not helpful to suggest that couples make immediate decisions about having future pregnancies at the acute time of the loss. For instance, the time of a pregnancy loss or termination would not be the ideal time to recommend various sterilization procedures to avoid having future pregnancies or, at the other extreme, to suggest they ‘forget about this loss’ and try to have another baby as soon as possible. It is usually most helpful to see individuals/couples back after the loss/termination to discuss future family planning issues, more details about recurrence risks, and reproductive options.


• Know that some couples undergo preconception genetic counseling and evaluation prior to becoming pregnant in order to determine their risks and prepare for future prenatal testing if desired. Understand this concept and the utility of such counseling.


• Understand the variable effects of prenatal diagnosis that results in pregnancy termination on gene frequency and disease frequency. In general, selective terminations of fetuses with later adult-onset autosomal diseases that have a low mutation rate and high reproductive fitness could have a significant effect on gene frequency whereas selective termination of fetuses with autosomal recessive disorders which are lethal in childhood would only effect the gene frequency if carriers would also decide to have less children, reducing the chance of having other carriers.




• Be able to generally describe the major kinds of prenatal diagnostic techniques. Know the indications, applications, benefits and limitations of the different types of prenatal diagnostic techniques.


• Be able to describe the general differences between the commonly applied techniques of amniocentesis and chorionic villus sampling (CVS).


• Know that CVS can be done earlier in the pregnancy (generally 9-12 weeks gestation) than amniocentesis (generally 16-20 weeks gestation) and the risk of fetal loss during CVS is relatively low, 1% or less. Risks from amniocentesis are even lower about .5% or slightly less. Thus since the risks are not dramatically different, many women prefer CVS since that can be done earlier providing results that may help them decide whether or not to terminate a pregnancy.


• The risks of fetal loss associated with percutaneous umbilical blood sampling (PUBS) or fetal blood sampling are higher than amniocentesis or CVS. The risks are relatively low if done later in the pregnancy (when the umbilical vessel is bigger) but this is at a time when pregnancy termination is no longer a potential option. For this reason, some individuals might accept the higher rate of loss (approximately 2%) associated with this technique during the early-mid second trimester in order to obtain a relatively rapid diagnosis.


• Cytogenetic studies on amniocytes and trophoblasts generally take 10-14 days, as they must be cultured before cytogenetic analysis can be done. DNA tests from CVS samples often do not require culturing and can be done often within 3-5 days if it is a PCR based test. Fetal blood cell cytogenetic analysis and DNA analyses can be done in 3-5 days.


• PUBS may be the best way to detect a disorder for which other biochemical, molecular, or cytogenetic studies are not yet available. Although there has been some progress in detecting fetal cells in maternal blood specimens, this is not yet state-of-the-art for most prenatal tests.


• Understand the potential utility and limitations of fetal ultrasounds in evaluating a fetus for structural birth defects.


• Know the difference between screening tests and more definite genetic tests.


• Understand that “AFP screening” is routinely done during most pregnancies and elevated measurements of maternal alpha fetal protein may indicate a neural tube abnormality and therefore requires further evaluation. Know that other factors such as wrong gestational dates, fetal death, and multiple gestations may cause erroneous elevations of serum AFPs. A lower than normal AFP screen can be associated with chromosomal trisomies such as Down syndrome but this is not very specific or sensitive. Use of AFP screening along with screening of other metabolites including unconjugated estriol and human chorionic gonadotropin increases the sensitivity of the screen and is reported to pick up approximately 60% of infants with Down syndrome. Because serum AFP screening alone and/or the “triple screen” is not even close to 100% specific or 100% sensitive it is imperative that these tests be recognized as only screening tests and that more definitive studies (e.g. detailed ultrasounds for elevated AFP levels and chromosome analyses if trisomy is being considered) must be done in order to establish or disprove a suspected diagnosis.


• Understand that the cytogenetic, biochemical, and molecular techniques used in prenatal diagnosis are generally similar to standard techniques but have different specimen requirements and, oftentimes, different urgency associated with the testing. Pregnancy terminations are legal only up to 24 weeks gestation in most states. Additionally, many couples note that termination is emotionally harder at later dates.


