Genetics is about family histories. Whether you are doing experimental breeding of mice or are exploring diversity in the human population, genetic traits are passed in family lineages. But when the focus is on a molecular or a developmental question, that relationship is easily taken for granted. On the other hand, pedigrees can be valuable when taking a broader view of gene expression, phenotypic variability, and patterns of transmission. Pedigrees can yield insights that single mating examples fail to provide. That is especially true for human genetics, where experimental matings typical of model organism studies cannot be performed.
Pedigrees are a simple way to summarize a lot of information about genetic relationships. One of the most famous pedigrees is that for hemophilia in the royal families of Europe (Figure 9-1). The most common form of this blood clotting condition is hemophilia A, a sex-linked trait associated with a defect in clotting factor VIII. Indeed, it was the first human genetic trait to be found to follow a sex-linked inheritance pattern. Other forms of hemophilia include hemophilia B affecting clotting factor IX, which is also sex-linked, and hemophilia C coding factor XI, which is autosomal. Although hemophilia A is more common, this type of trait heterogeneity can obviously complicate the genetic analysis of a pedigree if one carelessly ignores alternative explanations.
Figure 9-1. Well-publicized pedigree of hemophilia in the royal families of Europe.
In the case of sex-linked hemophilia, genetics and history are clearly intertwined. A law in the Jewish Talmud, dating from about AD 600, implicitly recognizes the biological associations for this trait by allowing male children to be excused from ritual circumcision based upon having relatives with a bleeding disease. In the case of the descendants of Queen Victoria, hemophilia had serious consequences, at least indirectly, for the stability of the Russian royal family, the Romanovs, which ended with the death of Tsar Nicholas II and his family. His young son Alexei, a great-grandchild of Queen Victoria, suffered from hemophilia. The story of this family’s isolation from the problems facing the Russian peasants and the powerful influence of the monk Rasputin form a sad tale of power, conflict, and human weakness. Alexei’s medical condition gave Rasputin an influence in political activities that contributed to the overthrow of the Romanovs.
The Romanov family’s execution generated famous rumors, including the supposed survival of the young sister, Anastasia, depicted in numerous books and movies. The story was finally resolved with establishment of the identities of family members taken from a hidden grave and confirmed using conclusive DNA evidence. In fact, the genetic study led to new information. The form of hemophilia seen in the European Royal families has generally been assumed to be the more common form, hemophilia A. But recent sequencing of the loci in preserved tissue samples from two members of the family, Alexei and his mother, the Russian Empress Alexandra, indicate that the locus was the less common sex-linked form, hemophilia B. Genetics and history are often linked in complex and interesting ways.
In this Chapter, we will begin by introducing some of the basic logic of representing genetic relationships in pedigrees. The Medical Genetics section will focus on actual cases and some of the difficulties encountered in evaluating the inheritance of often complex phenotypes. The general emphasis will be on the types of information that can be gained from a group of related individuals in contrast to our earlier focus on one mating or an individual alone.
Part 1: Background and Systems Integration
Pedigree Organization
In Chapter 6, we explored the genetic relationships among relatives by discussing basic Mendelian patterns of inheritance. Here we approach the analysis of gene transmission within families again, but in a slightly more formal way. Superficially, a pedigree is really nothing more than a series of Mendelian genetic crosses involving relatives. But we often find that seeing the patterns of expression in a pedigree can yield important clues about a genetic condition that the study of one isolated patient or family cannot.
Various approaches can provide information about patterns of inheritance. One of the first studies of this kind was done by George Darwin, the son of Charles Darwin, who explored the frequency of first cousin marriages in Great Britain. Indeed, George Darwin was the product of a first-cousin marriage between his father and his mother, Emma, a member of the Wedgwood china family. George Darwin’s focus was on marriages between people with the same surname and yielded a frequency of 2.25% to 4.5%, with the British upper classes being at the high end of the range. Studies now utilize DNA markers, especially short tandem repeats (STRs) in the paternally-transmitted Y chromosome and hypervariable region mutations in the maternally-transmitted mtDNA.
