Dosage of hydrocortisone during late infancy is positively associated with changes in body mass index during early childhood in patients with 21-hydroxylase deficiency

Abstract

Obesity is a major complication in children with 21-hydroxylase deficiency (21-OHD). There is evidence to show that higher body mass index (BMI) during infancy and early childhood is associated with an increased risk for the subsequent development of obesity in the general population; however, limited information is currently available on this issue in 21-OHD patients. Additionally, despite the frequent use of supraphysiological dosages of hydrocortisone in 21-OHD, the association between BMI and hydrocortisone dosage during these periods remains largely unclear; therefore, we retrospectively investigated BMI at approximately 1 and 3 years old and its association with hydrocortisone dosage in 56 children with 21-OHD. The median BMI-standard deviation score (SDS) was 0.28 (Interquartile range [IQR]: –0.53 to 1.09) and 0.39 (IQR: –0.44 to 1.14) at approximately 1 and 3 years old, respectively, and no association was observed between hydrocortisone dosage and BMI-SDS at either time-point; however, multivariate analysis revealed that hydrocortisone dosage at approximately 1 year old was positively associated with changes in BMI (β = 0.57, p = 0.013) and BMI-SDS (β = 0.59, p = 0.011) between approximately 1 and 3 years old after adjustment for age, sex, and changes in hydrocortisone dosage during the same period. The average dosage of hydrocortisone between approximately 6 months and 1 year old also showed similar results. These results indicate that a higher dosage of hydrocortisone during late infancy is associated with a higher BMI at approximately 3 years old, which may lead to the development of obesity later in life in children with 21-OHD.

21-HYDROXYLASE DEFICIENCY (21-OHD), the most frequent type of congenital adrenal hyperplasia, is a genetic disorder caused by loss-of-function variants in the CYP21A2 gene and leads to adrenal insufficiency and androgen excess when hydrocortisone (HC) is insufficiently replaced [1, 2]. Since excessive androgen production causes acceleration of bone age that results in the short stature and masculinization of external genitalia [1-3], appropriate suppression of the hypothalamic-pituitary-adrenal axis is requisite to prevent these complications; however, a supraphysiological dosage of HC is often required to prevent excessive production of androgen in adrenal glands, which may result in the development of obesity [1-6]. In fact, several reports have demonstrated that children and adults with 21-OHD are at higher risk for the development of obesity and its associated complications [7-12].

In general, body mass index (BMI) changes during infancy and early childhood, such that it rapidly increases during the first year of life and declines thereafter to reach a nadir level, which is followed by a gradual increase called the adiposity rebound (AR) [13, 14]. There is accumulating evidence to show that the disruption of normal changes in BMI during these periods is associated with the development of obesity and its related complications later in life [13, 14]. For example, the earlier occurrence of AR is associated with a subsequent risk for developing obesity [13]; therefore, multiple groups have investigated the effect of the timing of AR in children with 21-OHD and its association with the risk of developing obesity and found that it was earlier in patients with 21-OHD than that in the general population [15-17]. In addition to the earlier occurrence of AR, there is also evidence that higher BMI between 1–3 years of age is associated with subsequent obesity in the general population [18, 19]; however, this scenario has not been well investigated in children with 21-OHD. Additionally, despite the deleterious effect of supraphysiological dosages of HC on the development of obesity [1-6], the effect of HC dosage on changes in BMI during these periods has not been well evaluated in 21-OHD. Thus, we herein investigated the association between HC dosage and changes in BMI between 1 and 3 years of age in children with 21-OHD.

Materials and Methods

Ethical considerations

This study was approved by the Ethical Committee of Osaka Women’s and Children’s Hospital (Approval No. 1529). The opt-out recruitment method for participating in the study was applied with permission from the Ethical Review Board.