• Understand the importance of good prenatal care – avoidance of known teratogens AND the use of vitamin supplementation to reduce birth defects. Specifically, known about the importance of taking FOLIC ACID to reduce neural tube defects as well as other birth defects. All women of child bearing age should who are at “risk” of becoming pregnant should have an adequate intake of folic acid PRIOR to and during pregnancy.




• Understand that a variety of assisted reproductive technologies are available for couples to consider including (but not limited to): artificial insemination (donor sperm), sex selection based on sperm sorting followed by assisted reproductive techniques to achieve pregnancy, donor ovum with or without surrogate parenting, in-vitro fertilization, and even preimplantation diagnosis.


• Know that preimplantation diagnosis means that fertilization takes place in vitro and DNA tests are performed on single cells of very early embryos (4-16 cell stage). If the cell does not have the mutation being tested for, the embryo it was derived from is allowed to implant in a uterus prepared for pregnancy.


• Know that in-vitro fertilization techniques can result in multiple fetuses and that selective termination of some fetuses is sometimes done to increase the chances of having healthy babies born near term.


• Know that new technologies that have reproductive potential are being developed. Know what the issues are surrounding somatic cell mammalian cloning by nuclear transfer. Understand that this technique of taking the nucleus from an adult somatic cell and implanting it into an enucleated egg that is allowed to implant in an appropriate uterine environment has resulted in the birth of rodent and sheep clones. Know that worldwide discussions are taking place regarding potential applications of similar methods of human cloning.


• Know that it is standard of care to offer DNA based Tay Sachs, Sickle Cell Anemia and Cystic Fibrosis carrier testing to all women/couples of child bearing age in certain ethnic groups





Gene Therapy

Lecture #30

December 3 (Tuesday), 2002


Required Reading:               Principles of Medical Genetics

Gelerhter TD, Collins FS, Ginsburg D

1998 Williams and Wilkins


Pages:  Chapter 13


Understand information in this handout!


• Understand the differences between somatic and germline gene therapy and recognize that there are advantages, disadvantages, and limitations of each.


• Know that with somatic cell gene therapy, the therapy is usually targeted to a specific tissue or group of cells. Consider monogenic diseases you have learned about in this class such as cystic fibrosis, hemophilia, cancer, osteogenesis imperfecta, alpha-1 antitrypsin deficiency and think about how you might target gene therapy to treat these diseases.


• Know that different kinds of vectors can be used for gene transfer and understand the advantages and disadvantages of the different approaches as discussed in your text and outlined in table 13.1 of your text


• You do not need to know how retroviral and adenoviral gene therapy vectors are constructed as outlined in figures 13.3 and 13.4.


• Understand the differences between in vivo and ex vivo gene therapy as described in figure 13.5 of your text


• Recognize the current benefits of recombinant DNA technology in developing effective therapies for many diseases and the increasing role of gene therapy in medical practice of the future. Be able to recognize the major limitations of gene therapy to date that have hindered its wide scale use in the treatment of disease. Consider hemophilia as an example of a disease where gene cloning led to recombinant therapies and to gene therapy trials.


• Be aware of the scientific and ethical concerns associated with gene therapy.


• Understand what is meant by stem cell therapy and be familiar in general terms ofhow it may be used in the future.


• Be familiar with the basic strategy underlying cloning. Know that clones would not be exact copies of the original organism due to in utero and external environmental effects, the mitochondrial genome, and X-inactivation.



Huntington Disease –

Clinical Correlations and Patient Presentation

Lectures 31-32

Lecture will be followed by case presentation

December 6 (Friday), 2002


Required Reading:               Principles of Medical Genetics

Gelerhter TD, Collins FS, Ginsburg D

1998 Williams and Wilkins


Pages:  review 217-220


This Handout!


• Know the basic inheritance pattern and symptoms of Huntington disease:


• It is an autosomal dominant disorder with high penetrance.

