Van Wyk–Grumbach syndrome: a case report and review of the literature

Abstract

Van Wyk–Grumbach syndrome (VWGS) is a rare manifestation of acquired hypothyroidism that was first described in 1960. It is characterized by precocious puberty, delayed bone age, and, in some cases, galactorrhea. We report the case of a 9-yr-old girl with growth retardation, delayed bone age, and vaginal bleeding without pubic hair development. Laboratory tests showed severe hypothyroidism (TSH level: 1,805 µIU/mL; free T4: 0.1 ng/dL), suppressed LH level, elevated estradiol (53 pg/mL) level, and hyperprolactinemia (59.79 ng/mL). Bilateral ovarian cysts were observed. Levothyroxine normalized thyroid function and reduced the number of cysts; however, central puberty progressed within 5 mo, requiring GnRH analog therapy. A review of 44 previously reported female patients revealed consistent findings including delayed bone age, elevated TSH level, suppressed gonadotropin levels, and frequent vaginal bleeding despite the absence of pubic hair. This atypical sequence likely resulted from TSH-induced estradiol secretion without concurrent adrenal androgen activity. This atypical pubertal development sequence may serve as a useful clinical indicator of VWGS. Assessment of thyroid function is warranted in young girls presenting with isolated vaginal bleeding in the absence of pubic hair, not only to avoid misdiagnosis, but more importantly, to ensure the timely initiation of appropriate treatment for underlying hypothyroidism.

Highlights

● VWGS causes precocious puberty with paradoxical delayed bone age.

● Young VWGS patients experience vaginal bleeding before developing pubic hair.

● Thyroid function should be assessed in genital bleeding without growth of pubic hair.

Introduction

Van Wyk–Grumbach syndrome (VWGS) was first described in 1960 by Van Wyk and Grumbach, who reported three cases of juvenile-acquired hypothyroidism presenting with precocious puberty, delayed bone age, and galactorrhea (1). VWGS is a rare manifestation of acquired hypothyroidism. Although precocious puberty associated with hypothyroidism has frequently been reported, including several cases in Japan (2,3,4), no Japanese cases of Van Wyk-Grumbach syndrome have been explicitly reported in the medical literature.

Although the clinical triad of acquired hypothyroidism, precocious puberty, and multicystic ovaries was first described by Van Wyk and Grumbach in 1960, the term “Van Wyk–Grumbach syndrome” (VWGS) was not proposed by the authors themselves. The use of this eponym gradually emerged in literature in 2008. Although no formal diagnostic criteria have been established, this syndrome is generally defined as a constellation of acquired hypothyroidism, precocious puberty, ovarian cysts, and delayed bone age. Although only a small number of male patients have been reported, the vast majority of cases involve female patients.

Although several narrative and descriptive reviews of VWGS have been published, including a recent comprehensive review (5), none have systematically examined the sequence of pubertal events in female patients. In a review of previous case reports, we noted that several girls with VWGS presented with genital bleeding before the growth of pubic hair. However, as previous reports have not focused on pubarche, it remains unclear whether this pattern is characteristic.

The primary objective of this review was to investigate whether delayed pubarche relative to vaginal bleeding is a consistent feature of VWGS in girls. In addition, we sought to characterize the clinical profile of VWGS by collecting and analyzing a broad range of demographic, hormonal, and imaging data from the reported cases.

Case Presentation

A 9-yr-1-mo-old female patient presented with the chief complaint of growth retardation. Growth deceleration had been documented over the past year, prompting ongoing follow-up at a local clinic. During this period, the patient had also developed cold extremities and constipation. At the age of 8 yr and 5 mo, breast enlargement was observed. As growth impairment persisted and her height declined below −2.5 SD, she was referred to our department for further evaluation. Immediately before presentation, the patient experienced increased vaginal discharge, followed by genital bleeding.

Her medical history included periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome, all of which were in remission at the time of evaluation. The patient was not receiving any medications. She was born at 40 wk and 2 d of gestation, with a birth weight of 2,560 g. The patient had no family history of endocrine disorders.

