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Case Report ›››

Duodenal Atresia and Neonatal Cholestasis in R117H Cystic

Fibrosis
Jamie Harris, Shauna Sheppard, Bill Chiu, Ami Shah
 Department of Surgery (Pediatric Surgery), Rush University Medical Center, Chicago, IL, USA

ABSTRACT
Cystic fibrosis  (CF) has 20% associated rate of neonatal cholestasis. This presents in classic type  CF, which initially can be confused with
biliary atresia. Additionally, CF has been described with intestinal atresias but not duodenal atresia (DA). This is a case presentation highlighting
a previously unreported presentation of R117H 5T CF mutation: A mutation that has recently been described and is not well‑characterized. A
retrospective review of single case was done. The newborn screen was sent per protocol. A 32 and 6/7 week gestation male was born with DA.
Perinatal testing showed R117H mutation and 5T variant on separate chromosomes. His DA was repaired at 4 weeks of life. He had persistent
jaundice, hepatobiliary iminodiacetic acid scan failed to identify the gallbladder, and raising concern for biliary atresia. At laparotomy, biliary tree
was found to be normal on cholangiogram. Liver biopsy showed depleted interlobular bile ducts, with cholangiolar proliferation, consistent with
CF induced cholestasis. This is an abnormal presentation for CF induced neonatal cholestasis and DA in the R117H 5T mutation that traditionally
has been described as mild/atypical presentation of CF. Therefore, patients with this mutation who present with persistently elevated bilirubin
should be evaluated for liver disease associated with CF.

Key words:
Cholestasis, cystic fibrosis, duodenal atresia

INTRODUCTION CASE REPORT

Cystic fibrosis (CF) is an autosomal recessive disease
that results in a mutation in the CF transmembrane
regulator (CFTR).[1] Many mutations have been identified.
Currently the newborn screen uses immunoreactive
trypsinogen  (IRT) measurements, then CF screening if
the IRT is elevated. Classic CF manifests with pulmonary
symptoms, meconium ileus, recurrent pancreatitis or
pancreatic insufficiency, and focal biliary cirrhosis due to
obstruction of intrahepatic bile ducts.[1] This is a case report
of a previously unreported constellation of symptoms,
duodenal atresia  (DA), and neonatal cholestasis in the
R117H mutation of CF.
Address for correspondence:
Dr. Jamie Harris,
Department of Surgery (Pediatric Surgery),
Rush University Medical Center, 1725 W.
Harrison St. Suite 710, Chicago, IL 60612, USA.
E‑mail: jamie_c_harris@rush.edu
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A male was born at 32 and 6/7 weeks via cesarean section
for premature labor and breach presentation. Prenatally,
DA was diagnosed on ultrasound and confirmed
on abdominal X‑ray at birth  [Figure  1]. Due to his
prematurity, repair of his DA was postponed until he
weighed 2.5  kg, at 4  weeks. He was on total parenteral
nutrition for 38 days and progressed to full enteric feeding
by 5  weeks of life. His newborn screen showed elevated
IRT of 76.1. Subsequent testing demonstrated an R117H
mutation and 5T variant on separate chromosomes, a
mutation associated with CF. He had persistent jaundice,
total bilirubin of 9.2  mg/dL, and direct bilirubin of
6  mg/dL at the time of discharge. As an outpatient, he
underwent a hepatobiliary iminodiacetic acid scan that
demonstrated narrowing of the biliary ducts and did not
visualize a gallbladder [Figure 2].
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DOI: How to cite this article: Harris J, Sheppard S, Chiu B, Shah A.

10.4103/2249-4847.179911 Duodenal atresia and neonatal cholestasis in R117H cystic fibrosis.
J Clin Neonatol 2016;5:112-4.

112 © 2015 Journal of Clinical Neonatology | Published by Wolters Kluwer - Medknow

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Harris, et al.: Duodenal atresia and cholestasis in R117H CF

He was readmitted, and his total bilirubin was 12.4  mg/dL,

elevated aspartate aminotransferase of 134 U/L, and alkaline
phosphate of 994 U/L. An abdominal ultrasound had
nonvisualization of the gallbladder and a common bile duct
at the upper limit of normal, without intrahepatic bile duct
dilation. Other causes for liver dysfunction including TORCH
infections, alpha‑1 antitrypsin deficiency, hepatitis, history of
urinary tract infection, or hypothyroidism were excluded.

