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Review

Precocious Puberty in Boys with NR0B1 Variants

by
Atsushi Hattori
1,2,* and
Maki Fukami
1,2
1
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan
2
Division of Diversity Research, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan
*
Author to whom correspondence should be addressed.
Endocrines 2024, 5(4), 529-537; https://doi.org/10.3390/endocrines5040038
Submission received: 30 September 2024 / Revised: 5 November 2024 / Accepted: 13 November 2024 / Published: 15 November 2024
(This article belongs to the Section Pediatric Endocrinology and Growth Disorders)
Browse Figure
Review Reports Versions Notes

Highlights

What are the main findings?
  • Although NR0B1 variants typically cause X-linked adrenal hypoplasia congenita, some cases are associated with precocious puberty (PP), with rare instances in which PP precedes adrenal insufficiency.
  • Three underlying mechanisms (ACTH-dependent, gonadotropin-dependent, and ACTH- and gonadotropin-independent) have been proposed for PP associated with NR0B1 variants.
  • The responsiveness to treatment of PP varies among cases, potentially depending on the underlying mechanisms.
What is the implication of the main finding?
  • NR0B1 variants should be considered as a potential cause of PP, even in cases without clinical signs of adrenal insufficiency.
  • Comprehensive endocrine evaluations are essential to determine the underlying pathophysiology in cases of PP associated with NR0B1 variants.
  • Management strategies for PP should be tailored to the mechanisms contributing to the condition.

Abstract

:
Precocious puberty (PP) requires appropriate management to prevent short adult height, psychosocial issues, and other adverse outcomes. Genetic diagnosis potentially improves the management of PP. Pathogenic NR0B1 variants, which typically cause X-linked adrenal hypoplasia congenita, can also affect gonadal function. While boys with NR0B1 variants usually exhibit hypogonadotropic hypogonadism during adolescence, previous reports have suggested that minipuberty, a physiological transient activation of the hypothalamic–pituitary–gonadal axis during infancy, occurs in these patients and can persist beyond a typical duration. In rare cases, NR0B1 variants cause PP. PP associated with NR0B1 variants has unique features such as early onset and high serum testosterone levels that are often disproportionate to testicular size. Three underlying mechanisms have been proposed for the association between PP and NR0B1 variants: (1) adrenocorticotropic hormone (ACTH)-dependent, (2) gonadotropin-dependent, and (3) ACTH- and gonadotropin-independent mechanisms. The factors contributing to PP vary among cases. Determining the underlying mechanisms is crucial for adopting appropriate therapeutic strategies to control PP. However, as the detailed molecular networks mediating these mechanisms are largely unclear, further research is needed to pave the way for a more effective and personalized management of patients with PP associated with NR0B1 variants.

1. Introduction

Precocious puberty (PP) is defined as the onset of secondary sexual characteristics before the age of eight years in girls and nine in boys [1]. Appropriate management is critical to avoid short adult height and psychosocial issues caused by PP. More importantly, identifying the cause of PP is crucial because some underlying conditions have the potential to lead to life-threatening events or greatly impact the quality of life. PP is classified as gonadotropin-dependent PP, also known as central PP (CPP), or gonadotropin-independent PP, also referred to as peripheral PP (PPP). CPP is idiopathic in most affected girls [2]. Initially, more than half of affected boys were reported to have lesions in the central nervous system; however, recent studies have suggested that the prevalence of organic lesions is lower than previously reported in boys with CPP [2,3]. CPP can also be secondarily induced by exposure to sex steroids. The etiology of PPP includes McCune–Albright syndrome, familial male-limited PP, hormone-secreting tumors, congenital adrenal hyperplasia, and severe primary hypothyroidism. The genetic diagnosis of PP plays a substantial role in the management by predicting the natural course and occasionally guiding therapeutic options. Representative genes responsible for CPP include MKRN3 and DLK1, while those responsible for PPP include GNAS (McCune–Albright syndrome) and LHCGR (familial male-limited PP) [4,5,6]. Among genes responsible for PP, NR0B1 is unique in that PP associated with variants in this gene comprises various pathophysiologies, thus posing a challenge to clinicians in the management of PP. To the best of our knowledge, the comprehensive literature on PP associated with NR0B1 variants is limited. Herein, we introduce NR0B1 and describe its phenotypic effects. We also discuss the characteristics and putative mechanisms of PP associated with NR0B1 variants.