Vital signs including temperature, heart rate, blood pressure, and respiratory rate were not documented during the initial visit. On physical examination at presentation, her height was 115.5 cm (−2.7 SD), weight was 27.7 kg (−0.3 SD), and her obesity index was 37.8%. She was alert and oriented with no eyelid edema. There was no neck swelling, warmth, or tenderness; no cardiac murmurs; clear breath sounds; a soft, flat abdomen with normal bowel sounds; and no hepatosplenomegaly. Non-pitting edema was present on the dorsum of the hands, lower legs, and feet, with peripheral coldness. Her breast development was Tanner stage II and pubic hair development was Tanner stage I. Growth curve analysis showed a decline in growth velocity beginning at 7 yr and 6 mo (Fig. 1A).

Fig. 1.

Clinical course before and after treatment. (A) Growth chart. White dots represent bone age progression. (B) Changes in the size of ovarian cysts in the right ovary: the left image shows pre-treatment (maximum diameter: 87.4 mm × 51.2 mm), and the right image shows 1 mo after treatment initiation (maximum diameter, 48.7 mm × 28.0 mm). (C) Brain MRI findings at presentation: T1-weighted image (left) and T2-weighted image (right) demonstrating pituitary enlargement (pituitary height: 10 mm). (D) Timeline of treatment, blood test results, and bone age progression.

Blood tests (Table 1) revealed markedly elevated thyroid-stimulating hormone (TSH) levels at 1,805 µIU/mL and low free thyroxine (Free T4) levels at 0.1 ng/dL, consistent with severe hypothyroidism. Among the thyroid autoantibodies, anti-thyroglobulin antibody levels were elevated at 157.0 IU/mL. Estradiol (E2) levels were elevated to 53 pg/mL, reaching pubertal levels, whereas the basal luteinizing hormone (LH) level was suppressed to < 0.10 mIU/mL. A gonadotropin-releasing hormone (GnRH) stimulation test demonstrated persistently suppressed LH and a follicle-stimulating hormone (FSH) peak of 8.11 mIU/mL, supporting a diagnosis of peripheral precocious puberty. Although galactorrhea was not observed, prolactin (PRL) levels were elevated at 59.79 ng/mL. Serum testosterone and dehydroepiandrosterone sulfate levels were not assessed. Abdominal ultrasonography revealed bilateral ovarian cysts (Fig. 1B). Bone age assessment revealed a delay of 7 yr and 10 mo (Greulich and Pyle method), indicating a lagging chronological age.

Table 1. Laboratory results at first presentation.

Although thyroid ultrasonography was not performed, the absence of goiter, along with markedly elevated TSH levels, positive anti-thyroglobulin antibody, and negative TPO antibody suggested atrophic autoimmune thyroiditis. Brain magnetic resonance imaging (MRI) revealed pituitary hypertrophy (10 mm height) with a superiorly convex contour (Fig. 1C). The signal was homogeneous on the T1- and T2-weighted images, and the posterior bright spot was preserved. No stalk deviations or hemorrhages were observed.

A diagnosis of VWGS was established based on the presence of acquired hypothyroidism, peripheral precocious puberty, ovarian cysts, delayed bone age, and hyperprolactinemia. Levothyroxine therapy was initiated at 12.5 µg/d and gradually titrated upward (Fig. 1D). This gradual titration was performed to reduce the risk of complications such as pituitary apoplexy. Symptoms such as cold extremities and constipation resolved within approximately 1 mo. Free T4 levels normalized within 1 mo, whereas TSH levels normalized within 2 mo. Liver enzyme levels were elevated at baseline, but normalized within 6 wk of levothyroxine therapy. The ovarian cysts markedly decreased in size within 1 mo (Fig. 1B). Estradiol levels declined below the detection limit; however, they increased again 5 mo after treatment initiation. A repeat GnRH stimulation test revealed an LH peak of 13.90 mIU/mL, indicating central puberty activation. Consequently, GnRH analog therapy was initiated with 4-weekly injections. Thereafter, LH and estradiol levels remained suppressed, although bone age advanced relatively rapidly.

Ethical consideration

Informed consent for publication of this case report was obtained from the patient and her guardian.

