GM1.2 Compare and contrast, with examples, the inheritance patterns of
different types of Mendelian disorders.
Case for C1: Autosomal recessive inheritance - Cystic Fibrosis
A 22 year old caucasian male has had frequent respiratory illnesses throughout his
life. He has always been on the lower range of normal and smaller than his siblings.
His current primary care physician found his lung exam to be abnormal and
wondered if he had ever been tested for cystic fibrosis.
1) What test would you recommend?
• Cystic fibrosis results from loss of function of the CFTR gene (cyctic fibrosis
transmembrane conductance regulator). The classic diagnostic test for CF is
the measurement of sweat electrolyte levels (>60 mmol/l, diagnostic; 40-60
mmol/l, intermediate (but more likely to be diagnostic in infants); <40 mmol/l,
normal). Screening tests for infants are available as is genetic testing.
2) Explain the inheritance of cystic fibrosis, show how it is possible for an
individual to inherit a mutation in each CFTR allele and present with no
disease, mild disease or severe cystic fibrosis and explain how the screening
and diagnostic tests may predict different outcomes.
• Cystic fibrosis is the most common inherited disease in white populations (1 in
2500 newborns). It is an autosomal recessive disease with 70% of mutations
being loss of phenylalanine (ΔF508). With over 1600 described mutations in the
CFTR gene there is variable loss of function in the transporter yielding a wide
range of severity in clinical presentation.
3) Explain the normal physiologic function of the CFTR protein and which
tissues are affected by loss of CFTR function.
• The CFTR protein is an ion channel regulating liquid volume on epithelial
surfaces through chloride secretion and inhibition of sodium absorption. While
the channel exists in many tissues, the lungs and digestive tract are most
vulnerable.
4) Describe the pathophysiologic process that occurs in the lungs of patients
with severe CF that leads to bronchiectasis and chronic pneumonia including a
description of the histopathology as the disease progresses.
• A more viscous liquid covering the lung epithelium inhibits mucociliary
clearance. Because inhaled bacteria cannot be cleared effectively, chronic
infection and inflammation occurs.
•
Case continued - During the next year the patient develops pneumonia and
dies.
Autopsy Findings
A
B
5) Compare and contrast the gross pathology in A and B.
 Normal Lung; B- Bronchiectasis with peripheral bronchi filled with
mucopurulent secretions
A
B
C
D
6) Compare and contrast the histopathology in A, B, C and D.
 A- Normal Lung; B-extensive mucopurulent secretions in dilated airway; Calveolar lung parenchyma with mucus and acute and chronic inflammation; Dhigher power view of C.
•
7) Propose a treatment to correct the root cause of CF. Propose therapy to
minimize the symptoms of CF.