Congenital BA is the blockage of the intrahepatic and extrahepatic bile conduits, which can prompt cholestatic cirrhosis, and ultimately liver failure. It is one of the indications for liver transplantation in children and one of the most common digestive diseases in neonatal surgery. Patients with BA with hindered bile stream have determined jaundice, earth-like stool, hepatomegaly, and/or splenomegaly. If timely and reasonable intervention is not given in the early stage of the disease, most children may die at 2 years of age, with the cause of death mostly chronic liver disease (severe liver fibrosis, biliary cirrhosis, liver failure, etc.) (60). Hartley et al. (61) reported that the relative length of short telomeres in the peripheral blood of children was associated with the incidence of BA (adjusted for age and sex using logistic regression analysis). Their data also showed that the TL of patients with BA negatively correlated with the degree of liver cirrhosis. TL can also be used as one of the important indicators to evaluate the progress of BA in children (such as liver fibrosis) and is an important reference value for the timing of liver transplantation (5–7).

BPD is a chronic lung infection that causes constant respiratory misery. It is one of the most well-known serious diseases that influence preterm infants, particularly extremely preterm infants (Babies born before 28 weeks of pregnancy). In the long run, prolonged mechanical ventilation or oxygen inhalation may lead to stagnation of lung development, decline of vital capacity, emphysema, pulmonary hypertension, and even neurological and cognitive dysfunction. Nordlund et al. (62) suggested that BPD may damage the lung diffusion capacity of an infant. Airway hyperresponsiveness is more serious in premature infants than in full-term children with asthma at the same age. In a large-scale survey of young people with early pregnancy, Hadchouel et al. (8) showed that a shorter salivary TL was related with hindered lung capability. Previous studies also suggested that TL remained to be associated with forced expiratory flow at 25%–75% of the vital capacity in preterm adolescents, after adjusting for potential confounders by multiple linear regression. Henckel et al. (9) suggested that in children with early BPD, chitinase-3-like protein 1 and relative TL can be used as biomarkers for long-term lung development outcomes.

Neonatal HIE is a severe disease caused by hypoxia in perinatal babies. Its normal cause is the fetal pain in the womb caused by different sources, such as the umbilical cord on the neck and abnormal amniotic fluid. It is very common in children who have experienced serious and life-threatening diseases (hypoxia, neonatal asphyxia) during or after childbirth, and occasionally other diseases that endanger the brain. This ordinarily happens in full-term babies, yet it can likewise happen in untimely newborn children. It has been reported that its incidence rate in live births was 1.5 ‰ (63). A total of 25% of neonates with HIE have severe neurological complications sooner or later (64).Telomerase reverse transcriptase (TERT) encodes rate-limiting catalytic subunits and key regulators of telomerase activity(65). Some studies reported that TERT is a protective molecule against hypoxic-ischemic brain damage. This theory has been verified in HIE models of neonatal rats (10, 11). Li et al. (66) believed that TERT can promote cell proliferation, increase the migration and separation of sensory cells, and then reduce the apoptosis of neurons after hypoxia-ischemia. This theory has been fully confirmed in in vitro experiments. Moreover, the overexpression of TERT can activate myelination in the brain of newborn rodents. In addition, TERT overexpression reduced learning disabilities, memory ability, and neural function after hypoxic-ischemic brain injury. They also conducted in-depth research on the neuroprotective mechanism of TERT and found that the sonic hedgehog/glioma-associated oncogene 1 signaling pathway may play an important and positive role.

