Van Wyk-Grumbach syndrome: The importance of thyroid function tests in a child presenting with multicystic ovaries

Abstract

Introduction

Van Wyk-Grumbach syndrome (VWGS) is a rare presentation of long-standing hypothyroidism, characterized by delayed bone age, enlarged bilateral multicystic ovaries, and isosexual precocious puberty.

Case presentation

We report here the clinical details of the case of Van Wyk Grumbach Syndrome in an 11-year-old girl who was first presented to the pediatric surgeon for hemoperitoneum. The patient underwent an emergency exploratory laparotomy, which showed enlarged ovaries with multiple cysts that were bleeding. She also had severe hypothyroidism, hyperprolactinemia, hyperestrogenism, pituitary adenoma, and delayed bone age. Significant improvement in symptoms was noted after thyroid hormone replacement therapy.

Importance and conclusion

This case highlights that it is crucial to consider thyroid assessment in a patient with multicystic ovaries to avoid misdiagnosis, unnecessary investigations for malignancy and/or surgical intervention, and possible complications.

Highlights

• •This is the case of Van Wyk Grumbach Syndrome in an 11-year-old girl who first presented hemoperitoneum, with enlarged ovaries and multiple cysts that were bleeding.
• •She also had severe hypothyroidism, hyperprolactinemia, hyperestrogenism, pituitary adenoma, and delayed bone age.
• •After thyroid hormone replacement therapy, significant improvement in symptoms was noted.
• •It is crucial to consider thyroid assessment in a patient with multicystic ovaries to avoid misdiagnosis, unnecessary investigations.

1. Introduction

Ovarian cysts are a particular subgroup in the pediatric population that must be carefully evaluated since they could arise secondarily due to some endocrine disorder and, if undiagnosed, may lead to unnecessary surgical intervention. [1]. Van Wyk and Grumbach first reported the association of multicystic ovaries, hypothyroidism, and precocious puberty in 1960 [2]. In their case report, three girls presented with juvenile hypothyroidism, early menarche, galactorrhea, absence of pubic hair, and enlargement of sella turcica. Since then, few clinical case reports have appeared in the literature about this condition, but they remain ignored in the pediatric surgical literature [3]. We report here a case of juvenile primary hypothyroidism presenting as a surgical complication that could have been prevented by early recognition and treatment of this syndrome and by avoiding unnecessary investigations. The work has been reported in line with the SCARE criteria. [4]

2. Case report

Here, we describe the case of an 11-year-old girl who was referred to our pediatric endocrinology unit from the pediatric surgery department due to bilateral multicystic ovaries and enlargement of the pituitary gland. Our patient was the firstborn child of an uncomplicated pregnancy without antenatal or postnatal events. Her developmental milestones were normal, and her parents were not blood-related. She has a medical history of two previous hospitalizations at the pediatric surgery department of a peripheral hospital. The first hospitalization was for acute abdominal pain, and the second; which occurred five months later; was for acute surgical abdominal pain, swollen belly, and cold and pale skin resulting from hemoperitoneum following minimal abdominal trauma Figs. 1,2; imaging which includes a computed tomography (CT) scan showed abundant hemoperitoneum. Surgery was performed through median laparotomy straddling or across the umbilicus. And found enlarged ovaries with multiple cysts. About 200 ml of hemoperitoneum was evacuated. The patient underwent hemostatic suturing for a few larger cysts that were bleeding. The postoperative course was uneventful.

Figs. 1–2.

Clinical presentation of the patient.

The patient experienced intense pain several times prompting consultation with a private adult gynecologist who has ordered a hormone test and pelvic ultrasound, and put her on symptomatic treatment. Six months postoperatively, the patient was brought to the surgery department of our tertiary care hospital for a second opinion coinciding with another episode of surgical abdominal pain. Abdominal ultrasound and magnetic resonance imaging were performed (MRI, Figs. 3–5) showing the huge multicystic ovaries. The right ovary was enlarged measuring 97 × 55 mm. The left ovary was enlarged as well measuring 62 × 50 mm. Cysts were divided by septa showing contrast uptake. A malignant ovarian tumor was included in the differential diagnosis. The medical team ordered ovarian tumor markers, including, Alpha-fetoprotein (AFP): 4.37 ng/ml (0.00–7.00), CA125, 39.20 U/ml (0.00–36.00), CA19–9: 16.19 U/ml (0.00–33.00) and human chorionic gonadotropin (hCG): (<1.20mUI/ml) all were within the normal reference range. MRI of the pituitary revealed an enlargement of the pituitary gland measuring approximately 25 × 16 × 13 mm (Figs. 6,7,8,9).