Subjects

We retrospectively examined the medical records of patients with 21-OHD who visited Osaka Women’s and Children’s Hospital for medical management between 1991 and 2020. The definitive diagnosis of 21-OHD was based on genetic analysis or/and urine steroid profiling; however, in some individuals the diagnosis was based on clinical presentations, elevations in 17-hydroxy progesterone levels during the neonatal period, and adrenal hyperplasia in imaging analyses. To exclude the negative influence of body size at birth on anthropometric profiles at the time of evaluations, those born with a birthweight of lower than 2,500 g and/or small for gestational age were excluded. Small for gestational age was defined as either birthweight or length being lower than –2.0 standard deviations (SD) based on the sex-specific standard data on birth weight and length stratified by gestational age in the Japanese population [20]. A total of 56 subjects (10 males and 46 females) were included in the study. No subjects showed any disorders that are known to cause growth retardation or obesity except for 21-OHD.

Data collection and study design

Supine length and standing height, both of which are hereafter referred to as height (HT), were measured using an infant meter and stadiometer, respectively. Body weight (BW) was measured using a digital scale. BMI was calculated by dividing BW (kg) by HT squared (m²). The calculation of body surface area (BSA) is based on the formula of Du Bois, as follows: BSA (m²) = WT (kg)^0.425 × HT (cm)^0.725 × 0.007184. HT-SDS, BW-SDS, and BMI-SDS were determined based on normal growth standards for Japanese children from a national survey in 2020 [21, 22]. Anthropometric parameters including BW, HT, and the dosages of hydrocortisone (HC) and fludrocortisone (FC) were examined at two time points, at the 1-year-old and the 3-year-old evaluations. The 1-year-old evaluation was performed at approximately 1 year of age with a median age of 12.1 months (Interquartile range [IQR]: 11.6 to 12.7) and a range of between 10.1 and 14.2 months. The 3-year-old evaluation was performed at approximately 3 years of age with a median age of 36.5 months (IQR: 36.1 to 37.4) and a range of between 34.9 and 38.7 months. The data both at the 1-year-old and the 3-year-old evaluations were available for 32 subjects. Among the 32 subjects, the data on HC dosage at approximately 6 months old, with a median of 5.9 months (IQR: 5.5 to 6.3) and a range of between 5.0 and 7.6 months, which was referred to as the 6-month-old evaluation, were available for 29 subjects. The dosage of HC was divided by BSA (HC/BSA) to adjust for body size. To determine the effect of HC on anthropometric parameters, a correlation analysis between HC parameters (HC [mg/day] and HC/BSA [mg/m²/day]) and anthropometric parameters (HT-SDS and BMI-SDS) was performed at the 1-year-old and the 3-year-old evaluations. Correlations between HC parameters at the 1-year-old evaluation and changes in anthropometric parameters between the 1-year-old and the 3-year-old evaluations were also investigated.

Statistical analysis

Values are expressed as the median with the IQR. Comparisons of HT-, BW-, and BMI-SDS between the 1-year-old and the 3-year-old evaluations were performed by paired t-tests. In the case of comparisons between HT, BW, BMI, and dosages of HC and FC, Wilcoxon signed rank tests were utilized. Correlations were calculated using Spearman’s rank correlation coefficient. Correlation analysis was also performed using multiple regression analysis with adjustment for confounding variables as indicated in the text. P values less than 0.05 were considered significant. Statistical analyses were performed using JMP software version 14 (SAS Institute, Cary, NC).

