{"paper_id":"31302ce0-2984-4f80-a943-dbd6bc5ebe01","body_text":"Combination therapy of GnRHa, rhGH and Anastrozole to improve final adult height deficit in CAH children with CPP | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Combination therapy of GnRHa, rhGH and Anastrozole to improve final adult height deficit in CAH children with CPP Xiaoxiao Liu, Fei Liu, Yingyi Qi, Xinyi Han, Shifeng Ma, Rongxiu Zheng This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5573763/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 May, 2025 Read the published version in BMC Pediatrics → Version 1 posted 6 You are reading this latest preprint version Abstract Background To investigate the clinical and genetic characteristics of classic congenital adrenal hyperplasia (CAH) patients. To determine whether gonadotropin-releasing hormone analogs (GnRHa) + recombinant human growth hormone (rhGH) + Anastrozole combined therapy improves the final adult height of CAH patients with central precocious puberty (CPP). Methods We described the clinical and genetic characteristics of 16 classic CAH patients, and performed pathogenic analysis and structural modeling of the newly discovered mutation. By using the method of self-before and after control, we statistically analyzed bone age advancement, predicted adult height (PAH) and other indicators of 7 CAH children with CPP before and after combined treatment to observe its effect on adult height. Results All patients showed high levels of 17-hydroxyprogesterone, testosterone and adrenocorticotropic hormone. All patients had CYP21A2 gene mutations, and the newly discovered mutation c.79A > G (p.Ser27Gly) may change the hydrophilicity of the protein and affect its function. Seven CAH patients with CPP were diagnosed at 5.6 (3.5 to 7.3) years. Their target height was 0.18 (-1.2 to 0.78) SD, and The PAH at the start of treatment was − 3.01 (-3.75 to -2.89) SD. The ages at which CAH patients with CPP started to be treated with GnRHa, rhGH and Anastrozole were 5.8 (5.5 to 8.7), 7.1 (5.5 to 9.8), 8.7 (7.6 to 10.7) years old, and discontinued them at 8.8 (7.5 to 10.2), 10.4 (9.0 to 12.7), 11.0 (9.7 to 12.7) years old, respectively. The PAH at treatment end was − 0.28 (-1.2 to 0.4) SD. The final height was − 0.28 (-1 to 1.04) SD, significantly higher than the initial PAH ( P < 0.001) and similar to the target height ( P = 0.478). Conclusion GnRHa + rhGH + Anastrozole therapy can improve the final adult height of CAH patients with CPP. In addition, this study also discovered a new CYP21A2 gene mutation c.79A > G. 21 hydroxylase deficiency CYP21A2 gene central precocious puberty GnRHa rhGH Anastrozole Figures Figure 1 Figure 2 1. Introduction Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders, can be classified into two subtypes: classic form and non-classic form. The incidence of classic form is between 1/15,000 to 1/20,000, including salt wasting form (SW) and simple virilizing form (SV)[ 1 ]. SW form accounts for approximately 75% of classic cases, while the SV form accounts for 25%[ 1 ].21-hydroxylase deficiency (21-OHD) is the most common cause of CAH, which is caused by CYP21A2 gene mutations[ 2 ]. 21-OHD leads to the failure of 17-hydroxyprogesterone (17-OHP) to convert into corticosterone and deoxyicorticosl, resulting in a lack of cortisol (Cor) and aldosterone, excessive androgens, manifests as virilization and salt-wasting symptoms. Currently, the preferred treatment for CAH is adrenocortical hormone replacement therapy, including glucocorticoids and mineralocorticoids, which can replace insufficient adrenocortical hormone secretion, correct water and electrolyte disorders, and inhibit excessive adrenocorticotropic hormone (ACTH) synthesis[ 3 ]. Hydrocortisone is a glucocorticoid for growing children with a mean elimination half-life of 58 minutes, resulting in a return of adrenal steroids to pre-hydrocortisone dose concentrations after 4–5 hours[ 4 ]. As a result, CAH children are alternately exposed to hyper- and hypocortisolemia, resulting in elevated adrenal androgens. Chronic hyperandrogenism in prepubertal CAH patients may activate the hypothalamic-pituitary-gonadal axis and induce central precocious puberty (CPP)[ 5 ]. Affected children often experience accelerated linear growth during childhood with premature epiphyseal fusion, ultimately resulting in adult height below the target height established by their parents[ 6 ]. Numerous studies have shown that CAH patients are approximately 10 cm shorter than their parent-based target height[ 7 , 8 ]. A Chinese study in 2016 showed that the final adult height of classic CAH patients after receiving glucocorticoid and mineralocorticoid replacement therapy was − 1.9 ± 1.1 SD lower than that of healthy people[ 6 ]. For CAH patients with CPP, conventional treatment combined with gonadotropin-releasing hormone analogs (GnRHa) can effectively inhibit the development of sexual characteristics and slow down the progression of bone age by inhibiting the release of pituitary follicular stimulating hormone (FSH) and luteinizing hormone (LH)[ 9 ]. However, this approach is often accompanied by a deceleration in height growth. recombinant human growth hormone (rhGH) can effectively improve the height of children by stimulating chondrocyte proliferation[ 10 ]. The rhGH and GnRHa combined treatment has been shown to effectively improve predicted adult height (PAH)[ 11 , 12 ]. However, for CPP children who start treatment late, have significantly advanced bone age and impaired height growth potential, the treatment duration is limited. There is currently no ideal solution to improve their problems such as advanced bone age and impaired expected adult height. In 2000, aromatase inhibitors were first used in CAH patients[ 13 ]. By inhibiting the conversion of androgens to estrogens, they were able to inhibit bone age advancement and improve final adult height. In recent years, the advent of third-generation aromatase inhibitors represented by Anastrozole has further improved the inhibition rate of aromatase and reduced the incidence of adverse reactions. Studies have shown that aromatase inhibitors can improve the final adult height of children with short stature who have already started puberty or even in late puberty[ 14 ]. Aromatase inhibitors are expected to become a new hope for children who have missed the optimal treatment period of rhGH or GnRHa. This article retrospectively studied the clinical and genetic characteristics of classic CAH patients. This study aims to investigate the effectiveness of a combined treatment regimen (GnRHa + rhGH + Anastrozole) in enhancing final adult height in children with CAH patients with CPP. 2. Methods 2.1 Participants We collected clinical data of 16 children who were diagnosed with classical CAH from 2017 to 2024 in the Pediatric Department of the Tianjin Medical University General Hospital. All patients were from northern China. Their medical records were thoroughly reviewed, including clinical manifestations, physical examinations, growth histories, laboratory examinations, treatments, and follow-ups. Inclusion criteria of the patients were: (1) met the diagnostic criteria outlined in the clinical practice guidelines of 21-OHD published by the American Society for Endocrinology in 2018[ 15 ];(2) follow-up for more than 2 years; (3) the clinical data were complete. Exclusion criteria were: incomplete clinical data or loss of follow-up. The diagnostic criteria for CPP include: (1) males show secondary sexual characteristics before the age of 9 (testicular volume ≥ 4 mL) and females show secondary sexual characteristics before the age of 8 (breast development); (2) bone age at least 1 year advanced than the chronological age; and (3) pubertal response of LH peak > 5 IU/L or LH/FSH ratio > 0.6 after the GnRHa stimulation test[ 16 ]. This study was approved by the Ethics Committee of the Academy of Tianjin Medical University General Hospital (ZYY-IRB-SOP-019(F)-002-02). 2.2 Clinical data Laboratory examinations included measurements of serum sodium (Na + ), potassium (K + ), Cor, aldosterone, ACTH, FSH, LH, estradiol (E2), testosterone (T), etc. These hormones were measured by the chemiluminescence method. Additionally, 17-OHP was measured using high-performance liquid chromatography-tandem mass spectrometry. Testicular or utero-ovarian ultrasound and chromosome karyotype were also conducted. Bone age was determined using the Greulich–Pyle atlas from the non-dominant hand and wrist radiographs of the patients[ 17 ]. The Bayley–Pinneau method was used to figure out the PAH[ 18 ]. Target height, the genetic potential in stature, is commonly estimated by the corrected midparental height method[ 19 ]. Genetic testing was conducted for all participants in the study. Next-generation sequencing and multiplex ligation-dependent probe amplification (MLPA) were used for seeking CYP21A2 gene mutations. For CYP21A2 gene mutations analysis, multiple sequence alignments were performed by the UCSC database ( http://genome.ucsc.edu/ ) and Kalign ( https://www.ebi.ac.uk/Tools/msa/kalign/ ) to analyze the conservation of amino acid residues across different species. SWISS ( https://swissmodel.expasy.org/interactive ) and PyMOL 2.2 ( https://pymol.org/2/ ) were used to analyze the possible change of 21-hydroxylase structure after mutation. 2.3 Treatment and follow-up For CAH patients, conventional treatment includes hydrocortisone 15–20 mg/m 2 /d and fludrocortisone 100–150 ug/d. Children with SW < 1 year old can also be treated with sodium chloride 1–2 g/d. For patients with CPP and predicted impaired adult height, GnRHa (3.75 mg, Beijing Biotech) was injected subcutaneously every 4 weeks, rhGH was injected subcutaneously at a daily dose of 0.15–0.20 IU/kg/day (Jinsai, Jilin), and Anastrozole (1 mg/d, Huabang, Chongqing) was taken orally. Plasma electrolytes, 17-OHP, ACTH, and body weight were monitored monthly for infants before 3 months old, then were monitored every 3 months after that age. Blood samples were taken at around 8 am before daily oral drugs. The dosage of oral hydrocortisone and fludrocortisone should be readjusted according to the examination results. Growth condition was monitored carefully for all patients. Bone age was tested every 6 months after 2 years old. 2.4 Statistical Analysis SPSS 16.0 (SPSS Inc., Chicago, Ill., USA) was used for statistical analysis. Categorical variables were presented as percentages, whereas continuous variables were presented as medians (P25, P75). The Kruskal-Wallis test was used to analyse continuous clinical variables. Chi-square (χ 2 ) test was used for categorical data. Each time point was compared to the final evaluation by paired t Test. Paired t-test was also used to compare the hormone levels in each treatment period with those at the beginning of combined treatment. 3 Results 3.1 Baseline characteristics 16 CAH patients were included in this study. The chromosome karyotype was consistent with their social gender. All patients did not undergo neonatal screening. The symptoms of SW patients were mainly poor feeding and weight loss. Six patients developed adrenal crisis. Physical examination showed that 2 of the 4 girls had clitoromegaly (Prader 2), the other 2 girls had ambiguous external genitalia (Prader 3), and all 6 boys had scrotal pigmentation. SV patients mainly showed rapid growth and early pubic hair. The only girl diagnosed with SV in this study showed clitoromegaly (Prader 1). Laboratory tests showed that compared with SV patients, SW patients had lower Na + , higher K + , Cor, 17-OHP and T ( P < 0.05), and no significant difference was found in ACTH (Table 1 ). Table 1 Clinical features of patients with classical CAH SW SV P Sex (F/M) 4/6 1/5 0.33 Age of diagnosis (y) 0.1(0.9,0.2) 5.3(4.9,7.2) < 0.001 Na + (130–150 mmol/L) 126.2(124.7,128.35) 139.25(136.75,140.75) 0.001 K + (3.3–5.5 mmol/L) 6.05(5.775,7.675) 4.215(3.9975,4.9175) 0.001 Cor (5–25 ug/dl) 2.95(1.4,3.975) 5.8(3.55,19.975) 0.019 ACTH (0–46 pg/ml) 146.6(49.8,248.675) 129.6(93.275,210.975) 0.245 17-OHP (0.3-2.0 ng/ml) 320.75(236.3,1433) 231.1(108.375,259.25) 0.03 T (< 10 nmol/L) 209(86.25,256.75) 180.7(93.4,297.5) 0.014 Note: The Kruskal-Wallis test was used to analyse continuous clinical variables. Na + , sodium; K + , potassium; Cor, cortisol; ACTH, adrenocorticotropic hormone; 17-OHP, 17-hydroxyprogesterone; T, testosterone. CYP21A2 gene mutations were detected by MLPA. all of them were autosomal recessive inherited (Table 2 ). The mutation sites were scattered in the CYP21A2 gene (Fig. 1 A). Functional change of missense mutation c.79A > G (p. Ser27Gly) (Fig. 1 B) had not been recorded in the Human Gene Mutation Database, Human Cytochrome P450 Allele Nomenclature Committee and 1000 genomes database yet. The patient gained missense mutations c.79A > G (p. Ser27Gly) and c.518T > A (p.Ile173Asn) from his mother, and obtained the null mutation p.E4-6 Del himself (Fig. 1 C). We enquired about amino acid sequences around p. Ser27Gly using the UCSC database and Kalign (Fig. 1 D) and constructed 3D structures of 21 hydroxylase by PyMol2 software (Fig. 1 E). Bioinformatic software was applied to analyze the pathogenicity of p.Ser27Gly. It was located in the N-terminal region, and the hydrophilicity of the protein was changed after mutation, which might affect the anchoring in the cell membrane and reduce the activity of the enzyme. Table 2 Mutations of 16 patients in CYP21A2 gene Patient Allele 1 Location in CYP21A2 protein change Allele 2 Location in CYP21A2 protein change 1 c.293-13C > G Intron2 In2G c.293-13C > G Intron2 In2G 2 c.1451-1452delGGinsC Exon10 Arg484Profs E1-7 Del Exon1-7 - 3 c.293-13C > G Intron2 In2G c.293-13C > G Intron2 In2G 4 c.949C > T Exon8 Arg319* E1-10 Del Exon1-10 - 5 c.293-13C > G Intron2 In2G c.293-13C > G Intron2 In2G 6 c.293-13C > G Intron2 In2G c.293-13C > G Intron2 In2G 7 c.710 T > A Exon6 I1e237Asn E1-3 Del Exon1-3 - 8 c.293-13C > G Intron2 In2G E1-3 Del Exon1-3 - 9 c.710T > A; c.713T > A; c.719T > A Exon6 I1e237Asn; Val238Glu; Met240Lys c.1069C > T Exon8 Arg357Trp 10 c.293-13C > G Intron2 In2G c.1069C > T Exon8 Arg357Trp 11 c.518T > A Exon4 Ile173Asn c.955C > T Exon8 Gln319* 12 c.518T > A Exon4 Ile173Asn c.606G > A Exon5 Trp202* 13 c.518T > A; c.79A > G Exon4; Exon1 Ile173Asn; Ser27Gly E4-7 Del Exon4-7 - 14 c.518T > A Exon4 Ile173Asn c.293-13C > G Intron2 In2G 15 c.518T > A Exon4 Ile173Asn c.1225C > G Exon10 Arg409Gly 16 c.518T > A Exon4 Ile173Asn c.1306C > T Exon10 Arg434Cys 3.2 Complicated with CPP Seven children have been diagnosed with CPP in this study, including 2 SW (M:F = 1:1) and 5 SV (M:F = 4:1). We observed that the age of diagnosis CPP was 5.6 (3.5 to 7.3) years, representing a group of patients with delayed disease recognition. Ovarian and follicular enlargement occurred before 7.5 years in girls and penile and testicular growth occurred before 9 years in boys. LH and FSH were elevated, and LH peak/FSH peak higher than 0.6. At the time of diagnosis of CPP, the bone age had significantly improved by 6.3 (4.1 to 7.7) years, and PAH was − 3.10 (-3.75 to -2.89) SD. The data of chronological age and bone age progression observed at each time point during treatment are shown in Table 3 . The ages at which CAH patients with CPP started to be treated with GnRHa, rhGH and Anastrozole were 5.8 (5.5 to 8.7), 7.1 (5.5 to 9.8), 8.7 (7.6 to 10.7) years old, and discontinued them at 8.8 (7.5 to 10.2), 10.4 (9.0 to 12.7), 11.0 (9.7 to 12.7) years old, respectively. The duration of single GnRHa treatment was 1.4 (0.1 to 1.7) years, during which no further bone age progression was observed. At 1.4 (0.4 to 3.3) years of GnRHa + rhGH treatment, bone age progression decreased significantly to 4.9 years. At the end of 1.9 (0.3 to 2.7) years of rhGH + Anastrozole treatment, bone age decreased significantly to 4.3 years and remained near this value until the end of clinical evaluation. Table 3 Chronological age and bone age advancement (years) in CAH patients Chronological age (y) Bone age advancement (y) Median Range Median Range Diagnosis 5.6 3.5–7.3 6.1 3.5–7.5 Start of GnRHa 5.8 5.5–8.7 6.3 4.1–7.7 Start of rhGH 7.1 5.5–9.8 5.9 3.3–6.4 Start of Anastrozole 8.7 7.6–10.7 4.8 3.1–6.4 withdrawal GnRHa 8.8 7.5–10.2 4.9 3.0-6.4 withdrawal rhGH 10.4 9.0-12.7 4.5 2.5–4.9 withdrawal Anastrozole 11.0 9.7–12.7 4.3 2.5–5.3 Final height 11.4 11.2–13.9 4.1 2.9–5.1 Note: Bone age advancement (y) = bone age (y) - chronological age (y). The key height indicators of CAH patients with CPP are detailed in supplementary table 1 . Comparison of each time point during treatment with the final height assessment showed a gradual increase in height (Fig. 2 ). From diagnosis to the end of single GnRHa therapy, predicted height decreased significantly relative to height close to the final level ( P < 0.001). At the end of GnRHa + rhGH therapy, height decreased significantly relative to height close to the final level ( P = 0.004). At the end of rhGH + Anastrozole therapy, height still differed relative to final height ( P = 0.011). There was no difference in height relative to final height at the time of discontinuation of adjuvant therapy ( P = 0.063). The final height assessment was similar to the target height ( P = 0.478). The results of pituitary-gonadal axis hormone levels in male children during different treatment periods are shown in Table 4 . During the GnRHa treatment period, FSH and LH decreased (both P < 0.05), indicating that GnRHa treatment was effective. At the end of GnRHa treatment, sex hormone status was at puberty levels. During the Anastrozole treatment period, FSH and LH increased slightly, but there was no statistical difference, and the decrease in E2 ( P < 0.01), which was considered to be related to the addition of Anastrozole. There were only 2 cases in the female group, which were not analyzed. During the treatment period, the children did not experience symptoms such as hirsutism, severe acne, nausea, headache, bone pain, obesity, or hypertension, nor did they feel fatigued, regular monitoring of lipid profiles, electrolytes, liver function, kidney function, and coagulation function all yielded normal results. Table 4 Changes in sex hormones after treatment . Treatment period FSH(U/L) LH(U/L) E2(pmol/L) T(nmol/L) Diagnosis of CPP 2.1(1.5-3.0) 1.2(0.8–1.4) 13.0(10.3–15.5) 22.0(12.8–50.5) GnRHa treatment period 0.4(0.1–0.6) * 0.2(0.1–0.4) * 5.5(4.2–15.2) 11.3(11.1–22.1) * End of GnRHa treatment 1.9(1.6–3.2) 1.1(1.0-1.7) 35.5(25.5–50.3) 17.0(10.7–20.8) Anastrozole treatment period 2.2(1.7–2.8) 1.2(1.3–1.8) 6.5(5.7–13.6) ** 30.3(25.0-60.2) Note: The Paired t-test was used to compare the hormone levels in each treatment period with those at the beginning of combined treatment. *: P < 0.05; **: P < 0.01. FSH: follicle-stimulating hormone; LH: Luteinizing hormone; E2: Estradiol; T: Testosterone 4 Discussion This report is particularly important because it is the first report on the combined treatment regimen (GnRHa + rhGH + Anastrozole) for CAH patients with CPP and follow-up of their final adult height. Through long-term follow-up, the study verified the advantages of this combination therapy in improving patients' final adult height, providing a certain basis for future treatment optimization. Around 9% of individuals with 21-OHD may experience the development of CPP due to delayed or insufficient treatment[ 9 ]. The average age of CAH patients with CPP at diagnosis was 7.6 ± 1.8 years [ 20 , 21 ]. The 7 CAH patients in this study were diagnosed at 5.6 (3.5 to 7.3) years, and their bone age had advanced by 6.1 (3.5 to 7.5) years at the time of presentation. The age of diagnosis of CPP was 5.8 (5.5 to 8.7) years, and the bone age was further advanced, with a significant impairment of PAH by -3.10 (-3.75 to -2.89) SD. All children with CPP had signs of activation of the hypothalamic-pituitary-gonadal axis, including testicular enlargement in boys, breast development in girls, and gonadotropin response to GnRH stimulation during puberty. Because CPP in these patients was progressive, PAH was impaired. The target audience of this article is CAH patients with CPP who have significantly advanced bone age. In order to achieve greater height growth within a limited height growth time, this article adopts the combined treatment of GnRHa + rhGH + Anastrozole. GnRHa treatment is effective in regressing secondary sexual characteristics, suppressing the gonadal axis, and slowing skeletal maturation, and this is also true for children with other causes of CPP[ 22 , 23 ]. In 1997, AT Soliman proposed the first application of GnRHa in CAH patients with CPP[ 24 ]. Another study showed that height gain was not significantly correlated with GnRHa treatment duration, but age at the start of GnRHa treatment was significantly negatively correlated[ 25 ]. The duration of single GnRHa treatment in this article was 1.4 (0.1 to 1.7) years, and the standard deviation score of height at the end of treatment was − 2.9 (-3.70 to -1.96) SD. Single GnRHa treatment had little benefit on height, which considered to be related to the late start of treatment and the decreased height growth rate of the children in this article. rhGH is the most used drug for the treatment of short stature. It can stimulate the liver and other organs to produce insulin-like growth factor-1, and act on chondrocytes in the epiphyseal plate to promote protein synthesis and metabolism, playing an important role in promoting bone growth [ 26 ]. In the past two decades, rhGH alone or in combination with GnRHa has been shown to enhance the final adult height of CAH patients[ 8 , 11 , 25 , 27 , 28 ]. Compared with single GnRHa therapy, rhGH + GnRHa therapy increased the average growth rate from 5 ± 1.9 to 7.8 ± 1.6 cm/y [ 12 ]. It has been reported that after 2 years of rhGH + GnRHa treatment, the average PAH increased from 159 ± 11 cm to 170 ± 7.5 cm [ 12 ]. This article used rhGH + GnRHa treatment for 1.4 (0.4–3.3) years, with a height growth rate of about 6.3 (5.3–8.8) cm/y, and a height standard deviation score of -1.49 (-3.01 to 0.01) SD at the end of treatment. Compared with the previous situation, both the height growth rate and PAH were improved. Since estrogen is the primary hormone regulating epiphyseal fusion, the use of aromatase inhibitors is thought to inhibit the conversion of androgens to estrogen, slowing skeletal maturation and allowing for a longer period of growth [ 29 – 31 ]. The third-generation aromatase inhibitors, Letrozole and Anastrozole, have been shown to be safe and effective in treating short stature in children [ 32 , 33 ]. Anastrozole can delay skeletal maturation and improve final adult height in both classic and non-classic CAH [ 31 , 34 ]. A 6-year study of Anastrozole treatment for CAH showed that it increased PAH by the average of 13 cm in girls and 17 cm in boys[ 35 ]. Aromatase inhibitors can slow skeletal maturation in treating CAH, and this effect is realized without the necessity of raising hydrocortisone doses and without the manifestation of clinical symptoms related to androgen excess. Studies have shown that aromatase inhibitors combined with rhGH treatment have greater benefits in growth velocity and PAH in children and adolescents with short stature[ 32 ]. In this article, after rhGH + Anastrozole treatment 1.9 (0.3 to 2.7) years, the standard deviation score of height at the end of treatment bone age was − 1.02 (-1.83 to 0.20) SD. The height was similar to the target height when treatment was stopped. The final adult height score was − 0.28 (-1 to 1.04) SD. During aromatase treatment, liver and kidney function, blood glucose, blood lipids were all at normal levels, similar to previous reports[ 36 , 37 ]. This study has some limitations. First of all, the study sample size was small, which may have limited the representativeness and statistical significance of the findings. Another point is that a single-center study may limit the generalizability and external validity of the results. Finally, this study did not set up a control group, which may affect the accurate evaluation of CAH patient characteristics and treatment effects. In summary, the data in this article show that on the basis of conventional treatment, the regimen of rhGH + GnRHa + Anastrozole can be used for CAH children with CPP, especially those with significantly advanced bone age and impaired final adult height, to achieve the therapeutic goal of inhibiting bone age progression and increasing adult height. Abbreviations 21-OHD 21-hydroxylase deficiency Cor Cortisol CPP Central Precocious Puberty GnRHa Gonadotropin-Releasing Hormone Analogs rhGH Recombinant Human Growth Hormone SV Simple Virilizing SW Salt Wasting T Testosterone Declarations Acknowledgements All people contributed are listed as co-authors. We thank our patients for participating in the study. Conflict of interest disclosure The authors declare that they have no conflicts of interest concerning the publication of this manuscript. All authors have reviewed the contents of the manuscript, agree with its publication, and are jointly accountable for all aspects of the accuracy and integrity of the work. Ethics approval statement The data was got from medical record in our department, without disclosing personal identity information. This work was approved by Ethics Committee of Academy of Tianjin Medical University General Hospital (ZYY-IRB-SOP-019(F)-002-02). Data availability Due to patient privacy concerns, the data supporting the results of this study are not publicly available but can be obtained from the corresponding author upon reasonable request. The data are stored in a controlled access data repository at Tianjin Medical University General Hospital. Corresponding author email: [email protected] The data that support the findings of this study are available on request from the corresponding author, [initials]，upon reasonable request. Fundings This research was supported by General hospital Clinical research project (22ZYYLCCG03), Tianjin Key Medical Discipline (Specialty) Construction Project (TJWJ2022XK008, TJYXZDXK-068C), Tianjin Science and Technology Plan Project (22KPHDRC00120). Contributions RXZ and SFM conceived the idea and design of the article. FL, XXL, YYQ, and XYH performed the literature search, data acquisition, analysis and/or interpretation. FL, XXL, RXZ, and SFM drafted and critically reviewed the work. 