Case-Based Questions

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CHAPTER 6: Developmental Genetics

Case 1

A 2-year-old child is referred to geneticists because of a large head circumference above the 97th centile, although it is growing parallel to the centile lines. The parents would like to have another child and are asking about the recurrence risk. The cerebral ventricles are dilated and there has been much discussion with the neurosurgeons about possible ventriculoperitoneal shunting. On taking a full family history, it emerges that the paternal grandmother is under review by dermatologists for skin lesions, some of which have been removed, and a paternal uncle has had some teeth cysts removed by a hospital dentist.

1 Is there a diagnosis that embraces the various features in these different family members?
2 What investigations would be appropriate for the child’s father, and what is the answer to the couple’s question about recurrence risk?

Case 2

A 4-year-old girl is brought to a pediatrician because of behavioral difficulties, including problems with potty training. The pediatrician decides to test the child’s chromosomes because he has previously seen a case of 47,XXX (triple X) syndrome in which the girl had oppositional behavior. Somewhat to his surprise the chromosome result is 47,XY—i.e., the ‘girl’ is genetically ‘male’.

1 What are the most important causes of sex reversal in a 4-year-old child who is phenotypically female and otherwise physically healthy?
2 What should the pediatrician tell the parents, and which investigations should be performed?

CHAPTER 7: Patterns of Inheritance

Case 1

A 34-year-old man has developed some spasticity of his legs in the past few years and his family has noted some memory problems and alteration in behavior. He has very brisk peripheral reflexes. He is seen with his mother in the genetic clinic and she is found to have significantly brisk peripheral reflexes on examination but has no health complaints. It emerges that her own father probably had problems similar to her son’s in his thirties, but he was killed in the war.

1 Which patterns of inheritance need to be considered in this scenario?
2 What diagnostic possibilities should be considered?

Case 2

A couple has a child who suffers a number of bone fractures during early childhood after minor trauma and is told that this is probably a mild form of osteogenesis imperfecta. The parents did not suffer childhood fractures themselves, and when they have another child who also develops fractures they are told the inheritance is autosomal recessive. This includes an explanation that the affected children should not see the condition occur in their offspring in the future.

1 Is the information given to the parents correct?
2 If not, what is the most likely pattern of inheritance and explanation for the sibling recurrence of fractures?

CHAPTER 8: Population and Mathematical Genetics

Case 1

The incidence of a certain autosomal recessive disorder in population A is well established at approximately 1 in 10,000, whereas in population B the incidence of the same disorder is much higher at approximately 1 in 900. A man from the first population group and a woman from the second population group are planning to marry and start a family. Being aware of the relatively high incidence of the disorder in population B, they seek genetic counseling.

1 What essential question must be asked of each individual?
2 What is the risk of the disorder occurring in their first pregnancy, based on application of the Hardy-Weinberg equilibrium?

Case 2

Neurofibromatosis type 1 is a relatively common mendelian condition. In a population survey of 50,000 people in one town, 12 cases are identified, of which 8 all belong to one large affected family.

1 Based on these figures, what is the mutation rate in the neurofibromin gene?
2 Name some limitations to the validity of calculating the mutation rate from a survey such as this.

CHAPTER 9: Polygenic and Multifactorial Inheritance

Case 1

A 16-year-old requests oral contraceptives from her general practitioner. On taking a family history, it emerges that her mother had a deep vein thrombosis at the age of 40 years and died after a pulmonary embolism at age 55 years. There is no other relevant family history.

1 What genetic testing is appropriate?
2 What are the limitations of testing in this situation?

Case 2

A 35-year-old woman is diagnosed with diabetes and started on insulin treatment. She and her 29-year-old brother were adopted and have no contact with their birth parents. Her brother has no symptoms of hyperglycemia. Both have normal hearing and no other significant findings.

1 What possible subtypes of diabetes might she have and what are the modes of inheritance of these subtypes?
2 For each of these subtypes, what is the risk of her brother developing diabetes?

