Educational Case

Academic Pathology
Volume 4: 1–4
Educational Case: Autosomal Recessive ª The Author(s) 2017
Reprints and permission:

Inheritance: Cystic Fibrosis sagepub.com/journalsPermissions.nav

DOI: 10.1177/2374289517691769
journals.sagepub.com/home/apc

D. Yitzchak Goldstein, MD1 and Michael Prystowsky, MD, PhD1

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME),
a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and
Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and
a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040.

Keywords
pathology competencies, cystic fibrosis, developmental and functional abnormalities, disease mechanisms, genetic mechanisms,
inheritance patterns

Received November 01, 2016. Received revised December 25, 2016. Accepted for publication January 09, 2017.

Primary Objective and chronic lung infections) may be seen in other disease
states, such as primary ciliary dyskinesia (Kartagener syn-
Objective GM1.2: Inheritance Patterns. Compare and contrast the
drome) as well as asthma and should be excluded in this
inheritance patterns of different types of Mendelian disorders
patient. In CF, progressive scarring ultimately leads to atrophy
and give examples of each type of pattern.
of the vasa deferentia.
Competency 1: Disease Mechanisms and Processes; Topic
GM: Genetic Mechanisms; Learning Goal 1: Genetic Mechan-
isms of Developmental and Functional Abnormalities.
Questions/Discussion Points, Part 1
Patient Presentation What Testing is Available for this Patient and Which is
A 22-year-old Caucasian male presents with a recurrent cough. Recommended?
He has had frequent respiratory illnesses and abdominal discom- Cystic fibrosis results from loss of function of the CF trans-
fort throughout his life. He has always been on the lower range membrane conductance regulator (CFTR) protein caused by
of normal for height and significantly smaller than his siblings. mutations in the CFTR gene. The classic diagnostic test for
His current primary care physician found his lung examination CF is the measurement of sweat chloride levels. This would
to be abnormal (wheezing and crackles) as well as an absence of be the recommended test for a patient suspected of being
the vas deferens on genitourinary examination. affected with CF.

Diagnostic Findings, Part 1 1

Department of Pathology, Albert Einstein College of Medicine, Bronx,
NY, USA
What is Your Differential Diagnosis Based on the
Clinical History? Corresponding Author:
Michael Prystowsky, Department of Pathology, Albert Einstein College of
The patient presents with signs and symptoms that are classical Medicine, 1300 Morris Park Ave Belfer 713, Bronx, NY 10467, USA.
for cystic fibrosis (CF). Some similar findings (short stature Email: [email protected]

Creative Commons CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License
(http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further
permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
2 Academic Pathology

Figure 1. Autopsy findings. A, Normal lung. B, Lung affected by cystic fibrosis.

Biochemical screening tests for newborns typically measure in the CFTR gene produce wide variability in the effect that
plasma levels of immunoreactive trypsinogen (a proenzyme a given mutation will have on protein function and ulti-
that builds up in the blood due to disease-related pancreatic mately on the clinical phenotype.
duct dysfunction). These tests are advantageous for screening
neonates as they demonstrate high sensitivity, can be run on
dried blood spots, and proenzyme levels are altered regardless Explain the Normal Physiologic Function of the CFTR
of the specific etiologic genetic alteration. Protein and Which Tissues are Affected by the Loss
Genetic screening tests are useful for expectant parents to of CFTR Function
determine the “carrier status” of each parent and to assess the
The CFTR protein is an ion channel protein regulating chloride
risk that a child born to them might be affected by CF. Since
concentrations across epithelial surfaces. In a healthy individual,
many genetic tests only evaluate a subset of all possible patho-
negatively charged Cl ions are passively transported through the
genic mutations, patients must be counseled regarding the
membrane via the CFTR. Water can then passively diffuse
small residual possibility of having an affected child.3
through the membrane to areas of high solute concentration pro-
ducing typical mucus. The absence of a functional CFTR protein,
Explain the Inheritance of CF and Show How It is Possible either by a mutation that fails to transport it to the membrane or a
for an Individual to Inherit a Mutation in Each CFTR Allele mutation within a membrane-bound protein itself, leads to the
and Present With No Disease, Mild Disease, or Severe CF inability of chloride to move outward and chloride becomes
sequestered within the cell along with high concentrations of
Cystic fibrosis is the most common, lethal, inherited disease sodium. Since the movement of water passively follows solute
in white populations. Approximately 1 in 2500 newborns in concentration, secreted mucus in affected patients becomes vis-
the United States is born with the disease.1 It typically dis- cous and tenacious leading to complications of transport.2
plays autosomal recessive inheritance requiring each parent The CFTR also exists within the eccrine sweat glands of the
to provide a pathogenic allele to their child for the disease skin to balance the reabsorption of sodium and chloride (salt)
to manifest. A single genetic mutation is responsible for from initially excreted fluid. In the absence of a functional
70% of cases and consists of a 3-base pair deletion leading CFTR, the reabsorption of sodium chloride is ineffective and
to a loss of phenylalanine at codon 508 (DF508 or del508). the amount of Naþ and Cl in the excreted sweat remains high.
The DF508 mutation displays classical Mendelian inheri- The CFTR channel exists in many other tissues as well; how-
tance, whereby 2 carrier parents (each heterozygous for ever, the effects on the lungs and digestive tract become most
DF508) would have an expected risk of having an affected clinically apparent in an affected patient.1
child of 25% for each pregnancy (25% risk unaffected and
50% risk of carrier offspring). Not all parents will carry
identical mutations and a child may therefore inherit differ- Describe the Pathophysiologic Process that Occurs
ent mutations from each parent, with differing impacts on in the Lungs of Patients with Severe CF that Leads
the CFTR protein. This is one reason a spectrum of disease to Bronchiectasis and Chronic Pneumonia Including
phenotypes may be observed. Additionally, some mutations a Description of the Histopathology as the Disease
may only demonstrate a partial effect, which may only cre-
ate a CF phenotype when identified in concert with other
Progresses
specific mutations (R117 and poly[d]). This complexity and The more viscous secretions produced by failure of water to
the current identification of over 1800 described mutations thin the mucus covering the lung epithelium inhibits
Goldstein and Prystowsky 3