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J Clin Endocrinol Metab. 2024;109(2):498–504. Juan L, Huamei M, Zhe S, Yanhong L, Hongshan C, Qiuli C, et al. Near-final height in 82 Chinese patients with congenital adrenal hyperplasia due to classic 21-hydroxylase deficiency: a single-center study from China. J Pediatr Endocrinol metabolism: JPEM. 2016;29(7):841–8. Rivkees SA, Crawford JD. Dexamethasone treatment of virilizing congenital adrenal hyperplasia: the ability to achieve normal growth. Pediatrics. 2000;106(4):767–73. Lin-Su K, Vogiatzi MG, Marshall I, Harbison MD, Macapagal MC, Betensky B, et al. Treatment with growth hormone and luteinizing hormone releasing hormone analog improves final adult height in children with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2005;90(6):3318–25. Tsai MM, Tsai WY, Lee CT, Liu SY, Chien YH, Tung YC. Adult height of children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Formos Med Association = Taiwan yi zhi. 2023;122(2):106–12. Li P, Li Y, Yang CL. Gonadotropin releasing hormone agonist treatment to increase final stature in children with precocious puberty: a meta-analysis. Medicine. 2014;93(27):e260. Longui CA, Kochi C, Calliari LE, Modkovski MB, Soares M, Alves EF, et al. Near-final height in patients with congenital adrenal hyperplasia treated with combined therapy using GH and GnRHa. Arq Bras Endocrinol Metabol. 2011;55(8):661–4. Quintos JB, Vogiatzi MG, Harbison MD, New MI. Growth hormone therapy alone or in combination with gonadotropin-releasing hormone analog therapy to improve the height deficit in children with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2001;86(4):1511–7. Merke DP, Keil MF, Jones JV, Fields J, Hill S, Cutler GB Jr.. Flutamide, testolactone, and reduced hydrocortisone dose maintain normal growth velocity and bone maturation despite elevated androgen levels in children with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2000;85(3):1114–20. McGrath N, O'Grady MJ. Aromatase inhibitors for short stature in male children and adolescents. The Cochrane database of systematic reviews. 2015; 2015(10):Cd010888. Speiser PW, Arlt W, Auchus RJ, Baskin LS, Conway GS, Merke DP, et al. Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(11):4043–88. Zevin EL, Eugster EA. Central precocious puberty: a review of diagnosis, treatment, and outcomes. Lancet Child Adolesc health. 2023;7(12):886–96. Martín Pérez SE, Martín Pérez IM, Vega González JM, Molina Suárez R, León Hernández C, Rodríguez Hernández F, et al. Precision and Accuracy of Radiological Bone Age Assessment in Children among Different Ethnic Groups: A Systematic Review. Diagnostics (Basel). 2023;13(19):3124. Bayley N, Pinneau SR. Tables for predicting adult height from skeletal age: revised for use with the Greulich-Pyle hand standards. J Pediatr. 1952;40(4):423–41. Luo ZC, Low LC, Karlberg J. A comparison of target height estimated and final height attained between Swedish and Hong Kong Chinese children. Acta paediatrica (Oslo, Norway: 1992). 1999; 88(3):248–252. Maheshwari A, Khadilkar V, Gangodkar P, Khadilkar A. Long-term Growth in Congenital Adrenal Hyperplasia. Indian J Pediatr. 2019;86(2):154–8. Dayal D, Aggarwal A, Seetharaman K, Muthuvel B. Central Precocious Puberty Complicating Congenital Adrenal Hyperplasia: North Indian Experience. Indian J Endocrinol Metabol. 2018;22(6):858–9. Pescovitz OH, Cassorla F, Comite F, Loriaux DL, Cutler GB Jr.. LHRH analog treatment of central precocious puberty complicating congenital adrenal hyperplasia. Ann N Y Acad Sci. 1985;458:174–81. Tung YC, Lee JS, Tsai WY, Hsiao PH. The effects of gonadotropin releasing hormone analogue therapy on girls with gonadotropin-dependent precocious puberty. J Formos Med Association = Taiwan yi zhi. 2007;106(10):826–31. Soliman AT, AlLamki M, AlSalmi I, Asfour M. Congenital adrenal hyperplasia complicated by central precocious puberty: linear growth during infancy and treatment with gonadotropin-releasing hormone analog. Metab Clin Exp. 1997;46(5):513–7. Lin-Su K, Harbison MD, Lekarev O, Vogiatzi MG, New MI. Final adult height in children with congenital adrenal hyperplasia treated with growth hormone. J Clin Endocrinol Metab. 2011;96(6):1710–7. Wang QF, Xue WY, Zhao J. Effects of recombinant human growth hormone injection combined with Anastrozole on height and growth rate of adolescent idiopathic short stature and evaluation of adverse reactions. Pak J Pharm Sci. 2024;37(6):1271–80. Muthusamy K, Elamin MB, Smushkin G, Murad MH, Lampropulos JF, Elamin KB, et al. Clinical review: Adult height in patients with congenital adrenal hyperplasia: a systematic review and metaanalysis. J Clin Endocrinol Metab. 2010;95(9):4161–72. Mauras N, Ross JL, Gagliardi P, Yu YM, Hossain J, Permuy J, et al. Randomized Trial of Aromatase Inhibitors, Growth Hormone, or Combination in Pubertal Boys with Idiopathic, Short Stature. J Clin Endocrinol Metab. 2016;101(12):4984–93. Zegarra W, Ranadive S, Toulan D, Neely EK. Anastrozole vs Letrozole to Augment Height in Pubertal Males With Idiopathic Short Stature: A 3-Year Randomized Trial. J Endocr Soc. 2024;8(10):bvae141. Halper A, Sanchez B, Hodges JS, Dengel DR, Petryk A, Sarafoglou K. Use of an aromatase inhibitor in children with congenital adrenal hyperplasia: Impact of anastrozole on bone mineral density and visceral adipose tissue. Clin Endocrinol. 2019;91(1):124–30. Goedegebuure WJ, Hokken-Koelega ACS. Aromatase Inhibitor as Treatment for Severely Advanced Bone Age in Congenital Adrenal Hyperplasia: A Case Report. Hormone Res paediatrics. 2019;92(3):209–13. Wang K, Ye F, Wang DY, Lai PJ, Zhang LQ. Aromatase inhibitors for short stature in male children and adolescents treated with growth hormone: a meta-analysis of randomized controlled trials. BMC Pediatr. 2024;24(1):813. Zhang Y, Yuan X, McCormick K, Yang XH, Chen SJ, Chen RM. The efficacy and safety of rhGH treatment combined with letrozole/GnRHa in adolescent boys. BMC Pediatr. 2025;25(1):59. Liu SC, Suresh M, Jaber M, Mercado Munoz Y, Sarafoglou K. Case Report: Anastrozole as a monotherapy for pre-pubertal children with non-classic congenital adrenal hyperplasia. Front Endocrinol. 2023;14:1101843. Al-Rayess H, Wiersma R, Turner LE, Palzer E, Mercado Munoz Y, Sarafoglou K. Anastrozole improves height outcomes in growing children with congenital adrenal hyperplasia due to 21-OHD. J Clin Endocrinol Metab. 2024. Wang Q, Zhang S, Ma X, Li G, Wang Z, Wang F. [Efficacy of letrozole in treatment of children with congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency]. Zhejiang da xue xue bao Yi xue ban = Journal of Zhejiang University Medical sciences. 2020; 49(3):302–7. Papadimitriou DT, Dermitzaki E, Papagianni M, Papaioannou G, Papaevangelou V, Papadimitriou A. Anastrozole plus leuprorelin in early maturing girls with compromised growth: the GAIL study. J Endocrinol Investig. 2016;39(4):439–46. Additional Declarations No competing interests reported. Supplementary Files Supplementarytable1.docx Cite Share Download PDF Status: Published Journal Publication published 07 May, 2025 Read the published version in BMC Pediatrics → Version 1 posted Editorial decision: Accepted 21 Apr, 2025 Reviews received at journal 16 Apr, 2025 Reviewers agreed at journal 12 Apr, 2025 Reviewers invited by journal 11 Apr, 2025 Submission checks completed at journal 08 Apr, 2025 First submitted to journal 06 Apr, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-5573763\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":442123586,\"identity\":\"39c39589-f204-4900-9208-fb503a213fe5\",\"order_by\":0,\"name\":\"Xiaoxiao Liu\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Tianjin Medical University General Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Xiaoxiao\",\"middleName\":\"\",\"lastName\":\"Liu\",\"suffix\":\"\"},{\"id\":442123588,\"identity\":\"73d2e190-c64e-4b39-999d-e67feadb11da\",\"order_by\":1,\"name\":\"Fei Liu\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Tianjin Medical University General Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Fei\",\"middleName\":\"\",\"lastName\":\"Liu\",\"suffix\":\"\"},{\"id\":442123592,\"identity\":\"b91db7ab-cef1-460a-b6f6-6952b81e225b\",\"order_by\":2,\"name\":\"Yingyi Qi\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Tianjin Medical University General Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Yingyi\",\"middleName\":\"\",\"lastName\":\"Qi\",\"suffix\":\"\"},{\"id\":442123594,\"identity\":\"10e9b60c-6cda-44c7-bc58-0be72ee77bc1\",\"order_by\":3,\"name\":\"Xinyi Han\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Tianjin Medical University General Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Xinyi\",\"middleName\":\"\",\"lastName\":\"Han\",\"suffix\":\"\"},{\"id\":442123597,\"identity\":\"61bed8f4-0dad-4b77-9262-9bdb7fb71017\",\"order_by\":4,\"name\":\"Shifeng Ma\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Tianjin Medical University General Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Shifeng\",\"middleName\":\"\",\"lastName\":\"Ma\",\"suffix\":\"\"},{\"id\":442123598,\"identity\":\"f0dd6d33-f659-4013-b323-7056c6322951\",\"order_by\":5,\"name\":\"Rongxiu Zheng\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAvElEQVRIiWNgGAWjYFACHhBhg8QmUkuaBMlaDpOgxbz/7MHHBb/O1+nOSGB88LaNQd6ckBaZA+eSjWf23ZYwu5HAbDi3jcFwZwMBLRKMPWbSvD1gLWzSvG0MCQYHCGlh5jH/zdtzDqSF/TdxWth4zJh5fhwA28JMnBYeHmNp3oZkyW1nHjZLzjknYbiBoBb+M4afef7Y8ZsdTz744U2ZjTxBW8CAsQ1MNoCMIEY9CPwhVuEoGAWjYBSMSAAA+3Q5y8xlf0oAAAAASUVORK5CYII=\",\"orcid\":\"\",\"institution\":\"Tianjin Medical University General Hospital\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Rongxiu\",\"middleName\":\"\",\"lastName\":\"Zheng\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2024-12-03 16:08:11\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-5573763/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-5573763/v1\",\"draftVersion\":[],\"editorialEvents\":[{\"content\":\"https://doi.org/10.1186/s12887-025-05703-8\",\"type\":\"published\",\"date\":\"2025-05-07T15:57:48+00:00\"}],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":80588484,\"identity\":\"a5d78726-fde5-4dbc-b63a-5f5f20812fb2\",\"added_by\":\"auto\",\"created_at\":\"2025-04-15 01:45:21\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":1091903,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003ePoint mutations and predicated function change of mutation c.79A\\u0026gt;G. \\u003c/strong\\u003eA. Distribution of mutations was identified in the study. B. Missense mutation c.79A\\u0026gt;G in patient 13. C. Pedigree chart of family 13. D. Amino acid sequences around Ser27Gly. E. The position of Ser27Gly in protein structure. Black square represents patient; Slopek circle represents carrier; Blank squares represent healthy. The black arrow shows the site of Ser27.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Figure110.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-5573763/v1/4d2627b0cff96154617b80ef.png\"},{\"id\":80588153,\"identity\":\"b69b8549-4ed8-4c3d-8afc-b2fef20b045b\",\"added_by\":\"auto\",\"created_at\":\"2025-04-15 01:37:21\",\"extension\":\"png\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":56641,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eStature SDS calculated for PAH. \\u003c/strong\\u003e1. Diagnosis of CAH; 2. Diagnosis of CPP; 3. End of single GnRHa thepary; 4. End of combined thepary (GnRHa + rhGH); 5. End of combined thepary (rhGH + Anastrozole); 6. All treatment withdrawal; 7. Target height; 8. Final height.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Figure211.