Due to concern for biliary atresia, he underwent surgical

exploration. The liver was soft, pink, and healthy
appearing and the gallbladder was normal. Intraoperative
cholangiogram demonstrated normal biliary architecture
and passage of contrast into the duodenum  [Figure  3].
A  wedge liver biopsy demonstrated depleted interlobular Figure 1: Neonatal abdominal radiograph: Demonstrates nasogastric
bile ducts, prominent cholangiolar proliferation and tube in place as well as typical “double bubble” sign indicative of
severe cholestasis, with stage 2‑periportal fibrosis, without duodenal atresia
uniform bridging of cirrhotic nodularity. The diagnosis
of neonatal cholestasis secondary to his known CF was
made. Since surgery, his bilirubin has returned to normal,
and he does not require any additional medication for
hyperbilirubinemia.

DISCUSSION
The presentation of CF can be highly variable depending on
the mutation. Classic CF includes pulmonary complications
as well as possible gastrointestinal complications, including
hepatobiliary disease and meconium ileus.[1]

As in our case, CF can present with hepatobiliary

complications. Liver disease in association with CF has been Figure 2: Hepatobiliary iminodiacetic acid scan: No uptake within the
quoted as high as 30%, and in a recent retrospective review gallbladder after 5 h, suggesting possible biliary atresia
at 5.7% in infants.[2,3] Leeuwen et al. found that cholestasis
occurred more frequently in patients with meconium
ileus as compared to those without.[2] Additionally, in that
study, they found that all cases of cholestasis resolved, on
average by 9.2 months of age.[2] This, however, is not always
the outcome of patients with cholestasis secondary to CF.
Patients who fail to resolve their liver involvement can
progress to hepatic steatosis, fibrosis, or biliary cirrhosis.[4]
Molmenti et  al. found at their pediatric transplant center,
liver failure due to CF accounted for 3.5% of all pediatric
liver transplantation over a 16‑year period.[4] While the
exact pathogenesis remains unclear, it is known that liver
disease is a result of abnormal expression of CFTR in
the apical surface of the biliary epithelium. Defects in
this channel are hypothesized to affect bile fluidity and
viscosity.[5] This bile can then accumulate either intra or
Figure 3: Intraoperative cholangiogram: Done via gallbladder
extraheptically.[5,6] Clearance can be done either medical infundibulum that shows normal biliary tree (white arrow) with contrast
or mechanical  (cholagiogram) treatment as in our case. draining into the duodenum, excluding the diagnosis of biliary atresia
However, if disease progresses to stenosis and fibrosis of
the hepatic and common bile duct, surgical correction CF, c. 3871 G > T, presenting with cholestasis that initially
can become necessary.[6] Recently, a novel mutation of clinically resembled biliary atresia was described.[7] Our

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Harris, et al.: Duodenal atresia and cholestasis in R117H CF
patient’s mutation is R117H 5T; there have not been any
reports of neonatal cholestasis associated with this mutation
to our knowledge.
Another congenital anomaly that our patient had was
DA. DA is the result of a failure of recanalization of the
duodenum early during pregnancy, with an incidence of
1/10,000.[8] Almost half of children affected by this will also
present with another congenital abnormality, including
trisomy 21, cardiac abnormalities, annular pancreas, or
malrotation.[8] DA, however, has been described only once
in conjunction with CF. Akinloye et al. reported an infant
with trisomy 21 and DA, repaired on day of life two, with
continued failure to pass meconium after repair.[9] He had
a meconium ileus and genetic testing for CF was positive.
While atresias have been noted in CF, they are generally of
the distal small bowel or colon, and only once it has been
reported with DA, as in this case.[1]
Over 1500 mutations have been identified to cause CF.[1] Of
these mutations, only a small number are thought to cause
clinical significance. Our patient was identified as having
CF gene mutation, R117H, 5T Het, trans. The 5T variant
was found on two separate chromosomes. In previous
literature, there have been three variants within the R177H
group, 5T, 7T, and 9T, with 5T being the only group that has
shown to present with symptoms of classic CF.[10] The 5T
mutation causes aberrant splicing and reduces the number
of functional CFTR mRNA.[10] One common presentation
for this mutation is congenital bilateral absence of the vas
deferens, which leads to infertility in males.[10] There is no
literature to our knowledge describing this mutation in
association with neonatal liver disease or DA.
CONCLUSION
This case demonstrates an abnormal presentation for CF,
neonatal cholestasis as well as DA in the R117H 5T mutation
114
that traditionally has been described as mild/atypical
presentation of CF. Therefore, patients with this mutation
who present with persistently elevated bilirubin should be
evaluated for liver disease associated with CF.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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