Comparative analysis of the bone age of wrist bones in Chinese children with different causes of short stature and central precocious puberty

Introduction

Bone age (BA) represents the age of skeletal development, which is expressed as biological age in the form of age by evaluating the developmental morphology of bones at different stages (1). There are many methods for assessing BA, which can be broadly categorized into counting, mapping, and scoring methods, and the Greulich-Pyle wrist BA mapping method (abbreviated as GP mapping method) and the Chinese 05 method are widely used in China (2). Although the GP mapping method is simple, fast, and widely used, it is highly subjective and needs better stability (3). The Chinese 05 method is a score-based BA evaluation method proposed by Zhang et al. based on the TW3 method with a sample of Chinese children and adolescents, which is less subjective, more accurate, and stable than the GP atlas method, and was approved as a Chinese industry standard (TY/T3001-2006) in 2006 (4).

Previous studies have shown that the development and maturation of different types of bones (long bones, short bones, and flat bones) have different characteristics (5). The Chinese 05 method is divided into the TW3-C RUS (R) and TW3-C Carpal (C) methods, which can evaluate the R series BA (radius-ulnar-metacarpal-phalangeal) and the C series BA (carpal bones), respectively, and comprehensively assess the developmental status of children. However, the current studies based on this scoring method are mostly limited to the R series of BA, and the C series of BA needs to be addressed. Studies on the difference between the R-C BA of children with different etiologies of dwarfism and precocious puberty are very scarce (6-8). The purpose of this study was to compare and analyze the R-series and C-series BA of children with different causes of dwarfism and central precocious puberty (CPP), to explore the effects of different endocrine diseases on different types of bone maturation, and to provide a reference for the broader clinical application of the Chinese 05 method. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-669/rc).

Methods

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Nanfang Hospital, Southern Medical University (No. NFEC-2025-048), and the requirement for individual consent for this retrospective analysis was waived.

General information

A retrospective collection of 245 children who presented to our hospital between January 2019 and August 2022 and underwent BA radiographs of the left wrist was performed. The cases were divided into five groups according to diagnostic criteria and pathological findings (9-11), as follows: (I) growth hormone deficiency (GHD, 43 cases); (II) CPP (89 cases); (III) hormone-dependent or drug-resistant idiopathic nephrotic syndrome (INS, 49 cases) treated with glucocorticoid for more than 1 year; (IV) craniopharyngioma (25 cases); and (V) healthy control group (39 cases). The inclusion criteria were as follows: children aged 0–18 years in males or 0–17 years in females. Except for the INS group, all other groups had not received any endocrine or surgical treatment before the BA assessment. The INS group had been continuously receiving glucocorticoid treatment for more than 1 year to assess the impact of long-term glucocorticoid exposure on BA. The exclusion criteria were as follows: children whose BA was outside the range of the Chinese 05 method of assessment, the quality of the wrist X-ray images did not meet the diagnostic requirements, and the images contained skeletal deformities unrelated to BA.

Diagnostic criteria for the above four diseases:

• GHD: (I) height below –2 standard deviations (SD) of the normal mean; (II) annual growth rate <4 cm; (III) exclusion of other etiologies; (IV) peak growth hormone (GH) level <10 ng/mL in GH stimulation tests.
• CPP: (I) development of secondary sexual characteristics before 8 years of age in girls and 9 years of age in boys; (II) growth acceleration; (III) gonadal enlargement; (IV) peak luteinizing hormone (LH) level ≥5.0 U/L in gonadotropin-releasing hormone (GnRH) stimulation tests.
• INS: children with steroid-dependent or steroid-resistant nephrotic syndrome who have received glucocorticoid treatment for ≥1 year.
• Craniopharyngioma: confirmed by surgical pathology.

Equipment and methods

Using a GE Revolution XR/d model (GE HealthCare, Chicago, IL, USA) 800 mA digital radiography machine, left wrist BA radiographs were performed on all the participants (Figure 1): posterior-anterior radiographs were taken with the left forearm and hand straightened and posed, palm down, close to the imaging plate, with the five fingers naturally spread, the middle finger and forearm in the same straight line, and the thumb at 30° to the index finger. The centerline of projection was perpendicular to the palm, aligned with the third metacarpal bone, and the distance between the tubes was 75–90 cm; the posterior-anterior images of all the fingers, metacarpals, carpal bones, and the distal ulnar-radial apophysis of 2–3 cm were displayed, and the thumb showed an oblique image (12).