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-5573763/v1/d496d697c21a9d751965014b.png\"},{\"id\":82537658,\"identity\":\"db2ff48f-cd41-466f-ae38-c4ce824bf548\",\"added_by\":\"auto\",\"created_at\":\"2025-05-12 16:09:52\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":1880152,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-5573763/v1/824befe5-a1c4-4ad6-ac73-89a9907e48ad.pdf\"},{\"id\":80587958,\"identity\":\"080df9c9-05ea-4905-8838-57911f5d6ea9\",\"added_by\":\"auto\",\"created_at\":\"2025-04-15 01:29:21\",\"extension\":\"docx\",\"order_by\":4,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":17835,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Supplementarytable1.docx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-5573763/v1/6faf991bb2e81a7e36b981d3.docx\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Combination therapy of GnRHa, rhGH and Anastrozole to improve final adult height deficit in CAH children with CPP\",\"fulltext\":[{\"header\":\"1. Introduction\",\"content\":\"\\u003cp\\u003eCongenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders, can be classified into two subtypes: classic form and non-classic form. The incidence of classic form is between 1/15,000 to 1/20,000, including salt wasting form (SW) and simple virilizing form (SV)[\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e]. SW form accounts for approximately 75% of classic cases, while the SV form accounts for 25%[\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e].21-hydroxylase deficiency (21-OHD) is the most common cause of CAH, which is caused by \\u003cem\\u003eCYP21A2\\u003c/em\\u003e gene mutations[\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e]. 21-OHD leads to the failure of 17-hydroxyprogesterone (17-OHP) to convert into corticosterone and deoxyicorticosl, resulting in a lack of cortisol (Cor) and aldosterone, excessive androgens, manifests as virilization and salt-wasting symptoms.\\u003c/p\\u003e \\u003cp\\u003eCurrently, the preferred treatment for CAH is adrenocortical hormone replacement therapy, including glucocorticoids and mineralocorticoids, which can replace insufficient adrenocortical hormone secretion, correct water and electrolyte disorders, and inhibit excessive adrenocorticotropic hormone (ACTH) synthesis[\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e]. Hydrocortisone is a glucocorticoid for growing children with a mean elimination half-life of 58 minutes, resulting in a return of adrenal steroids to pre-hydrocortisone dose concentrations after 4\\u0026ndash;5 hours[\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e]. As a result, CAH children are alternately exposed to hyper- and hypocortisolemia, resulting in elevated adrenal androgens. Chronic hyperandrogenism in prepubertal CAH patients may activate the hypothalamic-pituitary-gonadal axis and induce central precocious puberty (CPP)[\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e]. Affected children often experience accelerated linear growth during childhood with premature epiphyseal fusion, ultimately resulting in adult height below the target height established by their parents[\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e]. Numerous studies have shown that CAH patients are approximately 10 cm shorter than their parent-based target height[\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e]. A Chinese study in 2016 showed that the final adult height of classic CAH patients after receiving glucocorticoid and mineralocorticoid replacement therapy was \\u0026minus;\\u0026thinsp;1.9\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.1 SD lower than that of healthy people[\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eFor CAH patients with CPP, conventional treatment combined with gonadotropin-releasing hormone analogs (GnRHa) can effectively inhibit the development of sexual characteristics and slow down the progression of bone age by inhibiting the release of pituitary follicular stimulating hormone (FSH) and luteinizing hormone (LH)[\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e]. However, this approach is often accompanied by a deceleration in height growth. recombinant human growth hormone (rhGH) can effectively improve the height of children by stimulating chondrocyte proliferation[\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e]. The rhGH and GnRHa combined treatment has been shown to effectively improve predicted adult height (PAH)[\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e]. However, for CPP children who start treatment late, have significantly advanced bone age and impaired height growth potential, the treatment duration is limited. There is currently no ideal solution to improve their problems such as advanced bone age and impaired expected adult height.\\u003c/p\\u003e \\u003cp\\u003eIn 2000, aromatase inhibitors were first used in CAH patients[\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e]. By inhibiting the conversion of androgens to estrogens, they were able to inhibit bone age advancement and improve final adult height. In recent years, the advent of third-generation aromatase inhibitors represented by Anastrozole has further improved the inhibition rate of aromatase and reduced the incidence of adverse reactions. Studies have shown that aromatase inhibitors can improve the final adult height of children with short stature who have already started puberty or even in late puberty[\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e]. Aromatase inhibitors are expected to become a new hope for children who have missed the optimal treatment period of rhGH or GnRHa.\\u003c/p\\u003e \\u003cp\\u003eThis article retrospectively studied the clinical and genetic characteristics of classic CAH patients. This study aims to investigate the effectiveness of a combined treatment regimen (GnRHa\\u0026thinsp;+\\u0026thinsp;rhGH\\u0026thinsp;+\\u0026thinsp;Anastrozole) in enhancing final adult height in children with CAH patients with CPP.\\u003c/p\\u003e\"},{\"header\":\"2. Methods\",\"content\":\"\\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e2.1 Participants\\u003c/h2\\u003e \\u003cp\\u003eWe collected clinical data of 16 children who were diagnosed with classical CAH from 2017 to 2024 in the Pediatric Department of the Tianjin Medical University General Hospital. All patients were from northern China. Their medical records were thoroughly reviewed, including clinical manifestations, physical examinations, growth histories, laboratory examinations, treatments, and follow-ups. Inclusion criteria of the patients were: (1) met the diagnostic criteria outlined in the clinical practice guidelines of 21-OHD published by the American Society for Endocrinology in 2018[\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e];(2) follow-up for more than 2 years; (3) the clinical data were complete. Exclusion criteria were: incomplete clinical data or loss of follow-up.\\u003c/p\\u003e \\u003cp\\u003eThe diagnostic criteria for CPP include: (1) males show secondary sexual characteristics before the age of 9 (testicular volume\\u0026thinsp;\\u0026ge;\\u0026thinsp;4 mL) and females show secondary sexual characteristics before the age of 8 (breast development); (2) bone age at least 1 year advanced than the chronological age; and (3) pubertal response of LH peak\\u0026thinsp;\\u0026gt;\\u0026thinsp;5 IU/L or LH/FSH ratio\\u0026thinsp;\\u0026gt;\\u0026thinsp;0.6 after the GnRHa stimulation test[\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003e This study was approved by the Ethics Committee of the Academy of Tianjin Medical University General Hospital (ZYY-IRB-SOP-019(F)-002-02).\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec4\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e2.2 Clinical data\\u003c/h2\\u003e \\u003cp\\u003eLaboratory examinations included measurements of serum sodium (Na\\u003csup\\u003e+\\u003c/sup\\u003e), potassium (K\\u003csup\\u003e+\\u003c/sup\\u003e), Cor, aldosterone, ACTH, FSH, LH, estradiol (E2), testosterone (T), etc. These hormones were measured by the chemiluminescence method. Additionally, 17-OHP was measured using high-performance liquid chromatography-tandem mass spectrometry. Testicular or utero-ovarian ultrasound and chromosome karyotype were also conducted. Bone age was determined using the Greulich\\u0026ndash;Pyle atlas from the non-dominant hand and wrist radiographs of the patients[\\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e]. The Bayley\\u0026ndash;Pinneau method was used to figure out the PAH[\\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e]. Target height, the genetic potential in stature, is commonly estimated by the corrected midparental height method[\\u003cspan citationid=\\\"CR19\\\" class=\\\"CitationRef\\\"\\u003e19\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eGenetic testing was conducted for all participants in the study. Next-generation sequencing and multiplex ligation-dependent probe amplification (MLPA) were used for seeking \\u003cem\\u003eCYP21A2\\u003c/em\\u003e gene mutations. For \\u003cem\\u003eCYP21A2\\u003c/em\\u003e gene mutations analysis, multiple sequence alignments were performed by the UCSC database (\\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttp://genome.ucsc.edu/\\u003c/span\\u003e\\u003cspan address=\\\"http://genome.ucsc.edu/\\\" targettype=\\\"URL\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e) and Kalign (\\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://www.ebi.ac.uk/Tools/msa/kalign/\\u003c/span\\u003e\\u003cspan address=\\\"https://www.ebi.ac.uk/Tools/msa/kalign/\\\" targettype=\\\"URL\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e) to analyze the conservation of amino acid residues across different species. SWISS (\\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://swissmodel.expasy.org/interactive\\u003c/span\\u003e\\u003cspan address=\\\"https://swissmodel.expasy.org/interactive\\\" targettype=\\\"URL\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e) and PyMOL 2.2 (\\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://pymol.org/2/\\u003c/span\\u003e\\u003cspan address=\\\"https://pymol.org/2/\\\" targettype=\\\"URL\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e) were used to analyze the possible change of 21-hydroxylase structure after mutation.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec5\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e2.3 Treatment and follow-up\\u003c/h2\\u003e \\u003cp\\u003eFor CAH patients, conventional treatment includes hydrocortisone 15\\u0026ndash;20 mg/m\\u003csup\\u003e2\\u003c/sup\\u003e/d and fludrocortisone 100\\u0026ndash;150 ug/d. Children with SW\\u0026thinsp;\\u0026lt;\\u0026thinsp;1 year old can also be treated with sodium chloride 1\\u0026ndash;2 g/d. For patients with CPP and predicted impaired adult height, GnRHa (3.75 mg, Beijing Biotech) was injected subcutaneously every 4 weeks, rhGH was injected subcutaneously at a daily dose of 0.15\\u0026ndash;0.20 IU/kg/day (Jinsai, Jilin), and Anastrozole (1 mg/d, Huabang, Chongqing) was taken orally.\\u003c/p\\u003e \\u003cp\\u003ePlasma electrolytes, 17-OHP, ACTH, and body weight were monitored monthly for infants before 3 months old, then were monitored every 3 months after that age. Blood samples were taken at around 8 am before daily oral drugs. The dosage of oral hydrocortisone and fludrocortisone should be readjusted according to the examination results. Growth condition was monitored carefully for all patients. Bone age was tested every 6 months after 2 years old.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec6\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e2.4 Statistical Analysis\\u003c/h2\\u003e \\u003cp\\u003eSPSS 16.0 (SPSS Inc., Chicago, Ill., USA) was used for statistical analysis. Categorical variables were presented as percentages, whereas continuous variables were presented as medians (P25, P75). The Kruskal-Wallis test was used to analyse continuous clinical variables. Chi-square (χ\\u003csup\\u003e2\\u003c/sup\\u003e) test was used for categorical data. Each time point was compared to the final evaluation by paired t Test. Paired t-test was also used to compare the hormone levels in each treatment period with those at the beginning of combined treatment.\\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"3 Results\",\"content\":\"\\u003cdiv id=\\\"Sec8\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e3.1 Baseline characteristics\\u003c/h2\\u003e \\u003cp\\u003e16 CAH patients were included in this study. The chromosome karyotype was consistent with their social gender. All patients did not undergo neonatal screening. The symptoms of SW patients were mainly poor feeding and weight loss. Six patients developed adrenal crisis. Physical examination showed that 2 of the 4 girls had clitoromegaly (Prader 2), the other 2 girls had ambiguous external genitalia (Prader 3), and all 6 boys had scrotal pigmentation. SV patients mainly showed rapid growth and early pubic hair. The only girl diagnosed with SV in this study showed clitoromegaly (Prader 1). Laboratory tests showed that compared with SV patients, SW patients had lower Na\\u003csup\\u003e+\\u003c/sup\\u003e, higher K\\u003csup\\u003e+\\u003c/sup\\u003e, Cor, 17-OHP and T (\\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05), and no significant difference was found in ACTH (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab1\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 1\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eClinical features of patients with classical CAH\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"4\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eSW\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eSV\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003eP\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eSex (F/M)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e4/6\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1/5\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.33\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAge of diagnosis (y)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e0.1(0.9,0.