http://informahealthcare.com/gye ISSN: 0951-3590 (print), 1473-0766 (electronic) Gynecol Endocrinol, 2014; 30(4): 272–276 ! 2014 Informa UK Ltd. DOI: 10.3109/09513590.2013.871523
PRECOCIOUS PUBERTY
Van Wyk and Grumbach syndrome: an unusual form of precocious puberty Anja Christens1, Lieve Sevenants1, Jaan Toelen1,2, Dominique Bullens1,3, and Kristina Casteels1,2 1
Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium, 2Department of Development and Regeneration, KU Leuven, Belgium, and Department of Microbiology and Immunology, KU Leuven, Belgium
Abstract
Keywords
An 8-year-old girl presented with precocious menstruation and growth delay. Laboratory data revealed hypothyroidism and an X-ray of the wrist showed a delayed bone age. The Van Wyk and Grumbach syndrome (VWGS) was diagnosed and thyroid replacement was started with resolution of the symptoms. The association of precocious puberty and/or polycystic ovaries, delayed bone age and hypothyroidism is known as the Van Wyk and Grumbach syndrome. Clinically this syndrome is a diagnostic challenge because hypothyroidism usually leads to pubertal and growth delay, whereas in case of VWGS hypothyroidism it leads to growth delay and precocious puberty. The pathophysiology of VWGS is not yet clear, but the most accepted theory states that the high concentrations of TSH are sufficient to cause activation of the FSH receptor and produce gonadal enlargement. Thyroid replacement therapy results in a resolution of all signs and symptoms. For this reason, conservative management of the ovarian masses is advocated. Our case is unique as this girl did not have breast development or multicystic ovaries (as the other cases in the literature). This may be due to an early recognition and relatively low TSH levels in comparison to other cases.
Hypothyroidism, ovarian cysts, precocious puberty, Van Wyk and Grumbach syndrome
Introduction The syndrome consisting of primary hypothyroidism, precocious puberty and massive ovarian cysts has been described since 1905 and in 1960 the term ‘‘Van Wyk and Grumbach syndrome’’ was first used [1]. All clinical and biochemical findings undergo complete remission when these patients are started on an adequate thyroid replacement therapy. Clinically this syndrome is a diagnostic challenge because hypothyroidism usually leads to pubertal and growth delay, whereas in case of VWGS hypothyroidism leads to growth delay with paradoxically precocious puberty. In this article we present an 8-year-old girl and give a review of the literature.
Case report An 8-year-old girl was referred to our university center because of moderate vaginal bleeding since 2 days. The patient’s past medical history and development were otherwise unremarkable. In the family history the maternal grandmother had hypothyroidism and an aunt had systemic lupus erythematosus. Further history revealed additional symptoms of excessive sweating, weight gain and poor growth. The parents also noted that their daughter was easily tired, irritable and emotionally unstable since a few months. On inspection she had a round puffy, pale face and a robust stature. There was no goitre. The abdomen was not distended and further clinical examination was without abnormalities. Address for correspondence: Kristina Casteels, Department of Pediatrics, University Hospitals Leuven, KU Leuven, Herestraat 49, 3000 Leuven, Belgium. Tel: +3216-343801. Fax: +3216-343981. E-mail: [email protected]
History Received 22 August 2013 Revised 12 November 2013 Accepted 29 November 2013 Published online 25 February 2014
Blood pressure and heart rate were in the normal range. Height 122.9 cm (p3) and weight 30.7 kg (p50) were appropriate for age, but inspection of the growth charts revealed a marked discordance between length and weight. There was also a weight gain of 4 kg over the last 8 months and a significant decline in growth velocity (Figure 1). Tanner stage was A1 P1 M2. Laboratory data revealed normal estrogen (55 ng/l) and prolactin (8.2 mg/l) levels. Tumor marker CA-125 was not raised. Luteinizing hormone (LH) (0.1 IU/l) and follicle-stimulating hormone (FSH) (3.4 IU/l) were at a pre-pubertal level. Levels of thyroid stimulating hormone (TSH) were elevated (152.3 mIU/l, normal range 0.27–4.20 mIU/ l) and levels of free thyroxin were decreased (T4 0.32 ng/dl, normal range 0.93–1.70 ng/dl). Antithyroglobulin (Tg Ab 248 IU/ ml, normal range 5115 IU/ml) and antithyroid peroxidase antibodies (TPO Ab 4600 IU/ml, normal range 534 IU/ml) were elevated. Abdominal ultrasound was normal with normal appearance of the uterus, ovaries and no visible endometrial line. X-ray of the wrist revealed a delayed bone age. Her chronological age at presentation was 8 years and 10 months. Her bone age was estimated at 7 years and 9 months, using the Tanner–Whitehouse Standard. Ultrasonography of the thyroid showed a heterogeneous and strongly vasculated thyroid gland, a finding highly suggestive for thyroiditis. The Van Wyk and Grumbach syndrome was diagnosed based on the co-occurrence of hypothyroidism, precocious puberty and delayed bone age. Daily therapy with levothyroxine, 50 mg per os (0.05 mg/m2), was started. The thyroid function was normalized after 2 months: TSH level dropped from 152.3 mIU/l to 3.88 mIU/l, with normal T4 concentrations. Given the satisfactory results, we continued levothyroxine at the same dosage. Serial follow-up consultations showed great improvement: the girl felt better, was more active and did not have vaginal blood
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Van Wyk and Grumbach syndrome
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DOI: 10.3109/09513590.2013.871523
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Figure 1. Growth chart. Weight in kilograms and height in centimetres by Flemish standards 2004, VUB Laboratory of Anthropogenesis and KUL Juvenile Health Care, with support of the Flemish government. www.vub.ac.be/groeicurven – 20040916 – EMD/006 en 20050604 – EMD/006 – vub.kul ß 2004. On the x-axis you can find the age in years (j).
loss anymore. Clinical examination was normal. She was scored Tanner A1 P1 M1.
