Central Precocious Puberty in Williams Syndrome: Two Cases Illustrating Diagnostic Challenges and Individualized Management

ABSTRACT

Central precocious puberty (CPP) is an increasingly recognized endocrine comorbidity in girls with Williams syndrome (WS), but its diagnosis and management may be complicated by the short stature and atypical growth pattern associated with WS. We report two girls with genetically confirmed WS and CPP who showed different clinical presentations and treatment courses. Both patients presented with advanced pubertal development and markedly advanced bone age. In Case 1, pubertal growth acceleration was not readily apparent on standard population‐based growth charts but became evident when assessed using WS‐specific growth charts. Gonadotropin‐releasing hormone agonist (GnRHa) therapy initially achieved sustained pubertal suppression, but the improvement in predicted adult height (PAH) was limited. Recombinant human growth hormone (GH) was subsequently added, and PAH progressively increased. In Case 2, rapid progression from breast development to menstrual bleeding prompted early combined treatment with GnRHa and GH. During follow‐up, bone‐age advancement remained limited and PAH increased above the mid‐parental height, allowing planned discontinuation of GnRHa and continuation of GH. These cases highlight the value of WS‐specific growth charts for recognizing abnormal growth acceleration and support individualized treatment strategies guided by pubertal progression, bone age advancement, growth velocity, and serial PAH assessment.

Key Clinical Message

In girls with Williams syndrome, standard growth charts often mask pubertal growth acceleration. WS‐specific charts are essential for early central precocious puberty recognition. Individualized treatment combining GnRHa and growth hormone may optimize predicted adult height, though its long‐term efficacy requires further study.

1. Introduction

Williams syndrome (WS) is a multisystem neurodevelopmental disorder caused by a hemizygous microdeletion of approximately 1.5–1.8 Mb on chromosome 7q11.23, which encompasses over 25 genes, including ELN and LIMK1 [1, 2]. With an estimated prevalence of 1 in 7500 births, WS presents with a characteristic phenotype that includes distinctive facial features, cardiovascular disease, and a unique cognitive‐behavioral profile [2, 3]. This profile is characterized by hypersociability and anxiety, alongside relative strengths in expressive language that contrast with underlying deficits in visuospatial construction and abstract reasoning [4, 5, 6].

A significant but often overlooked endocrine comorbidity in WS is central precocious puberty (CPP). Although CPP is uncommon in the general pediatric population, it has been reported more frequently among girls with WS, with its prevalence estimated to be as high as 15%–20%, representing a substantial increase that poses a complex diagnostic and therapeutic challenge for clinicians [7, 8].

The primary diagnostic challenge lies in the interaction of two opposing growth phenomena: the underlying tendency towards short stature in WS can effectively mask the pubertal growth acceleration that is a hallmark of CPP. Consequently, reliance on standard population‐based growth charts is often misleading, delaying diagnosis and potentially compromising final adult height. Therapeutically, a clinical dilemma arises: while gonadotropin‐releasing hormone agonist (GnRHa) therapy is the standard intervention for CPP, its potential to further suppress growth velocity raises significant concerns in a population already predisposed to restricted growth. Therefore, defining an optimal intervention that balances pubertal suppression with the preservation of adult height potential is crucial.

Although the association between WS and CPP is known, the marked clinical variability, diagnostic subtleties, and optimal management strategies, particularly the role of combined therapy, remain underexplored. This case report exemplifies the variability encountered in clinical presentation and treatment response by detailing two distinct cases of CPP in girls with WS. Specifically, this report emphasizes the unique diagnostic necessity of WS‐specific growth charts and evaluates the clinical rationale of an individualized, dual‐axis therapeutic approach, combining GnRHa and growth hormone (GH) therapy, aimed at navigating these complex clinical decisions and optimizing long‐term outcomes.