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e5.3(4.9,7.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eNa\\u003csup\\u003e+\\u003c/sup\\u003e (130\\u0026ndash;150 mmol/L)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e126.2(124.7,128.35)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e139.25(136.75,140.75)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.001\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eK\\u003csup\\u003e+\\u003c/sup\\u003e (3.3\\u0026ndash;5.5 mmol/L)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e6.05(5.775,7.675)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e4.215(3.9975,4.9175)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.001\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCor (5\\u0026ndash;25 ug/dl)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e2.95(1.4,3.975)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e5.8(3.55,19.975)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.019\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eACTH (0\\u0026ndash;46 pg/ml)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e146.6(49.8,248.675)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e129.6(93.275,210.975)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.245\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e17-OHP (0.3-2.0 ng/ml)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e320.75(236.3,1433)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e231.1(108.375,259.25)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.03\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eT (\\u0026lt;\\u0026thinsp;10 nmol/L)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e209(86.25,256.75)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e180.7(93.4,297.5)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.014\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003ctfoot\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"4\\\"\\u003eNote: The Kruskal-Wallis test was used to analyse continuous clinical variables. Na\\u003csup\\u003e+\\u003c/sup\\u003e, sodium; K\\u003csup\\u003e+\\u003c/sup\\u003e, potassium; Cor, cortisol; ACTH, adrenocorticotropic hormone; 17-OHP, 17-hydroxyprogesterone; T, testosterone.\\u003c/td\\u003e\\u003c/tr\\u003e \\u003c/tfoot\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003cem\\u003eCYP21A2\\u003c/em\\u003e gene mutations were detected by MLPA. all of them were autosomal recessive inherited (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e). The mutation sites were scattered in the \\u003cem\\u003eCYP21A2\\u003c/em\\u003e gene (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003eA). Functional change of missense mutation c.79A\\u0026thinsp;\\u0026gt;\\u0026thinsp;G (p. Ser27Gly) (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003eB) had not been recorded in the Human Gene Mutation Database, Human Cytochrome P450 Allele Nomenclature Committee and 1000 genomes database yet. The patient gained missense mutations c.79A\\u0026thinsp;\\u0026gt;\\u0026thinsp;G (p. Ser27Gly) and c.518T\\u0026thinsp;\\u0026gt;\\u0026thinsp;A (p.Ile173Asn) from his mother, and obtained the null mutation p.E4-6 Del himself (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003eC). We enquired about amino acid sequences around p. Ser27Gly using the UCSC database and Kalign (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003eD) and constructed 3D structures of 21 hydroxylase by PyMol2 software (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003eE). Bioinformatic software was applied to analyze the pathogenicity of p.Ser27Gly. It was located in the N-terminal region, and the hydrophilicity of the protein was changed after mutation, which might affect the anchoring in the cell membrane and reduce the activity of the enzyme.\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab2\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 2\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eMutations of 16 patients in \\u003cem\\u003eCYP21A2\\u003c/em\\u003e gene\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"7\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c7\\\" colnum=\\\"7\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ePatient\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eAllele 1\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eLocation in \\u003cem\\u003eCYP21A2\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eprotein change\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eAllele 2\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eLocation in \\u003cem\\u003eCYP21A2\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eprotein change\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ec.293-13C\\u0026thinsp;\\u0026gt;\\u0026thinsp;G\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eIntron2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eIn2G\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003ec.293-13C\\u0026thinsp;\\u0026gt;\\u0026thinsp;G\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eIntron2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eIn2G\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ec.1451-1452delGGinsC\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eExon10\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eArg484Profs\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eE1-7 Del\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eExon1-7\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e3\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ec.293-13C\\u0026thinsp;\\u0026gt;\\u0026thinsp;G\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eIntron2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eIn2G\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003ec.293-13C\\u0026thinsp;\\u0026gt;\\u0026thinsp;G\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eIntron2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eIn2G\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e4\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ec.949C\\u0026thinsp;\\u0026gt;\\u0026thinsp;T\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eExon8\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eArg319*\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eE1-10 Del\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eExon1-10\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e5\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ec.293-13C\\u0026thinsp;\\u0026gt;\\u0026thinsp;G\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eIntron2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eIn2G\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003ec.293-13C\\u0026thinsp;\\u0026gt;\\u0026thinsp;G\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eIntron2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eIn2G\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e6\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ec.293-13C\\u0026thinsp;\\u0026gt;\\u0026thinsp;G\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eIntron2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eIn2G\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003ec.293-13C\\u0026thinsp;\\u0026gt;\\u0026thinsp;G\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eIntron2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eIn2G\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e7\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ec.710 T\\u0026thinsp;\\u0026gt;\\u0026thinsp;A\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eExon6\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eI1e237Asn\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eE1-3 Del\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eExon1-3\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e8\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ec.293-13C\\u0026thinsp;\\u0026gt;\\u0026thinsp;G\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eIntron2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eIn2G\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eE1-3 Del\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eExon1-3\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e9\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ec.710T\\u0026thinsp;\\u0026gt;\\u0026thinsp;A;\\u003c/p\\u003e \\u003cp\\u003ec.713T\\u0026thinsp;\\u0026gt;\\u0026thinsp;A;\\u003c/p\\u003e \\u003cp\\u003ec.719T\\u0026thinsp;\\u0026gt;\\u0026thinsp;A\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eExon6\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eI1e237Asn;\\u003c/p\\u003e \\u003cp\\u003eVal238Glu;\\u003c/p\\u003e \\u003cp\\u003eMet240Lys\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003ec.1069C\\u0026thinsp;\\u0026gt;\\u0026thinsp;T\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eExon8\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eArg357Trp\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e10\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ec.293-13C\\u0026thinsp;\\u0026gt;\\u0026thinsp;G\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eIntron2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eIn2G\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003ec.1069C\\u0026thinsp;\\u0026gt;\\u0026thinsp;T\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eExon8\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eArg357Trp\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e11\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ec.518T\\u0026thinsp;\\u0026gt;\\u0026thinsp;A\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eExon4\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eIle173Asn\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003ec.955C\\u0026thinsp;\\u0026gt;\\u0026thinsp;T\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eExon8\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eGln319*\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e12\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ec.518T\\u0026thinsp;\\u0026gt;\\u0026thinsp;A\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eExon4\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eIle173Asn\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003ec.606G\\u0026thinsp;\\u0026gt;\\u0026thinsp;A\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eExon5\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eTrp202*\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e13\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ec.518T\\u0026thinsp;\\u0026gt;\\u0026thinsp;A; c.79A\\u0026thinsp;\\u0026gt;\\u0026thinsp;G\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eExon4;\\u003c/p\\u003e \\u003cp\\u003eExon1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eIle173Asn;\\u003c/p\\u003e \\u003cp\\u003eSer27Gly\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eE4-7 Del\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eExon4-7\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e14\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ec.518T\\u0026thinsp;\\u0026gt;\\u0026thinsp;A\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eExon4\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eIle173Asn\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003ec.293-13C\\u0026thinsp;\\u0026gt;\\u0026thinsp;G\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eIntron2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eIn2G\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e15\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ec.518T\\u0026thinsp;\\u0026gt;\\u0026thinsp;A\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eExon4\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eIle173Asn\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003ec.1225C\\u0026thinsp;\\u0026gt;\\u0026thinsp;G\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eExon10\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eArg409Gly\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e16\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ec.518T\\u0026thinsp;\\u0026gt;\\u0026thinsp;A\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eExon4\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eIle173Asn\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003ec.1306C\\u0026thinsp;\\u0026gt;\\u0026thinsp;T\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eExon10\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eArg434Cys\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec9\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e3.2 Complicated with CPP\\u003c/h2\\u003e \\u003cp\\u003eSeven children have been diagnosed with CPP in this study, including 2 SW (M:F\\u0026thinsp;=\\u0026thinsp;1:1) and 5 SV (M:F\\u0026thinsp;=\\u0026thinsp;4:1). We observed that the age of diagnosis CPP was 5.6 (3.5 to 7.3) years, representing a group of patients with delayed disease recognition. Ovarian and follicular enlargement occurred before 7.5 years in girls and penile and testicular growth occurred before 9 years in boys. LH and FSH were elevated, and LH peak/FSH peak higher than 0.6. At the time of diagnosis of CPP, the bone age had significantly improved by 6.3 (4.1 to 7.7) years, and PAH was \\u0026minus;\\u0026thinsp;3.10 (-3.75 to -2.89) SD.