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\begin{document}

\title{A Chinese Pediatric cystic fibrosis patient with the
c.1624G\textgreater{}T, p. Gly542x / c.223C\textgreater{}T, p. Arg75x
genotype}



\author[1]{Rui Zhang}%
\author[2]{Yao Sun}%
\affil[1]{Chengdu Women and Children's Central Hospital}%
\affil[2]{Children's Hospital of Nanjing Medical University}%


\vspace{-1em}



  
  \date{May 18, 2024}


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\selectlanguage{english}
\begin{abstract}
In conclusion, we present this case in order to complement CFTR gene
mutations data of Chinese children with cystic fibrosis and improve
clinicians' understanding of this disease in China. Besides, with the
development of molecular biology technology, gene detection was expected
to play an important role in the early diagnosis, early treatment, and
prognosis improvement of the disease.%
\end{abstract}%



\sloppy


A Chinese Pediatric cystic fibrosis patient with the
c.1624G\textgreater{}T, p. Gly542x / c.223C\textgreater{}T, p. Arg75x
genotype

To the Editor,

We read with great interest the article entitled ``A systematic review
of the clinical and genetic characteristics of Chinese patients with
cystic fibrosis'' by Ruihe Shi and colleagues (year 2020, volume 55,
issue 11). The authors reported that common CFTR gene mutations, such as
c.1624G\textgreater{}T, c.1652G\textgreater{}A, c.350G\textgreater{}A,
had not been reported in China \textsuperscript{{[}1{]}}.

Here, we report a case of a Chinese CF child with gene mutations of
1624G\textgreater{}T, p. Gly542x (heterozygous mutation, paternal) and
c.223C\textgreater{}T, p. Arg75x (heterozygous mutation, maternal)
(Figure 1). This 5-year-old female patient presented with chronic cough,
expectoration, wheezing, and growth retardation since the age of 3. Due
to recurrent pulmonary infection and repeated dyspnea, she was
hospitalized approximately 2 times every year. During her first
admission to our hospital when she was 33-month-old, sputum culture was
positive for Pseudomonas aeruginosa. On the 9\textsuperscript{th} day of
hospitalization, she suffered from abdominal distension and weakened
bowel sounds, and failure to pass flatus or bowel movements for 3 days
without obvious peritonitis. Abdominal CT showed that the colon was
narrow, part of the colon wall was thickened; liver density was
generally decreased. The surgery was performed given the diagnosis of
Hirschsprung's disease. Human whole exome sequencing was conducted by
Beijing Quanpu Medical Laboratory on the 23\textsuperscript{rd} day of
admission. On 13\textsuperscript{th} April 2022, during her third
admission to our hospital when she was 46-month-old due to aggravated
cough and wheezing, along with the gene mutations of
1624G\textgreater{}T, p. Gly542x and c.223C\textgreater{}T, p. Arg75x,
the diagnosis of cystic fibrosis was made. Sputum and bronchoalveolar
lavage fluid cultures were consistently positive for Pseudomonas
aeruginosa, aztreonam was administered for anti-infection. Serum vitamin
examination did not show lipo-soluble vitamins deficiency at that time.
Since inhaled tobramycin was not available in our country, her discharge
medications were oral cefixime, azithromycin, and inhaled hypertonic
saline.

During the most recent admission, she presented with malnutrition
(weight \textless{}25th centile) and chronic diarrhea. Serum vitamin
examination showed lipo-soluble vitamins deficiency, consequently, she
needed supplementation of lipo-soluble vitamins and pancreatic enzyme
replacement therapy. Increased secretions were seen under bronchoscopy.
Sputum culture was positive for both Staphylococcus aureus and
Pseudomonas aeruginosa, while bronchoalveolar lavage fluid culture was
only positive for Staphylococcus aureus. Linezolid plus
piperacillin-tazobactam were prescribed according to drug sensitivity
results for anti-bacterial treatment this time.