2. Case 1

2.1. Case History/Examination

A 9.0‐year‐old girl was referred to our clinic following a one‐day episode of moderate vaginal bleeding. Her medical history was notable for developmental delay, particularly in language acquisition. Physical examination revealed several dysmorphic features characteristic of WS, such as a low posterior hairline, mild cubitus valgus, and full lips (Figure 1A). At presentation, her height was 133.7 cm (+0.65 SD according to standard population charts), and pubertal development was advanced, consistent with Tanner stage B3 breasts and PH2 pubic hair.

FIGURE 1.

Clinical and radiological features of the two patients. (A) Facial features demonstrating characteristic WS dysmorphology in Case 1. (B) Left hand‐wrist radiograph showing advanced skeletal maturation. (C) Pelvic ultrasonography demonstrating pubertal uterine and ovarian morphology at diagnosis. (D) Cranial MRI obtained during follow‐up, showing normal intracranial anatomy. (E) Phenotypic presentation of Case 2. (F) Left hand‐wrist radiograph showing advanced bone age. (G) Pelvic ultrasonography demonstrating a pubertal uterus. (H) Midline sagittal brain MRI obtained at presentation, showing no organic intracranial lesion.

2.2. Differential Diagnosis

The differential diagnosis included central precocious puberty, peripheral precocious puberty, and nonendocrine causes of vaginal bleeding. The advanced bone age, pubertal gonadotropin response, elevated estradiol concentration, and pubertal pelvic ultrasonographic findings supported the diagnosis of CPP.

2.3. Investigations

A left hand‐wrist radiograph revealed a bone age (BA) of 11.2 years, representing an advancement of 2.2 years relative to her chronological age (CA) (Figure 1B). Her predicted adult height (PAH) was 152.8 cm, which was 5.2 cm below her mid‐parental height (MPH) of 158.0 cm.

The diagnosis of WS was confirmed by genetic testing, which identified a de novo 1.5‐Mb heterozygous deletion at chromosome 7q11.23. Echocardiography showed mild narrowing of the sinotubular junction with slightly elevated aortic flow velocities. Endocrine evaluation confirmed CPP, with a pubertal basal luteinizing hormone (LH) concentration of 2.5 IU/L, a peak LH concentration of 18.0 IU/L following GnRH stimulation, and an estradiol (E2) concentration of 45 pg/mL. Pelvic ultrasonography demonstrated pubertal uterine and ovarian morphology (Figure 1C). Given her age of more than 8 years, typical clinical and biochemical findings, and absence of neurological symptoms, cranial magnetic resonance imaging (MRI) was initially deferred. During subsequent follow‐up, cranial MRI was performed as part of a comprehensive syndromic evaluation and showed normal intracranial anatomy without organic lesions (Figure 1D). The final diagnosis was WS complicated by CPP.

2.4. Treatment

Leuprolide acetate (3.75 mg intramuscularly every 4 weeks) was initiated at a CA of 9.1 years. During follow‐up, hormonal suppression was maintained, as demonstrated by suppressed gonadotropin concentrations and the absence of recurrent vaginal bleeding (Table 1). After 8 months of GnRHa monotherapy, at a CA of 9.8 years, the increase in BA was smaller than the increase in CA; however, PAH had improved only marginally, from 152.8 to 153.6 cm, and remained substantially below the MPH of 158.0 cm.

TABLE 1.

Longitudinal clinical, anthropometric, and biochemical parameters of the two patients during treatment and follow‐up.