Figure 1 Bone age radiograph of the left wrist of a typical 10-year-old boy.

BA assessment method

In this study, the identifying information of all enrolled radiographs was removed, the examination numbers were retained and randomly ordered, and the radiographs were independently read in a double-masked fashion by two radiologists. The Chinese 05 method was applied to score the maturity of 13 tubular bones (distal epiphysis of the ulna-radius, metacarpal epiphyses of the 1st, 3rd, and 5th metacarpal phalanges) in the R series and seven carpal bones (7 carpal bones except the pea bone) in the C series, and then to determine the BA corresponding to the 50th percentile of the BA percentile standard based on the bone maturity scores to obtain the R and C BAs, respectively. The average of the two physicians was taken as the result and recorded as R and C. The results were compared with each group’s chronological age.

The difference between the R and C series of BA and chronological age was compared between the groups; subsequently, the difference between R and C BA and chronological age and the difference between R and C BA were calculated and recorded as R-CA, C-CA, and R-C, respectively. The difference between each case group and the control group was compared.

Statistical analysis

The software SPSS 26.0 (IBM Corp., Armonk, NY, USA) was used for data analysis. Measurements that conformed to normal distribution were expressed as mean ± standard deviation. The Kolmogorov-Smirnov test was utilized to verify the normality of age distribution across all groups. Analysis of variance (ANOVA) analyzed a comparison of R and C BA with chronological age, and two-by-two comparisons between groups were performed using the least significant difference (LSD)-t-test. To mitigate inflated type I error due to multiple testing, a significance threshold of 0.05/m was enforced for each pairwise comparison via Bonferroni correction, with m being the total number of hypothesis tests performed. Analysis of covariance (ANCOVA) was used to compare the case and control groups with sex as a fixed factor and age as a covariate to control for potential confounding. The intraclass correlation coefficient (ICC) and Bland-Altman analysis were used to analyze the agreement between the BA scores of the two physicians. An ICC >0.75 indicated good agreement. The Bland-Altman analysis further verified the consistency between the two observers by plotting the distribution of their differences. A P value <0.05 was considered statistically significant.

Results

Participant demographics

There were 93 (37.9%) males and 152 (62.1%) females out of 245 children with a mean age of 8.74±2.25 years. The age distribution across all groups conformed to a normal distribution. The demographic information of the enrolled patients is shown in Figure 2 and Table 1.

Figure 2 Distribution of 245 cases of children by age group.

Consistency analysis of BA scores of two radiologists

The concordance results of the two physicians’ scores for R BA and C BA were more significant than 0.90 (P<0.001). Bland-Altman analysis revealed that the mean difference in R BA and C BA scores between the two physicians was −0.011 years (95% limits of agreement: −0.370 to 0.348 years). All data points fell within the clinically acceptable range, and no significant systematic bias was observed. Detailed results are shown in Table 2 and Figure 3.

Figure 3 Bland-Altman plot for the agreement between radiologist A and radiologist B. C, carpal; R, radius-ulnar-metacarpal-phalangeal; SD, standard deviation.

Comparison between each case group and control group

The GHD group had an R-CA difference of −0.92±1.05 years, a C-CA difference of −2.09±1.03 years, and an R-C difference of 1.17±0.84 years. The CPP group had an R-CA difference of 1.58±0.63 years, a C-CA difference of 0.86±0.74 years, and an R-C difference of 0.71±0.38 years. The INS group had an R-CA difference of −0.53±1.28 years, a C-CA difference of −2.20±1.43 years, and an R-C difference of 1.68±1.19 years. The R-CA difference in the craniopharyngioma group was −2.04±1.13 years, the C-CA difference was −2.70±1.16 years, and the R-C difference was 0.66±0.55 years. In the control group, the R-CA difference was 0.16±0.43 years, the C-CA difference was 0.01±0.43 years, and the R-C difference was 0.14±0.38 years. The R-CA, C-CA, and R-C differences were statistically significant in all case groups compared to the control group. Detailed results are shown in Table 3.

Comparison between BA and chronological age in each group

Compared with the chronological age, the R BA results were significantly earlier in the CPP group and delayed in the craniopharyngioma group, and the differences were statistically significant. The C BA results were significantly delayed in the GHD group, the INS group, and the craniopharyngioma group, and the C BA results were earlier in the CPP group. The differences were statistically significant in all cases.