\\u003c/p\\u003e \\u003cp\\u003eThe data of chronological age and bone age progression observed at each time point during treatment are shown in Table\\u0026nbsp;\\u003cspan refid=\\\"Tab3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e. The ages at which CAH patients with CPP started to be treated with GnRHa, rhGH and Anastrozole were 5.8 (5.5 to 8.7), 7.1 (5.5 to 9.8), 8.7 (7.6 to 10.7) years old, and discontinued them at 8.8 (7.5 to 10.2), 10.4 (9.0 to 12.7), 11.0 (9.7 to 12.7) years old, respectively. The duration of single GnRHa treatment was 1.4 (0.1 to 1.7) years, during which no further bone age progression was observed. At 1.4 (0.4 to 3.3) years of GnRHa\\u0026thinsp;+\\u0026thinsp;rhGH treatment, bone age progression decreased significantly to 4.9 years. At the end of 1.9 (0.3 to 2.7) years of rhGH\\u0026thinsp;+\\u0026thinsp;Anastrozole treatment, bone age decreased significantly to 4.3 years and remained near this value until the end of clinical evaluation.\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab3\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 3\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eChronological age and bone age advancement (years) in CAH patients\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"6\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e \\u003cth align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c3\\\" namest=\\\"c2\\\"\\u003e \\u003cp\\u003eChronological age (y)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e \\u003cth align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c6\\\" namest=\\\"c5\\\"\\u003e \\u003cp\\u003eBone age advancement (y)\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eMedian\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eRange\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eMedian\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eRange\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eDiagnosis\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e5.6\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e3.5\\u0026ndash;7.3\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e6.1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e3.5\\u0026ndash;7.5\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eStart of GnRHa\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e5.8\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e5.5\\u0026ndash;8.7\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e6.3\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e4.1\\u0026ndash;7.7\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eStart of rhGH\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e7.1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e5.5\\u0026ndash;9.8\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e5.9\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e3.3\\u0026ndash;6.4\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eStart of Anastrozole\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e8.7\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e7.6\\u0026ndash;10.7\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e4.8\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e3.1\\u0026ndash;6.4\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ewithdrawal GnRHa\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e8.8\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e7.5\\u0026ndash;10.2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e4.9\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e3.0-6.4\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ewithdrawal rhGH\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e10.4\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e9.0-12.7\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e4.5\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e2.5\\u0026ndash;4.9\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ewithdrawal Anastrozole\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e11.0\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e9.7\\u0026ndash;12.7\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e4.3\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e2.5\\u0026ndash;5.3\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eFinal height\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e11.4\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e11.2\\u0026ndash;13.9\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e4.1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e2.9\\u0026ndash;5.1\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003ctfoot\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"6\\\"\\u003eNote: Bone age advancement (y)\\u0026thinsp;=\\u0026thinsp;bone age (y) - chronological age (y).\\u003c/td\\u003e\\u003c/tr\\u003e \\u003c/tfoot\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003eThe key height indicators of CAH patients with CPP are detailed in supplementary table \\u003cspan refid=\\\"MOESM1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e. Comparison of each time point during treatment with the final height assessment showed a gradual increase in height (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e). From diagnosis to the end of single GnRHa therapy, predicted height decreased significantly relative to height close to the final level (\\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001). At the end of GnRHa\\u0026thinsp;+\\u0026thinsp;rhGH therapy, height decreased significantly relative to height close to the final level (\\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.004). At the end of rhGH\\u0026thinsp;+\\u0026thinsp;Anastrozole therapy, height still differed relative to final height (\\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.011). There was no difference in height relative to final height at the time of discontinuation of adjuvant therapy (\\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.063). The final height assessment was similar to the target height (\\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.478).\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003cp\\u003eThe results of pituitary-gonadal axis hormone levels in male children during different treatment periods are shown in Table\\u0026nbsp;\\u003cspan refid=\\\"Tab4\\\" class=\\\"InternalRef\\\"\\u003e4\\u003c/span\\u003e. During the GnRHa treatment period, FSH and LH decreased (both \\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05), indicating that GnRHa treatment was effective. At the end of GnRHa treatment, sex hormone status was at puberty levels. During the Anastrozole treatment period, FSH and LH increased slightly, but there was no statistical difference, and the decrease in E2 (\\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.01), which was considered to be related to the addition of Anastrozole. There were only 2 cases in the female group, which were not analyzed. During the treatment period, the children did not experience symptoms such as hirsutism, severe acne, nausea, headache, bone pain, obesity, or hypertension, nor did they feel fatigued, regular monitoring of lipid profiles, electrolytes, liver function, kidney function, and coagulation function all yielded normal results.\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab4\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 4\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eChanges in sex hormones after treatment\\u003c/b\\u003e.\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"5\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eTreatment period\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eFSH(U/L)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eLH(U/L)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eE2(pmol/L)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eT(nmol/L)\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eDiagnosis of CPP\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e2.1(1.5-3.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1.2(0.8\\u0026ndash;1.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e13.0(10.3\\u0026ndash;15.5)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e22.0(12.8\\u0026ndash;50.5)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eGnRHa treatment period\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e0.4(0.1\\u0026ndash;0.6) *\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0.2(0.1\\u0026ndash;0.4) *\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e5.5(4.2\\u0026ndash;15.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e11.3(11.1\\u0026ndash;22.1) *\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eEnd of GnRHa treatment\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e1.9(1.6\\u0026ndash;3.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1.1(1.0-1.7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e35.5(25.5\\u0026ndash;50.3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e17.0(10.7\\u0026ndash;20.8)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAnastrozole treatment period\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e2.2(1.7\\u0026ndash;2.8)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1.2(1.3\\u0026ndash;1.8)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e6.5(5.7\\u0026ndash;13.6) **\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e30.3(25.0-60.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003e Note: The Paired t-test was used to compare the hormone levels in each treatment period with those at the beginning of combined treatment. *:\\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05; **:\\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.01. FSH: follicle-stimulating hormone; LH: Luteinizing hormone; E2: Estradiol; T: Testosterone\\u003c/div\\u003e\"},{\"header\":\"4 Discussion\",\"content\":\"\\u003cp\\u003eThis report is particularly important because it is the first report on the combined treatment regimen (GnRHa\\u0026thinsp;+\\u0026thinsp;rhGH\\u0026thinsp;+\\u0026thinsp;Anastrozole) for CAH patients with CPP and follow-up of their final adult height. Through long-term follow-up, the study verified the advantages of this combination therapy in improving patients' final adult height, providing a certain basis for future treatment optimization.\\u003c/p\\u003e \\u003cp\\u003eAround 9% of individuals with 21-OHD may experience the development of CPP due to delayed or insufficient treatment[\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e]. The average age of CAH patients with CPP at diagnosis was 7.6\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.8 years [\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e]. The 7 CAH patients in this study were diagnosed at 5.6 (3.5 to 7.3) years, and their bone age had advanced by 6.1 (3.5 to 7.5) years at the time of presentation. The age of diagnosis of CPP was 5.8 (5.5 to 8.7) years, and the bone age was further advanced, with a significant impairment of PAH by -3.10 (-3.75 to -2.89) SD. All children with CPP had signs of activation of the hypothalamic-pituitary-gonadal axis, including testicular enlargement in boys, breast development in girls, and gonadotropin response to GnRH stimulation during puberty. Because CPP in these patients was progressive, PAH was impaired. The target audience of this article is CAH patients with CPP who have significantly advanced bone age. In order to achieve greater height growth within a limited height growth time, this article adopts the combined treatment of GnRHa\\u0026thinsp;+\\u0026thinsp;rhGH\\u0026thinsp;+\\u0026thinsp;Anastrozole.\\u003c/p\\u003e \\u003cp\\u003eGnRHa treatment is effective in regressing secondary sexual characteristics, suppressing the gonadal axis, and slowing skeletal maturation, and this is also true for children with other causes of CPP[\\u003cspan citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e]. In 1997, AT Soliman proposed the first application of GnRHa in CAH patients with CPP[\\u003cspan citationid=\\\"CR24\\\" class=\\\"CitationRef\\\"\\u003e24\\u003c/span\\u003e]. Another study showed that height gain was not significantly correlated with GnRHa treatment duration, but age at the start of GnRHa treatment was significantly negatively correlated[\\u003cspan citationid=\\\"CR25\\\" class=\\\"CitationRef\\\"\\u003e25\\u003c/span\\u003e]. The duration of single GnRHa treatment in this article was 1.4 (0.1 to 1.7) years, and the standard deviation score of height at the end of treatment was \\u0026minus;\\u0026thinsp;2.9 (-3.70 to -1.96) SD. Single GnRHa treatment had little benefit on height, which considered to be related to the late start of treatment and the decreased height growth rate of the children in this article.