Mutations in CFTR, the gene encoding the epithelial ion channel that
normally transports chloride and bicarbonate, lead to impaired mucus
hydration and clearance \textsuperscript{{[}2{]}}. Despite the high
morbidity in Caucasian, it is still a rare disease in China. At present,
about 200 CF patients have been reported in China, however, no
population-based prevalence was calculated \textsuperscript{{[}3{]}}.
Recent study revealed that the prevalence of Chinese CF ranged from
1/153,825 to 1/110,127 \textsuperscript{{[}4{]}}. The most common CFTR
gene mutations in Chinese CF patients, which presented with c.2909G-A,
are different from those in Caucasian patients\textsuperscript{{[}1{]}}.
However, the child in our report carried a common gene mutation among
Caucasian patients but rare among Chinese patients. By searching the
CFTR2 database (http://www.cftr2.org), we found that there were only 4
patients with this variant combination in the CFTR2 database and this
variant combination may able to cause pancreatic insufficiency. She
experienced colostomy due to neonatal megacolon, and surgery for
meconium ileus. Although her clinical manifestations were typical for
CF, without sufficient understanding of this disease and newborn
screening, the age at CF diagnosis is relatively older. Sweat detection
is an important and accurate method for detecting CF,in which the
chloride ion concentration is usually higher than 60 mmol/L, however, we
did not find an institution that could perform this test during her
first admission in our hospital.

The population-specific genetic spectrum of CF is still unknown, and CF
prevalence would be significantly underestimated in Chinese if using the
Caucasian-specific screening panel. Thus, recent study recommended the
53 pathogenic/likely-pathogenic variants as CF screening panel for
Chinese population, especially the six variants with high allele
frequencies: G970D (c.2909G\textgreater{}A), D979A
(c.2936A\textgreater{}C), M469V (c.1405A\textgreater{}G), G622D
(c.1865G\textgreater{}A), L88X (c.263T\textgreater{}G), and
1898+5G-\textgreater{}T (c.1766+5G\textgreater{}T), which could also be
used in clinical diagnosis process \textsuperscript{{[}4{]}}. Besides,
in a most recent systematic review of gene mutations of Chinese CF
patients, c.1624G\textgreater{}T was not reported as
well\textsuperscript{{[}5{]}}. To our knowledge, this is the first
report of c.1624G\textgreater{}T mutation among Chinese patients with CF
and this gene mutation would be a complementary for Chinese-specific
screening panel.

In conclusion, we present this case in order to complement CFTR gene
mutations data of Chinese children with cystic fibrosis and improve
clinicians' understanding of this disease in China. Besides, with the
development of molecular biology technology, gene detection was expected
to play an important role in the early diagnosis, early treatment, and
prognosis improvement of the disease.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Figure 1 results of genetic testing of this patient (A: Standard DNA
sequence; B: index case c.223C\textgreater{}T, p. Arg75x, heterozygous
mutation, maternal; C: Standard DNA sequence; D: 1624G\textgreater{}T,
p. Gly542x, heterozygous mutation, paternal)

Reference:

{[}1{]} Shi R, Wang X, Lu X, et al. A systematic review of the clinical
and genetic characteristics of Chinese patients with cystic fibrosis.
Pediatr Pulmonol. 2020;55(11):3005-3011. doi:10.1002/ppul.24980

{[}2{]} Shteinberg M, Haq IJ, Polineni D, Davies JC. Cystic fibrosis.
Lancet. 2021;397(10290):2195-2211. doi:10.1016/S0140-6736(20)32542-3

{[}3{]} Chinese Experts Cystic Fibrosis Consensus Committee; Chinese
Alliance for Rare Lung Diseases; Chinese Alliance for Rare Diseases,
Bronchiectasis-China. Chinese experts consensus statement: diagnosis and
treatment of cystic fibrosis (2023). Chin J Tuberc Respir Dis, 2023,
46(4): 352-372. DOI: 10.3760/cma.j.cn112147-20221214-00971.

{[}4{]} Ni Q, Chen X, Zhang P, et al. Systematic estimation of cystic
fibrosis prevalence in Chinese and genetic spectrum comparison to
Caucasians. Orphanet J Rare Dis. 2022;17(1):129. Published 2022 Mar 21.
doi:10.1186/s13023-022-02279-9

{[}5{]} Na Zhang. Analysis of 8 cases of cystic fibrosis and literature
review{[}D{]}. ShiJiaZhuang: Hebei Medical University,2022.

Rui Zhang\textsuperscript{1}, Yao Sun\textsuperscript{2*}

\textsuperscript{1}Department of Pharmacy, Chengdu Women's and
Children's Central Hospital, School of Medicine, University of
Electronic Science and Technology of China, Chengdu, 611731, China.

\textsuperscript{2}Department of Pharmacy, Children's Hospital of
Nanjing Medical University, Nanjing, 210008, China.

*Corresponding author:

Yao Sun, M.D, Department of Pharmacy, Children's Hospital of Nanjing
Medical University, 72 Guangzhou Road, Nanjing 210008, China.

E-mail: sarah\_0515@163.com

\textbf{Funding:}

This study didn't receive any funding.

\textbf{Conflict of interests:}

The authors declare that they have no conflict of interests.\selectlanguage{english}
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