Result

Characteristics of subjects

Clinical characteristics at birth and at the 1-year-old evaluation are shown in Table 1. All subjects were born at equal to or later than gestational week 36, indicating that there were no preterm subjects in this study. Diagnosis of 21-OHD was based on genetic testing in 9 patients, biochemical analysis of urine steroid profiling in 19 patients, and both in 3 patients. The remaining 25 patients were clinically diagnosed based on clinical features, elevation of blood 17-hydroxyprogesterone levels, and the presence of adrenal hypertrophy in imaging analysis. Among the 25 patients, 17 showed 17-OHP levels over the detection limit, 2 between 80 and 90 ng/mL, and 5 between 50 and 80 ng/mL. One patient showed 17-OHP levels of 28 ng/mL. The data on anthropometric parameters and medications for HC and FC were available for 56 children (10 males and 46 females) at the 1-year-old evaluation (median age of 12.1 months [IQR: 11.6 to 12.7]). Twenty patients were referred to our hospital for genital reconstructive surgery, which has created a female predominance in this study. All patients received both HC and FC. At the 1-year-old evaluation, the medians for HT- and WT-SDS were –1.24 and –0.76, respectively. The median BMI-SDS was 0.28, ranging between –2.2 and 2.2, and 2 out of 56 subjects showed a BMI-SDS of over 2.0. These results suggest that there is a tendency toward a smaller body size and that most subjects did not show an obese phenotype at the 1-year-old evaluation. The median values of HC and HC/BSA at the 1-year-old evaluation were 9 mg/day and 24.4 mg/m²/day, respectively. Current age was positively associated with the dosage of HC (rS = 0.47, p < 0.001) and HC/BSA (rS = 0.52, p < 0.001) at the 1-year-old evaluation, suggesting that a higher dosage of HC was used in older patients.

Table 1 Characteristics of subjects at birth and at the 1-year-old evaluation

Number	56
M/F	10/46
At birth
Gestational age, week	39.4 (38.4 to 40.4)
Birth weight, g	3,132 (2,845 to 3,265)
Birth weight SD score	0.46 (0.38 to 1.11)
Birth length, cm	50.0 (48.1 to 50.4) (N = 45)
Birth length SD score	0.36 (–0.25 to 0.92) (N = 45)
At the 1-year-old evaluation
Age, month	12.1 (11.6 to 12.7)
HT, cm	69.9 (67.9 to 71.5)
HT-SDS	–1.24 (–1.86 to –0.57)
WT, kg	8.10 (7.55 to 8.85)
WT-SDS	–0.76 (–1.41 to 0.02)
BMI, kg/m2	16.78 (15.58 to 17.72)
BMI-SDS	0.28 (–0.53 to 1.09)
HC, mg	9 (7 to12)
HC/BSA, mg/m2	24.3 (19.8 to 34.3)
FC, mg	0.05 (0.05 to 0.075)

A median with an interquartile range in parenthesis is shown.

M: male, F: female, HT: height, WT: weight, BMI: body mass index, HC: hydrocortisone, BSA: body surface area, FC: fludrocortisone

In 32 out of 56 subjects, data on anthropometric parameters and medications were available at both evaluations (Table 2). The 3-year-old evaluation was performed at a median age of 36.5 months (IQR: 36.1 to 37.4). We compared these parameters between the 1-year-old and the 3-year-old evaluations and found that HC and HC/BSA were significantly lower at the 3-year-old evaluation compared to those observed at the 1-year-old evaluation, whereas FC showed a slight and significant increase at the 3-year-old evaluation (Table 2). HT-SDS did not show any significant difference between two time points (Table 2). Although WT-SDS showed a significant increase, BMI-SDS was unchanged (Table 2). The median BMI-SDS at the 3-year-old evaluation was 0.39, ranging between –2.1 and 1.996, indicating that no patients were obese at the 3-year-old evaluation.

Table 2 Characteristics of subjects with data available at both the 1-year-old and the 3-year-old evaluations

