Clinical Topics Conference:Chapter 6, Developmental and Genetic Diseases

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  1. Chromosome Disorders
  2. Developmental and Newborn Disorders
  3. Autosomal Dominant Disorders
  4. Autosomal Recessive Disorders
  5. X-linked Recessive Disorders

Case 1: Chromosome Disorders

Clinical vignette 1

A 39 year-old gravida 3, para 2 female undergoing prenatal care in a normal uneventful pregnancy was offered amniocentesis at 16 weeks gestation. Seven days following the procedure the physician was informed cytogenetic analysis of the amniotic fluid revealed 47,XY,+21.

Discussion Topics

  1. Why was the patient offered amniocentesis? Will ammiotic fluid analysis of women over 35 years of age detect most cases of Down syndrome? Describe two forms of chromosomal abnormalities associated with Down syndrome. Why is it important to differentiate between them? What are the phenotypic and pathologic features of Down syndrome? Are there screening tests for Down syndrome in women under 35 years of age?

  2. Discuss the main pathologic and clinical findings in the sex chromosome disorders of Turner and Klinefelter syndrome. When (general age) is Turner syndrome usually diagnosed? Describe the ovaries in a women with Turner syndrome and the testes in a male with Klinefelter syndrome.

  3. Describe the chromosomal and molecular changes associated with Fragile-X syndrome. Is this a common disorder?

  4. What is the significance of determining that an individual carries a balanced translocation? What is the frequency of balanced translocation carriers in the general population?

  5. Differentiate between hereditary, familial and congenital disorders. Can a disease be hereditary but not congenital? Congenital but not hereditary?

    References

    1. MMWR 44 (RR-9), 1995. Chorionic villus sampling and amniocentesis. Recommendations for prenatal counseling.

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    Case 2: Developmental and Newborn Disorders

    Clinical vignette 2

    A 965 gm twin male infant was born to a gravida 2, para 1 19-year-old mother at 24 weeks gestation. Despite intubation and O2 supplementation the infant's condition gradually deteriorated and the patient expired on the 12th hospital day.

    Discussion Topics:

    1. Define fetal pulmonary maturity and describe how immaturity of lungs cause respiratory distress syndrome of the newborn.

    2. Describe TORCH syndrome and list the four most common causes of this set of malformations.

    3. Describe the different types of neural tube defects. Which types may be diagnosed pre-natally? What tests or procedures are used for their pre-natal diagnosis?

    4. Describe the pathogenic events leading to erythroblastosis fetalis. Why does erythroblastosis fetalis not ordinarily occur during the first pregnancy? Can it be prevented? How is it treated?

    5. Are there modes other than a normal pregnancy and delivery for sensitizing an Rh-negative women to Rh-positive cells?

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      Case 3: Autosomal Dominant Disorders

      Clinical vignette 3

      A 27 year-old female has been trying to conceive for 6 years, and visits her gynecologist for fertility counseling. In the process of a routine physical exam, her weight is determined to be 50 kg, and her serum cholesterol level is >600 mg/dl. She attends 3 aerobics classes per week, and eats a low-fat diet.

      Discusion topics:

      1. What autosomal dominant disorder does this patient probably have? What is the incidence of heterozygosity in the population? What is the incidence of homozygosity in the population?

      2. What clinical signs/symptoms would you expect to see in these individuals? Is this woman at risk for atherosclerosis? Why or why not?

      3. What is the molecular mechanism(s) responsible for causing this autosomal dominant disorder?

      4. Discuss autosomal dominant inheritance of familial hypercholesterolemia. If this patient is a heterozygote, will she transmit the trait to her future children? Will both male and female children be affected?

      5. Discuss Marfan Syndrome and Neurofibromatosis in the context of the above questions. (i.e., incidence, clinical signs, pathogenesis, and molecular mechanism)

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      Case 4: Autosomal Recessive Disorders

      Clinical vignette 4

      An 18-month old female presents with abdominal distention. Her mother reports large stools and poor weight gain. The child has suffered from persistent pulmonary infections since infancy.

      Discussion topics:

      1. Name the likely autosomal recessive disease afflicting this child. How is it diagnosed? What are the clinical features of cystic fibrosis? Describe the pathogenesis of cystic fibrosis (CF) in lung, pancreas, liver, and gastrointestinal tract.

      2. Discuss the molecular basis of the disease. What is the role of the cystic fibrosis transmembrane conductance regulator (CFTR) in this disease? What is the frequency of CF disorder in newborns, and what is the carrier frequency?

      3. Discuss the lysosomal storage disorders Gaucher disease and Tay Sachs disease. What is the pathogenesis of these disorders? What are the clinical features?

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      Case 5: X-linked Recessive Disorders

      Clinical vignette 5

      A 3 year-old male child visits his pediatrician for an annual check-up. The mother mentions that he has a funny way of getting up off the floor, and she has noticed that his calves are "well-developed".

      Discussion topics

      1. What X-linked recessive disorder would you suspect is present? Describe the clinical features and pathogenesis of the disease.

      2. What is this patient's prognosis? Would you expect this disease to also develop in this child's sister? What are the features of X-linked recessive inheritance patterns.

      3. What is known about the molecular basis for this disease?

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