Discussion Epidemiology Precocious puberty is a known, but rare complication of severe acquired juvenile hypothyroidism, and was first described by Kendle in 1905. It was not until 1960 when the term ‘‘Van Wyk and Grumbach syndrome’’ was coined [1]. Van Wyk and Grumbach described a syndrome of precocious menstruation in juvenile hypothyroidism, with reversion to a pre-pubertal state following the administration of thyroid hormone. A clue to the diagnosis is the delayed bone age, because VWGS is the only form of precocious puberty in which the bone age is delayed [1,2]. In our literature search we resulted with a total of 33 patients (articles with no electronic full text version available were excluded from our patient group). Thirty patients were female and all of them presented with multicystic ovaries (Table 1). In our table, only three cases describe boys with the Van Wyk–Grumbach syndrome. They all presented with macro-orchidism [3–5]. Seven additional case reports were found, but no full text was available and therefore these were excluded from our patient group [6–12]. The low number of male patients could be due to the fact that thyroid disorders are more common in girls [2]. The girls typically presented with vaginal bleeding, poor growth and abdominal masses or pain. In 21 patients the TSH level had increased above the concentration of 100 mIU/ml [2,13–23] and 12 investigators reported to have found raised levels of gonadotropins on biochemical analysis [3,15–21,24–26]. Prolactin (PRL) levels were elevated in 13 patients [3,13–18,21,23,25,26]. All of them were successfully treated with levothyroxine. Our case did not present with multicystic ovaries, abdominal pain or masses. We consider this as the result of an early recognition and the relatively
low TSH elevation. There was no increase in gonadotropins in our case. Most cases of VWGS concern pre-pubertal children, but it has also been described in young women (Table 1) [2]. The predominance in pre-pubertal children can be explained by the assumption that the pre-pubertal gonads are more susceptible to stimulation by TSH, because they are primed to be activated by very low levels of FSH, as at the onset of puberty (cfr. ‘‘FSH theory’’ below) [4]. Pathophysiology VWGS is thought to be caused by a preceding thyroiditis. Typically the levels of TSH exceed 100 mIU/l. Most cases also describe the presence of autoantibodies against TPO or thyroglobulin. However, the syndrome can also appear in cases of congenital hypothyroidism, ectopic thyroid tissue or tumors that cause hypothyroidism. The exact mechanism is still unknown. We hereby provide an overview of the most relevant hypotheses. In longstanding hypothyroidism, PRL levels can be high. It has been hypothesized that pituitary stimulation by thyroid releasing hormone (TRH) leads to an increased level of both TSH and PRL and that high levels of PRL enhance the sensitivity of the ovaries to circulating gonadotrophines by increasing ovarian LH receptors [15,27,28]. Prolactin levels, however, are not always increased as shown in our case (Table 1). Mandl hypothesized in 1980 that continuous high TRH concentrations would stimulate not only TSH, but FSH secretion as well [29]. This had already been put forward by Van Wyk and Grumbach in 1960 and was later named the ‘‘overlap theory’’ [1,17]. Various studies, however, demonstrate that gonadotropins are not routinely elevated in the VWGS (Table 1) [12].
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Table 1. Characteristics of described cases in literature.
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Ref
Age
Sex
Presentation
Laboratory findings
Case
8
G
Vaginal bleeding, breast development, weight gain, poor growth, delayed bone age
TSH 152.3 mIU/l (0.27 – 4.20 mIU/l) T4 0.32 ng/dl (0.93 – 1.70 ng/dl). Normal PRL and Estradiol
[16]
11 y
G
Bilateral ovarian mass, vaginal bleeding, pelvic pain, lethargy, weight gain
TSH 1889.9 mIU/ml (0.27 – 4.20 mIU/ml) T4 0.3 ng/dl (0.93 – 1.70 ng/dl) PRL 77 ng/ml (3 – 23.2 ng/ml) Estradiol 568 pg/ml (2 – 15 pg/ml)
[19]
15 y
G
Ovarian mass, abdominal pain, lethargy, breast development, normal bone age, poor growth
TSH 1582.33 mIU/ml (0.27 – 4.20 mIU/ml) Estradiol 591.2 pg/ml (2 – 15 pg/ml) TPO Ab 3205 IU/ml (540 IU/ml)
[18]
12 y
G
Multicystic ovaries, thyroiditis, normal bone age
TSH 939 mIU/ml (0.27 – 4.20 mIU/ml) T4 0.6 ng/dl (0.93 – 1.70 ng/dl) PRL 1242 mIU/ml (60 - 525 mIU/ml) Estradiol 639 pg/ml (2 – 15 pg/ml) TPO Ab 71 IU/ml (540 IU/ml) Tg Ab 59 IU/ml (535 IU/ml)