• It is a neurodegenerative disorder that most often progresses over a 10-25 years

• Symptoms generally appear between 30-50 years of age, but have appeared as old as 90 and as young as two years of age.

• Symptoms include:

Involuntary choreiform movements.

Ataxic gait.

Psychiatric symptoms including depression, mood swings.

Swallowing difficulties (dysphasia).

Speech difficulties (dysarthria).

• Approximately 1 in 10,000 individuals will develop HD -- currently over 30,000 individuals have the disease and over 150,000 individuals are at risk of inheriting the disorder in the United States alone.

• It affects all races and ethnic groups.


• Understand the basic genetic etiology and genetic abnormality:


• The gene was mapped to 4p in 1983 and cloned in 1993.

• The HD gene contains a CAG trinucleotide repeat:


Normal individuals have 10-33 copies of this repeat on both HD alleles.

Affected individuals generally have over 39 copies of the repeat on one allele.

Individuals with 34-39 copies fall into an intermediate “gray zone.”

All individuals who inherit a clearly expanded allele from one parent will eventually develop the disease if they live long enough.


• The specific pathophysiology is poorly understood, but autopsy study of affected individuals’ brains show atrophy, especially of the caudate nucleus.



• Know that PCR-based DNA testing can be done to confirm a diagnosis or “presymptomatically.” Understand the interpretation of a DNA test for HD. Know that this test cannot predict the age of onset or exact course or progression of symptoms.


• Know the Huntington Disease Society of America recommendations for the process of presymptomatic HD testing which include:


• Genetic counseling.

• Neurological evaluation.

• Psychological evaluation.

• Presence of a support person.

• Identification of a local counselor.

• Results disclosure in person.

• Minors tested only if clinically indicated.



Understand that at-risk individuals, even within the same families, may have different motivations and desires to undergo or not undergo testing. Each person must be treated individually and give informed consent to undergo testing. Although testing other family members is not required, especially for those asymptomatic or presymptomatic individuals, it is often useful to confirm the diagnosis of the disease in an affected family member by DNA testing as other neurological disorders may mimic HD.






Ethical Issues related to the Practice of Medical Genetics

Lecture 33

December 9 (Monday), 2002


Required Reading:               Principles of Medical Genetics

Gelerhter TD, Collins FS, Ginsburg D

1998 Williams and Wilkins


Pages:  329-339


• Understand the complexities and challenging ethical issues related to the practice of clinical genetics that may arise.


• Be able to define and understand the concepts of



Beneficence and Nonmaleficence

Privacy and Confidentiality

Justice and Equity


• Be able to recognize and consider those concepts in light of your own moral framework and experience when confronted with cases involving challenging ethical issues related to prenatal diagnosis, confidentiality issues as related to risks to other family members, experimental therapies, predictive testing, predictive genetic testing of minors, pregnancy termination, and genetic discrimination.



HG501 – Ethics Cases


READ these cases prior to class.

For each of the following please put yourself in the role of the health care provide in each case and consider the following questions:


What are the options available to your patient(s)?

What are the ethical issues that need to be considered in this case?

Where do you stand on the issues?

In your opinion, what is the most ethically justified course of action?

What other information, if any, would help you resolve this ethical issue?


Case 1: Ethical Uses of Preimplantation Genetic Diagnosis?


A two-year old boy develops Fanconi’s anemia, an autosomal recessive genetic condition associated with severe life threatening anemia. He will need a bone marrow transplant within the next two years if he is going to have any chance to survive. No family members are good matches to be a bone marrow donor. Their are no suitable donors found in the bone marrow registry. Transplantation could be done with an unmatched donor, but would likely be associated with increased post-transplant complications.


His parents would like you to use assisted reproductive technology to help them achieve a pregnancy of a child that would be a matched donor unaffected with Fanconi’s anemia. They want to use in vitro fertilization and preimplantation diagnosis where, at approximately eight-cell stage of embryogenesis, one cell from each embryo will be examined to determine which embryos lacking two FA mutations would be a perfect match. Embryos that are a good match and do not have the disease will be placed in the uterus. Cord blood of a child resulting from this pregnancy would be used to save their son.