Pedigrees are organized by generation. Symbols used to summarize information about the phenotypes and biological relationships are shown in Figure 9-2. Here is a useful hint: to begin to interpret an inheritance pattern, reverse the way you normally think about gene transmission. Rather than looking for the appearance of a trait among the progeny of a family, look from the progeny generation backward toward the parents. In other words, begin by looking at transmission patterns by moving your attention up the pedigree, not down it. If, for example, a child shows a dominant trait, then you expect one of the parents to show it. The other direction is not as certain. Just because a parent has a dominant trait does not mean that one of their few children will necessarily inherit it. Examples of this logic are explored in the next section.
Figure 9-2. Symbols used in pedigree construction.
The proband (or propositus [male], proposita [female]) is the first member in a family to be evaluated by the physician. If affected, that individual is the index case for the pedigree. Relatives may be first degree (parents, siblings, offspring of the proband), second degree (grandparents, grandchildren, uncles, aunts, nieces, nephews), or third degree (cousins, and so forth).
Finally, as with any analysis of human inheritance, pedigrees are susceptible to confusion by what we might call extramarital involvements. Even adoption is not always acknowledged publicly. Sensitivity to such issues is a natural and necessary element of all human genetic analyses. There can be a fine balance when issues of privacy and scientific accuracy are in play. Although pedigrees might only rarely include complications of this type, such possibilities should never be forgotten.
Basic Pedigree Analysis
One way to approach a pedigree is to ask a simple set of questions, since the number of common inheritance patterns is fairly small. To outline a logical approach, a few simplifying assumptions will be made. We will assume that the pedigree reflects the accurate biological relationships among genetically-related individuals and that the trait is a single-gene Mendelian characteristic, rather than a multiple-gene, or polygenic, predisposition.
First determine whether the trait is dominant or recessive. Dominance is easily recognized.
• If the trait is dominant, each affected child will have an affected parent. The lineage of the trait can be traced continuously up the pedigree (Figure 9-3).
• Furthermore, unaffected siblings will have only normal offspring.
Figure 9-3. Sample pedigree for a simple dominant trait.
But, if the trait commonly skips generations so that an affected child has phenotypically normal parents, then it does not fit the pattern of a dominant. The alternate hypothesis, recessive inheritance, is supported (Figure 9-4). To confirm recessive inheritance, note that if two affected individuals (both being recessive homozygotes) have offspring, all of the offspring will have the trait. Also be aware that recessive traits may show up more often in pedigrees involving consanguineous marriages (matings between close relatives).
Figure 9-4. Representative pedigree showing an autosomal recessive trait. The appearance of affected offspring from normal parents is consistent with recessive inheritance. For offspring II-8 to -10, there is evidence the trait is autosomal, since a homozygous female for a sex-linked trait must pass it to all of her sons. Can you find another piece of evidence in support of autosomal linkage?
If a trait generally follows one of these common patterns but an occasional exception occurs, then consider additional factors like incomplete penetrance (Figure 9-5). A dominant trait that occasionally appears to skip a generation may simply be non-penetrant in an affected member of the family and thus undetectable by general visual assessment.
Figure 9-5. This pedigree is consistent with dominant inheritance, except for individual III-3, who apparently passes on the dominant trait but does not express it. This can be interpreted as an example of incomplete penetrance.
The next step is to determine linkage relationships (Figure 9-6). Is the trait or DNA marker sex-linked (i.e., transmitted on an X chromosome or, more rarely, on a Y) or is it autosomal? For sex-linkage, we will limit our attention to the X chromosome. A good way to approach this question is to look for exceptions to the pattern expected for a sex-linked trait. If an exception to sex-linked transmission is found, the trait must be autosomal.
Figure 9-6. Representative pedigree for a sex-linked trait. Passage is never from father to a son, but an affected female has only affected sons. Here is a “test yourself” question: could the parents III-3 and III-4 be theoretically able to produce an affected daughter? The answer is “no.” Why not?