2. NR0B1 and X-Linked Adrenal Hypoplasia Congenita (AHC)

NR0B1 (HGNC ID, HGNC:7960), located on Xp21.2, is responsible for X-linked AHC. The encoded protein, NR0B1 (NP_000466), is also known as the dosage-sensitive sex reversal, adrenal hypoplasia congenita critical region on the X chromosome protein 1 (DAX1). NR0B1 is expressed in the adrenal glands, testes, ovaries, hypothalamus, and pituitary gland [7], and plays critical roles in the function of the hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal (HPG) axis. X-linked AHC is caused by pathogenic single-nucleotide variants (SNVs), small indels, or large deletions involving NR0B1. Typical clinical manifestations of X-linked AHC are adrenal insufficiency and hypogonadotropic hypogonadism (HH) [8].

3. Gonadal Functions of Boys with NR0B1 Variants

Boys with NR0B1 variants exhibit variable gonadal functions. Copy number variants (especially duplications) involving NR0B1 can result in gonadal dysgenesis [9,10], whereas SNVs, small indels, and deletions in NR0B1 are rarely associated with cryptorchidism or micropenis [11,12].
During infancy and childhood, boys with X-linked AHC typically lack hypogonadism. Previous reports have suggested that boys with X-linked AHC experience minipuberty, a transient physiological activation of the HPG axis during infancy [13,14,15]. Moreover, boys with X-linked AHC can have prolonged minipuberty [16,17], possibly reflecting a repressive role of NR0B1 in the regulation of the HPG axis at the end of minipuberty. In rare cases, boys with NR0B1 variants present with PP, as described in the next section [18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34].
During adolescence, boys with X-linked AHC fail to enter puberty or experience arrested pubertal progression because of HH [11,35,36]. In adulthood, males with X-linked AHC typically present with azoospermia or oligozoospermia [11,35,36,37,38], which can be associated with Sertoli cell-only syndrome [37] and testicular dysgenesis [38].

4. Clinical Manifestations of PP Cases with NR0B1 Variants

PP rarely occurs in patients with X-linked AHC. It is speculated that, in most cases, the loss of NR0B1 function is masked by other genetic, epigenetic, and/or environmental factors that influence the HPG axis during the prepubertal period. To date, at least 20 cases of PP associated with NR0B1 variants have been reported [19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34].
PP was noted after the diagnosis of adrenal insufficiency in most patients (Table 1). The median and mean ages at the onset of puberty in previous cases of PP associated with NR0B1 variants were one year and two years, respectively (Table 1). These onset ages are remarkably earlier than those in boys with PP caused by other etiologies [39,40]. In three cases of X-linked AHC, PP was the first noted clinical sign, followed by the identification of adrenal insufficiency [19,27,34]. Rarely, PP can be an isolated manifestation without signs of adrenal insufficiency [26]. Therefore, the possibility of NR0B1 variants cannot be excluded based on the absence of adrenal insufficiency.
Common manifestations of PP associated with NR0B1 variants include penile growth, pubic hair, testicular enlargement, linear growth acceleration, and bone age advancement (Table 1) [17,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34]. Less frequently reported manifestations include frequent erections, ejaculation, hyperactivity, and acne [19,23,27,28,34]. Some of these manifestations, combined with adrenal insufficiency, can mimic hyperandrogenism associated with congenital adrenal hyperplasia [22,27]. Distinguished clinical features in PP associated with X-linked AHC include adrenal hypoplasia and elevated serum testosterone levels without the evidence of excessive adrenal androgen production [24,28,29,30,32]. Notably, more than half of the patients with available data showed high serum testosterone levels that were disproportionate to their testicular volumes, based on previously reported reference ranges of serum testosterone specific to testicular volume (Table 2) [41]. This may imply the involvement of PPP, in which testicular volumes are relatively small compared to those in CPP. Alternatively, the relatively small testicular volumes may be explained by disorganized seminiferous tubules caused by NR0B1 variants [42], given that the increase in testicular size during puberty mainly depends on the expansion of seminiferous tubules [13]. In contrast, two patients have been reported to have isolated testicular enlargement without any other secondary sexual characteristics or elevated gonadotropin and testosterone levels [43,44]. Gonadotropin levels vary among PP cases associated with NR0B1 variants, ranging from prepubertal to pubertal levels (Table 1). No genotype–phenotype correlation has been observed regarding the onset, manifestations, or putative mechanisms of PP (Table 1).
Limited data are available on whether secondary sexual characteristics resume after cessation of treatment to suppress pubertal progression or whether puberty progresses fully in boys with NR0B1 variants. Two patients showed no signs of secondary sexual characteristics at the age of 15 [22,33], while one patient exhibited Tanner stage 4–5 pubic hair, facial hair, and laryngeal development [32]. Further data are needed to clarify gonadal functions in adolescent patients who have experienced PP associated with NR0B1 variants.