\\u003c/p\\u003e \\u003cp\\u003erhGH is the most used drug for the treatment of short stature. It can stimulate the liver and other organs to produce insulin-like growth factor-1, and act on chondrocytes in the epiphyseal plate to promote protein synthesis and metabolism, playing an important role in promoting bone growth [\\u003cspan citationid=\\\"CR26\\\" class=\\\"CitationRef\\\"\\u003e26\\u003c/span\\u003e]. In the past two decades, rhGH alone or in combination with GnRHa has been shown to enhance the final adult height of CAH patients[\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR25\\\" class=\\\"CitationRef\\\"\\u003e25\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR27\\\" class=\\\"CitationRef\\\"\\u003e27\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR28\\\" class=\\\"CitationRef\\\"\\u003e28\\u003c/span\\u003e]. Compared with single GnRHa therapy, rhGH\\u0026thinsp;+\\u0026thinsp;GnRHa therapy increased the average growth rate from 5\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.9 to 7.8\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.6 cm/y [\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e]. It has been reported that after 2 years of rhGH\\u0026thinsp;+\\u0026thinsp;GnRHa treatment, the average PAH increased from 159\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;11 cm to 170\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;7.5 cm [\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e]. This article used rhGH\\u0026thinsp;+\\u0026thinsp;GnRHa treatment for 1.4 (0.4\\u0026ndash;3.3) years, with a height growth rate of about 6.3 (5.3\\u0026ndash;8.8) cm/y, and a height standard deviation score of -1.49 (-3.01 to 0.01) SD at the end of treatment. Compared with the previous situation, both the height growth rate and PAH were improved.\\u003c/p\\u003e \\u003cp\\u003eSince estrogen is the primary hormone regulating epiphyseal fusion, the use of aromatase inhibitors is thought to inhibit the conversion of androgens to estrogen, slowing skeletal maturation and allowing for a longer period of growth [\\u003cspan additionalcitationids=\\\"CR30\\\" citationid=\\\"CR29\\\" class=\\\"CitationRef\\\"\\u003e29\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR31\\\" class=\\\"CitationRef\\\"\\u003e31\\u003c/span\\u003e]. The third-generation aromatase inhibitors, Letrozole and Anastrozole, have been shown to be safe and effective in treating short stature in children [\\u003cspan citationid=\\\"CR32\\\" class=\\\"CitationRef\\\"\\u003e32\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR33\\\" class=\\\"CitationRef\\\"\\u003e33\\u003c/span\\u003e]. Anastrozole can delay skeletal maturation and improve final adult height in both classic and non-classic CAH [\\u003cspan citationid=\\\"CR31\\\" class=\\\"CitationRef\\\"\\u003e31\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR34\\\" class=\\\"CitationRef\\\"\\u003e34\\u003c/span\\u003e]. A 6-year study of Anastrozole treatment for CAH showed that it increased PAH by the average of 13 cm in girls and 17 cm in boys[\\u003cspan citationid=\\\"CR35\\\" class=\\\"CitationRef\\\"\\u003e35\\u003c/span\\u003e]. Aromatase inhibitors can slow skeletal maturation in treating CAH, and this effect is realized without the necessity of raising hydrocortisone doses and without the manifestation of clinical symptoms related to androgen excess. Studies have shown that aromatase inhibitors combined with rhGH treatment have greater benefits in growth velocity and PAH in children and adolescents with short stature[\\u003cspan citationid=\\\"CR32\\\" class=\\\"CitationRef\\\"\\u003e32\\u003c/span\\u003e]. In this article, after rhGH\\u0026thinsp;+\\u0026thinsp;Anastrozole treatment 1.9 (0.3 to 2.7) years, the standard deviation score of height at the end of treatment bone age was \\u0026minus;\\u0026thinsp;1.02 (-1.83 to 0.20) SD. The height was similar to the target height when treatment was stopped. The final adult height score was \\u0026minus;\\u0026thinsp;0.28 (-1 to 1.04) SD. During aromatase treatment, liver and kidney function, blood glucose, blood lipids were all at normal levels, similar to previous reports[\\u003cspan citationid=\\\"CR36\\\" class=\\\"CitationRef\\\"\\u003e36\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR37\\\" class=\\\"CitationRef\\\"\\u003e37\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eThis study has some limitations. First of all, the study sample size was small, which may have limited the representativeness and statistical significance of the findings. Another point is that a single-center study may limit the generalizability and external validity of the results. Finally, this study did not set up a control group, which may affect the accurate evaluation of CAH patient characteristics and treatment effects.\\u003c/p\\u003e \\u003cp\\u003eIn summary, the data in this article show that on the basis of conventional treatment, the regimen of rhGH\\u0026thinsp;+\\u0026thinsp;GnRHa\\u0026thinsp;+\\u0026thinsp;Anastrozole can be used for CAH children with CPP, especially those with significantly advanced bone age and impaired final adult height, to achieve the therapeutic goal of inhibiting bone age progression and increasing adult height.\\u003c/p\\u003e\"},{\"header\":\"Abbreviations\",\"content\":\"\\u003cdiv class=\\\"DefinitionList\\\"\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003e\\u003cb\\u003e21-OHD\\u003c/b\\u003e\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003e21-hydroxylase deficiency\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003e\\u003cb\\u003eCor\\u003c/b\\u003e\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eCortisol\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003e\\u003cb\\u003eCPP\\u003c/b\\u003e\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eCentral Precocious Puberty\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003e\\u003cb\\u003eGnRHa\\u003c/b\\u003e\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eGonadotropin-Releasing Hormone Analogs\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003e\\u003cb\\u003erhGH\\u003c/b\\u003e\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eRecombinant Human Growth Hormone\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003e\\u003cb\\u003eSV\\u003c/b\\u003e\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eSimple Virilizing\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003e\\u003cb\\u003eSW\\u003c/b\\u003e\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eSalt Wasting\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003e\\u003cb\\u003eT\\u003c/b\\u003e\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eTestosterone\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003c/div\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eAcknowledgements\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eAll people contributed are listed as co-authors. We thank our patients for participating in the study.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConflict of interest disclosure\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe authors declare that they have no conflicts of interest concerning the publication of this manuscript. All authors have reviewed the contents of the manuscript, agree with its publication, and are jointly accountable for all aspects of the accuracy and integrity of the work.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eEthics approval statement\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe data was got from medical record in our department, without disclosing personal identity information. This work was approved by Ethics Committee of Academy of Tianjin Medical University General Hospital (ZYY-IRB-SOP-019(F)-002-02).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eData availability\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eDue to patient privacy concerns, the data supporting the results of this study are not publicly available but can be obtained from the corresponding author upon reasonable request. The data are stored in a controlled access data repository at Tianjin Medical University General Hospital. Corresponding author email: rzheng@tmu.edu.cn\\u003c/p\\u003e\\n\\u003cp\\u003eThe data that support the findings of this study are available on request from the corresponding author, [initials]，upon reasonable request.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFundings\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis research was supported by General hospital Clinical research project (22ZYYLCCG03), Tianjin Key Medical Discipline (Specialty) Construction Project (TJWJ2022XK008, TJYXZDXK-068C), Tianjin Science and Technology Plan Project (22KPHDRC00120).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eContributions\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eRXZ and SFM conceived the idea and design of the article. FL, XXL, YYQ, and XYH performed the literature search, data acquisition, analysis and/or interpretation. FL, XXL, RXZ, and SFM drafted and critically reviewed the work. All the authors have read and approved the final version.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConsent for publication\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eNot applicable.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCompeting interests\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe authors declare no competing interests.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\u003cli\\u003e\\u003cspan\\u003eBacila IA, Lawrence NR, Badrinath SG, Balagamage C, Krone NP. Biomarkers in congenital adrenal hyperplasia. Clin Endocrinol. 2024;101(4):300\\u0026ndash;10.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eBaumgartner-Parzer S, Witsch-Baumgartner M, Hoeppner W. EMQN best practice guidelines for molecular genetic testing and reporting of 21-hydroxylase deficiency. Eur J Hum genetics: EJHG. 2020;28(10):1341\\u0026ndash;67.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eItonaga T, Hasegawa Y. Monitoring treatment in pediatric patients with 21-hydroxylase deficiency. Front Endocrinol. 2023;14:1102741.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eDebono M, Price JN, Ross RJ. Novel strategies for hydrocortisone replacement. Best practice \\u0026amp; research Clinical endocrinology \\u0026amp; metabolism. 2009; 23(2):221\\u0026ndash;232.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eFlokas ME, Wakim P, Kollender S, Sinaii N, Merke DP. Gonadotropin-Releasing Hormone Agonist Therapy and Longitudinal Bone Mineral Density in Congenital Adrenal Hyperplasia. J Clin Endocrinol Metab. 2024;109(2):498\\u0026ndash;504.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eJuan L, Huamei M, Zhe S, Yanhong L, Hongshan C, Qiuli C, et al. Near-final height in 82 Chinese patients with congenital adrenal hyperplasia due to classic 21-hydroxylase deficiency: a single-center study from China. J Pediatr Endocrinol metabolism: JPEM. 2016;29(7):841\\u0026ndash;8.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eRivkees SA, Crawford JD. Dexamethasone treatment of virilizing congenital adrenal hyperplasia: the ability to achieve normal growth. Pediatrics. 2000;106(4):767\\u0026ndash;73.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eLin-Su K, Vogiatzi MG, Marshall I, Harbison MD, Macapagal MC, Betensky B, et al. Treatment with growth hormone and luteinizing hormone releasing hormone analog improves final adult height in children with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2005;90(6):3318\\u0026ndash;25.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eTsai MM, Tsai WY, Lee CT, Liu SY, Chien YH, Tung YC. Adult height of children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Formos Med Association = Taiwan yi zhi. 2023;122(2):106\\u0026ndash;12.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eLi P, Li Y, Yang CL. Gonadotropin releasing hormone agonist treatment to increase final stature in children with precocious puberty: a meta-analysis. Medicine. 2014;93(27):e260.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eLongui CA, Kochi C, Calliari LE, Modkovski MB, Soares M, Alves EF, et al. Near-final height in patients with congenital adrenal hyperplasia treated with combined therapy using GH and GnRHa. Arq Bras Endocrinol Metabol. 2011;55(8):661\\u0026ndash;4.