The incidence rate of childhood obesity is rising rapidly, as well as its related comorbidities, including obstructive sleep apnea syndrome, psychological problems, cardiovascular diseases, type 2 diabetes, and cancer. They seriously threaten the short- and long-term health of children. The telomerase plays a crucial role in human embryonic development. Telomerase action can result in a uniform TL in cells of different tissues, as well as differentiated cells (67–69). The shortening rates of telomeres are high during the first three years of life (approximately 250 bp/year) and reach a stable phase at 4 years of age. The loss rate of telomeres is stable or may decrease (approximately 50 bp/year) from the age of 4 years to youth and old age (approximately 50 bp/year) (70–74). In children with obesity, the wear rate of telomeres is increased (12, 13, 15). Different scholars hold different views on whether obesity is related to TL. Some research showed that there was a clear correlation between childhood obesity and shorter telomeres (14, 75, 76). In contrast, others reported that there was no clear correlation between obesity and TL (16, 17). Liu et al. (18) reported that in preschool children with obesity, leukocyte TL shortening negatively correlated with the body mass index. They also reported that the TL of peripheral blood lymphocytes negatively correlated with arachidonic acid (AA)/ docosahexaenoic acid (DHA) ratio but positively correlated with saturated fatty acid and DHA levels, respectively. In any case, no affiliation was found between erythrocyte DHA levels and the methylation of the TERT promoter. One study likewise focused on the effect of the sex distinctions of children with obesity on TL. Other relevant studies also indicated that only the shortening of TL in males was found to be associated with the incidence of obesity; however, this association was not obvious in females (14).

Diabetes in children is an endocrine and metabolic illness caused by the lack of insulin emission. This mainly results in carbohydrate, protein, and fat metabolism disorders, giving rise to fasting, postprandial hyperglycemia, and urine sugar. Type 1 diabetes (T1D) is common in young people and often occurs during childhood. Its main disease feature is the absolute lack of insulin, and it is a chronic immune system disease (77, 78). Previous studies showed that the TL of children with T1D was significantly shorter than that of healthy children. In-depth follow-up studies reported that shorter telomeres were associated with all-cause mortality (19, 20). Tesovnik et al. (21) reported that the average TL of young people with T1D was adversely connected with the body mass index standard deviation score, and that serum vitamin D levels were not associated with TL in these individuals. In another study by Tesovnik et al. (22), they reported that a shorter telomere indicates an earlier and longer onset and duration of T1D; however, TL negatively correlated with glycated hemoglobin A1c. In the study of Törn et al. (79), after a comprehensive sequencing test of the gene level of thousands of children with T1D, results showed that the age of onset negatively correlated with TL, and that children with HLA-DR4/4 or HLA-DR4/X phenotypes had longer telomeres compared with children with HLA-DR3/3 or HLA-DR/9 genes.

Trisomy 21 syndrome, also known as Down syndrome (DS), is caused by chromosomal abnormalities (an additional chromosome 21). Moreover, 60% of Trisomy 21 pregnancies were miscarried in the early fetal period. Children with DS have clear mental retardation, exceptional faces, developmental obstacles, and multiple malformations. A comparative study of three different Indian trisomy 21 data sets by Bhattacharya et al. (23) indicated that the TL of children with trisomy 21 syndrome decreased by 58 bps/year. In contrast, the TL of normal children decreased by 38 bps/year. The telomere attenuation rate of children with trisomy 21 was evidently higher. However, Nakamura et al. (80) tested the peripheral lymphocytes (diploid, 10; trisomy 18, 10; trisomy 21, 11) of 31 live newborns. They observed that there was no measurable difference in TL among trisomy 18, trisomy 21, and diploid infants. In contrast, some studies showed that normal children have longer TL than children with trisomy 21 (81, 82). Thus, the above views on the divergence between TL and trisomy 21 must be further studied.

Dyskeratosis congenita (DC), a multisystem inherited condition, is characterized by skin symptoms and can lead to bone marrow regeneration disorder or tumor. The inheritance of DC can be X-linked latent, autosomal predominant, or autosomal passive. Practically, patients with X-linked latent DC were male. Hoyeraal–Hreidarsson disease, Revesz syndrome, or Coats plus disease is usually the first symptom of DC (83–86). Some sporadic, non-classical cases are usually related to DC-related reproductive biological gene mutations, which mainly manifested as aplastic anemia, familial myelodysplastic syndromes/acute myeloid leukemia (AML) carriers, etc (87–90).. Mutations in the genes encoding TERT, telomerase RNA component (TERC), and dyskerin pseudo uridine synthase 1 (DKC1) genes are all related to the pathogenesis of DC (91–93). Mitchell et al. (24) reported that the level of TERC RNA in the DKC1-mutant cells of patients with DC was reduced. In the past years, there has been increasing evidence that gene mutations that maintain telomere gene length may increase the incidence of DC by 70%. At present, 13 known genes have this effect (25–28). They include the genes encoding telomerase-associated components [TERC, TERT, DKC1, nucleolar protein 10, H/ACA ribonucleoprotein complex subunit 2, telomerase Cajal body protein 1, nuclear assembly factor 1, and poly(A)-specific ribonuclease], shelterin proteins (TERF1-interacting nuclear factor 2, tripeptidyl-peptidase 1), and other regulators of TL and replication (regulator of telomere elongation helicase 1, CTC1, STN1).

