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[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[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)[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>G variant on the
other allele and eventually supplemented the genetic data.
The c.3874-4522A>G is
a deep intron mutation that has never been reported in Chinese
population. Bergougnoux et al [8]reported 10 cases
with c.3874-4522A>G and found that
c.3874-4522A>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>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[8].
The estimated median survival age of CF patients, which is close to 50
years today[9], is expected to continue to improve
in the future, with the recent advent of CFTR modulator
therapies[10]. The major clinical characterization
of Chinese individuals with CF was the presence of high frequency of
respiratory disease[4]. Meanwhile, many studies
demonstrate that progression to end-stage lung disease and death is more
rapid in those with chronic P. aeruginosa infection than in those
without[11]. Therefore, early eradication ofP. 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.