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eQuintos JB, Vogiatzi MG, Harbison MD, New MI. Growth hormone therapy alone or in combination with gonadotropin-releasing hormone analog therapy to improve the height deficit in children with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2001;86(4):1511\\u0026ndash;7.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eMerke DP, Keil MF, Jones JV, Fields J, Hill S, Cutler GB Jr.. Flutamide, testolactone, and reduced hydrocortisone dose maintain normal growth velocity and bone maturation despite elevated androgen levels in children with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2000;85(3):1114\\u0026ndash;20.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eMcGrath N, O'Grady MJ. Aromatase inhibitors for short stature in male children and adolescents. The Cochrane database of systematic reviews. 2015; 2015(10):Cd010888.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSpeiser PW, Arlt W, Auchus RJ, Baskin LS, Conway GS, Merke DP, et al. Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(11):4043\\u0026ndash;88.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eZevin EL, Eugster EA. Central precocious puberty: a review of diagnosis, treatment, and outcomes. Lancet Child Adolesc health. 2023;7(12):886\\u0026ndash;96.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eMart\\u0026iacute;n P\\u0026eacute;rez SE, Mart\\u0026iacute;n P\\u0026eacute;rez IM, Vega Gonz\\u0026aacute;lez JM, Molina Su\\u0026aacute;rez R, Le\\u0026oacute;n Hern\\u0026aacute;ndez C, Rodr\\u0026iacute;guez Hern\\u0026aacute;ndez F, et al. Precision and Accuracy of Radiological Bone Age Assessment in Children among Different Ethnic Groups: A Systematic Review. Diagnostics (Basel). 2023;13(19):3124.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eBayley N, Pinneau SR. Tables for predicting adult height from skeletal age: revised for use with the Greulich-Pyle hand standards. J Pediatr. 1952;40(4):423\\u0026ndash;41.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eLuo ZC, Low LC, Karlberg J. A comparison of target height estimated and final height attained between Swedish and Hong Kong Chinese children. Acta paediatrica (Oslo, Norway: 1992). 1999; 88(3):248\\u0026ndash;252.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eMaheshwari A, Khadilkar V, Gangodkar P, Khadilkar A. Long-term Growth in Congenital Adrenal Hyperplasia. Indian J Pediatr. 2019;86(2):154\\u0026ndash;8.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eDayal D, Aggarwal A, Seetharaman K, Muthuvel B. Central Precocious Puberty Complicating Congenital Adrenal Hyperplasia: North Indian Experience. Indian J Endocrinol Metabol. 2018;22(6):858\\u0026ndash;9.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003ePescovitz OH, Cassorla F, Comite F, Loriaux DL, Cutler GB Jr.. LHRH analog treatment of central precocious puberty complicating congenital adrenal hyperplasia. Ann N Y Acad Sci. 1985;458:174\\u0026ndash;81.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eTung YC, Lee JS, Tsai WY, Hsiao PH. The effects of gonadotropin releasing hormone analogue therapy on girls with gonadotropin-dependent precocious puberty. J Formos Med Association = Taiwan yi zhi. 2007;106(10):826\\u0026ndash;31.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSoliman AT, AlLamki M, AlSalmi I, Asfour M. Congenital adrenal hyperplasia complicated by central precocious puberty: linear growth during infancy and treatment with gonadotropin-releasing hormone analog. Metab Clin Exp. 1997;46(5):513\\u0026ndash;7.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eLin-Su K, Harbison MD, Lekarev O, Vogiatzi MG, New MI. Final adult height in children with congenital adrenal hyperplasia treated with growth hormone. J Clin Endocrinol Metab. 2011;96(6):1710\\u0026ndash;7.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eWang QF, Xue WY, Zhao J. Effects of recombinant human growth hormone injection combined with Anastrozole on height and growth rate of adolescent idiopathic short stature and evaluation of adverse reactions. Pak J Pharm Sci. 2024;37(6):1271\\u0026ndash;80.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eMuthusamy K, Elamin MB, Smushkin G, Murad MH, Lampropulos JF, Elamin KB, et al. Clinical review: Adult height in patients with congenital adrenal hyperplasia: a systematic review and metaanalysis. J Clin Endocrinol Metab. 2010;95(9):4161\\u0026ndash;72.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eMauras N, Ross JL, Gagliardi P, Yu YM, Hossain J, Permuy J, et al. Randomized Trial of Aromatase Inhibitors, Growth Hormone, or Combination in Pubertal Boys with Idiopathic, Short Stature. J Clin Endocrinol Metab. 2016;101(12):4984\\u0026ndash;93.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eZegarra W, Ranadive S, Toulan D, Neely EK. Anastrozole vs Letrozole to Augment Height in Pubertal Males With Idiopathic Short Stature: A 3-Year Randomized Trial. J Endocr Soc. 2024;8(10):bvae141.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eHalper A, Sanchez B, Hodges JS, Dengel DR, Petryk A, Sarafoglou K. Use of an aromatase inhibitor in children with congenital adrenal hyperplasia: Impact of anastrozole on bone mineral density and visceral adipose tissue. Clin Endocrinol. 2019;91(1):124\\u0026ndash;30.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eGoedegebuure WJ, Hokken-Koelega ACS. Aromatase Inhibitor as Treatment for Severely Advanced Bone Age in Congenital Adrenal Hyperplasia: A Case Report. Hormone Res paediatrics. 2019;92(3):209\\u0026ndash;13.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eWang K, Ye F, Wang DY, Lai PJ, Zhang LQ. Aromatase inhibitors for short stature in male children and adolescents treated with growth hormone: a meta-analysis of randomized controlled trials. BMC Pediatr. 2024;24(1):813.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eZhang Y, Yuan X, McCormick K, Yang XH, Chen SJ, Chen RM. The efficacy and safety of rhGH treatment combined with letrozole/GnRHa in adolescent boys. BMC Pediatr. 2025;25(1):59.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eLiu SC, Suresh M, Jaber M, Mercado Munoz Y, Sarafoglou K. Case Report: Anastrozole as a monotherapy for pre-pubertal children with non-classic congenital adrenal hyperplasia. Front Endocrinol. 2023;14:1101843.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eAl-Rayess H, Wiersma R, Turner LE, Palzer E, Mercado Munoz Y, Sarafoglou K. Anastrozole improves height outcomes in growing children with congenital adrenal hyperplasia due to 21-OHD. J Clin Endocrinol Metab. 2024.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eWang Q, Zhang S, Ma X, Li G, Wang Z, Wang F. [Efficacy of letrozole in treatment of children with congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency]. Zhejiang da xue xue bao Yi xue ban\\u0026thinsp;=\\u0026thinsp;Journal of Zhejiang University Medical sciences. 2020; 49(3):302\\u0026ndash;7.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003ePapadimitriou DT, Dermitzaki E, Papagianni M, Papaioannou G, Papaevangelou V, Papadimitriou A. Anastrozole plus leuprorelin in early maturing girls with compromised growth: the GAIL study. J Endocrinol Investig. 2016;39(4):439\\u0026ndash;46.\\u003c/span\\u003e\\u003c/li\\u003e\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":true,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"bmc-pediatrics\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"bped\",\"sideBox\":\"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)\",\"snPcode\":\"\",\"submissionUrl\":\"https://www.editorialmanager.com/bped/default.aspx\",\"title\":\"BMC Pediatrics\",\"twitterHandle\":\"BMC_series\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"BMC Series\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true},\"keywords\":\"21 hydroxylase deficiency, CYP21A2 gene, central precocious puberty, GnRHa, rhGH, Anastrozole\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-5573763/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-5573763/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003ch2\\u003eBackground\\u003c/h2\\u003e \\u003cp\\u003eTo investigate the clinical and genetic characteristics of classic congenital adrenal hyperplasia (CAH) patients. To determine whether gonadotropin-releasing hormone analogs (GnRHa)\\u0026thinsp;+\\u0026thinsp;recombinant human growth hormone (rhGH)\\u0026thinsp;+\\u0026thinsp;Anastrozole combined therapy improves the final adult height of CAH patients with central precocious puberty (CPP).\\u003c/p\\u003e\\u003ch2\\u003eMethods\\u003c/h2\\u003e \\u003cp\\u003eWe described the clinical and genetic characteristics of 16 classic CAH patients, and performed pathogenic analysis and structural modeling of the newly discovered mutation. By using the method of self-before and after control, we statistically analyzed bone age advancement, predicted adult height (PAH) and other indicators of 7 CAH children with CPP before and after combined treatment to observe its effect on adult height.\\u003c/p\\u003e\\u003ch2\\u003eResults\\u003c/h2\\u003e \\u003cp\\u003eAll patients showed high levels of 17-hydroxyprogesterone, testosterone and adrenocorticotropic hormone. All patients had \\u003cem\\u003eCYP21A2\\u003c/em\\u003e gene mutations, and the newly discovered mutation c.79A\\u0026thinsp;\\u0026gt;\\u0026thinsp;G (p.Ser27Gly) may change the hydrophilicity of the protein and affect its function. Seven CAH patients with CPP were diagnosed at 5.6 (3.5 to 7.3) years. Their target height was 0.18 (-1.2 to 0.78) SD, and The PAH at the start of treatment was \\u0026minus;\\u0026thinsp;3.01 (-3.75 to -2.89) SD. The ages at which CAH patients with CPP started to be treated with GnRHa, rhGH and Anastrozole were 5.8 (5.5 to 8.7), 7.1 (5.5 to 9.8), 8.7 (7.6 to 10.7) years old, and discontinued them at 8.8 (7.5 to 10.2), 10.4 (9.0 to 12.7), 11.0 (9.7 to 12.7) years old, respectively. The PAH at treatment end was \\u0026minus;\\u0026thinsp;0.28 (-1.2 to 0.4) SD. The final height was \\u0026minus;\\u0026thinsp;0.28 (-1 to 1.04) SD, significantly higher than the initial PAH (\\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001) and similar to the target height (\\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.478).\\u003c/p\\u003e\\u003ch2\\u003eConclusion\\u003c/h2\\u003e \\u003cp\\u003eGnRHa\\u0026thinsp;+\\u0026thinsp;rhGH\\u0026thinsp;+\\u0026thinsp;Anastrozole therapy can improve the final adult height of CAH patients with CPP. In addition, this study also discovered a new \\u003cem\\u003eCYP21A2\\u003c/em\\u003e gene mutation c.79A\\u0026thinsp;\\u0026gt;\\u0026thinsp;G.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Combination therapy of GnRHa, rhGH and Anastrozole to improve final adult height deficit in CAH children with CPP\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2025-04-15 01:21:16\",\"doi\":\"10.21203/rs.3.rs-5573763/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"decision\",\"content\":\"Accepted\",\"date\":\"2025-04-21T07:32:56+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2025-04-16T19:31:33+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"70730057589435911847931259744091163511\",\"date\":\"2025-04-12T19:29:27+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewersInvited\",\"content\":\"\",\"date\":\"2025-04-11T08:23:59+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"checksComplete\",\"content\":\"\",\"date\":\"2025-04-08T14:36:54+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"BMC Pediatrics\",\"date\":\"2025-04-06T20:32:03+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"bmc-pediatrics\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"bped\",\"sideBox\":\"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)\",\"snPcode\":\"\",\"submissionUrl\":\"https://www.editorialmanager.com/bped/default.aspx\",\"title\":\"BMC Pediatrics\",\"twitterHandle\":\"BMC_series\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"BMC Series\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"396f7209-31ff-4e5a-9290-ef34e16ccf90\",\"owner\":[],\"postedDate\":\"April 15th, 2025\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"published-in-journal\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2025-05-12T16:06:37+00:00\",\"versionOfRecord\":{\"articleIdentity\":\"rs-5573763\",\"link\":\"https://doi.org/10.1186/s12887-025-05703-8\",\"journal\":{\"identity\":\"bmc-pediatrics\",\"isVorOnly\":false,\"title\":\"BMC Pediatrics\"},\"publishedOn\":\"2025-05-07 15:57:48\",\"publishedOnDateReadable\":\"May 7th, 2025\"},\"versionCreatedAt\":\"2025-04-15 01:21:16\",\"video\":\"\",\"vorDoi\":\"10.1186/s12887-025-05703-8\",\"vorDoiUrl\":\"https://doi.org/10.1186/s12887-025-05703-8\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-5573763\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-5573763\",\"identity\":\"rs-5573763\",\"version\":[\"v1\"]},\"buildId\":\"XKTyCvWXoU3ODBz1xrDgd\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}