The difference in R and C BA between the CPP and INS groups was statistically significant. There was no statistically significant difference between R and C BA and chronological age in the control group. Detailed results are shown in Table 4. One case from each subgroup was selected for detailed illustration, as shown in Figure 4.

Figure 4 Left wrist radiographs for bone age assessment in each disease subgroup. (A) Male with growth hormone deficiency. Chronological age was 7 years 1 month, R bone age was 7 years 4 months, C bone age was 5 years 7 months. (B) Female with central precocious puberty. Chronological age was 7 years 11 months, R bone age was 9 years 8 months, C bone age was 8 years 7 months. (C) Male with nephrotic syndrome. Chronological age was 7 years, R bone age was 7 years and 4 months, C bone age <3 years. (D) Female with craniopharyngioma. Chronological age was 9 years 9 months, R bone age was 6 years 11 months, and C bone age was 6 years 4 months. C, carpal; R, radius-ulnar-metacarpal-phalangeal.

Discussion

BA can reflect the growth and development of children. Typically, children’s BA is the same as the chronological age; when affected by endocrine, nutritional, genetic, environmental, and other factors, BA will be advanced or delayed. By comparing the differences in the BA of radius, ulna, metacarpophalangeal, and carpal bones in the wrist of normal children in five cities in China, Zhang et al. observed that the difference between R BA and C BA was close to 0 years of age on average in the course of normal growth and development (13).

However, certain diseases have different effects on the development of different types of bones in the wrist in children (14). Children with GHD have a more severe delay in carpal BA than they do in calcaneal BA. Children with Turner syndrome primarily exhibit delayed wrist BA before puberty, whereas during puberty, delayed tubular bone growth predominates (15). This is due to the different developmental and maturation characteristics of the different types of bones (long, short, and flat bones) and their varying sensitivity to different endocrine factors (16-18). In early childhood, the emergence of primary ossification centers in the carpal bones and secondary ossification centers in the metacarpophalangeal bones and radial-ulnar bones reflects the process of cartilage osteogenesis. In late childhood and adolescence, longitudinal growth of the growth plate and epiphyseal closure reflect cartilage development and chondrogenesis. Cartilage development and osteogenesis are called enchondral ossification and are regulated by different endocrine factors (19). For instance, growth hormone is the main stimulating factor for cartilage osteogenesis, whereas it promotes cartilage development to a lesser extent; thyroid hormone has a significant promoting effect on cartilage osteogenesis; glucocorticoid has an inhibitory effect on cartilage osteogenesis; sex hormones mainly act on cartilage development and chondrogenesis, and have little impact on cartilage osteogenesis. Therefore, it is necessary to consider both R and C BA in clinical practice, which can help to diagnose and differentiate endocrine diseases.

The results of this study suggest that the R-CA, C-CA, and R-C differences were statistically significant in all four groups of cases compared to healthy controls, which shows that endocrine disorders, long-term glucocorticoid therapy, and craniopharyngiomas can adversely affect children’s growth and development. Among them, the CPP group exhibited advancement of both R and C BA (1.58±0.63, 0.88±0.74 years, P<0.001), which was attributed to the fact that CPP is a common endocrine disorder of premature activation of hypothalamic-pituitary-gonadal axis (HPGA) function, resulting in the early appearance of secondary sexual characteristics (10). Premature secretion of sex hormones leads to accelerated skeletal maturation, early BA, and even premature epiphyseal closure, thus affecting the final adult height (FAH) of the affected children. The level of BA development in children with GHD, INS, and craniopharyngiomas is delayed compared to that of the healthy population. Numerous studies have reported a higher incidence of growth disorders in children with hormone-dependent and frequently relapsing INS (20,21). Robinson et al. included 531 children with nephrotic syndrome, 30% of whom frequently relapsed within 1 year; they also found an increased risk of new-onset short stature in children with frequent relapses within 1 year of diagnosis or steroid-dependent nephrotic syndrome at a median of 4.1 years of follow-up (20). In this study, there was no significant delay in R BA in children with hormone-dependent or drug-resistant INS treated with glucocorticoids for more than 1 year. Still, the delay in C BA was significant, and the difference between the two methods was statistically significant, which was inconsistent with some Chinese and international reports. The reason for this may be that the INS disease itself does not have a substantial effect on growth hormone, but the pulse of growth hormone at night is significantly reduced in children, as well as the long-term use of glucocorticoids. Deficiency of growth hormone and the long-term use of glucocorticoids can both cause severe damage to the process of cartilage osteogenesis, while having a relatively small impact on cartilage development, thereby resulting in a significant delay in the C BA in children, whereas the R BA does not show a significant delay. The delay in both R and C BA in children with craniopharyngiomas may be related to the lack of multiple pituitary hormones, such as growth hormone, thyroid hormone, sex hormones, and other combined hormones, which have a more significant impact on the development and maturation of the skeleton, and the mechanism is complex.