[2]
10 y
G
Vaginal bleeding, pelvic pain, delayed bone age
8y
G
Bilateral multicystic ovaries, vaginal bleeding
16 y
G
Cystic ovary, recurrent ascites, hypothyroidism
17 y
G
Bilateral multicystic ovaries, oligomenorrhea
15 y
G
Abdominal distension, dyspnoe, hypothyroidism
TSH 494 mU/ml (0.37 – 6 mU/ml) T4 51.05 mg/dl (5 – 12 mg/dl) TSH 954 mU/ml (0.37 – 6 mU/ml) T4 6.6 mg/dl (5 – 12 mg/dl) TSH 39 mU/ml (0.37 – 6 mU/ml) T4 6.6 mg/dl (5 – 12 mg/dl) TSH 27.08 mU/ml (0.37 – 6 mU/ml) T4 5.0 mg/dl (5 – 12 mg/dl) TSH 15.8 mU/ml (0.37 – 6 mU/ml) T4 2.5 mg/dl (5 – 12 mg/dl)
[24]
9y
G
Vaginal bleeding, abdominal pain, lethargy, breast development, delayed bone age, poor growth
TSH 475 mIU/ml (0.5 – 5.1 mIU/ml) T4 0.3 ng/dl (0.712 – 1.85 ng/dl) Estradiol 3.58 pg/ml (2 – 15 pg/ml)
[14]
7y
G
Abdominal mass, vaginal bleeding, breast development, delayed bone age
TSH 4100 mIU/ml (0.37 – 6 mU/ml) T4 0.3 mg/dl (5 – 12 mg/dl) Estradiol 463 pg/ml (571 pg/ml) PRL 160 ng/ml (525 ng/ml) TPO Ab 41000 IU/ml (540 IU/ml) Tg Ab 55 IU/ml (535 IU/ml)
[22]
7y
G
Unilateral ovarian cysts, vaginal bleeding, poor growth
TSH 480 mIU/ml (0.37 – 6 mU/ml)
[15]
9y
G
Unilateral ovarian cyst, vaginal bleeding, delayed bone age
TSH 4100 IU/ml (0.27 – 4.20 IU/ml) PRL 175 ng/ml (525 ng/ml) Estradiol 632 pg/ml (2 – 15 pg/ml)
G,G, B
Precocious sexual development
Elevated TSH, PRL, LH, FSH, Estradiol
[3] [17]
7y
G
Metrorrhagia, breast development, delayed bone age
TSH 792 mIU/l (0.5 – 4 mIU/ml) T4 3 pmol/l (10 - 20 pmol/l) PRL 33 ng/ml (2 – 18 ng/ml) Oestradiol 98 pg/ml (2 – 15 pg/ml) TPO Ab highly positive
[20]
4y
G
Multicystic ovaries, vaginal bleeding, breast development
TSH 4500 mIU/ml (0.37 – 6 mU/ml) T4 0.4 ng/dl (0.7 – 1.48 ng/dl) Oestradiol 117.7 pg/ml (2 – 15 pg/ml)
[33]
8y 3y
G G
Ovarian hypertrophy, vaginal bleeding Ovarian hypertrophy, vaginal bleeding
Hashimoto thyroiditis Thyroid dysgenesis
[4]
13 y
G
Breast development, pubic hair, vaginal bleeding, enlarged ovaries
16 y
G
Breast development, galactorrhea, pubic hair, enlarged ovaries
12 y
G
Goiter, enlarged ovaries
TSH 1058 mU/l (0.5 – 4 mU/l) T4 2.5 pmol/l (10 – 20 pmol/l) Oestradiol 3.0 nmol/l PRL 381 mg/l (2.8 – 29.2 mg/l) TSH 732 mU/l (0.5 – 4 mU/l) T4 5.1 pmol/l (10 – 20 pmol/l) Oestradiol 0.15 nmol/l PRL 38 mg/l (2.8 – 29.2 mg/l) TSH 526 mU/l (0.5 – 4 mU/l) T4 2.5 pmol/l (10 – 20 pmol/l) Oestradiol 0.05 nmol/l PRL 20 mg/l (2.8 – 29.2 mg/l) (continued )
Van Wyk and Grumbach syndrome
DOI: 10.3109/09513590.2013.871523
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Ref
Age
Sex
Presentation
275
Laboratory findings
8y
B
Secondary sexual characteristics, enlarged testes
TSH 366 mU/l (0.5 – 4 mU/l) T4 2.5 pmol/l (10 – 20 pmol/l) TSH 436 mU/l (0.5 – 4 mU/l) T4 5.1 pmol/l (10 – 20 pmol/l) TSH 1180 mU/l (0.5 – 4 mU/l) T4 2.5 pmol/l (10 – 20 pmol/l) Oestradiol 0.57 nmol/l PRL 75 mg/l (2.8 – 29.2 mg/l) TSH 254 mU/l (0.5 – 4 mU/l) T4 3.8 pmol/l (10 – 20 pmol/l) Oestradiol 0.07 nmol/l PRL 28 mg/l (2.8 – 29.2 mg/l) TSH 1376 mU/l (0.5 – 4 mU/l) T4 1.3 pmol/l (10 – 20 pmol/l) Oestradiol 0.56 nmol/l PRL 84.5 mg/l (2.8 – 29.2 mg/l)
8y
G
Enlarged ovaries
8y
G
Breast development, delayed bone age, goiter, enlarged ovaries
8y
G
Breast development, pubic hair, delayed bone age, enlarged ovaries
9y
G
Breast development, pubic hair, enlarged ovaries
[26]
7y
G
Unilateral ovarian cyst, vaginal bleeding, delayed bone age
Elevated gonadotrofins Normal oestradiol Elevated PRL
[5]
12 y
B
Weight gain, short stature, enlarged testes, delayed bone age
TSH 4100 mU/l (0.5 – 4 mU/l) T4 55.15 pmol/l (10 – 20 pmol/l) PRL 28.2 ng/ml (2.8 – 29.2 ng/ml) Tg Ab 470 IU/ml
[13]
8y
G
Breast development, abdominal pain, weight gain, enlarged ovaries, vaginal bleeding
TSH 995 mU/l (0.5 – 4 mU/l) T4 53.9 pmol/l (10 – 20 pmol/l) Oestradiol 550 pmol/l PRL 1310 mU/l (5440 mU/l) TPO Ab 378 kU/l (0 – 35 kU/l)
[21]
10 y
G
Breast development, vaginal bleeding, enlarged ovaries, delayed bone age
TSH 4150 mIU/ml (0.35 – 5.5 mIU/ml) T4 1.0 ng/ml (4.5 – 12.6 ng/ml) PRL 185.8 ng/ml (2.8 – 29.2 ng/ml)
[23]
10 y
G
Breast development, vaginal bleeding, unilateral ovarian cysts
TSH 578 mIU/ml (0.5 – 4.5 mIU/ml) T4 50.1 ng/dl (0.70 – 1.8 ng/dl) PRL 32.4 ng/ml (3 – 23 ng/ml) TPO Ab positive
[25]
9y
G
Breast development, bilateral multicystic ovaries, delayed bone age
TSH 81.30 mIU/ml (0.5 – 4.5 mIU/ml) T4 0.30 ng/dl (0.70 – 1.8 ng/dl)
G: girl. B: boy. TSH: thyroid stimulating hormone. T4: thyroxin. PRL: prolactin. TPO Ab: thyroid peroxidase antibodies. Tg Ab: thyroglobulin antibodies.