Review of the Literature

Method

To better characterize the clinical features of abnormal pubertal progression in girls with acquired hypothyroidism, we reviewed previously reported pediatric cases presenting with pubertal signs, such as breast development, vaginal bleeding, or ovarian cysts.

A literature search was performed using the PubMed and MEDLINE databases through April 2025 with the search terms “Van Wyk–Grumbach syndrome” or the combination of “hypothyroidism” and “precocious puberty.” Since our primary aim was to explore vaginal bleeding in the absence of pubic hair development, a pattern specific to female patients, we included only girls in this review. Male patients identified in the literature were excluded from analysis.

The inclusion criteria were: [1] female pediatric patients with acquired hypothyroidism; [2] the presence of at least one pubertal sign (breast development, vaginal bleeding, or ovarian cysts); and [3] laboratory confirmation of hypothyroidism. Cases involving congenital hypothyroidism, central precocious puberty, lack of sufficient clinical information, or male patients were excluded.

The extracted data included patient age at presentation, chief complaint, Tanner stage for breast and pubic hair development, presence of vaginal bleeding, bone age, and hormone levels (TSH, FT4, LH, FSH, E2, and PRL). Pituitary imaging results and thyroid antibody status were recorded.

Results

We identified 44 female patients from 38 English-language publications that met the inclusion criteria (Supplementary Table 1). One relevant Japanese case was excluded to maintain consistency in the review methodology.

Among the cases found of female patients with acquired hypothyroidism and pubertal signs, several characteristic clinical features were identified. Of the 44 cases, 33 were explicitly described as having Van Wyk–Grumbach syndrome in the original reports. Notably, a significant delay in bone maturation, defined as a difference of more than 2 yr between chronological age and bone age (6), was consistently observed, with a median bone age delay of 2.6 yr compared to chronological age (Table 2). Vaginal bleeding was the most common chief complaint at presentation, reported in 66% of the cases; it was observed in 93% of the cases. Despite these pubertal signs, pubic hair development was generally absent, with 75% of patients remaining at the Tanner stage I of pubic hair growth. The endocrinological evaluation demonstrated markedly elevated TSH levels (median 484.6 µIU/mL) and severely decreased FT4 levels (median 0.23 ng/dL), consistent with profound hypothyroidism. E2 levels were significantly elevated (median 106.0 pg/mL), while LH levels remained markedly suppressed (median 0.10 mIU/mL), indicating a non-central mechanism of pubertal progression. The PRL levels were also elevated, with a median value of 63.0 ng/mL.

Table 2. Clinical characteristics of girls with acquired hypothyroidism presenting with pubertal signs.

Discussion

In the present case, a 9-yr-old girl presented with peripheral precocious puberty characterized by vaginal bleeding without pubic hair development, delayed bone age, bilateral ovarian cysts, and hyperprolactinemia with acquired hypothyroidism. Although precocious puberty secondary to hypothyroidism has been reported sporadically, Van Wyk and Grumbach first described this constellation of findings in 1960 (1), and the syndrome has since been referred to as Van Wyk–Grumbach Syndrome (VWGS). The present case was found to exhibit clinical features consistent with the classic presentation of VWGS.

Our literature review and analysis revealed that a significant proportion of girls with VWGS exhibit vaginal bleeding despite the lack of pubic hair development. Supplementary Fig. 1 illustrates this atypical sequence of pubertal progression, showing that many patients remained at Tanner stage I for pubic hair, even at the onset of vaginal bleeding. During normal pubertal development, pubic hair growth typically precedes or occurs simultaneously with menarche due to rising adrenal androgen levels. However, in VWGS, the sequence is reversed, likely because of gonadotropin-independent estradiol secretion triggered by excessive TSH stimulating the ovaries without concurrent activation of adrenal androgen production. This distinctive pattern of pubertal development and vaginal bleeding preceding pubic hair emergence may serve as a useful diagnostic clue for VWGS and underscores the importance of considering underlying hypothyroidism in girls who present with isolated vaginal bleeding at an early age.