5. Proposed Mechanism of PP Associated with NR0B1 Variants

PP associated with NR0B1 variants is likely to be mediated by various factors. At least three mechanisms have been proposed based on clinical observations in boys with NR0B1 variants, phenotypes of Nr0b1-deficient mice, and in vitro functional studies: (1) adrenocorticotropic hormone (ACTH)-dependent mechanism, (2) gonadotropin-dependent mechanism, and (3) gonadotropin- and ACTH-independent mechanism (Figure 1). No single mechanism sufficiently explains the presentations of all previous cases of PP associated with NR0B1 variants. Factors contributing to PP differ depending on the case, and multiple factors may be involved in some cases (Table 1).

5.1. ACTH-Dependent Mechanism

In 2001, Domenice et al. reported a case of PP associated with X-linked AHC and suggested that the prolonged elevation of plasma ACTH levels caused PP [19]. The boy was noted to have penile growth and pubic hair at six months of age. The initial evaluation showed elevated testosterone (1.9–6.2 nmol/L; reference range, <1.0 nmol/L) and prepubertal levels of gonadotropins, suggesting the diagnosis of PPP. At the age of three years, he was noted to have adrenal insufficiency for the first time when he had an upper respiratory infection. After glucocorticoid and mineralocorticoid supplementation and normalization of plasma ACTH levels, the patient presented a clear decrease in testicular size and normalization of the serum testosterone levels. Interestingly, the serum testosterone levels increased under physical stress and returned normal after the stress was resolved [19]. These observations suggest that ACTH plays a critical role in PP associated with NR0B1 variants. This hypothesis is supported by subsequently reported cases with similar observations [20,28,31,33]. On the other hand, high ACTH levels do not appear necessary for pubertal progression because some patients exhibited pubertal progression without the elevation of plasma ACTH levels [22,25,26,30].
It remains unclear how elevated plasma ACTH levels stimulate testosterone production. Unlike congenital adrenal hyperplasia, in which high concentrations of ACTH stimulate the zona reticularis to produce androgens, testosterone production is unlikely to originate from the adrenal glands in PP associated with NR0B1 variants. This speculation is based on the fact that boys exhibiting PP associated with NR0B1 variants did not show increased production of adrenal androgen metabolites, such as DHEA, DHEAS, and androstenedione, in contrast to increased testosterone production [24,27,28,29,30,32,34]. Instead, it is hypothesized that ACTH acts on the melanocortin receptors of Leydig cells, thereby promoting testosterone biosynthesis [19]. If this hypothesis is true, NR0B1 may inhibit ACTH-dependent testosterone production in healthy Leydig cells. Alternatively, hyperandrogenism in boys with poorly controlled 21-hydroxylase deficiency may also be partly caused by ACTH-dependent testosterone production in Leydig cells. Future research is needed to determine whether melanocortin receptor signaling in Leydig cells underlies ACTH-dependent testosterone production.