	First evaluation	Second evaluation	p-value
Number	32
M/F	8/24
Age, month	12.4 (10.2 to 14.2)	36.5 (36.1 to 37.4)
HT	69.7 (67.2 to 71.4)	87.9 (85.0 to 90.8)	<0.001**
HT-SDS	–1.39 (–2.26 to –0.88)	–1.30 (–2.10 to –0.49)	0.30*
WT	8.1 (7.3 to 8.8)	12.1 (10.9 to 13.7)	<0.001**
WT-SDS	–0.81 (–1.66 to –0.14)	–0.66 (–1.66 to 0.34)	0.048*
BMI	16.6 (15.5 to 17.6)	15.8 (14.9 to 16.9)	<0.001**
BMI-SDS	0.21 (–0.57 to 0.99)	0.39 (–0.44 to 1.14)	0.57*
HC, mg	10 (8 to14.3)	10 (8 to 12)	0.014**
HC/BSA, mg/m2	27.3 (22.1 to 38.2)	18.6 (15.8 to 23.4)	<0.001**
FC, mg	0.05 (0.05 to 0.073)	0.055 (0.05 to 0.079)	0.045**

A median with an interquartile range in parenthesis is shown.

HT: height, WT: weight, BMI: body mass index, BSA: body surface area, HC: hydrocortisone, FC: fludrocortisone

*: Statistical analysis is performed using paired t-test.

**: Statistical analysis is performed using Wilcoxon signed rank test.

Significant differences are in bold.

The dosages of HC and HC/BSA did not correlate with anthropometric parameters

As shown in Table 3, correlation analyses revealed that HC parameters including HC (mg/day) and HC/BSA (mg/m²/day) did not correlate with HT-SDS at either evaluation. Although univariate analysis showed a significant negative correlation between HC/BSA and BMI-SDS at the 1-year-old evaluation, a significant difference was not observed after adjustment for sex and age. No significant differences were observed between HC parameters and BMI-SDS at the 3-year-old evaluation.

Table 3 Correlation analysis between anthropometric parameters and the dose of hydrocortisone

	1-year-old evaluation (N = 56)				3-year-old evaluation (N = 32)
	Univariate		Multivariate		Univariate		Multivariate
	rS	p-value	β	p-value	rS	p-value	β	p-value
HT-SDS
HC, mg/day	0.050	0.72	0.085*	0.20	0.32	0.071	–0.036*	0.70
HC/BSA, mg/m2/day	–0.11	0.42	–0.13**	0.34	0.053	0.77	0.17**	0.39
BMI-SDS
HC, mg/day	–0.15	0.26	–0.084*	0.50	0.32	0.071	0.025*	0.88
HC/BSA, mg/m2/day	–0.27	0.042	–0.19**	0.17	0.16	0.70	0.15**	0.43

rS: Spearman’s rank correlation coefficient, β: standardized partial regression coefficient, HT: height, BMI: body mass index, HC: hydrocortisone, BSA: body surface area

*: Correlations are adjusted for sex, age in days at evaluation, and BSA

**:Correlations are adjusted for sex and age in days at evaluation

Significant values are in bold.

The dosages of HC and HC/BSA at approximately 1 year of age were positively correlated with a subsequent change in BMI and BMI-SDS during early childhood

As shown in Table 4, multivariate analysis revealed that HC and HC/BSA at the 1-year-old evaluation showed a significant positive correlation with changes in BMI parameters between the 1-year-old and the 3-year-old evaluations, including the percent change in BMI (%ΔBMI) and the change in BMI-SDS (ΔBMI-SDS) after controlling for sex, age, and changes in HC (ΔHC) or HC/BSA (ΔHC/BSA) during the same period. In contrast, multivariate analysis failed to reveal a correlation between changes in BMI parameters and ΔHC or ΔHC/BSA after adjustment for confounding variables including sex, age, and HC or HC/BSA at the 1-year-old evaluation, respectively. These results indicate that the dosage of HC at approximately 1 year of age predicts subsequent alterations in BMI between approximately 1 and 3 years old independent of changes in the dosage of HC during the same period. The dosage of HC at the 1-year-evaluation did not correlate with changes in HT-SDS between the 1-year-old and the 3-year-old evaluations after controlling for sex, age, and changes in the dosage of HC during the same period (Table 4).