A recent systematic review of VWGS (5) summarized 99 clinical cases from 68 publications, of which 92.1% were female. The median age was 8.75 yr, which is comparable to our findings. In that review, delayed bone age was reported to be on average, 43.2 mo behind the chronological age, which is consistent with our results. Abnormal vaginal bleeding was the most common presenting symptom (80.5%), followed by abdominal pain, which is consistent with the findings of the present review. However, the review did not provide specific data regarding Tanner staging or laboratory findings including gonadotropin and thyroid hormone levels. These clinical details are addressed in this study.

TSH, LH, and FSH share a common α subunit, with each possessing a hormone-specific β subunit that confers biological specificity. These glycoprotein hormones exhibit high structural homology at the molecular level (7), and cross-reactivity with distinct receptors has been proposed based on the receptor structure and ligand interactions. Both LH and FSH are involved in estrogen synthesis (8); however, FSH plays a critical role in early follicular development and estrogen production by stimulating FSH receptors expressed in granulosa cells. Given the presence of multicystic ovarian lesions and excessive estradiol secretion in VWGS, FSH receptor overstimulation is presumed to be a key contributing factor to its pathophysiology.

Excessive estrogen exerts a negative feedback on the hypothalamus and suppresses GnRH secretion. While this would typically result in a reduction in both LH and FSH secretion, our case and previously reported cases of VWGS demonstrated disproportionately suppressed LH with relatively preserved FSH levels. Several hypotheses can explain this phenomenon. First, the frequency of GnRH pulsatility may play a role; higher pulse frequencies preferentially stimulate LH secretion, whereas lower frequencies favor FSH secretion (9). Therefore, residual low-frequency GnRH pulses may support continued FSH release in VWGS. Second, FSH secretion is regulated by GnRH-independent mechanisms involving activin, inhibin, and follistatin (8), which may contribute to its maintenance despite hypothalamic suppression.

In contrast, pubic hair development predominantly depends on adrenal androgen secretion rather than on ovarian estrogen production. Therefore, the progression of puberty in VWGS may bypass pubarche, leading to an atypical sequence in which vaginal bleeding precedes pubic hair development. This may help distinguish this syndrome from other causes of precocious puberty.

In typical cases of central precocious puberty, increased estradiol levels promote rapid skeletal maturation, leading to advanced bone age. However, in VWGS, despite elevated E₂ levels, bone maturation is paradoxically delayed due to a profound deficiency in thyroid hormones, which are essential for normal skeletal development. This paradoxical phenomenon is another key diagnostic clue for VWGS.

Hyperprolactinemia is also commonly observed in patients with VWGS. This is thought to result from increased thyrotropin-releasing hormone stimulation of prolactin secretion by the anterior pituitary gland secondary to primary hypothyroidism (10).

From a clinical perspective, when a young girl presents with vaginal bleeding in the absence of pubic hair development, especially with delayed bone age, underlying hypothyroidism should be considered a potential cause. Prompt measurement of serum TSH and FT4 levels can facilitate an accurate diagnosis, enabling the timely initiation of thyroid hormone replacement therapy. Recognizing this atypical pattern of pubertal progression is therefore essential not only to avoid misdiagnosis, but also to ensure appropriate and effective management of profound hypothyroidism.

This study has several limitations. First, our analysis was based on previously reported case series and case reports, which are inherently subject to publication bias and variability in the completeness and quality of clinical data. Second, information on the duration of hypothyroidism before diagnosis and the natural history of pubertal progression following thyroid hormone replacement therapy was not uniformly available across cases. Despite these limitations, this study provides a novel and systematic characterization of atypical pubertal sequences observed in VWGS. Future prospective studies are warranted to better elucidate the natural course of pubertal development in VWGS and refine the diagnostic criteria based on longitudinal data.

Conclusion

VWGS is characterized by an atypical sequence of pubertal progression, in which vaginal bleeding precedes pubic hair development, along with a paradoxical bone age delay despite elevated estradiol levels. Awareness of this atypical presentation can assist in preventing misdiagnosis and ensuring timely treatment of hypothyroidism.

Conflict of interests

The authors declare no conflicts of interest.