CHAPTER 10: Hemoglobin and the Hemoglobinopathies

Case 1

A Chinese couple residing in the United Kingdom has had two pregnancies and the outcome in both was a stillborn edematous baby (hydrops fetalis). These pregnancies occurred when they lived in Asia and they have no living children. They seek some genetic advice about the chances of this happening again, but no medical records are available for the pregnancies.

1 What diagnostic possibilities should be considered?
2 What investigations are appropriate to this situation?

Case 2

A young adolescent whose parents are of West Indian origin is admitted from accident and emergency after presenting with severe abdominal pain and some fever. An acute abdomen is suspected and the patient undergoes laparotomy for possible appendicitis. However, no surgical pathology is identified. Subsequently the urine appears dark.

1 What other investigations might be appropriate at this stage?
2 What form of follow-up is appropriate?

CHAPTER 11: Biochemical Genetics

Case 1

A 2-year-old boy, who has a baby sister age 4 months, is admitted to hospital with a vomiting illness and drowsiness. Despite his vomiting symptoms improving quite quickly with intravenous fluid support, his blood glucose remains low and intravenous fluids are required longer than might normally be expected. The parents say that something like this happened before, although he recovered without seeing a doctor.

1 What does this history suggest?
2 What investigations are appropriate?

Case 2

A 28-year-old woman has become aware over several years that she does not have the same energy as she did at the age of 20 years. She tires relatively easily on exertion and family members have noticed that she has developed slightly droopy eyelids as well as wondering whether her hearing is deteriorating, which she vigorously denies.

1 How might a detailed family history help towards a diagnosis in this case?
2 What investigations should be performed?

CHAPTER 13: Immunogenetics

Case 1

A 32-year-old man has had low back pain and stiffness for 2 years and recently developed some irritation in his eyes. Radiography is performed and a diagnosis of ankylosing spondylitis made. He remembers his maternal grandfather having similar back problems as well as arthritis in other joints. He has three young children.

1 Is it likely that his grandfather also had ankylosing spondylitis?
2 What is the risk of passing the condition to his three children?

Case 2

A 4-year-old girl suffers frequent upper respiratory infections with chest involvement, and each episode lasts longer than in her preschool peers. Doctors have always assumed this is somehow a consequence of her stormy early months, when she had major heart surgery for tetralogy of Fallot. She also has nasal speech and in her neonatal record a radiologist commented on the small size of the thymus gland.

1 Is there another diagnosis that could explain her frequent and prolonged upper respiratory infections?
2 What further management of the family is indicated?

CHAPTER 14: Cancer Genetics

Case 1

A 38-year-old woman, who recently had a mastectomy for breast cancer, requests a referral to the genetic service. Her father had some bowel polyps removed in his fifties and a cousin on the same side of the family had some form of thyroid cancer in her forties. The general practitioner consults a set of guidelines that suggest a familial form of breast cancer is unlikely because she is the only one affected, even though quite young. He is reluctant to refer her.

1 Could the history suggest another familial condition? If so, which one?
2 What other clinical features might give a clue to the diagnosis?

Case 2

A 30-year-old is referred for genetic counseling because she is concerned about her risk of developing breast cancer. The consultand’s mother has recently been diagnosed with breast cancer at 55 years of age. Her brother’s daughter (the consultand’s cousin) had bilateral breast cancer diagnosed at age 38 years and died 5 years ago from metastatic disease. The cousin had participated in a research study that identified a BRCA2 gene mutation. The clinical geneticist suggests that the consultand’s mother should be tested before predictive testing is offered to her daughter. They are surprised when a negative result is reported by the laboratory.

1 What are the possible explanations for this result?
2 What is the risk of the consultand’s uncle developing breast cancer?

CHAPTER 15: Genetic Factors in Common Diseases

Case 1

A 2-year-old girl presents with partial seizures. The episode is brief and unaccompanied by fever. Because the child is well with no neurological deficit, a decision is made not to treat with an anticonvulsant drug. A year later she suffers a generalized seizure, again without fever. On this occasion, her 30-year-old mother asks whether this might have anything to do with her own seizures that began at the age of 15 years, although she has had only two episodes since. She had undergone computed tomography of the brain and the doctors mentioned a condition whose name she could not remember. Magnetic resonance imaging of the child’s brain shows uncalcified nodules on the lateral ventricular walls.