Table 4 Correlation analysis of the change in anthropometric parameters between the 1-year-old and the 3-year-old evaluations with the dose of hydrocortisone

	ΔHT-SDS (N = 32)				ΔBMI-SDS (N = 32)				%ΔBMI (N = 32)
	Univariate		Multivariate		Univariate		Multivariate		Univariate		Multivariate
	rS	p-value	β	p-value	rS	p-value	β	p-value	rS	p-value	β	p-value
HC at the 1-year-old evaluation, mg/day	–0.25	0.16	–0.37*	0.12	0.33	0.063	0.59*	0.011	0.30	0.096	0.57*	0.013
HC/BSA at the 1-year-old evaluation, mg/m2/day	–0.22	0.24	–0.49**	0.17	0.30	0.099	0.69**	0.042	0.27	0.14	0.67**	0.048
ΔHC, mg/day	0.068	0.71	–0.087†	0.70	0.039	0.83	0.16†	0.45	0.041	0.82	0.14†	0.49
ΔHC/BSA, mg/m2/day	0.098	0.59	–0.31††	0.36	–0.14	0.46	0.30††	0.35	–0.14	0.45	0.29††	0.36

rS: Spearman’s rank correlation coefficient, β: standardized partial regression coefficient, HT: height, BMI: body mass index, HC: hydrocortisone, BSA: body surface area, Δ: changes between the 1-year-old and the 3-year-old evaluations

*: Correlations are adjusted for sex, age in days at the 1-year-old evaluation, and ΔHC.

**: Correlations are adjusted for sex, age in days at 1st evaluation, and ΔHC/BSA.

^†: Correlations are adjusted for sex, and age in days, and HC at the 1-year-old evaluation.

^††: Correlations are adjusted for sex, and age in days, and HC/BSA at the 1-year-old evaluation.

Significant values are in bold.

The HC dosage during late infancy was positively correlated with a subsequent change in BMI and BMI-SDS during early childhood

Finally, we investigated the association between the dosage of HC during late infancy and changes in BMI between the 1-year-old and the 3-year-old evaluations. Among 32 subjects, data on HC dosage at the 6-month-old evaluation were available for 29 subjects. There was a significant positive correlation in the dosages of HC between the 6-month-old and the 1-year-old evaluations (HC: rS = 0.84, p < 0.001, HC/BSA: rS = 0.85, p < 0.001), suggesting that those with greater HC dosage at the 1-year-old evaluation likely received higher HC during late infancy. To understand the effect of HC dosage during late infancy on changes in BMI between the 1-year-old and the 3-year-old evaluations, we calculated the mean HC dosage between the 6-month-old and the 1-year-old evaluations and performed correlation analysis. As shown in Table 5, multivariate analysis revealed that the average HC during late infancy was significantly and positively correlated with ΔBMI-SDS and %ΔBMI. A positive correlation was also observed between average HC/BSA and ΔBMI-SDS or %ΔBMI, although it did not reach statistical significance (Table 5).

Table 5 Correlation analysis of the change in anthropometric parameters between the 1-year-old and the 3-year-old evaluations with the average dose of hydrocortisone during late infancy

	ΔHT-SDS (N = 29)				ΔBMI-SDS (N = 29)				%ΔBMI (N = 29)
	Univariate		Multivariate		Univariate		Multivariate		Univariate		Multivariate
	rS	p-value	β	p-value	rS	p-value	β	p-value	rS	p-value	β	p-value
HC during late infancy†, mg/day	–0.15	0.43	–0.23*	0.38	0.33	0.076	0.56*	0.027	0.29	0.13	0.53*	0.034
HC/BSA during late infancy†, mg/m2/day	–0.10	0.62	–0.25**	0.48	0.3	0.12	0.66**	0.055	0.25	0.2	0.60**	0.063

rS: Spearmanv’s rank correlation coefficient, β: standardized partial regression coefficient, HT: height, BMI: body mass index, HC: hydrocortisone, BSA: body surface area

Δ: changes between the 1-year-old and the 3-year-old evaluations

*: Correlations are adjusted for sex, age in days at the 1-year-old evaluation, and ΔHC.

