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\begin{document}

\title{Case Report of a Chinese Cystic Fibrosis Boy with the
c.1521\_1523delCTT/c.3874-4522A\textgreater{}G Genotypes}



\author[1]{Yanyan Su}%
\author[2]{xiaolei tang}%
\author[2]{Yuelin Shen}%
\author[1]{Yu Tang}%
\affil[1]{Children's Hospital Affiliated to Zhengzhou University Henan children's hospital Zhengzhou children's Hospital}%
\affil[2]{Beijing Children's Hospital Capital Medical University}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\selectlanguage{english}
\begin{abstract}
This report entails a case of an 11-year-old Chinese boy with cystic
fibrosis (CF), who bears the
c.1521\_1523delCTT/c.3874-4522A\textgreater{}G genotype, which is
extremely rare in Chinese population. Notably, the deep intron mutation
c.3874-4522A\textgreater{}G was the first time identified among Chinese
patients, which was reported mainly associated with mild phenotype. It
is generally considered that a mild allele sustains \emph{CFTR} function
in a dominant fashion, even if paired with a severe allele. However, in
the present report, the c.3874-4522A\textgreater{}G mutation was found
related to severe pulmonary diseases, including early symptom onset,
progressive bronchiectasis, recurrent airway \emph{P. aeruginosa}
combined with MRSA, rapid decline of lung function, and poor weight
gain, which suggesting severe phenotype. Despite intensive chest care
and optimized therapy, the child ultimately died of cardiopulmonary
failure 3 months after discharge.%
\end{abstract}%



\sloppy


\textbf{INTRODUCTION}

Cystic fibrosis (CF) is a serious and life-shortening autosomal
recessive disorder, affecting approximately 100,000 persons worldwide,
and characterized by defective chloride transport channel in epithelial
cells of exocrine tissues\textsuperscript{{[}1{]}}. The progression of
the disease may result in multi-system dysfunction, including
sinopulmonary disease, meconium ileus, pancreatic insufficiency and
sweat electrolyte abnormalities. To date, approximately 2000 mutations
in the \emph{CFTR} gene have been reported
worldwide\textsuperscript{{[}2{]}}. The epidemiology of CF is well
studied in Caucasians from developed countries, however, the data on the
incidence of CF in China mainly come from studies with small sample size
or case reports over the past 4 decades. Up to now, only approximately
110 CF patients of Chinese origin were reported in
literature\textsuperscript{{[}3{]}}. In this report, we present a
pediatric case with severe CF phenotype and
c.1521\_1523delCTT/c.3874-4522A\textgreater{}G genotype, which is
extremely rare in Chinese population.

\textbf{CASE REPORT}

An 11-year-old Chinese boy presented with chronic coughing,
expectoration, recurrent wheezing, and failure to thrive since his 2
months of age (Figure 1). He was frequently hospitalized due to
recurrent pneumonia and repeated respiratory distress approximately 6-10
times per year. In between all the admissions, the patient still
developed cough, wheeze, and occasional dyspnea. The first time he
presented to Henan children's hospital was at his 7 years of age. Chest
CT scan and bronchoscope both showed bronchiectasis with mucus plugging.
Sputum/BALF culture was consistently positive with \emph{P. aeruginosa}
. Lung function rapid declined (FEV1 29.0\%, FVC 33.0\%). Due to a
strong suspicion of CF, the first genetic test was performed.
Unfortunately, only c.1521\_1523delCTT variant on maternal allele was
detected, without any variant observed on paternal allele. At 9 years of
life, this patient got exercise intolerance and was unable to wean off
oxygen until now. Another airway organism MRSA was isolated, which was
only sensitive to vancomycin.