5.2. Gonadotropin-Dependent Mechanism

Previously, the diagnosis of CPP was made in seven cases with NR0B1 variants (Table 1) [21,23,24,25,26,32,34]. Although idiopathic CPP is typically responsive to gonadotropin-releasing hormone agonist (GnRHa) therapy, the responses of CPP patients with NR0B1 variants may vary. Four of the seven previous CPP cases were treated with GnRHa [23,24,25,26]. Among these, three cases were reported to respond to the therapy [23,24,25]. However, in the case reported by Shima et al., testicular enlargement, pubic hair, and bone age advancement persisted even after GnRHa therapy was initiated, although the serum levels of gonadotropins and testosterone were partially reduced [26]. The authors speculated that these observations implied that PP in this case was caused by both gonadotropin-dependent and -independent mechanisms. Notably, elevations of gonadotropins can be induced by prolonged testosterone production due to PPP. In such cases, GnRHa monotherapy cannot control the pubertal progression.
Although the precise mechanism of CPP associated with NR0B1 variants is unclear, we speculate that failure to repress the hypothalamic–pituitary unit after the physiological period of minipuberty may be a contributing factor. This notion is consistent with the fact that the onset of PP associated with NR0B1 variants is generally earlier than that of PP caused by other etiologies (Table 1) [39,40]. As mentioned earlier, previous reports have suggested that boys with NR0B1 variants undergo minipuberty during infancy and occasionally beyond the normal physiological duration [14,16,17]. These observations in boys with NR0B1 variants during infancy and early childhood are in contrast with HH during adolescence. Therefore, it is speculated that the function of NR0B1 in the hypothalamic–pituitary unit during early life differs from that during adolescence. Disruption of this time-specific NR0B1 function may underlie CPP associated with NR0B1 variants. Consistent with this speculation, NR0B1 has been reported to interact with NR5A1, thereby downregulating the transactivation of the murine Nos1 exon 2 promoter [45]. In the hypothalamus, NOS1 synthesizes nitric oxide, which is thought to play an essential role in the pulsatile secretion of luteinizing hormone by regulating GnRH release [46]. Taken together, NR0B1 might repress the activity of the hypothalamic–pituitary unit by downregulating NOS1. However, the detailed mechanisms underlying CPP associated with NR0B1 variants largely remain to be investigated.

5.3. Gonadotropin- and ACTH-Independent Mechanism

The above-mentioned two mechanisms cannot sufficiently explain all clinical courses of previously reported cases. PP associated with NR0B1 variants can progress even if both gonadotropin and ACTH levels are controlled. Indeed, several boys have been reported to exhibit prolonged progression of puberty without an apparent elevation in ACTH and gonadotropin levels [26,30]. Androgen receptor inhibitors may be an option for controlling PP caused by gonadotropin- and ACTH-independent mechanisms. In a case presumably caused by this mechanism, cyproterone acetate ameliorated the clinical signs of PP [30].
Consistent with these observations, NR0B1 has been reported to repress the transcription of various steroidogenic genes. Specifically, in vitro reporter assays have shown that NR0B1 downregulates the promoters of steroidogenic genes such as STAR, CYP11A1, CYP17A1, and HSD3B2 [47,48]. Furthermore, Leydig cell-specific Nr0b1 knockout mice exhibited increased testosterone production compared to wild-type mice during the first four weeks after birth [49]. Additionally, these mutant mice showed increased expression of steroidogenic genes such as Star, Cyp11a1, Cyp17a1, and Hsd3b1. To summarize, loss of NR0B1 function may disrupt the transcriptional repression of these steroidogenic genes, resulting in autonomous testosterone production independent of gonadotropin or ACTH.