Other investigators hypothesize that the nuclear thyroid receptors in the granulosa cells are stimulated by the high levels of TSH, leading to raised aromatization of androstenedione into estrogen [30]. Raised estrogen levels are, however, not a consistent finding in the clinical cases. Later, it was shown that TSH could interact directly with the FSH receptor to elicit gonadal stimulation. This is probably due to a ‘‘spill-over effect’’ of glycoprotein hormones, a concept also called ‘‘molecular mimicking’’. TSH, which is markedly increased in the VWGS, has a small FSH and LH-like effect. The FSH effect leads to stimulating of the ovaries, which can explain the findings of multicystic ovaries, uterine bleeding and breast enlargement, without an increase in androgens. Anasti et al. explored this hypothesis in vitro using recombinant TSH and a human FSH receptor bioassay. The study demonstrated that TSH could elicit a dose-dependent cAMP response at the FSH receptor. This suggests that the highly elevated levels of TSH in hypothyroidism can act on the FSH receptor to induce ovarian hyperstimulation and precocious puberty [31]. Various
explanations have been put forward for this overlap theory. Noteworthy is the fact that the required level of TSH to stimulate the FSH receptor was many magnitudes higher than FSH [31]. TSH and FSH, along with LH and human chorionic gonadotropin (hCG) are closely related tropic hormones. The alpha-units of all four hormones are essentially identical and described from the same gene, with only variability in glycosylation. The beta-subunit is specific for each hormone, although they all show some degree of homology because they bind to a common alpha-subunit [32]. Ryan et al. evaluated eight pediatric patients with hypothyroidism associated with gonadal hyperstimulation, to study whether they carry a mutant FSH receptor or a specific allelic variant that results in a lower threshold to stimulation by TSH. They did not detect a mutation. In vitro experiments did show that there were no differences in the sensitivities of the human FSH receptor allelic combinations to recombinant human TSH. This does not exclude that there may be other actions mediated by the high levels of TSH that cause the gonadal FSH receptor to be more sensitive to TSH in vivo [4].
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In conclusion, this theory considers the extremely high concentrations of TSH in patients with VWGS sufficient to cause activation of the (wild type) FSH receptor, regardless of the allelic variant, and to produce gonadal enlargement, multicystic ovaries and/or downstream estrogenic effects mimicking puberty. Treatment Treatment of precocious puberty with hypothyroidism, in the VWGS, consists of replacement therapy with thyroid hormone. This will result in regression of all clinical symptoms and signs. Large ovarian masses, in association with one or more tumor markers would generally imply malignancy but it is important to stress that hypothyroidism should be first excluded. Surgery (ovariectomy) should be avoided, as the ovarian cysts all resolve after initiating hormonal treatment.
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Conclusion The VWGS should be kept in mind when children present with precocious puberty or young women with ovarian masses. This case demonstrates that VWGS should be kept in mind even in cases without clear ovarian involvement (no breast development, no multicystic ovaries). Replacement therapy with thyroid hormone will result in a complete regression of all clinical findings including the multicystic ovaries. Surgery should be avoided. The exact pathophysiological mechanism is not yet known, but in vitro studies lead to the hypothesis that gonadal stimulation in these patients is TSH-mediated. Further (in vivo) studies are necessary to confirm this theory.
Acknowledgements We would like to thank Marleen Jannis for her help in the preparation of this manuscript.
Declaration of interest The authors declare that they have no conflict of interest.
References 1. Van Wyk J, Grumbach M. Syndrome of precocious menstruation and galactorrhea in juvenile hypothyroidism: an example of hormonal overlap in pituitary feedback. J Pediatr 1960;57:416–35. 2. Browne LP, Boswell HB, Crotty EJ, et al. Van Wyk and Grumbach syndrome revisited: imaging and clinical findings in pre- and postpubertal girls. Pediatr Radiol 2008;38:538–42. 3. Hemady ZS, Siler-Khods TM, Najar S. Precocious puberty in juvenile hypothyroidism. J Pediatr 1978;92:55–9. 4. Ryan GL, Feng X, d’Alva CB, et al. Evaluating the roles of folliclestimulating hormone receptor polymorphisms in gonadal hyperstimulation associated with severe juvenile primary hypothyroidism. J Clin Endocrinol Metab 2007;92:2312–17. 5. Yin F, Omran A, Peng J, et al. Male child with Van Wyk Grumbach Syndrome and other complications of long standing primary hypoyhyroidism: a case report. Case Rep Pediatr 2012:352751. 6. Brudes JM, Samuels MH, Brenner WJ, et al. Hypothyroidisminduced macroorchidism: use of a gonadotropin-releasing hormone agonist to understand its mechanism and augment adult stature. J Clin Metab 1995;80:11–16. 7. Esen I, Demirel F. Hypothyroidism-associated testicular enlargement: is it a form of precocious puberty or not? A case report. Turkish J Pediatr 2011;53:210–12. 8. Gordon CM, Austin DJ, Radovick S, Laufer MR. Primary hypothyroidism presenting as severe vaginal bleeding in a prepubertal girl. J Pediatr Adolesc Gynecol 1997;10:35–38. 9. Jannini EA, Ulisse S, D’Armiento M. Macroorchidism in juvenile hypothyroidism. J Clin Endocrinol Metab 1995;80:2543–4.