At this time of admission, the boy presented in worse general condition.
Physical examination revealed a poor nutritional status (peripheral
oedema, weight \textless{} 3rd centile), hypoxemia with desaturation
down to 80\% on room air, tachypnoea with nasal flaring (respiratory
rate of 36/min), bilateral generalized rhonchi and rales,
hepatosplenomegaly, and finger clubbing. Repeated CT scan showed the
deterioration of the lung structure and progressive bronchiectasis with
extensive mucus plugging (Figure 2). Expanded genetic testing for CF
revealed the c.3874-4522A\textgreater{}G variant deeply located in
intron 23 of the paternal allele and the diagnosis of CF was eventually
confirmed.

The boy was put on CPAP 7 days for worsening bronchospasm with
CO\textsubscript{2} retention (73 mmHg), and weaned down to
NPO\textsubscript{2} 2L/min. He completed 14 days of IV antibiotic
regimen (ceftazidime combined with vancomycin), and treated with inhaled
hypertonic saline, inhaled tobramycin, and bronchoalveolar lavage (3
times) meanwhile. He got clinical improved and discharge on home oxygen
therapy after 14 days. Bilateral lung transplantation was recommended.
However, limited clinical experience and shortage of lung donors in
China made transplantation difficult. 3 months after discharge, he died
of cardiopulmonary failure.

\textbf{DISCUSSION}

The diagnosis of CF remains very difficult in China, due to inadequate
awareness of the disease by Chinese physicians for decades, the
inaccessibility of sweat chloride testing facility, as well as atypical
clinical manifestations and different genetic spectrum compared to
Caucasians\textsuperscript{{[}4{]}}. It is well identified that the
genotypic spectrum of CF varies widely among different populations based
on their geographic and ethnic origins. The most common mutation in the
Caucasians is c.1521\_1523delCTT(p.F508del), with approximately 70\% of
patients being heterozygous for this mutation\textsuperscript{{[}5{]}}.
However, it is quite rarely seen in Asia, especially East Asia. The
c.1521\_1523delCTT (p.F508del) was only observed in 2 patients of
Chinese origin currently (1 child in homozygosity and 1 adult in
compound heterozygosity)\textsuperscript{{[}6, 7{]}}. No cases have ever
been reported in other East Asian countries so far. The parents of the
child are both from Kaifeng City, Henan Province, which located in the
central region of China. Historically, the Henan Province was ruled by
the Mongol armies for 130 years. The Mongol armies were predominantly
Mongolian, but they also included a small number of Caucasian. Based on
this, we speculate that the origin of the c.1521\_1523delCTT (p.F508del)
variant in China most likely came from the Mongol armies, which may be
due to the intermarriage between Chinese and Caucasians during the
colonial period.

The first time the boy presented to us was at his 7 years of age.
However, due to the limited sequencing methods at that time, we only
detected a c.1521\_1523delCTT variant on one allele. With the pathogenic
role of deep intron mutations in CF disease are gradually recognized, 4
years later, we found the c.3874-4522A\textgreater{}G variant on the
other allele and eventually supplemented the genetic data. The
c.3874-4522A\textgreater{}G is a deep intron mutation that has never
been reported in Chinese population. Bergougnoux et al
\textsuperscript{{[}8{]}}reported 10 cases with
c.3874-4522A\textgreater{}G and found that c.3874-4522A\textgreater{}G
is associated with divergent phenotypes, from milder phenotype including
few symptoms, delayed symptom onset and better nutritional state (most
of the cases) to typical CF with pancreatic insufficiency (only 1 case).
In this report, the c.3874-4522A\textgreater{}G was found in a Chinese
boy with severe pulmonary diseases from 2 months early infancy,
including progressive bronchiectasis, significant lung function defect,
and poor weight gain which suggesting severe phenotype. The phenotypic
variability might be contributed to the modifier genes, encoding
proteins involved in the defense against pathogens or in splicing
regulation, and possibly an age-related exhaustion of the splicing
machinery\textsuperscript{{[}8{]}}.