1 The mother asks whether the epilepsy is genetic and whether it could happen again if she has another child. What can she be told?
2 What diagnoses should be considered and can genetic testing be offered?

Case 2

A 5-year-old child is admitted to hospital with an unexplained fever and found to have a raised blood glucose level. He makes a good recovery, but 2 weeks later his fasting blood glucose level is shown to be increased at 7 mmol/L. There is a strong family history of diabetes on his mother’s side, with his mother, maternal uncle, and maternal grandfather all affected. His father has no symptoms of diabetes, but his sister had gestational diabetes during her recent pregnancy. Molecular genetic testing identifies a heterozygous glucokinase gene mutation in the child.

1 The parents believe that their son’s hyperglycemia is inherited from the mother’s side of the family. Is this correct?
2 What are the consequences of finding a glucokinase gene mutation for this family?

CHAPTER 16: Congenital Abnormalities and Dysmorphic Syndromes

Case 1

A young couple has just lost their first pregnancy through fetal abnormality. Polyhydramnios was diagnosed on ultrasonography as well as a small fetal kidney on one side. Amniocentesis was performed and the karyotype showed a normal 46,XY pattern. The couple was unsure what to do, but eventually elected for a termination of pregnancy at 21 weeks. They were very upset and did not want any further investigations performed, including an autopsy. They did agree to a whole-body radiography of the fetus and some of the upper thoracic vertebrae were misshapen.

1 The couple asks whether such a problem could recur—they do not feel they can go through this again. What can they be told?
2 What further investigations might have helped to inform the genetic risk?

Case 2

On routine neonatal examination on the second day, a baby is found to have a cleft palate. The pregnancy was uneventful with no exposure to potential teratogens, and the family history is negative. The pediatric registrar also wonders whether the limbs are slightly short. The baby’s birth weight is on the 25th percentile, with length on the 2nd percentile.

1 What diagnoses might be considered?
2 What are the management issues in a case like this?

CHAPTER 17: Genetic Counseling

Case 1

A couple has a son with dysmorphic features, short stature, and moderately severe developmental delay. On the second occasion when his karyotype is analyzed, he is found to have a subtle chromosome translocation that was missed first time. The father is found to be a balanced translocation carrier. His family has always blamed the mother for the child’s condition because of her history of drug abuse, with the result that the couple no longer talks to his wider family. However, through friends he has learned that his sister is trying to start a family.

1 What are the important genetic issues?
2 What other issues does this case raise?

Case 2

A couple has a child who is diagnosed with cystic fibrosis (CF) at age 18 months. The child is homozygous for the common ΔF508 mutation. They request prenatal diagnosis in the next pregnancy, but DNA analysis shows that the father is not a carrier of ΔF508. It must be assumed he is not the biological father of the child with CF, and this is confirmed when further analysis shows that the child does not have a haplotype in common with him.

1 What medical issue does this information raise?
2 What counseling issues are raised by these results?

CHAPTER 18: Chromosome Disorders

Case 1

A newborn baby girl looks somewhat dysmorphic, is diagnosed with an atrioventricular septal defect (AVSD) congenital heart, and the pediatricians think this may be Down syndrome. This is discussed with the parents and a karyotype performed. The result comes back as normal: 46,XX. The baby is very ‘good’ during infancy with very little crying, and no further investigations are done. Subsequently the child shows global developmental delay, head-banging, wakes every night for about 3 hours, and has mild brachydactyly. The pediatricians refer her to a geneticist for an opinion.

1 Does the history suggest a diagnosis?
2 What investigation should be requested?

Case 2

The parents of a 10-year-old girl seek a follow-up appointment in the genetics clinic. At the age of 4 years, she had some behavioral problems and chromosomes were tested from a blood sample. The result came back as 47,XXX, and it was explained that these girls sometimes have behavioral problems, are usually tall, fertility is normal, and ‘everything would be alright’. However, by age 10 years, she is the smallest girl in the class and still has the slightly webbed neck that was present at birth.