Do you feel this is an appropriate use of genetic testing and reproductive technology? Why or why not?


Case 2: Difficult Decisions about DNA and Dad


A 45 yo man with adult polycystic kidney disease due to an APKD1 mutation is in end-stage renal failure. A kidney transplant from a matched living related unaffected donor will give him the best chance for long term survival. Although he has been estranged from his biological family for 5 years, he persuades four adult children to undergo tissue typing and DNA testing to determine which individuals are eligible donors. His children agree to testing knowing that results will be provided to their father and his doctor. They affirm their willingness to donate a kidney to their father.


The father pays you $3000 for mutation testing and genetic counseling for his children. Only his 22 year old fraternal twin sons, Sam and Seth, are good matches. Seth, however, inherited the APKD1 mutation. Sam did not and understands that he is the only eligible living related donor. He initially plans to donate a kidney but after further consideration changes his mind. He realizes he would also be a suitable donor for his brother and would like to keep his kidneys in the event that Seth requires a transplant in the future.


Although Sam initially gave written consent for his test result to be given to his father, he now requests that his results be deleted or falsified on the report being generated for his father and father’s doctor. As you try to figure out what to do, the father demands to have all results released to him as soon as possible in accordance with your written agreement.


Would you honor the requests of the son, Sam, or the father? Why?


Case 3: When Mom Must Know and Dad Declines


A woman is seven weeks pregnant and interested in having her fetus tested for Huntington Disease. Her asymptomatic 35-year-old husband, the baby’s father, is at risk of having inherited the condition from his affected mother. He previously received genetic counseling from you regarding his precise risk and options for predictive DNA mutation testing. He elected not to undergo predictive DNA testing, as he did not want to know if he inherited the mutation.


His wife is now independently seeing you for genetic testing of their fetus. She requests this testing be done without any involvement of her husband who has no idea she is seeing you. She tells you that if an HD mutation is found she will terminate the pregnancy and tell her husband that she mis-carried the baby. She notes that he will never need to find out about the test as it would upset him to know that she even considered having an abortion for something like this.


Would you proceed with prenatal HD testing in this case without involvement of the husband? Why or why not?


Case 4: Doctor’s Duties and Decisions about Disclosure


A 40 year old man has a child with Down syndrome due to an unbalanced translocation of chromosome 21 and another autosome. Upon testing him you find out that he is a balanced translocation carrier which you thought was likely given the fact his mother had several miscarriages. He has several younger sibling of child bearing age who are at risk of having the same balanced translocation. Thus, they may have an increased incidence of miscarriages and of having a live born child with a chromosomal disorder.


Given this you recommend he share this information about the translocation with all of his first-degree relatives. He notes he can not do this as he already has a strained relationship with other family members. He notes they can find out the same way he did.


You are surprised by his reaction as you suspected he would agree with you that it would be important for other family members to know this information.


Should you disclose this information to other family members against the patient’s wishes?


Case 5: We Know A Family Secret, Do We Need to Tell?


A couple has a child with severe cystic fibrosis who is homozygous for a three base pair deletion (delta F508) in both copies of her CFTR gene. During the next pregnancy the couple undergoes prenatal testing for CF as the wish to avoid having another child with classic severe CF. Surprisingly, this male fetus is a compound heterozygote for one delta F508 allele and a different CF mutation usually associated with a more mild form of CF when seen in a compound heterozygous state with delta F508. The reported phenotype most often associated with this genotype has been male infertility and some chronic pulmonary symptoms in older adolescents and adults. Younger children are usually healthy. Since neither parent has any pulmonary symptoms or infertility; a sample mix-up or non-paternity is considered.


