Pubertal characteristics, final height, and associated factors in patients with nonclassical congenital adrenal hyperplasia: a single center experience

Introduction

Non-classical congenital adrenal hyperplasia (NCCAH) is an autosomal recessive disorder most commonly resulting from partial deficiency of 21-hydroxylase, an enzyme involved in adrenal steroidogenesis, although defects in other enzymes have also been reported. Mutations in the CYP21A2 gene, especially c.844G>T (p.Val282Leu), c.92C>T (p.Pro31Leu), and c.1360C>T (p.Pro454Ser), are the most common causes of this enzymatic impairment [1], [2], [3]. In NCCAH, residual 21-hydroxylase activity ranges between 20 and 70 %, and approximately 25–50 % of patients are homozygous or compound heterozygous for two mild alleles. The global incidence of NCCAH is estimated at one in 1.000 live births [4]. Unlike classical forms, NCCAH does not typically present with adrenal insufficiency. Clinical manifestations usually develop in late childhood, adolescence, or even adulthood and are primarily attributed to hyperandrogenism. Premature pubarche is the earliest and most common clinical sign, occurring in approximately 92 % of affected children, particularly in girls before age eight and boys before age 9 [5]. Other signs include accelerated growth velocity, advanced bone age, hirsutism, cystic acne, menstrual irregularities, and, less commonly, alopecia. Male patients may remain asymptomatic, making diagnosis more challenging [2]. Glucocorticoid therapy is reserved for symptomatic individuals and aims to suppress excessive adrenal androgen production [6], 7].

The age at which puberty and menarche begin in NCCAH females receiving glucocorticoid treatment is considered normal [8], 9]. If NCCAH patients are left untreated, they may reach puberty sooner than the normal population, which might impact their final height and cause them to be short [1]. Chronically high levels of adrenal androgens can also raise the frequency of the GnRH pulse in GnRH neurons, which may activate the pituitary–gonadal axis and cause puberty to start early. Central precocious puberty (CPP) might be the first sign of NCCAH [10].

Although many children with NCCAH achieve adult heights within their genetically determined target ranges, advanced bone age and delayed diagnosis may impair growth potential [2], 11]. Evidence suggests that earlier diagnosis and milder phenotypes are associated with more favorable height outcomes [12].

In this study, we aim to evaluate the clinical, auxological, and metabolic characteristics of NCCAH patients who have reached their final height, focusing on identifying key factors influencing growth and pubertal progression.

Subjects and methods

Results

A total of 27 patients with NCCAH who reached final height were included in the study (20 females, seven males). The most common presenting complaint was precocious pubarche, observed in 70 % (n=19), followed by hirsutism or menstrual irregularity (15 %, n=4), central precocious (11 %, n=3), and a positive family history (4 %, n=1). The mean age at diagnosis was 8.8 ± 3.2 years. The mean height SDS at diagnosis was 0.76 ± 1.1, and the body mass index (BMI) SDS was 0.84 ± 0.83. The mean bone age to chronological age ratio (BA/CA) was 1.24 ± 0.24. The mean predicted adult height (PAH) SDS was −0.64 ± 0.95, and the target height (TH) SDS was 0.02 ± 0.9 (Table 1).

The mean basal 17OHP value of the cases was 14.1 ± 13.9 ng/mL, the peak 17OHP value in the ACTH stimulation test was 34.3 ± 27.7 ng/mL, and the peak cortisol value was 19.3 ± 6.8 mcg/dl. Twenty-four cases (88 %) received GC treatment, with a mean GC dose of 12.5±3 mg/m²/d, which reflects past treatment practices and may appear higher than current recommendations. Genetic analysis showed that 33 % (n=9) were homozygous for the c.844G>T (p.Val282Leu) mutation, 52 % (n=14) were heterozygous for c.844G>T (p.Val282Leu), and 15 % (n=4) had other CYP21A2 gene mutations.

Of the cases, 10/27 were pubertal at the time of diagnosis, 17/27 were prepubertal, and the mean age of puberty onset was 9.1 ± 1.2 years (girls: 8.7 ± 0.9, boys: 10.4 ± 1). The mean height SDS at puberty onset was 0.66 ± 1, and the mean BMI SDS was 1.8 ± 4.1. CPP and rapidly progressive puberty were observed in a total of 9 cases (three patients had a CPP complaint at presentation, three patients developed CPP during follow-up, and rapidly progressive puberty developed in 3 cases). All of the cases were female, and 78 % (n=7) of these patients received GnRH analog treatment, with a mean treatment duration of 2.4 ± 0.69 years. None of the male patients exhibited precocious puberty or received GnRH treatment (Table 1).