**: Correlations are adjusted for sex, age in days at the 1-year-old evaluation, and ΔHC/BSA.

^†: HC dosage during late infancy is determined by calculating the average dose between the 6-month-old and the 1-year-old evaluations.

Significant values are in bold.

Discussion

Therapeutic management of 21-OHD includes optimization of the dosage of HC to prevent excessive production of androgen without increasing the risk for the development of adrenal insufficiency, which often requires a supraphysiological dosage of HC, including the use of synthetic steroids such as prednisolone and dexamethasone; however, this approach has been associated with a higher risk for developing obesity [1-6]. As there is evidence that a higher BMI during infancy and early childhood is associated with an increased risk for the development of subsequent obesity in the general population [18, 19], controlling the appropriate BMI during these periods may have a beneficial influence on reducing the risk for developing obesity in children with 21-OHD; however, the factors associated with higher BMI during this period remain largely unknown in 21-OHD patients. As a supraphysiological dosage of HC is known to be a risk factor for developing obesity, we herein investigated the effect of HC dosage on BMI during this period and have provided evidence that the dosage of HC during late infancy is positively associated with an increase in BMI during early childhood in 21-OHD patients.

To understand the effect of HC dosage on the development of obesity in children with 21-OHD, we first investigated the association between the dosage of HC and BMI at approximately 1 and 3 years old and found that the HC dosage was not associated with BMI-SDS at these time points after adjustment for confounding variables. Although a negative association between HC/BSA and BMI-SDS at the 1-year-old evaluation was observed by Spearman’s rank correlation coefficient, this result may be biased by the positive association between BSA and BMI. To overcome this limitation, we performed multivariate analysis to investigate the association between HC and BMI-SDS with correction for BSA, which resulted in the lack of association between HC and BMI. Based on these, we concluded that there was no association between HC dosage and BMI at the 1-year-old evaluation. These findings are in line with a previous paper showing that the dosage of HC during infancy has only a marginal impact on developing obesity [23].

We next examined the effect of the dosage of HC during late infancy on subsequent changes in BMI between 1 and 3 years old, because there is evidence that higher BMI during this period is associated with the subsequent development of obesity in the general population [18, 19]. For example, Aris et al. demonstrated that BMI peak during infancy was associated with increased adiposity during adolescence [19]. Additionally, Freedman et al. recently reported that BMI at 3 years of age is more strongly associated with BMI after the age of 14 years than at the age of AR in healthy populations [18]. There is also evidence from a systematic review to show that weight gain during ages up to 2 years of age is associated with the subsequent development of obesity [24]. Based on these findings, we investigated the association between the dosage of HC and changes in BMI between approximately 1 and 3 years old and found that the dosage of HC during late infancy was positively associated with a subsequent increase in BMI. The BSA-adjusted dosage of HC also showed similar results. Given evidence of the importance of BMI during infancy and early childhood in subsequent obesity, the present results indicate that HC should be adjusted to an appropriate dosage by the age of 1 year old to prevent the development of obesity later in life.

In contrast, multivariate analysis failed to show a correlation between changes in HC dosage between the 1-year-old and the 3-year-old evaluations and changes in BMI parameters during the same period, which may be contradictory to the widely accepted tenet of the deleterious effect of HC overdose on BMI. As a supraphysiological dosage of HC was still used at the 3-year-old evaluations, this may have resulted in the marginal effect of changes in HC dosage on changes in BMI. Further analysis that compares the effect of HC dosage on BMI with that in patients in which HC dosage is adjusted according to the current guideline is clearly required to understand the effect of HC dosage during this period on BMI.