6. Conclusions

PP with NR0B1 variants presents complex and multifaceted clinical challenges. Pubertal progression typically occurs during infancy or early childhood, combined with adrenal insufficiency caused by adrenal hypoplasia. PP in these patients may be ACTH-dependent, gonadotropin-dependent, and/or gonadotropin- and ACTH-independent. Determining the mechanisms that contribute to pubertal progression in each case is crucial for adopting appropriate therapeutic strategies, although the detailed pathophysiology and optimal treatment for each etiology remain to be elucidated. Further research will pave the way for more effective and personalized management of patients with PP associated with NR0B1 variants.

Author Contributions

Conceptualization, A.H.; writing—original draft preparation, A.H.; writing—review and editing, A.H and M.F.; funding acquisition, A.H. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Japan Society for the Promotion of Science, grant number 22K15932 (to A.H.).

Conflicts of Interest

The authors declare no conflicts of interest.

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Endocrines 05 00038 g001
Figure 1. Three proposed mechanisms underlying precocious puberty in boys with NR0B1 variants. Pink circles represent the location where gonadotropin-releasing hormone (GnRH) neurons reside. Arrows and T-shaped bars represent stimulatory and inhibitory effects, respectively. ACTH, adrenocorticotropic hormone; LH, luteinizing hormone; NO, nitric oxide.
Figure 1. Three proposed mechanisms underlying precocious puberty in boys with NR0B1 variants. Pink circles represent the location where gonadotropin-releasing hormone (GnRH) neurons reside. Arrows and T-shaped bars represent stimulatory and inhibitory effects, respectively. ACTH, adrenocorticotropic hormone; LH, luteinizing hormone; NO, nitric oxide.
Endocrines 05 00038 g001
Table 1. Clinical features and etiologies of previously reported cases of precocious puberty (PP) associated with NR0B1 variants.
Table 1. Clinical features and etiologies of previously reported cases of precocious puberty (PP) associated with NR0B1 variants.
CaseAge at OnsetPhysical FindingsEndocrinological Data (Age)Putative Mechanism aVariantRef.
AIPPGonadotropinsTestosteroneACTH
13.2 y0.5 yPG, TE, PH, frequent erection, hyperactivityPrepubertal (2.3 y)Elevated (2.3 y)Elevated (2.3 y)(1)p.(Ser144Argfs*9)[19]
20.1 y0.8 yPG, PHPrepubertal (0.8 y)Elevated (0.8 y)Not elevated (0.8 y)(1)p.(Gly122Valfs*142)[20]
3<0.1 y6 yPG, TE, PHPubertal (6 y)Elevated (6 y)NA(2)Deletion[21]
4-A26 d6 yPGNANANAUnknownDeletion[22]
4-B10.1 y0.5 yPG, TEBorderline (1.5 y)Elevated (0.8 y)Elevated (1.5 y)UnknownDeletion[22]
4-B3<0.1 y0.8 yPG, TENAElevated (12 d)Elevated (12 d)UnknownDeletion[22]
4-C10.1 y2.5 yPG, TEPrepubertal (9.8 y)NANAUnknownp.(Ser153*)[22]
4-D10.2 y1.5 yPG, TEBorderline (1.0 y)Elevated (1.0 y)NAUnknownc.183-1G>C[22]
50.1 y0.8 yPG, PH, frequent erection, uneasyPubertal (0.8 y)Elevated (0.1 y)NA(2)p.(Gln155*)[23]
60.2 y3.8 yTE, PHPubertal (3.8 y)Elevated (1.2 y)Elevated (2.1 y)(2)Deletion[24]
79 d0.8 yPG, TE, PHPubertal (0.9 y)Elevated (0.9 y)Not elevated (0.8 y)(2)p.(Gln208*)[25]
8−4.7 yTE, PH, LGA, BAPubertal (4.7 y)Elevated (4.7 y)Not elevated (4.7 y)(2), (3)p.(Glu3fsAla*16)[26]