DMD is an X-chromosome recessive disease, which mainly occurs in males. Approximately one in each 3,500 newborn infants have this disease. Patients usually experience progressive degeneration of skeletal muscles, which gradually leads to muscle atrophy and eventually loss of motor function. These manifestations generally occur during the early-school age. It is mainly characterized by the gradual replacement of necrotic skeletal muscle cells by fibrocytes and adipocytes. Gradually, patients lose their exercise ability before and after school age, leading to death during adulthood when respiratory muscles are involved in serious cases. This disease is caused by the lack of proteins connecting the cytoskeleton and extracellular matrix, resulting in serious destruction of the integrity of the skeletal muscle cell membrane. The main genetic factors of this disease have been studied; however, its main pathogenesis must be further investigated (94). Sacco et al. (29) reported that the TL of dystrophin-deficient (mdx) mouse muscle cells lacking telomerase RNA components was shortened, leading to extremely severe malnutrition, which gradually worsened with age. The severity of muscle atrophy parallels the decline of the regeneration ability of muscle stem cells. Vita et al. (30) showed that in an mdx mouse model, the TL of the diaphragm was significantly shortened, and exercise factors could accelerate the telomere wear rate. Chang et al. (31) showed that telomere shortening is progressive, contraction-dependent, and mechanically sensitive in cardiomyocytes of DMD mice.

NB is the most common extracranial tumor in children and may originate from early nerve cells of the sympathetic nerve system. Currently, only a few human tumors are known to spontaneously degenerate from undifferentiated malignant tumors to completely benign tumors, including NB. Lindner et al. (32) reported that the increased expression of TERT was detected in most NBs. Telomerase activation occurs in parallel with telomere shortening in NB (33, 96). Ackermann et al. (97) reported that repeated genome rearrangement in the proximal 5 p15.33 chromosome region may be the reason for the overexpression of TERT in NB cells. In the biological behavior of NBs, telomerase activation and the maintenance of TL are very important and necessary links that provide relatively accurate molecular mechanisms that determine the clinical phenotype of the tumor (33).

Leukemia is a malignant proliferative disease of the human hematopoietic system, which seriously threaten children's lives. Among the types of childhood leukemia, acute lymphoblastic leukemia (ALL) and AML are the two most common, accounting for approximately 3% of childhood malignant tumors (98, 99). A study by Engelhardt et al. (34) used data from the telomerase activity of peripheral blood monocytes. Compared with healthy children, the telomerase activity of children with ALL was 10–20 times higher. Similarly, Hu et al. (35) reported that the methylation of the cyclin dependent kinase inhibitor 2B gene was closely related to the telomerase activity in childhood cancer, and that telomerase activation is one of the important monitoring indicators for childhood cancer. It is interesting to note that, unlike previous perceptions, the mutation of the gene with reduced TERT activity is an important risk factor for the disease in children with AML (36). The telomerase activity of bone marrow cells positively correlated with prognosis in adult patients with AML, but negatively correlated with prognosis in children with AML (37).

Intracranial tumors are the most common tumors during childhood, which makes it a serious threat to the life and health of children. Its overall incidence in the population ranks second (only next to the incidence of leukemia). People of all ages may have this disease; however, its peak of occurrence is during 5–8 years of age. In recent years, some studies have shown the close relationship between the maintenance mechanism of TL and occurrence of intracranial tumors in children (100–102). In pediatric glioma, the level of differentiation is related to telomerase activity. Some studies suggested that according to the standards of the World Health organization, telomerase activity was significantly reduced in low-grade gliomas in children (38, 39). In contrast, telomerase activity is significantly enhanced in most children with high-grade glioma (40, 41). Telomerase activity was increased in primary medulloblastoma but did not change in secondary medulloblastoma (101, 103).