1 What diagnosis should be considered and what investigation should now be offered?
2 How are the genetic counseling and future management modified by the new diagnosis?

CHAPTER 19: Single-Gene Disorders

Case 1

A 31-year-old woman would like to start a family but is worried because her 39-year-old brother was diagnosed as having Becker muscular dystrophy nearly 30 years ago and she remembers having being told that the condition affects boys but the women pass it on. Her brother is still living, but is now quite disabled by his condition. There is no wider family history of muscular dystrophy.

1 Is the original diagnosis reliable?
2 What are the next steps in managing this situation?

Case 2

A middle-aged couple is devastated when their 21-year-old daughter collapses at a dance and cannot be resuscitated. At post-mortem examination, all toxicology tests are negative and no cause of death is found. The mother recalls that her father died suddenly in his fifties from what was presumed at the time to be a cardiac cause, and her sister has had some dizzy spells but has not thought it necessary to see her doctor. The couple has three other children who are young, sport-loving adults and wonder whether this could happen again.

1 What investigations are appropriate?
2 What advice should the family be given?

CHAPTER 20: Screening for Genetic Disease

Case 1

A 32-year-old man is tall and thin, and 20 years ago his father died suddenly at age 50 years. The general practitioner wonders whether his patient has Marfan syndrome and refers him to a genetics clinic. He has some features of Marfan syndrome but, strictly speaking, would meet the accepted criteria only if the family history was definitely positive for the disorder. He has a brother of average height and three young children who are in good health.

1 In terms of genetic testing, what are the limitations to screening if the diagnosis is Marfan syndrome?
2 What are the screening issues for the family?

Case 2

A screening test for cystic fibrosis (CF) is being evaluated on a population of 100,000 newborn babies. The test is positive in 805 babies, of whom 45 are eventually shown to have CF by a combination of DNA analysis and sweat testing. Of those babies whose screening test is negative, five subsequently develop symptoms and are diagnosed with CF.

1 What is the sensitivity and specificity of this screening test?
2 What is the positive predictive value of the screening test?

CHAPTER 21: Prenatal Testing and Reproductive Genetics

Case 1

A 36-year-old pregnant woman elects to undergo prenatal testing by chorionic villus biopsy after the finding of increased nuchal translucency on ultrasonography. The initial result, using FISH probes, is good news—there is no evidence for trisomy 21—and the woman is greatly relieved. However, on the cultured cells more than 2 weeks later, it emerges that there is mosaicism for trisomy 20. She undergoes amniocentesis a week later, and 3 weeks after that the result also shows some cells with trisomy 20.

1 Why was an amniocentesis performed in addition to the chorionic villus biopsy?
2 What else can be done following the amniocentesis result?

Case 2

A couple has two autistic sons and would very much like to have another child. They are prepared to do anything to ensure that the problem does not recur. They acquire a lot of information from websites and learn that boys are more commonly affected—the male : female sex ratio is approximately 4 : 1. As they see it, the simple solution to their problem is sex selection by preimplantation genetic diagnosis (PGD).

1 What investigations might be performed on the autistic sons?
2 If tests on the sons fail to identify a diagnosis, can the request of the couple for sex selection by PGD be supported by the geneticist?

CHAPTER 22: Risk Calculation

Case 1

In the pedigree shown below, two cousins have married and would like to start a family. However, their uncle died many years ago from Hurler syndrome, one of the mucopolysac-charidoses, an inborn error of metabolism following autosomal recessive inheritance. No tissue samples are available for genetic studies.

1 What is the risk that the couple’s first child will be affected by Hurler syndrome?
2 Can the couple be offered anything more than a risk figure?

Case 2

A woman has a brother and a maternal uncle affected by hemophilia A. She herself has had two unaffected sons and would like more children. She is referred to a genetics clinic to discuss the risk and the options.

1 Purely on the basis of the information given, what is the woman’s carrier risk for hemophilia A?
2 Can anything be done to modify her risk?

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