Figs. 3–5.

(Left to right) Pelvic MRI in T2 sequence coronal section (3), axial section (4), and T1 sequence injected axial section (5) showing enlarged multicystic ovaries measuring for the right ovary: 97 × 55 mm, and for the left ovary: 62 × 50 mm.

Figs. 6–9.

(Left to right) MRI of the Brain T2 coronal (5), T1 coronal (6), T1 coronal injected (7), T1 sagittal injected (8) showing significant hypertrophy of the pituitary gland measuring 25 × 16 × 13 mm, with homogeneous uptake after contrast without an endosellar mass.

The child was referred to our pediatric endocrinology unit with a possible diagnosis of a pituitary tumor based on her magnetic resonance imaging (MRI) findings. After conducting a detailed interview with the parents, it was revealed that the patient had a history of constipation, a decreased activity level, and gaining weight for 1 year. For the last 6 months, she had excess sleep and spontaneous galactorrhea on and off from her left breast. There was no history of any, headaches, nocturia, polyuria, visual disturbances, or vomiting. She had been performing poorly in school over the past 6 months, with her grades gradually declining. On admission, the patient was lethargic and pale. She had puffiness on her face. The vital signs were normal: Blood pressure 120/67 mmHg, temperature at 37 Celsius, peripheral pulse 73 beats/min, respiratory 20 rate/min. The patient weighed 43 kg (+1 SD) with a height of 142 cm (−0.5 SD) and in the absence of previous measurements, the reconstruction of the growth curve was not done, her body mass index was at 21 kg/m². Tanner's sexual maturity rating was A1B3P1 (A = axillary hair growth, B = breast development, P = pubic hair growth). Enlargement of the breasts and absent pubic or axillary hair were noted with brittle hair and dry scaly skin. Thyroid and lymph node enlargement were not noted. The abdomen was distended and tender on the right and left iliac fossa. There was no hepatosplenomegaly. The rest of the systemic examination was normal.

Laboratory tests revealed microcytic hypochromic anemia with hemoglobin of 10.3 g/dl. Blood glucose, liver function tests, renal function tests, and electrolytes were normal. Her bone age was estimated to be 9–10 years. Considering clinical presentation, signs of hypothyroidism, precocious puberty, and imaging reporting delayed skeletal growth, multiple cysts in both ovaries (Figs. 1,2,3,4), and the enlargement of the pituitary gland in the MRI, we suspected that she had Von Wyk Grumbach (VWG) syndrome. Hormonal investigations revealed profound hypothyroidism with thyroid-stimulating hormone (TSH) >500 μIU/ml ([normal range (NR): 0.5–4.3]), T3: 1.46 (NR:0.98–1.63), T4: 0.076 ng/dL (NR: 0.51–4.3), anti-thyroid peroxidase antibody: 109.7 IU/ml: (NR: 2.5–3.9) and anti-thyroglobulin antibodies 29.9 IU/ml (NR: 2.5–3.9) confirming a diagnosis of autoimmune thyroiditis. Follicle-stimulating hormones were high (FSH): 7.91mUI/ml (NR: 0.15–3.1), luteinizing hormone was normal (LH): 0.09mUI/ml, suggestive of FSH dominant precocious pseudopuberty. Prolactin levels were very high: 248 ng/ml (NR: 0.30–12.9), normal PTH at 44.90 pg/ml (NR: 9–45). Serum estradiol level also was high: 1576 pg/ml, vitamin D: 4.7 ng/ml, Inhibine B: 2509 pg/ml (NR: 30–340). A diagnosis of multicystic and pituitary enlargement secondary to untreated hypothyroidism of autoimmune etiology was made and the patient was started on levothyroxine 50 μg per day, then increased progressively to a dose of 100 μg per day. She was also given calcium and vitamin D. Galactorrhea stopped—a week after starting levothyroxine. On further follow-up after 1 month, the size of ovarian cysts has reduced. Serum TSH levels came to normal after 2 months (TSH: 1.45 μIU/ml). A recent follow-up 3 months after starting treatment showed an improvement in her growth (height 102 cm, weight 16 kg), and breast development regressed significantly. The pituitary enlargement associated with hypothyroidism is known to regress with levothyroxine treatment, an MRI was performed 6 months afterward showing a normal-sized pituitary gland 21 × 12 × 5 mm (Figs. 10,11,12).

Figs. 10–12.

(Left to right) MRI of the Brain T1 coronal (9), T1 coronal injected (10), T2 coronal (11) showing normal sized pituitary gland measuring 21 × 12 × 5 mm.