Case ID	Time point	CA (years)	Height (cm)	Height Z‐score	Annual growth rate (cm/year)	WS‐specific growth assessment	Weight (kg)	BMI (kg/m2)	BMI Z‐score	BA (years)	Treatment	LH (IU/L)	FSH (IU/L)	E2 (pg/mL)
1	Diagnosis	9.0	133.7	+0.65	—	Advanced BA at diagnosis	33.1	18.5	+1.07	11.2	—	2.5	6.1	45
1	1 month	9.1	133.2	+0.52	—	Not interpretable	33.95	18.9	+1.15	11.2	GnRHa	< 0.3	3.5	18
1	8 months	9.8	136.6	+0.47	4.86	Below the WS reference mean	39.3	21.0	+1.68	11.5	GnRHa	< 0.3	1.8	< 10
1	12 months	10.0	139.5	+0.76	14.5	Above the WS 97th percentile	38.2	19.6	+0.88	11.4	GnRHa + GH	< 0.3	1.5	< 10
1	20 months	10.8	143.4	+0.47	4.88	Below the WS reference mean	45.1	21.9	+1.56	12.0	GnRHa + GH	< 0.3	1.0	< 10
2	Diagnosis	9.9	139.0	+0.82	—	Advanced BA at diagnosis	31.55	16.3	+0.15	11.9	—	3.5	7.0	55
2	1 month	10.0	140.0	+0.91	10.0	Above the WS 97th percentile	32.7	16.7	+0.28	12.0	GnRHa + GH	< 0.3	1.9	< 10
2	6 months	10.4	142.2	+0.93	5.5	Around the WS reference mean	34.7	17.2	+0.40	12.2	GnRHa + GH	< 0.3	1.7	< 10
2	12 months	10.9	144.3	+0.88	4.2	Below the WS reference mean	37.8	18.0	+0.70	12.4	GnRHa + GH	< 0.3	1.5	< 10
2	19 months	11.6	149.2	+1.05	7.0	Above the WS reference mean	39.7	17.8	+0.54	12.8	GH	0.4	2.3	12

Note: Annual growth rate was calculated from consecutive height measurements and annualized according to the interval between measurements. Growth rate was not calculated for the 1‐month assessment in Case 1 because the interval was too short and the small change in height may reflect measurement variability. WS‐specific growth assessments were based on the reference growth charts reported by Partsch et al. Small differences in serial bone‐age estimates may reflect inter‐assessment variability.

At a CA of 10.0 years, recombinant human GH (0.05 mg/kg/day) was added to GnRHa therapy. Following the addition of GH, growth velocity and PAH improved during follow‐up. As shown in Figure 2 and Table 1, the difference between BA and CA decreased from 2.2 years at diagnosis to 1.2 years at the most recent assessment. In Figure 2, PAH increased to 159.7 cm at a CA of 10.8 years. These findings suggest that individualized combined therapy may support linear growth while maintaining pubertal suppression, although treatment efficacy cannot be established from a single case.

FIGURE 2.

Longitudinal growth dynamics and treatment response in Case 1. The graph illustrates changes in chronological age, current height, bone age, and PAH during follow‐up. MPH is shown as a reference line. Arrows indicate initiation of GnRHa therapy and subsequent addition of GH. Following GH initiation, PAH increased and bone‐age progression remained relatively limited.

3. Case 2

3.1. Case History/Examination

A 9.9‐year‐old girl with previously diagnosed WS was referred to our department after experiencing her first menstrual bleeding 5 days earlier. Her medical history was notable for mild intellectual disability and the characteristic hypersociable behavioral profile associated with WS. Breast development had first been noted at a CA of 8.1 years, followed by rapid progression to menstrual bleeding. Physical examination showed the characteristic dysmorphic features of WS and advanced pubertal development, corresponding to Tanner stage B4 breast development and PH2 pubic hair (Figure 1E). Her BA was 11.9 years, representing an advancement of 2.0 years relative to her CA (Figure 1F). Although her PAH of 153.1 cm was close to her MPH of 153.9 cm, menstrual bleeding occurring only 1.8 years after the initial signs of puberty indicated a rapidly narrowing window for further growth.

3.2. Differential Diagnosis

The differential diagnosis included central precocious puberty, peripheral precocious puberty, and other causes of abnormal vaginal bleeding. The rapid progression from breast development to menstrual bleeding, pubertal basal LH and estradiol concentrations, advanced bone age, and pubertal uterine morphology supported the diagnosis of CPP.