Multiple publications, including meta-analyses, have revealed that adult height in 21-OHD patients was shorter than in reference populations [1, 2, 25, 26]. Both under and over-treatment with HC in 21-OHD are known to influence adult height by over-production of adrenal androgen that inappropriately accelerates bone maturation and suppresses chondrocyte differentiation/maturation, respectively [26, 27]. In addition to the importance of the dosage of HC during puberty, there is also evidence to show that in individuals with the salt-wasting form, HT at 2 years old is positively associated with the dosage of HC during the first 2 years, indicating the importance of HC dosage on HT during this period [23]. A similar finding was also reported independently [28]. Based on these findings, we investigated the association between the dosage of HC and HT-SDS and found that the dosage of HC did not correlate with HT-SDS at the 1-year-old and the 3-years-old evaluations. Additionally, the dosage of HC at the 1-year-evaluation did not correlate with subsequent changes in HT-SDS. These observations indicate that HC might have limited influence on HT at least during infancy and early childhood; however, it is important to note that the current analysis did not incorporate target height, which clearly indicates the necessity for additional studies to clarify the association between the dosage of HC and HT.

A major limitation of this study is that the dosage of HC at the 1-year-old evaluation (19.8–34.3 mg/m²/day) was much higher than the recommended HC dosage (10–15 mg/m²/day) in the current guidelines [26, 29]. This was probably due to the inclusion of older subjects in this study, because a higher dosage of HC had previously been used. This is also supported by the finding of the positive correlation between current age and HC dosage at the 1-year-old evaluation. Consistent with this result, Matsubara et al. previously reported that the average dosage of HC at 1 year old fell between 20 and 30 mg/m²/day in Japanese patients with 21-OHD who reached at least 15 years old between 1989 and 2008, which was higher than the recommended dosage in the current guidelines published by the Japanese Society for Pediatric Endocrinology [29, 30]. In addition, a higher dosage (25–100 mg/m²/day) of HC is often used to treat acute adrenal crisis during the neonatal period in Japan [29]; therefore, a higher dosage of HC may be used during the infantile period due to a delayed deceleration. These findings indicate that the current result may be restricted to those treated with higher dosages of HC than the current recommendations. Additional studies in those treated based on the current recommendation are necessary to fully understand the effect of HC dosage on the development of obesity in 21-OHD patients. Furthermore, many patients were referred to our hospital for genital reconstructive surgery and this has created a female predominance and an insufficient availability of anthropometric data, the latter of which has resulted in a broad range of ages at evaluations and prevented us from performing the analysis using integrated anthropometric parameters based on multiple measurements. Furthermore, the diagnoses of 21-OHD were based on clinical, laboratory, and imaging analyses in 25 patients, in part because of the lack of accessibility to genetic testing and/or urine steroid profiling in older subjects. This raises a concern as to the accuracy of the diagnosis of 21-OHD, because increases in 17-OHP levels are also observed in patients with 11-beta-hydroxilase deficiency, 3-beta-hydroxiysteroid dehydrogenase deficiency, and Cytochrome P450 oxidoreductase deficiency. Nevertheless, considering that 21-OHD is the most predominant cause of congenital adrenal hyperplasia with elevations in 17-hydroxyprogesterone levels, we believe that the current results are minimally affected by the lack of a definitive diagnosis of 21-OHD.

In conclusion, we herein provide evidence that the dosage of HC during late infancy was positively associated with a subsequent increase in BMI between approximately 1 and 3 years old in children with 21-OHD. Although the long-term influence of the dosage of HC during late infancy on the subsequent development of obesity has not been evaluated in the present study, given that a higher dosage of HC is often used in Japan during the neonatal period to prevent adrenal crisis, the current results may emphasize the importance of deceleration of HC dosage during the infantile period to reduce the risk of developing obesity later in life.

Author Contributions

T.W., S.N., and M.K. conceived and designed the manuscript. T.W., S.N., and M.K. collected data. T.W. and M.K. wrote the manuscript. All authors analyzed the data. All authors read and approved the submission of the manuscript.

Conflict of Interest Statement

The authors have no conflicts of interest to disclose.

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