In this study, we found that the results of the difference analysis between R and C BA and the chronological age could assist clinicians in distinguishing between different patient populations. The advancement of R BA was more pronounced in the CPP group, and the R-C difference was statistically significant, suggesting that sex hormones had a greater influence on the development of R BA. A previous study showed that sex hormones exert differential effects on the maturation of various types of wrist bones. In 25 children with CPP, Satoh et al. observed that the maturity of short bones was more advanced than that of long bones and carpal bones (15), a finding consistent with the results of this study. Additionally, an earlier longitudinal study reported that there were different degrees of delay in BA of various types of bones in the wrist in children with GHD, among which the delay in BA of the carpal bone was the most obvious, and its sensitivity to growth hormone replacement therapy was also higher (14). In this study, C BA was significantly delayed in the GHD group, indicating that growth hormone had a greater effect on C BA, consistent with the results reported in the literature. However, the difference between R BA and chronological age was not statistically significant. The reason for this may be the inclusion of older participants and that the maturation of the radial-ulnar and metacarpophalangeal bones in late childhood mainly reflect the process of cartilage development. Although growth hormone is the primary stimulus for cartilage osteogenesis, it stimulates cartilage development to a lesser extent, resulting in an insignificant delay in R BA. The delay in the C BA of the children with INS was more apparent, and the difference in R-C was statistically significant. In INS children, the delay in C BA was more pronounced, and the R-C difference was statistically significant. Long-term application of glucocorticoids and lack of growth hormone in this group of patients can lead to severe impairment of the cartilage osteogenesis process, which has a lesser impact on cartilage development, resulting in a significant delay in the C BA of the children. This study showed that the delay of R and C BA was evident in the craniopharyngioma group, in which the delay of R BA was 2.04±1.13 years. The delay of C BA was 2.70±1.16 years, which was the most apparent delay in all the case groups, and there were even cases with a delay of BA of more than 5 years. Therefore, if the delay of R and C BA is noticeable in clinical work, we should be alerted to the possibility of combined hormone deficiency. Nonetheless, we cannot only diagnose the disease caused by the BA delay. Still, we also need to consider it with other clinical information, imaging, and test results.

Current studies based on the scoring method are mostly limited to R BA, and C BA is often ignored, and fewer studies have been conducted on C BA. Previous studies have concluded that R BA could predict FAH, and the FAH prediction methods based on the scoring method were calculated based on R BA, whereas the correlation between C BA and FAH remained uninvestigated (22).

Although this study better confirms the different maturation characteristics of R and C BA in children with various endocrine diseases, there are some limitations: (I) it is only a single-center retrospective analysis with a relatively small sample size, which needs to be verified by a large-sample study; and (II) this cross-sectional study did not observe the dynamics of endocrine factors affecting the maturation characteristics of R and C BAs, and was unable to evaluate the effect of endocrine treatment. In the future, its deep patterns can be further explored by observing the changes of R and C BAs before and after endocrine treatment in the prospective study. Prospective studies can be conducted to explore the underlying patterns further.

Conclusions

The maturation characteristics of R and C BAs of children with different endocrine diseases are different, and a single R or C BA often cannot reflect the actual condition well; in clinical work, it is necessary to combine the R and C BAs with clinical information to accurately assess the diagnosis and identification of endocrine diseases and the treatment effect.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-669/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-669/dss

Funding: The work was supported by the National Natural Science Foundation of China (No. 82171929) and the President Foundation of Nanfang Hospital, Southern Medical University (No. 2024B010).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-669/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Nanfang Hospital, Southern Medical University (No. NFEC-2025-048), and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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