Telling the parents the laboratory is concerned about sample mix-up, you send samples from the parents to the laboratory. Both parents are heterozygous for one normal allele and the delta F508 allele. Neither has the other mutation identified in the fetus. Further testing done in the laboratory to make sure there wasn’t a sample mix-up or technical problem with the analysis confirms non-paternity. The parents are scheduled to come to clinic together regarding these test results and plan to schedule a pregnancy termination if the fetus is predicted to have CF symptoms like their other child.


Should you tell them that the results suggest non-paternity? If so, whom should you tell and how should you tell them?


Case 6: Problematic Phenylalanine Levels in Pregnancy


A 30-year-old woman with PKU wants a baby. Due to her parents’ poor compliance with her low phenylalanine diet during infancy and early childhood, she is mildly mentally retarded (IQ – mid 60s) with psychiatric problems, poor impulse control, and attention deficit disorder. She dropped out of school and has had intermittent part time jobs since then. She lives with her father, an unemployed alcoholic, and her 19-year-old boy friend who is unemployed, has a longstanding history of drug abuse, and was just released from jail. Her boyfriend thinks it would be “cool” to be a dad and thinks a baby might help him “settle down.”


You provide extensive counseling about the risks of having a baby with maternal PKU syndrome (congenital cardiac defect, microcephaly, and mental retardation). You instruct her that she must go on a low PHE diet prior to pregnancy and maintain a low phenylalanine level throughout pregnancy to protect her fetus. She notes she’ll do her best she won’t give up cheeseburgers and that the PKU formula stinks. Due to poor compliance, her PHE levels remain in the range where there is a high probability of teratogenicity to a fetus. Despite this she becomes pregnant.


You do as much counseling and education as possible and even see her at least once a week during her first 12 weeks of pregnancy, but unfortunately with minimal impact. You realize the high potential for a negative outcome on the fetus.


Should you be more aggressive in her management? If so, what would you do?


Case 7: Even if He’s Not My Patient, Do I Have an Obligation?


You are a stellar fourth year medical student going into Pediatrics who excelled in your 1st year medical genetics course. During Thanksgiving dinner with one of your medical school classmates you meet her 14-year old nephew. You noted he had bluish/gray sclera, lots of bruises, increased flexibility, and translucent skin. He notes that he has always bruised very easy but that it has been especially noticeable after he joined his school’s basketball team. You suspected he might have the vascular type of Ehlers-Danlos syndrome, and could be at risk for severe internal complications.


You mention this to your medical student friend, the boy’s aunt, who skipped the 1st year med school lecture on connective tissue disorders and is not at all struck by his phenotype. She tells you not to worry as her brother, the boy’s father, had exactly the same features when he was little but that he was always very healthy. He unfortunately died from complications after a car accident a few years ago when he was only 33 yo. She also notes there are no genetic diseases in the family but that she doesn’t know much about her father’s family since her dad died when she was only 3 years of age from some sort of internal bleeding problem.



Should you tell the boy’s mother or his doctor that he may have a life threatening connective tissue disorder?


Case 8: Predictive DNA Testing: Does Father Know Best?


A man brings in his 16-year-old daughter for Huntington Disease testing. Her mother died with HD at 32 years of age after a 12-year course initially characterized by irrational behavior, severe mood swings, and psychiatric problems. The 16-year-old daughter has had problems with substance abuse, depression, and school since she was 14. She is currently on probation for shoplifting. She is sexually active and refuses to use contraceptives.


The father is very concerned that her behaviors reflect very poor judgment consistent with early manifestations of HD. He would like her tested to confirm his suspicion. He notes that the results may be helpful in the court and school system so that her caseworkers and teachers understand that she has a disease and is not just a bad kid. He also feels it may help convince her to use contraception.


She does not want to know if she inherited the HD mutation. She denies having any symptoms noting that her behaviors stem from her unhappiness living without a mother and living with a domineering father. She notes that if she found out that she inherited the mutation she would “give up.” You do a complete neurological exam and do not find any objective signs of HD.


Her father requests that testing be done. She states she is willing to be tested just to get her father off her back. She notes, however, that she never wants to find out the results.


Should you proceed with HD testing? If so, who should get the results?