3.3. Investigations

Genetic testing confirmed a pathogenic 1.53‐Mb heterozygous deletion at chromosome 7q11.23. Basal endocrine studies were pubertal, with an LH concentration of 3.5 IU/L and an E2 concentration of 55 pg/mL. Pelvic ultrasonography confirmed a pubertal uterus (Figure 1G). Because of the unusually rapid progression from breast development to menstrual bleeding, cranial MRI was performed to exclude intracranial pathology despite the patient's age. The MRI was unremarkable, and the final diagnosis was CPP in the context of WS (Figure 1H).

3.4. Treatment

Because of the advanced pubertal stage and the limited remaining period for linear growth, combined treatment with triptorelin acetate (3.75 mg intramuscularly every 4 weeks) and recombinant human GH (somatropin, 0.05 mg/kg/day) was initiated at a CA of 10.0 years. During follow‐up, gonadotropin concentrations remained suppressed and growth parameters improved. BA increased from 11.9 years at diagnosis to 12.4 years at the 12‐month assessment and to 12.8 years at the most recent assessment at 11.6 years of age. PAH increased from 153.1 cm at diagnosis to 155.5 cm during combined therapy and subsequently to 157.1 cm at the most recent follow‐up (Figure 3).

FIGURE 3.

Longitudinal growth dynamics and treatment course in Case 2. The graph illustrates changes in chronological age, current height, bone age, and PAH during follow‐up. MPH is shown as a reference line. Combined GnRHa and GH therapy was initiated at 10.0 years of age. During follow‐up, bone age advanced from 11.9 to 12.8 years, and PAH increased from 153.1 cm to 157.1 cm, exceeding the MPH. GnRHa therapy was discontinued at approximately 11.5 years after multidisciplinary assessment, with GH continued thereafter.

At a CA of approximately 11.5 years, with a BA of approximately 12.5 years, GnRHa therapy was discontinued after multidisciplinary review. The decision was based on the improvement in PAH, stabilization of growth velocity on WS‐specific growth charts, and the assessment that further pubertal suppression was unlikely to provide substantial additional height benefit. The family also preferred a more age‐appropriate progression of pubertal development. GH was continued as monotherapy. At the most recent follow‐up, at a CA of 11.6 years, the patient's height was 149.2 cm, BA was 12.8 years, and PAH was 157.1 cm.

4. Discussion

The co‐occurrence of CPP in individuals with WS presents distinct clinical challenges, arising from the complex interplay between the syndrome's underlying pathophysiology and its characteristic growth patterns [7]. The two cases detailed in this report offer a longitudinal perspective on these issues, emphasizing the need for diagnostic approaches tailored to the syndrome and individualized management strategies. Given the rarity of WS and the relatively high prevalence of CPP within this population, understanding how these two conditions interact is important for reducing diagnostic delay and optimizing long‐term endocrine outcomes.

The accurate diagnosis of CPP in patients with WS is frequently hindered by the syndrome's distinctive growth trajectory, which typically involves prenatal growth restriction followed by persistent postnatal growth deceleration resulting in short stature [9]. This atypical baseline creates a significant diagnostic challenge because the pubertal growth spurt, a primary clinical indicator of CPP, may be incorrectly interpreted as “normal” linear growth when evaluated against standard population‐based charts. For example, at the time of diagnosis, Case 1 exhibited a height at +0.65 SD on a standard chart; such a finding would not typically prompt further investigation in the general population. However, the application of WS‐specific growth charts, together with markedly advanced bone age, revealed a growth velocity that was inconsistent with the natural history of the syndrome. This observation underscores that WS‐specific growth charts are not merely supplementary references but useful clinical tools for monitoring growth dynamics [10]. Their consistent use is important for interpreting growth velocity accurately, facilitating timely diagnosis, and supporting early intervention to preserve predicted adult height.

The precise pathophysiological mechanisms underlying the elevated occurrence of CPP in WS remain uncertain. Haploinsufficiency of genes within the 7q11.23 microdeletion region may influence neuroendocrine development or regulation of the hypothalamic–pituitary‐gonadal axis, but the specific genes and pathways involved have not been established [11, 12]. The normal neuroimaging findings in our patients do not exclude molecular or functional abnormalities, but they provide no evidence of a structural intracranial cause [13]. Further studies in larger WS cohorts are needed to clarify the genetic and neuroendocrine mechanisms underlying CPP in this population.