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10. Laron Z, Karp M, Dolberg L. Juvenile hypothyroidism with testicular enlargement. Acta Paediatr Scand 1970;59:317–22. 11. Patni N, Cervantes LF, Diaz A. Elevated a-fetoprotein levels in Van Wyk-Grumbach syndrome: a case report and review of literature. J Pediatr Endocr Met 2012;25:761–7. 12. Riddlesberger MM, Kuhn JP, Munschauer RW. The association of juvenile hypothyroidism and cystic ovaries. Radiology 1981;139: 77–80. 13. Baranowski E, Ho¨gler W. An unusual presentation of acquired hypothyroidism: the Van Wyk-Grumbach syndrome. Eur J Endocrinol 2012;166:537–42. 14. Campaner AB, Scapinelli A, Machado R, et al. Primary hypothyroidism presenting as ovarian tumor and precocious puberty in a prepubertal girl. Gynecol Endocrinol 2006;22:395–8. 15. Chattopadhyay A, Kumar V, Marulaiah K. Polycystic ovaries, precocious puberty and acquired hypothyroidism: the Van Wyk and Grumbach syndrome. J Pediatr Surg 2003;38:1390–2. 16. Durbin K, Diaz-Montes T, Loveless M. Van Wyk and Grumbach syndrome: an unusual case and review of the literature. J Pediatr Adolesc Gynecol 2011;24:93–6. 17. Chemaitilly W, Thalassinos C, Emond S, Thibaud E. Metrorrhagia and precocious puberty revealing hypothyroidism in a child with Down’s syndrome. Arch Dis Child 2003;88:330–1. 18. Hunold A, Alzen G, Wudy SA, et al. Ovarian tumor in a 12 year old female with severe hypothyroidism: a case of Van Wyk and Grumbach syndrome. Pediatr Blood Cancer 2009;52:677–9. 19. Krishnamurthy S, Seth A, Puri A, et al. Ovarian tumors with elevated CA-125 levels and severe juvenile hypothyroidism: a need for increased awareness. Indian J Pediatr 2010;77:693–4. 20. Orgen T, Gu¨ven A, Aydin M. Precocious puberty in a girl with Down syndrome due to primary hypothyroidism. Turkish J Pediatr 2009;51:381–3. 21. Rastogi A, Bhadada SK, Bhansali A. An unusual presentation of a usual disorder: Van Wyk-Grumbach syndrome. Indian J Endocrinol Metab 2011;15:141–3. 22. Singh BM, Ammini AC, Kriplani A. Ovarian cysts in juvenile hypothyroidism. Arch Gynecol Obstet 2005;271:262–3. 23. Tran S, Kim EE, Chin AC. Severe menorrhagia, unilateral ovarian mass, elevated inhibin levels, and severe hypothyroidism: an unusual presentation of Van Wyk and Grumbach syndrome. J Pediatr Surgery 2013;48:E51–4. 24. Indumathi CK, Bantwal G, Patil M. Primary hypothyroidism with precocious puberty and bilateral cystic ovaries. Indian J Pediatr 2007;74:781–3. 25. Lim HH, Kil HR, Kim JY. Unusual presentations of a girl with Down syndrome: Van Wyk-Grumbach syndrome. J Pediatr Endocr Met 2012;25:1209–12. 26. Rakover Y, Weiner E, Shalev E, Luboshitsky R. Vaginal bleeding: presenting symptom of acquired primary hypothyroidism in a seven year-old girl. J Pediatr Endocrinol 1993;6:197–200. 27. Advis JP, Richards JS, Ojeda SR. Hyperprolactinemia induced precocious puberty: studies on the mechanism(s) by which prolactin enhances ovarian progesterone responsiveness to gonadotrophins in prepubertal rats. Endocrinology 1981;108:1333–42. 28. Radaideh AM, Nusier M, El-Akawi Z, Jaradat D. Precocious puberty with congenital hypothyroidism. Neuro Endocrinol Lett 2005;26: 253–6. 29. Mandl AM. Factors influencing ovarian sensitivity to gonadotropins. J Endocrinol 1957;15:448–57. 30. Dobozy O, Csaba G, Hetenyi G. Investigation of gonadotropinthyrotropin overlapping and hormonal imprinting in the rat testis. Acta Physiol Hung 1985;66:169–75. 31. Anasti JN, Flack MR, Froehlich J, et al. A potential novel mechanism for precocious puberty in juvenile hypothyroidism. J Clin Endocrinol Metab 1995;80:276–9. 32. Ryan RJ, Charlesworth MC, McCormick DJ, et al. The glycoprotein hormones: recent studies of structure-function relationships. FASEB J 1988;2:2661–9. 33. Sanjeevaiah AR, Sanjay S, Deepak T, et al. Precocious puberty and large multicystic ovaries in young girls with primary hypothyroidism. Endocr Pract 2007;13:652–5.
PRECOCIOUS PUBERTY
Van Wyk and Grumbach syndrome: an unusual form of precocious puberty Anja Christens1, Lieve Sevenants1, Jaan Toelen1,2, Dominique Bullens1,3, and Kristina Casteels1,2 1
Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium, 2Department of Development and Regeneration, KU Leuven, Belgium, and Department of Microbiology and Immunology, KU Leuven, Belgium
Abstract
Keywords
An 8-year-old girl presented with precocious menstruation and growth delay. Laboratory data revealed hypothyroidism and an X-ray of the wrist showed a delayed bone age. The Van Wyk and Grumbach syndrome (VWGS) was diagnosed and thyroid replacement was started with resolution of the symptoms. The association of precocious puberty and/or polycystic ovaries, delayed bone age and hypothyroidism is known as the Van Wyk and Grumbach syndrome. Clinically this syndrome is a diagnostic challenge because hypothyroidism usually leads to pubertal and growth delay, whereas in case of VWGS hypothyroidism it leads to growth delay and precocious puberty. The pathophysiology of VWGS is not yet clear, but the most accepted theory states that the high concentrations of TSH are sufficient to cause activation of the FSH receptor and produce gonadal enlargement. Thyroid replacement therapy results in a resolution of all signs and symptoms. For this reason, conservative management of the ovarian masses is advocated. Our case is unique as this girl did not have breast development or multicystic ovaries (as the other cases in the literature). This may be due to an early recognition and relatively low TSH levels in comparison to other cases.
Hypothyroidism, ovarian cysts, precocious puberty, Van Wyk and Grumbach syndrome
Introduction The syndrome consisting of primary hypothyroidism, precocious puberty and massive ovarian cysts has been described since 1905 and in 1960 the term ‘‘Van Wyk and Grumbach syndrome’’ was first used [1]. All clinical and biochemical findings undergo complete remission when these patients are started on an adequate thyroid replacement therapy. Clinically this syndrome is a diagnostic challenge because hypothyroidism usually leads to pubertal and growth delay, whereas in case of VWGS hypothyroidism leads to growth delay with paradoxically precocious puberty. In this article we present an 8-year-old girl and give a review of the literature.