Figure 2. Histopathology. A, Normal Lung with patent airspaces. B, Extensive mucopurulent secretions in dilated airway. C, Alveolar lung
parenchyma with mucus and acute and chronic inflammation. D, Higher power view of C demonstrating the mixed inflammatory infiltrate
associated with cystic fibrosis.

mucociliary clearance and causes mucus plugging of the secretions is seen. The secretions give a more
airways. This in effect seals off the terminal airspaces. “glossy” appearance to the cut surface. Note also the
Inhaled bacteria cannot be cleared effectively and chronic peripheral coalescence of airspaces with mucoid con-
infections are the result. The body’s attempts to contain taining cyst-like spaces. These become continually
these infections lead to an exuberant inflammatory response, infected and fibrotic over the course of the disease,
progressive fibrosis, dilatation, and ultimately destruction of hence, the given name of the disease, “cystic
the airways. fibrosis”.
Case continued—During the next year, the patient develops
a severe pneumonia and is hospitalized. Respiratory cultures Compare and Contrast the Histopathology in Figure 2A-D
grew out Pseudomonas aeruginosa and the patient’s oxygena-
tion continued to decline. Antibiotics could not clear the Panel A demonstrates a low power view of a slide from a
patient’s infection, and he was placed on ventilator support but healthy individual. The majority of airspaces are intact and
ultimately progressed and died. lined by thin walled alveoli. The bronchioles present are patent
and are typically composed of a low columnar to cuboidal
epithelium. Panel B demonstrates a similar power view from
Diagnostic Findings, Part 2 an individual affected by cystic fibrosis with abundant muco-
purulent material within an expanded airway. Panels C and D
Compare and Contrast the Gross Pathology in Figure 1A show higher power views of the mixed inflammatory infiltrate
and B which is seen within the individual alveoli in patients affected
with cystic fibrosis.
A. Normal Lung: Note the spongy appearance of the cut
surface and gradual tapering of airways toward the
periphery of the tissue. The surface has a “dry” Questions/Discussion Points, Part 2
appearance as it is actually made up of numerous
tiny alveoli.
What Therapies May Minimize the Symptoms of CF?
B. Lung affected by CF: Bronchiectasis (airway space There are a variety of biomechanical techniques that are aimed
enlargement with associated wall thickening) with at clearing the thickened mucus from the airways and often
bronchi filled with excessive mucopurulent involve some forms of percussion or vibration. Several
4 Academic Pathology

categories of medications are also available to aid in fighting there is a possibility that in the future, site-directed gene
infections, thinning mucus, and in some cases (given specific editing may hold promise for a broader therapy unique to the
causative mutations) potentiating the CFTR channel to allow patient’s own disease and impacting and improving all
for increased chloride transport. affected organ systems.

What are Some Possible Therapies that have a More

Definitive Impact on the Disease? Teaching Points
The severe damage caused by the course of the disease leaves  Cystic fibrosis is the most common inherited autosomal
few medical options for improved pulmonary function; how- recessive disease in the Caucasian population.
ever, for some patients, lung transplantation can provide a  The disease affects multiple organ systems and can have
much more definitive impact on lung function as well as the a wide variety of clinical presentations.
overall survival. Most importantly, however, lung transplanta-  Genetic mutations of the CFTR gene lead to an ineffec-
tion is not a “cure” as it only alleviates the pulmonary symp- tive chloride transporter that explains many of the clin-
toms of the patient. The other organs affected by the disease are ical symptoms.
not modulated by a transplant.  There is hope that modern technological advancements
Recent investigations involving large-scale mathematical and could lead to not only symptomatic control but also
chemical libraries have identified several possible drug molecules possibly even cures for the disease in the future.
that target precise causes of the disease created by individual
mutations. Given the diverse impacts the various CF mutations
can have on protein production, processing, and regulation, it is References
not surprising that different drugs are necessary to provide differ- 1. Ratjen F, Döring G. Cystic fibrosis. Lancet. 2003;361(9358):681-689.
ing corrective effects. Some drugs work by increasing shuttling of 2. Stoltz DA, Meyerholz DK, Welsh MJ. Origins of cystic fibrosis
the CFTR to the membrane, while others act to improve chloride lung disease. N Engl J Med. 2015;372(4):351-362.
transport through the CFTR and even others attempt to overcome 3. American College of Obstetricians and Gynecologists Committee
nonsense mutations by allowing the ribosome to “read through” on Genetics. ACOG Committee Opinion No. 486: update on carrier
premature stop codons during translation.4 screening for cystic fibrosis. Obstet Gynecol. 2011;117(4):
Given that the disease is inherited in a patient’s DNA and 1028-1031.
many of the causative genetic mutations have been elucidated, 4. Cystic Fibrosis. https://en.wikipedia.org/wiki/Cystic_fibrosis.