In the linear regression analysis evaluating predictors of pubertal onset age in patients with NCCAH, a trend toward earlier puberty was observed in those with higher height SDS at presentation (p=0.054). Although no statistically significant difference was observed between mutation subgroups in terms of age at puberty onset, precocious puberty was observed more frequently in compound heterozygous and other mutation groups compared to the c.844G>T (p.Val282Leu) homozygous group (p=0.038). A significant association was observed between mutation subtype and age at menarche (p=0.006). In this analysis, the c.844G>T (p.Val282Leu) compound heterozygous mutation had a notably later age at menarche (mean=13.06 years) than both those with the c.844G>T (p.Val282Leu) homozygous mutation (mean=11.47 years) and the other mutation group (mean=10.00 years). No significant associations were found between BA/CA ratio (p=0.23) or BMI SDS at presentation (p=0.32) and age at pubertal onset.

Twenty-seven patients reached final adult height (FAH). The mean FAH SDS was −0.33 ± 0.98 (girls:-0.21 ± 1, boys:-0.68 ± 0.83). There was no statistical significance between girls and boys. The mean difference between FAH SDS and TH SDS was −0.35 ± 1.2 (girls:-0.21 ± 1, boys:-0.7 ± 1.5) (Table 1). A strong positive association was observed between height SDS at presentation and final height SDS (r = +0.59, p=0.0009), indicating that children who were taller at diagnosis predicted a better final height outcome. The mean PAH SDS was −0.64 ± 0.95, and the mean FAH-PAH SDS was 0.36 ± 1 (Table 2).

A statistically significant positive correlation was found between pubertal onset-height SDS and final height SDS (r = +0.68, p=0.0001), indicating that individuals taller at the onset of puberty tended to reach greater final height. Pubertal height SDS was significantly and positively correlated with the difference between final and target height SDS (p=0.0135), showing that a taller height at puberty is associated with exceeding the expected genetic height (Table 2). Similarly, FAH-PAH SDS showed a positive correlation with pubertal height SDS (p=0.03).

The mean age at GnRH analog treatment initiation was 7.9 ± 0.3. There was a statistically significant negative association between age at GnRH analog treatment initiation and the difference between final and target height SDS (p=0.0338), implying that earlier treatment may help patients surpass their genetically expected height.

The difference between final height and target height was not significantly influenced by mutation group, age at presentation, or BA/CA ratio at presentation. The presence or absence of early puberty was not significantly associated with final height SDS (p=0.18) (Table 2). Since precocious puberty is only seen in girls, when boys were excluded and girls with and without CPP were compared, no significant effect on FAH SDS was found. The mutation subgroups did not considerably influence final height SDS (p=0.47). There were no significant differences in final height SDS between the GC-treated and untreated patients in our research; however, the small number of untreated patients limits the statistical power of these results.

Among female patients who completed puberty, 30 % (n=6) reported menstrual irregularities and 35 % (n=7) had hirsutism. Metabolic syndrome was identified in 11 % (n=3) of the total cohort, and 29.6 % (n=8) were classified as obese. There was no statistically significant difference in the prevalence of obesity between patients with and without early puberty (p=0.73).

Discussion

In this retrospective study, we analyzed the final height, pubertal outcomes, and clinical course of 27 patients with NCCAH, of whom the majority were treated with glucocorticoids.

In line with the literature, the majority of cases in our study included females (74 %), and the most frequent complaint was premature pubarche (70 %) [3]. Although this data did not suggest a significant incidence of the condition in females, it was likely caused by the fact that hyperandrogenism-related symptoms in boys, who are often identified later, were sometimes difficult to detect or unidentifiable [2], 13].

In our cohort, mild mutations (e.g., c.844G>T (p.Val282Leu)) in homozygous or compound heterozygous form were predominant, consistent with earlier research [3]. Although the difference in stimulated cortisol levels between genotype groups was not statistically significant (p=0.144), patients with compound heterozygous mutations tended to show lower cortisol responses compared to patients who were homozygous for c.844G>T (p.Val282Leu). This suggests a genotype-dependent reduction in adrenal reserve and supports the idea that the compound heterozygous mutation group lies between classic and nonclassic CAH on the disease spectrum [3], 14].

Chronic adrenal androgen excess may enhance GnRH pulsatility, triggering early activation of the hypothalamic–pituitary–gonadal axis and resulting in CPP, which can be the first sign of NCCAH [10]. Given the lack of routine NCCAH screening, clinical clues distinguishing idiopathic from NCCAH-associated CPP are important but limited, especially in girls [10]. If bone age advancement or reduced predicted adult height is observed, GnRH analog therapy may be considered [5].