Case report An 8-year-old girl was referred to our university center because of moderate vaginal bleeding since 2 days. The patient’s past medical history and development were otherwise unremarkable. In the family history the maternal grandmother had hypothyroidism and an aunt had systemic lupus erythematosus. Further history revealed additional symptoms of excessive sweating, weight gain and poor growth. The parents also noted that their daughter was easily tired, irritable and emotionally unstable since a few months. On inspection she had a round puffy, pale face and a robust stature. There was no goitre. The abdomen was not distended and further clinical examination was without abnormalities. Address for correspondence: Kristina Casteels, Department of Pediatrics, University Hospitals Leuven, KU Leuven, Herestraat 49, 3000 Leuven, Belgium. Tel: +3216-343801. Fax: +3216-343981. E-mail: [email protected]
History Received 22 August 2013 Revised 12 November 2013 Accepted 29 November 2013 Published online 25 February 2014
Blood pressure and heart rate were in the normal range. Height 122.9 cm (p3) and weight 30.7 kg (p50) were appropriate for age, but inspection of the growth charts revealed a marked discordance between length and weight. There was also a weight gain of 4 kg over the last 8 months and a significant decline in growth velocity (Figure 1). Tanner stage was A1 P1 M2. Laboratory data revealed normal estrogen (55 ng/l) and prolactin (8.2 mg/l) levels. Tumor marker CA-125 was not raised. Luteinizing hormone (LH) (0.1 IU/l) and follicle-stimulating hormone (FSH) (3.4 IU/l) were at a pre-pubertal level. Levels of thyroid stimulating hormone (TSH) were elevated (152.3 mIU/l, normal range 0.27–4.20 mIU/ l) and levels of free thyroxin were decreased (T4 0.32 ng/dl, normal range 0.93–1.70 ng/dl). Antithyroglobulin (Tg Ab 248 IU/ ml, normal range 5115 IU/ml) and antithyroid peroxidase antibodies (TPO Ab 4600 IU/ml, normal range 534 IU/ml) were elevated. Abdominal ultrasound was normal with normal appearance of the uterus, ovaries and no visible endometrial line. X-ray of the wrist revealed a delayed bone age. Her chronological age at presentation was 8 years and 10 months. Her bone age was estimated at 7 years and 9 months, using the Tanner–Whitehouse Standard. Ultrasonography of the thyroid showed a heterogeneous and strongly vasculated thyroid gland, a finding highly suggestive for thyroiditis. The Van Wyk and Grumbach syndrome was diagnosed based on the co-occurrence of hypothyroidism, precocious puberty and delayed bone age. Daily therapy with levothyroxine, 50 mg per os (0.05 mg/m2), was started. The thyroid function was normalized after 2 months: TSH level dropped from 152.3 mIU/l to 3.88 mIU/l, with normal T4 concentrations. Given the satisfactory results, we continued levothyroxine at the same dosage. Serial follow-up consultations showed great improvement: the girl felt better, was more active and did not have vaginal blood
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Van Wyk and Grumbach syndrome
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DOI: 10.3109/09513590.2013.871523
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Figure 1. Growth chart. Weight in kilograms and height in centimetres by Flemish standards 2004, VUB Laboratory of Anthropogenesis and KUL Juvenile Health Care, with support of the Flemish government. www.vub.ac.be/groeicurven – 20040916 – EMD/006 en 20050604 – EMD/006 – vub.kul ß 2004. On the x-axis you can find the age in years (j).
loss anymore. Clinical examination was normal. She was scored Tanner A1 P1 M1.
Discussion Epidemiology Precocious puberty is a known, but rare complication of severe acquired juvenile hypothyroidism, and was first described by Kendle in 1905. It was not until 1960 when the term ‘‘Van Wyk and Grumbach syndrome’’ was coined [1]. Van Wyk and Grumbach described a syndrome of precocious menstruation in juvenile hypothyroidism, with reversion to a pre-pubertal state following the administration of thyroid hormone. A clue to the diagnosis is the delayed bone age, because VWGS is the only form of precocious puberty in which the bone age is delayed [1,2]. In our literature search we resulted with a total of 33 patients (articles with no electronic full text version available were excluded from our patient group). Thirty patients were female and all of them presented with multicystic ovaries (Table 1). In our table, only three cases describe boys with the Van Wyk–Grumbach syndrome. They all presented with macro-orchidism [3–5]. Seven additional case reports were found, but no full text was available and therefore these were excluded from our patient group [6–12]. The low number of male patients could be due to the fact that thyroid disorders are more common in girls [2]. The girls typically presented with vaginal bleeding, poor growth and abdominal masses or pain. In 21 patients the TSH level had increased above the concentration of 100 mIU/ml [2,13–23] and 12 investigators reported to have found raised levels of gonadotropins on biochemical analysis [3,15–21,24–26]. Prolactin (PRL) levels were elevated in 13 patients [3,13–18,21,23,25,26]. All of them were successfully treated with levothyroxine. Our case did not present with multicystic ovaries, abdominal pain or masses. We consider this as the result of an early recognition and the relatively
low TSH elevation. There was no increase in gonadotropins in our case. Most cases of VWGS concern pre-pubertal children, but it has also been described in young women (Table 1) [2]. The predominance in pre-pubertal children can be explained by the assumption that the pre-pubertal gonads are more susceptible to stimulation by TSH, because they are primed to be activated by very low levels of FSH, as at the onset of puberty (cfr. ‘‘FSH theory’’ below) [4]. Pathophysiology VWGS is thought to be caused by a preceding thyroiditis. Typically the levels of TSH exceed 100 mIU/l. Most cases also describe the presence of autoantibodies against TPO or thyroglobulin. However, the syndrome can also appear in cases of congenital hypothyroidism, ectopic thyroid tissue or tumors that cause hypothyroidism. The exact mechanism is still unknown. We hereby provide an overview of the most relevant hypotheses. In longstanding hypothyroidism, PRL levels can be high. It has been hypothesized that pituitary stimulation by thyroid releasing hormone (TRH) leads to an increased level of both TSH and PRL and that high levels of PRL enhance the sensitivity of the ovaries to circulating gonadotrophines by increasing ovarian LH receptors [15,27,28]. Prolactin levels, however, are not always increased as shown in our case (Table 1). Mandl hypothesized in 1980 that continuous high TRH concentrations would stimulate not only TSH, but FSH secretion as well [29]. This had already been put forward by Van Wyk and Grumbach in 1960 and was later named the ‘‘overlap theory’’ [1,17]. Various studies, however, demonstrate that gonadotropins are not routinely elevated in the VWGS (Table 1) [12].
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Table 1. Characteristics of described cases in literature.