• Are there examples of both a father and a son expressing a dominant trait? Here the focus is on excluding sex-linkage by finding exceptions. The father only passes his X chromosome to his daughters. If a son inherits the trait from the father, it cannot be sex-linked (see, for example, Figure 9-5). Of course, one must be careful when a trait is common in the population or when both sides of the family carry it. In those cases a son and father might both be affected with a sex-linked condition, but the son inherited from the mother, not the father.
• For a recessive sex-linked trait, all sons of an affected (i.e., homozygous) mother will express the trait.
• When a sex-linked trait is recessive, it will appear most commonly, and perhaps exclusively, in the males of a pedigree. With only one X chromosome, a male will express a trait no matter whether it is dominant or recessive in females. But if the sex-linked trait is dominant, it might be expected to occur somewhat more frequently in females if a large number of individuals in a population are screened. This is simply because 2/3 of all X chromosomes are found in females.
Of course, there will be exceptions to these typical patterns. One must combine information about the pattern of inheritance with knowledge about the phenotype. If the trait is gender-specific, like female lactation, or is sex-influenced, like pyloric stenosis found more often in males or lupus erythematosis in females, then a simple analysis of affected genders in the pedigree alone can be misleading. Pedigree analysis is, after all, a kind of puzzle.
Sample Pedigree Evaluation: Applying the Rules
One reason to determine the mode of transmission and expression for a pedigree is to allow predictions about children who will be born into it. Once a trait has been characterized, it is possible to assign genotypes, or at least probabilities of a given genotype, to members of the pedigree and use that information to predict the trait’s expression in the next generation.
Consider the pedigree in Figure 9-7. The first question is the type of expression, dominant or recessive. In this case, we hypothesize that the trait is recessive. The affected daughter in the second generation (II-7) shows the trait, but both parents are normal. Next, is the trait inherited autosomally or on the X chromosome? If the trait were sex-linked, the affected daughter would be homozygous and must have inherited the trait from both parents. With only one X chromosome, the father must express it, but he does not. Thus, we can conclude that the recessive trait is autosomally inherited.
Figure 9-7. A pedigree to evaluate as a sample problem (see text).
Now knowing the manner of transmission, we can begin to assign genotypes to some individuals. For example, the first generation parents in the right-hand side of the pedigree (the female I-3 and male I-4) must both be heterozygous since they produce a homozygous recessive daughter. For convenience, let us assign the symbol A for the dominant and a for the recessive alleles (Figure 9-7b). On the left-hand side, a phenotypically normal AAfemale I-1 and affected aa male I-2 have a phenotypically normal, thus heterozygous, daughter (II-3). In the absence of any conflicting evidence, we always assume that individuals, like male II-4, marrying into the pedigree are genetically normal for the trait. The mating that gives rise to male III-1 is, therefore, Aa× AA, and there is a ½ chance that male III-1 is heterozygous Aa.
Returning again to the right-hand side of the pedigree, let’s consider the genotype of male II-5. In order for the child of interest (IV-1) to be homozygous for the a allele, the allele must be passed on by male II-5. What is his probability of his being heterozygous? The answer is 2/3. This number might initially surprise you (a common error is to say the probability is ½), but the logic is simple. Of the four possible outcomes of a mating between two heterozygous parents, one is eliminated by the pedigree; the male II-5 is not aa since he does not express the recessive trait. Thus, among the remaining three possible outcomes involving phenotypically normal offspring, two are Aa heterozygotes and the third is homozygous normal (AA). Then, if II-5 is heterozygous, there is a 0.5 chance of his passing the recessive allele to his daughter, III-2. For the yet-to-be-born child, IV-1, to show the recessive trait (a ¼ chance if both parents are heterozygotes), then all of these transmission events must have occurred. The overall probability requires applying the product rule.
The product rule applied to probabilities is simply that the likelihood of two or more events occurring together is the product of their individual probabilities. For example, the probability of flipping two nickels and getting a head both times is ½ (the probability of a head the first time) times ½ (the probability of getting a head the second time) = ¼. The other three outcomes are: head + tail; tail + tail; and tail + head. An assumption is, of course, that the events in question are independent.