The estimated median survival age of CF patients, which is close to 50
years today\textsuperscript{{[}9{]}}, is expected to continue to improve
in the future, with the recent advent of CFTR modulator
therapies\textsuperscript{{[}10{]}}. The major clinical characterization
of Chinese individuals with CF was the presence of high frequency of
respiratory disease\textsuperscript{{[}4{]}}. Meanwhile, many studies
demonstrate that progression to end-stage lung disease and death is more
rapid in those with chronic \emph{P. aeruginosa} infection than in those
without\textsuperscript{{[}11{]}}. Therefore, early eradication
of\emph{P. aeruginosa} treatment can improve the outcome significantly.
We believe CF in China has been underestimated due to the lack of
clinical suspicion and the inaccessibility of sweat chloride testing
facility, which is the gold standard in diagnosing CF. In patients with
unexplained bronchiectasis, meconium ileus, and steatorrhea, CF
screening including genetic test need to be performed by Chinese
pediatricians.

\textbf{ACKNOWLEDGMENT}

The authors thank the patient's parents for their permission to share
their son's clinical history and imaging studies.

\textbf{ETHICS STATEMENT}

Written consent was obtained from the patient's parents for publishing
this case report.

\textbf{REFERENCES}

{[}1{]} Shteinberg M, Haq IJ, Polineni D, Davies JC. Cystic fibrosis.
Lancet. 2021; 397(10290): 2195-2211.

{[}2{]} Cystic Fibrosis Mutation Database.
http://www.genet.sickkids.on.ca/cftr/StatisticsPage.html. Accessed
January 8, 2022.

{[}3{]} Chen Q, Shen Y, Zheng J. A review of cystic fibrosis: Basic and
clinical aspects. Animal Model Exp Med. 2021; 4(3): 220-232.

{[}4{]} Shen Y, Liu J, Zhong L, et al. Clinical Phenotypes and Genotypic
Spectrum of Cystic Fibrosis in Chinese Children. J Pediatr. 2016;171:
269-76.e1.

{[}5{]} Burgel PR, Munck A, Durieu I, et al. Real-Life Safety and
Effectiveness of Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis.
Am J Respir Crit Care Med. 2020;201(2): 188-197.

{[}6{]} Shen Y, Tang X, Liu J, Li H, Zhao S. Pseudo-Bartter syndrome in
Chinese children with cystic fibrosis: Clinical features and genotypic
findings. Pediatr Pulmonol. 2020;55(11): 3021-3029.

{[}7{]} Tian X, Liu Y, Yang J, et al. p.G970D is the most frequent CFTR
mutation in Chinese patients with cystic fibrosis. Hum Genome Var.
2016;3: 15063.

{[}8{]} Bergougnoux A, D\selectlanguage{ngerman}élétang K, Pommier A, et al. Functional
characterization and phenotypic spectrum of three recurrent
disease-causing deep intronic variants of the CFTR gene. J Cyst Fibros.
2019;18(4): 468-475.

{[}9{]} Scotet V, L\&\#x27, Hostis C, Férec C. The Changing Epidemiology
of Cystic Fibrosis: Incidence, Survival and Impact of the CFTR Gene
Discovery. Genes (Basel). 2020;11(6).

{[}10{]} Bell SC, Mall MA, Gutierrez H, et al. The future of cystic
fibrosis care: a global perspective. Lancet Respir Med. 2020;8(1):
65-124.

{[}11{]} Parkins MD, Somayaji R, Waters VJ. Epidemiology, Biology, and
Impact of Clonal Pseudomonas aeruginosa Infections in Cystic Fibrosis.
Clin Microbiol Rev. 2018;31(4).

Figure 1. Timeline of the course of disease for an 11-year-old Chinese
boy with CF\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Figure 2. Chest CT images of a Chinese boy with CF at the first time
presented to Henan children's hospital (A) and the last hospitalization
before his death (B), showing the deterioration of the lung structure
and progressive bronchiectasis with extensive mucus plugging.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

A
B\selectlanguage{english}
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\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

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