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Ref
Age
Sex
Presentation
Laboratory findings
Case
8
G
Vaginal bleeding, breast development, weight gain, poor growth, delayed bone age
TSH 152.3 mIU/l (0.27 – 4.20 mIU/l) T4 0.32 ng/dl (0.93 – 1.70 ng/dl). Normal PRL and Estradiol
[16]
11 y
G
Bilateral ovarian mass, vaginal bleeding, pelvic pain, lethargy, weight gain
TSH 1889.9 mIU/ml (0.27 – 4.20 mIU/ml) T4 0.3 ng/dl (0.93 – 1.70 ng/dl) PRL 77 ng/ml (3 – 23.2 ng/ml) Estradiol 568 pg/ml (2 – 15 pg/ml)
[19]
15 y
G
Ovarian mass, abdominal pain, lethargy, breast development, normal bone age, poor growth
TSH 1582.33 mIU/ml (0.27 – 4.20 mIU/ml) Estradiol 591.2 pg/ml (2 – 15 pg/ml) TPO Ab 3205 IU/ml (540 IU/ml)
[18]
12 y
G
Multicystic ovaries, thyroiditis, normal bone age
TSH 939 mIU/ml (0.27 – 4.20 mIU/ml) T4 0.6 ng/dl (0.93 – 1.70 ng/dl) PRL 1242 mIU/ml (60 - 525 mIU/ml) Estradiol 639 pg/ml (2 – 15 pg/ml) TPO Ab 71 IU/ml (540 IU/ml) Tg Ab 59 IU/ml (535 IU/ml)
[2]
10 y
G
Vaginal bleeding, pelvic pain, delayed bone age
8y
G
Bilateral multicystic ovaries, vaginal bleeding
16 y
G
Cystic ovary, recurrent ascites, hypothyroidism
17 y
G
Bilateral multicystic ovaries, oligomenorrhea
15 y
G
Abdominal distension, dyspnoe, hypothyroidism
TSH 494 mU/ml (0.37 – 6 mU/ml) T4 51.05 mg/dl (5 – 12 mg/dl) TSH 954 mU/ml (0.37 – 6 mU/ml) T4 6.6 mg/dl (5 – 12 mg/dl) TSH 39 mU/ml (0.37 – 6 mU/ml) T4 6.6 mg/dl (5 – 12 mg/dl) TSH 27.08 mU/ml (0.37 – 6 mU/ml) T4 5.0 mg/dl (5 – 12 mg/dl) TSH 15.8 mU/ml (0.37 – 6 mU/ml) T4 2.5 mg/dl (5 – 12 mg/dl)
[24]
9y
G
Vaginal bleeding, abdominal pain, lethargy, breast development, delayed bone age, poor growth
TSH 475 mIU/ml (0.5 – 5.1 mIU/ml) T4 0.3 ng/dl (0.712 – 1.85 ng/dl) Estradiol 3.58 pg/ml (2 – 15 pg/ml)
[14]
7y
G
Abdominal mass, vaginal bleeding, breast development, delayed bone age
TSH 4100 mIU/ml (0.37 – 6 mU/ml) T4 0.3 mg/dl (5 – 12 mg/dl) Estradiol 463 pg/ml (571 pg/ml) PRL 160 ng/ml (525 ng/ml) TPO Ab 41000 IU/ml (540 IU/ml) Tg Ab 55 IU/ml (535 IU/ml)
[22]
7y
G
Unilateral ovarian cysts, vaginal bleeding, poor growth
TSH 480 mIU/ml (0.37 – 6 mU/ml)
[15]
9y
G
Unilateral ovarian cyst, vaginal bleeding, delayed bone age
TSH 4100 IU/ml (0.27 – 4.20 IU/ml) PRL 175 ng/ml (525 ng/ml) Estradiol 632 pg/ml (2 – 15 pg/ml)
G,G, B
Precocious sexual development
Elevated TSH, PRL, LH, FSH, Estradiol
[3] [17]
7y
G
Metrorrhagia, breast development, delayed bone age
TSH 792 mIU/l (0.5 – 4 mIU/ml) T4 3 pmol/l (10 - 20 pmol/l) PRL 33 ng/ml (2 – 18 ng/ml) Oestradiol 98 pg/ml (2 – 15 pg/ml) TPO Ab highly positive
[20]
4y
G
Multicystic ovaries, vaginal bleeding, breast development
TSH 4500 mIU/ml (0.37 – 6 mU/ml) T4 0.4 ng/dl (0.7 – 1.48 ng/dl) Oestradiol 117.7 pg/ml (2 – 15 pg/ml)
[33]
8y 3y
G G
Ovarian hypertrophy, vaginal bleeding Ovarian hypertrophy, vaginal bleeding
Hashimoto thyroiditis Thyroid dysgenesis
[4]
13 y
G
Breast development, pubic hair, vaginal bleeding, enlarged ovaries
16 y
G
Breast development, galactorrhea, pubic hair, enlarged ovaries
12 y
G
Goiter, enlarged ovaries
TSH 1058 mU/l (0.5 – 4 mU/l) T4 2.5 pmol/l (10 – 20 pmol/l) Oestradiol 3.0 nmol/l PRL 381 mg/l (2.8 – 29.2 mg/l) TSH 732 mU/l (0.5 – 4 mU/l) T4 5.1 pmol/l (10 – 20 pmol/l) Oestradiol 0.15 nmol/l PRL 38 mg/l (2.8 – 29.2 mg/l) TSH 526 mU/l (0.5 – 4 mU/l) T4 2.5 pmol/l (10 – 20 pmol/l) Oestradiol 0.05 nmol/l PRL 20 mg/l (2.8 – 29.2 mg/l) (continued )
Van Wyk and Grumbach syndrome
DOI: 10.3109/09513590.2013.871523
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Ref
Age
Sex
Presentation
275
Laboratory findings
8y
B
Secondary sexual characteristics, enlarged testes
TSH 366 mU/l (0.5 – 4 mU/l) T4 2.5 pmol/l (10 – 20 pmol/l) TSH 436 mU/l (0.5 – 4 mU/l) T4 5.1 pmol/l (10 – 20 pmol/l) TSH 1180 mU/l (0.5 – 4 mU/l) T4 2.5 pmol/l (10 – 20 pmol/l) Oestradiol 0.57 nmol/l PRL 75 mg/l (2.8 – 29.2 mg/l) TSH 254 mU/l (0.5 – 4 mU/l) T4 3.8 pmol/l (10 – 20 pmol/l) Oestradiol 0.07 nmol/l PRL 28 mg/l (2.8 – 29.2 mg/l) TSH 1376 mU/l (0.5 – 4 mU/l) T4 1.3 pmol/l (10 – 20 pmol/l) Oestradiol 0.56 nmol/l PRL 84.5 mg/l (2.8 – 29.2 mg/l)
8y
G
Enlarged ovaries
8y
G
Breast development, delayed bone age, goiter, enlarged ovaries
8y
G
Breast development, pubic hair, delayed bone age, enlarged ovaries
9y
G
Breast development, pubic hair, enlarged ovaries
[26]
7y
G
Unilateral ovarian cyst, vaginal bleeding, delayed bone age
Elevated gonadotrofins Normal oestradiol Elevated PRL
[5]
12 y
B
Weight gain, short stature, enlarged testes, delayed bone age
TSH 4100 mU/l (0.5 – 4 mU/l) T4 55.15 pmol/l (10 – 20 pmol/l) PRL 28.2 ng/ml (2.8 – 29.2 ng/ml) Tg Ab 470 IU/ml
[13]
8y
G
Breast development, abdominal pain, weight gain, enlarged ovaries, vaginal bleeding
TSH 995 mU/l (0.5 – 4 mU/l) T4 53.9 pmol/l (10 – 20 pmol/l) Oestradiol 550 pmol/l PRL 1310 mU/l (5440 mU/l) TPO Ab 378 kU/l (0 – 35 kU/l)
[21]
10 y
G
Breast development, vaginal bleeding, enlarged ovaries, delayed bone age
TSH 4150 mIU/ml (0.35 – 5.5 mIU/ml) T4 1.0 ng/ml (4.5 – 12.6 ng/ml) PRL 185.8 ng/ml (2.8 – 29.2 ng/ml)
[23]
10 y
G