Each member in a pedigree is the product of an independent fertilization event. The probability of inheriting the mutant a allele from a Aa heterozygote is, therefore, ½. The overall probability of a given outcome can be calculated by multiplying the probabilities of each required step leading to that hypothetical outcome. We can multiply the required steps in any order we wish, as long as all are included in the calculation. Ignoring the certainties (a probability of 1.0) and moving from generation II through IV, the calculation is 2/3 × ½ × ½ × ¼ = 1/24 of child IV-1 being aa and showing this recessive condition.
The analysis of a pedigree is, therefore, a combination of applying known information and calculating probabilities for elements that are unknown. By first determining the probable mode of transmission, one can convert individual phenotypes into genotypes. Then, breaking the pedigree down into individual families, one can predict the likelihood of specific transmission events. The overall assessment factors in these individual probabilities. Having a logical structure like this to work from allows you to approach even the most complex pedigree in an organized and confident manner.
Part 2: Medical Genetics
Why pay money to have your family tree traced? Go into politics and your opponent will do it for you.
- Mark Twain
The Importance of the Family History
In a very real sense this is the most important chapter in this book. Most of you, the readers, will not be going into a career in medical genetics. Still, as we have stressed throughout the previous chapters, a working knowledge of medical genetics is a must for all current and future health care professionals. A detailed family history should be part of the medical record of each and every patient. This information is as critical to the chart as vital signs, examination findings and laboratory results. In addition, a carefully constructed and appropriately interpreted family history is an incredibly powerful diagnostic tool. Throughout this book we emphasize all of the amazing advances in molecular genetics. Exciting new tools are being developed continuously. And in the overall diagnostic yield (i.e., what will give you a tangible answer) the family history is equally effective as all of the available genetic testing options combined!
For centuries people interested in human genetic disorders have relied on the family history as an invaluable source of information. As technological advances have emerged at an amazing rate over the past few years, the question arises, “Is there still a role for the family history in the ‘age of genomics’?” The answer is an emphatic “yes.” Despite all of the advances in genetic technology, the family history still remains one of the most informative tools in a medical practice—of any type.
Traditional medical education about family history has been sorely underemphasized. All physicians should be skilled in obtaining and interpreting family history information. Every patient should have complete family history information as part of their medical record. This information should be systematically and periodically updated throughout the life course. It should then be incorporated into the overall medical plan. It can aid in diagnosis, treatment, and prevention of a host of illnesses.
The surgeon general, in cooperation with other agencies within the U.S. Department of Health and Human Services, launched a national public health campaign called the Surgeon General’s Family History Initiative in November 2004. This initiative was developed to encourage all American families to learn more about their family health history. Every year since then, the surgeon general has declared Thanksgiving to be National Family History Day. Families are encouraged to discuss and record health problems that seem to run in their family as they are gathered together. The goals of this initiative are listed in Table 9-1.
Family Relationships
Pedigrees are simply graphic representations of members of a kindred and their relationship to each other. All health care providers should be comfortable in constructing and interpreting medical pedigrees. If the reader needs to review this process, it is reviewed in the first section of this chapter.
An important element in calculating risks for the transmission of a condition found in one family member for another is determining the degree of relationship of the person in question to the affected individual. In this context, relatives may be:
• First Degree: parents, siblings, offspring of the proband
• Second Degree: grandparents, grandchildren, uncles, aunts, nieces, nephews
• Third Degree: cousins, etc.
These (and other) degrees of relationships can be mathematically defined. Numbers such as the coefficient of relationship can be used to essentially describe the relative number of genes two individuals are expected to share based upon ancestry. The reader is referred back to Figures 6-27 and 6-28 for a quick review.
Obtaining a Family History in the Clinical Setting
At all levels, major health care organizations and authorities have come forth in support of the central role family health plays in the provision of clinical services. Besides the surgeon general’s initiative, formal endorsements and resources have come from organizations like the American Medical Association and the American Academy of Family Practitioners. Current “standard of practice” recommendations are that every patient, in any practice setting should have family history as part of their medical record. It is recommended that a three generation pedigree should be obtained and periodically updated on all families in a medical practice. For pediatric patients, that would include the patient, their siblings, parents, aunts, uncles, cousins, and grandparents. For an adult it may also include the patient’s children and grandchildren. Further generations should be included if the patient is aware of other relevant health history for more distant relatives. The typical type of information to be obtained in a family history is listed in Table 9-2.