In our cohort, the mean pubertal onset age was 9.1 years; CPP/rapidly progressive puberty developed in 33 % of patients at presentation or during the follow-up period, and among these, nearly 78 % received GnRH analog treatment. There are various publications in the literature reporting that the incidence of precocious puberty in NCCAH patients ranges from 12 to 45 % [15], 16]. Earlier initiation of GnRH analogs was associated with better final height outcomes (β = −0.53, p=0.0249), emphasizing the importance of early detection. Consistent with prior studies, recognition of precocious puberty and starting GnRH analogs helped slow bone maturation and protect height potential [15]. Specifically, the mean BA/CA ratio decreased from 1.28±0.19 to 1.10±0.14 over treatment, and pubertal growth velocity normalized after the first year of therapy. While menarche occurred within the normal age range across NCCAH subtypes, genotype appeared to affect pubertal timing. Unlike previous studies, [9], 17], our study did not observe any differences between mutation subgroups in terms of pubertal onset. Interestingly, menarche was later in the compound heterozygous group (mean 13.06 years) compared to the homozygous and other mutation groups (11.47 and 10.00 years, p=0.006). This may reflect a slower pubertal tempo related to genotype or delayed menarche due to GnRH analog therapy. These data indicate that both genetics and treatment affect pubertal development in NCCAH. For the detection of early growth acceleration or bone age advancement in NCCAH, auxological measurements and pubertal examinations should be performed every 3–6 months before puberty and every 2–4 months thereafter, while bone age should be assessed annually. When growth velocity exceeds the 97th percentile or ΔBA/ΔCA>1, androgen levels and treatment should be reassessed. Early recognition and timely management of precocious puberty, especially before the age of eight, are essential to improve final height and preserve height potential [1], 2], 7], 15].

A complex interplay of growth patterns, bone maturation, and hormonal exposure affects final height outcomes in children with NCCAH. Although growth velocity during childhood is often normal or mildly accelerated, this is typically accompanied by advanced bone age, which can limit pubertal growth and compromise final height due to early epiphyseal closure [2].

Most studies show that reported final heights in untreated NCCAH patients fall within the normal range, indicating that the patients’ increased androgens do not significantly impair growth. Nevertheless, one study by New et al. found that individuals with untreated NCCAH had a final height that was lower than the target height [9].

In a multicenter analysis of 258 male and female NCCAH patients, the adult height of those treated as children was lower than that of those identified during adolescence, but still comparable to their target height [16]. Particularly, CPP was observed only among girls in that cohort. In contrast, our study did not reveal a significant correlation between age at presentation and final height SDS. A key strength of our work is the longitudinal follow-up from diagnosis through final height, allowing for a more integrated assessment of the impact of treatment timing, pubertal progression, and growth dynamics across the entire developmental course.

A retrospective multicenter study involving 192 children with NCCAH demonstrated that adult height and the difference from target height were significantly associated with chronological age at diagnosis, BA/CA ratio, height at diagnosis, and target height. Notably, genotype, biochemical parameters, and hydrocortisone treatment had no significant impact on final height outcomes [2]. Similarly, in our cohort, a strong positive correlation was observed between height SDS at presentation and final height SDS (p=0.0009). We also found a significant positive correlation between pubertal height SDS and final height SDS (p=0.0001), suggesting that taller height at pubertal onset predicts better height prognosis.

A retrospective analysis of 109 female patients with NCCAH reported that adult height was positively correlated with both target height and height SDS at diagnosis, whereas no significant associations were found with age at diagnosis, advanced bone age, treatment duration, or treatment dose. Additionally, neither the presence of precocious puberty nor pubertal status at diagnosis had a significant impact on final height [15]. Following those results, our research showed that there was no significant correlation between precocious puberty and final height SDS (p=0.18). Similarly, mutation group, age at presentation, and BA/CA ratio at diagnosis did not substantially affect final adult height in our study group.

Metabolic consequences such as insulin resistance and obesity in NCCAH patients are relatively unknown [8]. Both treated with hydrocortisone and untreated NCCAH patients may exhibit increased insulin resistance compared to healthy controls. Glucocorticoid therapy, while necessary, can negatively impact metabolic and cardiovascular health, especially at higher doses; therefore, the lowest effective dose should be used. Hyperandrogenism itself also contributes to cardiometabolic risk, requiring careful treatment balance [9]. Although CAH patients generally tend to have higher BMI, findings in NCCAH are inconsistent – some studies report no increased obesity risk [18], 19]. One study found increased obesity and reduced insulin sensitivity in adults, but not in children with NCCAH [19]. In our cohort, neither early puberty nor history of glucocorticoid treatment was associated with increased final obesity.

While the sample size is a limitation, the inclusion of both clinical and genetic data provides valuable insight. Although the retrospective design restricts causal interpretation, the consistency with international literature strengthens our conclusions. Moreover, a major strength of our study is the long-term follow-up of patients, whether diagnosed at a prepubertal or pubertal stage, until final height is achieved.

Conclusions

This study demonstrates that final height in NCCAH patients is primarily influenced by height SDS at diagnosis and at the onset of puberty, rather than by genotype or age at diagnosis. Central precocious puberty was frequently observed, particularly among female patients. These findings highlight the importance of regular auxological follow-up, early detection of pubertal changes, and individualized treatment approaches to optimize adult height outcomes in NCCAH.