90.8 y0.8 yPG, TE, PH,
frequent erection,
hyperactivity		Prepubertal (13 y)Elevated (0.8 y)Elevated (0.8 y)(1) or (3)p.(Tyr64*)[27]
100.1 y0.8 yPG, acnePrepubertal (0.8 y)Elevated (0.8 y)NA(1)p.(Gly122Valfs*142)[28]
115.8 y1.9 yPG, TEPrepubertal (3 y)Elevated (3 y)Elevated (6 y)(1) or (3)p.(Phe364Cys)[29]
120.1 y4.5 yPG, PHBorderline (4.6 y)Elevated (4.5 y)Not elevated (4.5 y)(3)Nonsense variant[30]
1316 d0.6 yPGPrepubertal (0.8 y)Elevated (0.8 y)Elevated (0.8 y)(1)p.(Trp291*)[31,34]
145.9 y5.9 yPG, PHPubertal (5.9 y)Elevated (5.9 y)Elevated (5.9 y)(2)p.(*471Glnext*18)[32]
153 y3 yPG, TE, PHPrepubertal (3 y)Elevated (3 y)Elevated (3 y)(1) or (3)Deletion[33]
160.9 y0.3 yPG, TE, PH,
Frequent erection		Pubertal (0.9 y)Elevated (0.9 y)Elevated (0.9 y)(2)p.(Gln305*)[34]
AI, adrenal insufficiency; BA, bone age advancement; d, days; LGA, linear growth acceleration; NA, not available; PG, penile growth; PH, pubic hair; PP, precocious puberty; Ref, reference; TE, testicular enlargement; y, years. a Putative mechanisms are classified as (1) ACTH-dependent, (2) gonadotropin-dependent, or (3) gonadotropin- and ACTH-independent, where applicable.
Table 2. Comparison between the testicular volumes and serum testosterone levels.
Table 2. Comparison between the testicular volumes and serum testosterone levels.
CaseAge at OnsetTesticular Volume mL (Age)Testosterone nmol/L (Age)Reference Ranges Based on Testicular Sizes aPutative Mechanism bRef.
20.8 y2 (0.8 y)8.1 (0.8 y)0.02–0.26(1)[20]
36 y4 (6 y)21.5 (6 y)0.10–3.87(2)[21]
70.8 y3–4 (0.8 y)18.4 (0.9 y)0.10–3.87(2)[25]
84.7 y6–8 (4.7 y)4.9 (4.7 y)0.89–16.7(2), (3)[26]
90.8 y5 (0.8 y)45.7 (0.8 y)0.21–6.07(1) or (3)[27]
100.8 y3 (0.8 y)11.1 (0.8 y)0.04–2.01(1)[28]
124.5 y2.5 (4.5 y)1.7 (4.5 y)0.04–2.01(3)[30]
130.6 y2 (0.6 y)19.1 (0.8 y)0.02–0.26(1)[31]
145.9 y3 (5.9 y)1.5 (5.9 y)0.04–2.01(2)[32]
153 y5 (3 y)1.4 (3 y)0.21–6.07(1) or (3)[33]
160.3 y2.5 (0.9 y)13.4 (0.9 y)0.04–2.01(2)[34]
Testosterone levels above the reference ranges based on testicular sizes are bold-faced. Ref, reference; y, years. a Reference ranges of testosterone levels are based on data reported by Madsen et al. [41]. The lower and upper limits represent the 2.5th and 97.5th percentile, respectively. b Putative mechanisms are classified as (1) ACTH-dependent, (2) gonadotropin-dependent, or (3) gonadotropin- and ACTH-independent.
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Hattori, A.; Fukami, M. Precocious Puberty in Boys with NR0B1 Variants. Endocrines 2024, 5, 529-537. https://doi.org/10.3390/endocrines5040038

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Hattori A, Fukami M. Precocious Puberty in Boys with NR0B1 Variants. Endocrines. 2024; 5(4):529-537. https://doi.org/10.3390/endocrines5040038

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Hattori, Atsushi, and Maki Fukami. 2024. "Precocious Puberty in Boys with NR0B1 Variants" Endocrines 5, no. 4: 529-537. https://doi.org/10.3390/endocrines5040038

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Hattori, A., & Fukami, M. (2024). Precocious Puberty in Boys with NR0B1 Variants. Endocrines, 5(4), 529-537. https://doi.org/10.3390/endocrines5040038

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