Table 9-1. Goals of the United States Surgeon General’s American Family Health Initiative
• Increase the public’s awareness of the importance of family history in their own health
• Provide publically accessible tools to gather, understand, evaluate, and use family history information for lay individuals and health professionals
• Increase the awareness of health professionals about the importance of family history
• Increase the utilization of the family history by health care professionals and communicate this with their patients
• Increase genomics and health literacy
• Prepare both the American public and their health professionals for the coming era in which genomics will be an integral part of regular health care
Despite the resounding endorsements from major medical organizations, in reality the use of the family history in general medical practice falls far short of the published recommendations. Busy clinicians simply do not feel that they have sufficient time to obtain, organize, and analyze family history information. The solution requires innovative approaches to the family history that require the least amount of time of the practitioner. One of the best tools in this regard is to use a family history questionnaire. This form can be filled out in the waiting room at the time the patient is also filling out demographic intake information. The questionnaire can generate family history information from which a basic pedigree may be drawn by trained office staff. The completed pedigree can then be available on the chart as the practitioner enters the room along with the other important information typically provided like chief complaint, vital signs, and past medical history. At that point, all the physician needs to do is review the completed pedigree and apply the knowledge gained from training to interpret and act upon the information. Several good tools exist if the physician wants to use tools already developed. Most are readily available through internet sources. A few of the more well-known tools include:
Table 9-2. Typical Information To Be Obtained in a Three-Generation Pedigree
• Age or year of birth
• Age and cause of death (for those deceased)
• Ethnic background of each grandparent
• Relevant health information (e.g., height, weight)
• Illnesses and age at diagnoses
• Information regarding prior genetic counseling and testing
• Information regarding pregnancies (stillbirths, infertility, spontaneous miscarriages, complications, prematurity)
• In association with the family history initiative discussed earlier, the surgeon general has created a computerized tool for obtaining a family’s health history. It is written to walk nonmedical persons through the process in an easy and fun context. It can be accessed at:
° https://familyhistory.hhs.gov/fhh-web/home.action
• The American Medical Association also has tools for obtaining a family medical history. This site has separate forms for pediatric, adult, or prenatal patients. These can be accessed at:
° http://www.ama-assn.org/ama/pub/physician-resources/medical-science/genetics-molecular-medicine/family-history.page
• The National Human Genome Research Institute also has several resources available at:
° http://www.genome.gov/11510372
Families are indeed unique and complex. It is important that the person obtaining the family history information be aware of possible confounding issues. Certain family situations can lead to erroneous conclusions being drawn from the pedigree. For instance, it is estimated that 10% to 15% of people have mis-assigned paternity. That is, the person assumed to be the father is actually not the biological ancestor. Besides the obvious psychosocial implications of this information, it would of course obviate much of the information obtained in a pedigree were this information not revealed. This is also important in DNA testing, as will be discussed in a future chapter. By the nature of such testing, errantly-assigned paternity may be revealed unintentionally. Among other important considerations, this should be discussed during the informed consent process prior to obtaining the requisite samples.
Consanguinity is defined as the mating of two closely related individuals. The biological and genetic implications of this situation have been discussed in an earlier chapter. From the standpoint of obtaining a family history, there are several important points. Of course, there is the obvious stigma, and even legal ramifications, of such a union. For that reason, family members will often be hesitant to come forward with this information. Surprisingly, some individuals may not even be aware of a common ancestor and may actually identify this relationship through the process of obtaining the family history. Other potential sources of confusion include alternative relationships such as adoption, half-siblings, and persons with children via several different mates. Care must be taken to identify these relationships if at all possible in order to have the family history information accurately reflect the biological and genetic relationships within the family.