Standard GnRHa therapy is effective in suppressing pubertal progression in CPP, but in patients with WS it presents a particular therapeutic challenge because further slowing of growth velocity may compromise already limited height potential [10]. Our cases suggest that combined treatment with GnRHa and GH may help address this issue, although its use should be determined on an individual basis rather than applied uniformly. In both patients, treatment decisions were guided by serial assessments of PAH. In Case 1, GnRHa monotherapy achieved satisfactory pubertal suppression but resulted in only minimal improvement in PAH, which remained substantially below MPH. GH was subsequently added to address the limited height prognosis. PAH increased to 159.7 cm during follow‐up, exceeding the MPH; however, this temporal association does not establish a treatment effect. Because Case 2 presented shortly after her first menstrual bleeding and at a more advanced pubertal stage, combined therapy was initiated from the outset. This approach resulted in the improvement of PAH beyond her MPH and allowed subsequent discontinuation of GnRHa at a developmentally appropriate time point (Figure 3). Taken together, these two cases illustrate that management of CPP in WS should be individualized, with treatment intensity and duration adjusted according to pubertal status, growth pattern, and longitudinal PAH evaluation.

Previous studies have documented an increased incidence of CPP in patients with WS and have reported the use of GnRHa therapy in this setting [7, 8]. However, evidence regarding how to balance pubertal suppression with preservation of height potential remains limited. In this context, our report adds to the existing literature in several respects. Unlike most previous reports that primarily offer cross‐sectional observations, we provide detailed longitudinal data on predicted adult height. This longitudinal tracking allows for a quantitative assessment of how different treatment strategies influenced height prognosis, an outcome that has not been adequately described in most previous case reports. In addition, we describe the clinical course of combined GnRHa and GH therapy in two patients with distinct presentations, including the rationale for treatment initiation, modification, and discontinuation. By presenting these contrasting scenarios, we highlight a practical approach to individualized decision‐making in the management of CPP in WS. At the same time, the findings of this report should be interpreted cautiously. As a case report involving only two patients, its observations cannot be generalized, and the apparent benefits of treatment require confirmation in larger prospective multicenter studies. Although the favorable changes in predicted adult height are encouraging, PAH remains an estimated rather than definitive outcome, and continued follow‐up to final adult height is necessary to determine the long‐term effectiveness of the treatment strategies described here. Future research should focus on developing more standardized approaches to CPP screening in WS, evaluating the long‐term safety and efficacy of combined GnRHa and GH therapy, and clarifying the genetic and neuroendocrine mechanisms through which the 7q11.23 deletion may contribute to premature activation of the hypothalamic–pituitary–gonadal axis.

In conclusion, the management of CPP in children with WS requires careful assessment beyond the standard approach used in the general CPP population. The use of WS‐specific growth charts is important for accurate and timely diagnosis. Treatment should be individualized, and combined GnRHa and GH therapy may be considered in selected patients to improve height outcomes, guided by close monitoring of PAH in relation to genetic height potential. These cases provide longitudinal clinical observations that may assist clinical decision‐making while also highlighting the need for further studies to define the long‐term efficacy and safety of this approach.

Author Contributions

Kangxiang Liu: conceptualization, funding acquisition, project administration, supervision, writing – original draft. Sha Zhao: data curation, investigation, writing – review and editing. Xinghan Wu: formal analysis, investigation, writing – review and editing. Xiaomei Jiang: data curation, investigation, writing – review and editing. Xiaoming Li: formal analysis, investigation, writing – review and editing.

Funding

This work was supported by the Provincial Natural Science Foundation of Hunan (Grant No. 2025JJ80634).

Ethics Statement

This study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Hunan Children's Hospital.

Consent

Written informed consent was obtained from the parents/legal guardians of the patients for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor‐in‐Chief of this journal.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. The primary data supporting the findings of this study are contained within the manuscript.