3. Discussion

Primary Hypothyroidism is classically associated with failure to grow and to have proper sexual development with delayed bone age [5]. However, in cases of long-standing untreated hypothyroidism, our patient presented with precocious puberty, multi-cystic enlarged ovaries, breast development, and galactorrhea without pubic and axillary hair development. All of these findings lead to the diagnosis of Van Wyk-Grumbach syndrome [2]. Also, enlargement of the sella turcica is not uncommon. It results from the loss of thyroxine inhibitory feedback and subsequent overproduction of thyrotropin-releasing hormone (TRH). Pituitary hyperplasia has been reported in patients with long-term undiagnosed and untreated primary hypothyroidism, and it is known to regress with treatment [6].

We noticed that in our patient before obtaining a thyroid profile, a brain MRI was carried out, and this case was thought to be macro adenoma. The multicystic ovarian enlargement seen in our case was misinterpreted as ovarian neoplasm. Ovarian tumor markers including AFP, CA125, CA19-9, and hCG were recommended by the medical team, which were within the normal reference range. However, the elevation of tumor markers [such as AFP, CA-125, LDH, and Inhibin] has also been described in other case reports of Van Wyk-Grumbach syndrome. This case of VWGS was diagnosed only after performing thyroid function tests and other hormonal profiles. It is important to recognize VWG Syndrome and the relationship between hypothyroidism and cystic ovaries to avoid unnecessary investigations.

Several mechanisms have been proposed for ovarian cyst formation in this condition. Although it was previously hypothesized that thyrotropin-releasing hormone (TRH) induces the overproduction of gonadotropins and prolactin [5,6], the focus has shifted to the structural similarities between FSH and other hormones like TSH, and HCG, and their receptor interactions. Therefore, it is highly probable that the extremely elevated levels of TSH, typically associated with long-standing hypothyroidism, might activate wild-type FSH receptors non-selectively, resulting in ovarian hyperstimulation [5,7,8]. The resulting ovarian hyperstimulation causes the ovaries to enlarge and produce high levels of estrogen, which may explain breast enlargement, early menarche, and enlarged multi-cystic ovaries in the absence of pubic and axillary hair development. In boys, this leads to macroorchidism with minimal penile but no significant signs of virilization. Similar to other reported cases in the literature, our patient exhibited bilateral ovarian masses. A review of the literature reveals that most patients with VWG present with bilateral rather than unilateral masses [9]. Severely overstimulated ovaries and the resulting cystic mass may be large enough to cause torsion or rupture, as was the case in this patient.

Galactorrhea, another common finding, was also present in our patient. Hyperprolactinemia has two etiologies. Some speculate that the thyrotrope hyperplasia in the pituitary compresses the pituitary stalk, thereby disrupting hypothalamic inhibition of prolactin. Others claim that TRH is also known to stimulate prolactin [10]. Our patient had galactorrhea, which resolved after T4 replacement. Other features of hypothyroidism are usually present [3]. Chronic constipation, weight gain, excessive sleepiness, decreased activity, and facial swelling found on examination suggested a diagnosis of hypothyroidism in this case.

The treatment approach is clear in this condition. Surgery should only be considered for complications of ovarian cysts, such as torsion [3]. Almost all patients with VWGS respond well to thyroid replacement therapy. Usually, ovarian enlargement resolves within 3 to 6 months of T4 therapy [11]. In our patient, the multi-cysts were monitored regularly by ultrasound and reduced in size at each assessment. She improved clinically, with improvement in skin texture, constipation, and reduced hair loss over the following 6 weeks.

4. Conclusion

While the clinical signs of hypothyroidism are present, the diagnosis is often significantly delayed due to the masking effect of abnormal symptoms resulting from ovarian hyperstimulation and pituitary enlargement. It is essential for the surgical community to gain a deeper understanding of this specific syndrome and prioritize thyroid evaluation to prevent misdiagnosis and unnecessary surgical interventions.

Ethical approval

All ethical considerations have been taken into account. No personal data has been exposed. Our ethical committee is Oujda Biomedical Research Ethics Committee (CERBO).

Funding

We declare that we do not have any source of funding.

Author contribution

Study Concept and design: Pr Amal Hamami

Data Collection and interpretation: Dr Nour El Houda Ouerradi

Writing the paper: Dr Aziza El Ouali

Imaging analysis: Pr Kamaoui Imane

Revising the article: Pr Rkain Maria and Pr Abdeladim Babakhouya

Guarantor

Aziza El Ouali.

Consent

Written informed consent was obtained from the patient's parents/legal guardian for publication and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Conflict of interest statement

We declare that we do not have any financial or personal relationships with people or organizations that could inappropriately influence our work.

No conflict of interest is to be declared.