The issue of confidentiality is a crucial one in all aspects of clinical care. Because genetic conditions involve families and not just individuals, protecting confidentiality can require extraordinary efforts on the part of the practitioner. This is especially true for family practice physicians in which several members of the same family may receive their medical care from a single provider. Every effort must be made to keep each individual’s information in strictest confidence. Such information should only be shared with other family members in the context of explicit and documented consent or when it affects the health of another person.
Interpreting the Family History
The recommended standard of practice, then, is to have an up-to-date three generational pedigree as part of every patient’s medical record. Of course, this is just the first step. Simply having a pedigree on the chart does not by itself help in the care of the patient. The purpose of a book like this one is to prepare physicians to incorporate the principles of medical genetics into their daily practice. Thus, the practicing physician should be adept at interpreting the pedigree information for each patient. The pedigree should be scanned for relevant information. The practitioner should be comfortable in identifying what is significant in a family history. Every family will have medically notable conditions in some individuals. The trick is to identify when something is significant or not. Clearly, experience helps in this regard. The typical “red flags” that should alert the reviewer are by and large intuitive (Table 9-3). Factors such as the number of affected individuals, unusual presentations, and the degree of relationship should be considered. The practitioner should be alert to characteristics of the pattern of affected individuals. If it appears to be simple Mendelian inheritance (Chapter 6), then a monogenic etiology may be expected. If the pattern is clearly familial but does not follow a single gene pattern, a more complex explanation should be considered (Chapter 10). The Clinical Correlation section of this chapter provides an example of the way this might look in practice.
Responding to the Family History
Finally, it is not enough simply to obtain a family history and interpret it. The final step is to use the information to modify the patient’s care. If the review of the pedigree identifies a significant family history, the practitioner should respond accordingly. In the event of a significant positive family history he or she should:
• Counsel the family—within their own comfort level for the particular condition
• Order specific indicated tests
• Identify at-risk family members
• Offer preventative strategies
• Utilize consultation as needed
Table 9-3. Review of the Family History
“Red flags” in a family history
Number of relatives affected
Degree of relationship to proband
Age of onset
Least affected sex
Related disorders
Positive family history
Mendelian pattern
Monogenic conditions
Non-Mendelian pattern
Complex disorder
Within the context of evidence-based medicine, the family history can actually be used to modify screening guidelines and recommended management protocols for many common disorders (Tables 9-4 and 9-5).
Table 9-4. Conditions in Which Established Population Screening Guidelines Are Influenced by the Family History
Breast cancer
Cardiomyopathy
Colon cancer
Coronary artery disease
Diabetes
Dyslipidemia
Hearing impairment
Hip dysplasia
Hypertension
Iron def anemia
Liver cancer
Osteoporosis
Prostate cancer
Thromboembolism
Thyroid disease
Visual impairment
Data from Guttmacher AE: The Importance of Family History in Health. SACGHS. October 11, 2004. Available at: http://oba.od.nih.gov/oba/SACGHS/meetings/October2004/Guttmacher.pdf. Accessed August 28, 2012.
Table 9-5. Conditions in Which Established Management Guidelines Are Influenced by the Family History
Breast cancer
Colon cancer
Coronary heart disease
Developmental delay
Diabetes
Emphysema & COPD
Heart failure
Hypertension
Pancreatitis
Syncope
Thromboembolism
Thyroid cancer
Urticaria
Data from Guttmacher AE: The Importance of Family History in Health. SACGHS. October 11, 2004. Available at: http://oba.od.nih.gov/oba/SACGHS/meetings/October2004/Guttmacher.pdf. Accessed August 28, 2012.
Part 3: Clinical Correlation
Case 1
Within the context of regular medical practice, the family history can be used to modify care. For example, let’s say that a new patient presents for “an office physical” to your practice. Your staff greets him at the reception desk and gives him the requisite forms to fill out. As part of this packet he is asked for demographic and insurance information. Another part of that packet collects information about his past medical history and other health care providers who have worked with him. Knowing what has been discussed in this chapter; your packet also has a printout of a family history tool, which he fills out. Your trained office staff takes the information from the packet and constructs a pedigree. When you enter the room, you note from his newly-constructed chart that the patient is a 52-year-old hispanic male who presents for a work physical. On the family history form he has checked “Yes” for a positive family history of diabetes, cancer, and heart disease. What intervention should you do based on this family history? If you are scratching your head, you are thinking “I don’t have enough information”—and of course you are correct. So you flip the page and review the pedigree your staff has constructed for you. Look at Figure 9-8. Your patient is individual IV.1. In this pedigree, the family history does not look very remarkable, does it? There is only one person with cancer. This was pancreatic cancer at an advanced age. Likewise, he only reports single occurrences of diabetes and heart disease with neither looking particularly remarkable.
Figure 9-8. Possible pedigree from a new patient (IV-1) who presents for a work physical. On his intake form, the patient marked a positive family history of heart disease, diabetes, and cancer. (ASHD = atherosclerotic heart disease. DM = Diabetes mellitus)
But look at Figure 9-9. We think you would agree that this looks quite different from the first pedigree, and yet would have had the same “yes’s” marked on the intake form. This pedigree is significant. There are multiple affected individuals with heart attacks and strokes. The ages of onset are quite early. In fact, upon further questioning, you are told that individual III-1, who died at 52 of a heart attack, actually had his first myocardial infarction at 38. Also note a 36-year-old first cousin (III-3), who is a female, died of a heart attack at 36! Finally, a quick review of the pedigree suggests autosomal dominant inheritance. In this case, your response is very different. Even though your patient is a healthy individual who simply came in for a physical exam, his family history screams at you: “do something.” Here is your chance. You can actually be part of intervention before the problem, i.e., real prevention. What would you do next? At a minimum the easiest and least expensive step would simply be to gather more information. Asking for medical records (with signed releases) from the affected family members would be a great start. The rest of the answer is beyond the scope of this chapter. Look forward to Chapter 10 to get an idea of what your thought process might be in this scenario.
Figure 9-9. Second scenario of the new patient visit. Patient IV-1 has marked the same positive family history as in Figure 9-8. Notice the very different implications. (ASHD = atherosclerotic heart disease. DM = Diabetes mellitus)
Case 2
Consider the following case. You are a resident in orthopedic surgery. As part of your clinical rotations, you are assigned to an interdisciplinary cerebral palsy clinic. During the clinic you see a 20-year-old young man who has the diagnosis of “cerebral palsy.” He has carried this diagnosis since early childhood. While looking through his chart, you notice that a family history is not part of his medical record. So you ask the simple question: “has anyone else in the family had cerebral palsy?” His mother is amazed by your question and answers, “yes.” You then obtain a forma family history and construct the pedigree. The completed product looks like Figure 9-10a. Being the astute well-trained young doctor that you are, you look at this pedigree and quickly come to the conclusion that this looks like an X-linked recessive disorder. Your knowledge of the diagnosis of cerebral palsy causes you to question the accuracy of the diagnosis. Ultimately, an MRI of the brain is obtained and the patient is found to have the findings of an olivopontocerebellar atrophy (Figure 9-10b). This is an actual case that we reported in 1989 as a rare case of an X-linked olivopontocerebellar atrophy. It highlights the power of simply asking the patient about his or her family.
Figure 9-10. (a) Pedigree of a young adult (III-6) with the diagnosis of cerebral palsy. Note the affected uncle and cousin. (b) MRI of the brain of patient III-6.
Board-Format Practice Questions
Questions 1–5 correspond to Figures 9-11–9-15, respectively. For each pedigree identify the most likely mode of inheritance. For some there may be more than one possible inheritance pattern. For test questions like these and on the board exams, you will be asked to select the best answer.
Figure 9-11. Pedigrees: sample board format questions. See answer section for explanation.
Figure 9-12. Pedigrees: sample board format questions. See answer section for explanation.
Figure 9-13. Pedigrees: sample board format questions. See answer section for explanation.
Figure 9-14. Pedigrees: sample board format questions. See answer section for explanation.
Figure 9-15. Pedigrees: sample board format questions. See answer section for explanation.