Breast development, vaginal bleeding, unilateral ovarian cysts
TSH 578 mIU/ml (0.5 – 4.5 mIU/ml) T4 50.1 ng/dl (0.70 – 1.8 ng/dl) PRL 32.4 ng/ml (3 – 23 ng/ml) TPO Ab positive
[25]
9y
G
Breast development, bilateral multicystic ovaries, delayed bone age
TSH 81.30 mIU/ml (0.5 – 4.5 mIU/ml) T4 0.30 ng/dl (0.70 – 1.8 ng/dl)
G: girl. B: boy. TSH: thyroid stimulating hormone. T4: thyroxin. PRL: prolactin. TPO Ab: thyroid peroxidase antibodies. Tg Ab: thyroglobulin antibodies.
Other investigators hypothesize that the nuclear thyroid receptors in the granulosa cells are stimulated by the high levels of TSH, leading to raised aromatization of androstenedione into estrogen [30]. Raised estrogen levels are, however, not a consistent finding in the clinical cases. Later, it was shown that TSH could interact directly with the FSH receptor to elicit gonadal stimulation. This is probably due to a ‘‘spill-over effect’’ of glycoprotein hormones, a concept also called ‘‘molecular mimicking’’. TSH, which is markedly increased in the VWGS, has a small FSH and LH-like effect. The FSH effect leads to stimulating of the ovaries, which can explain the findings of multicystic ovaries, uterine bleeding and breast enlargement, without an increase in androgens. Anasti et al. explored this hypothesis in vitro using recombinant TSH and a human FSH receptor bioassay. The study demonstrated that TSH could elicit a dose-dependent cAMP response at the FSH receptor. This suggests that the highly elevated levels of TSH in hypothyroidism can act on the FSH receptor to induce ovarian hyperstimulation and precocious puberty [31]. Various
explanations have been put forward for this overlap theory. Noteworthy is the fact that the required level of TSH to stimulate the FSH receptor was many magnitudes higher than FSH [31]. TSH and FSH, along with LH and human chorionic gonadotropin (hCG) are closely related tropic hormones. The alpha-units of all four hormones are essentially identical and described from the same gene, with only variability in glycosylation. The beta-subunit is specific for each hormone, although they all show some degree of homology because they bind to a common alpha-subunit [32]. Ryan et al. evaluated eight pediatric patients with hypothyroidism associated with gonadal hyperstimulation, to study whether they carry a mutant FSH receptor or a specific allelic variant that results in a lower threshold to stimulation by TSH. They did not detect a mutation. In vitro experiments did show that there were no differences in the sensitivities of the human FSH receptor allelic combinations to recombinant human TSH. This does not exclude that there may be other actions mediated by the high levels of TSH that cause the gonadal FSH receptor to be more sensitive to TSH in vivo [4].
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In conclusion, this theory considers the extremely high concentrations of TSH in patients with VWGS sufficient to cause activation of the (wild type) FSH receptor, regardless of the allelic variant, and to produce gonadal enlargement, multicystic ovaries and/or downstream estrogenic effects mimicking puberty. Treatment Treatment of precocious puberty with hypothyroidism, in the VWGS, consists of replacement therapy with thyroid hormone. This will result in regression of all clinical symptoms and signs. Large ovarian masses, in association with one or more tumor markers would generally imply malignancy but it is important to stress that hypothyroidism should be first excluded. Surgery (ovariectomy) should be avoided, as the ovarian cysts all resolve after initiating hormonal treatment.
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Conclusion The VWGS should be kept in mind when children present with precocious puberty or young women with ovarian masses. This case demonstrates that VWGS should be kept in mind even in cases without clear ovarian involvement (no breast development, no multicystic ovaries). Replacement therapy with thyroid hormone will result in a complete regression of all clinical findings including the multicystic ovaries. Surgery should be avoided. The exact pathophysiological mechanism is not yet known, but in vitro studies lead to the hypothesis that gonadal stimulation in these patients is TSH-mediated. Further (in vivo) studies are necessary to confirm this theory.
Acknowledgements We would like to thank Marleen Jannis for her help in the preparation of this manuscript.
Declaration of interest The authors declare that they have no conflict of interest.
References 1. Van Wyk J, Grumbach M. Syndrome of precocious menstruation and galactorrhea in juvenile hypothyroidism: an example of hormonal overlap in pituitary feedback. J Pediatr 1960;57:416–35. 2. Browne LP, Boswell HB, Crotty EJ, et al. Van Wyk and Grumbach syndrome revisited: imaging and clinical findings in pre- and postpubertal girls. Pediatr Radiol 2008;38:538–42. 3. Hemady ZS, Siler-Khods TM, Najar S. Precocious puberty in juvenile hypothyroidism. J Pediatr 1978;92:55–9. 4. Ryan GL, Feng X, d’Alva CB, et al. Evaluating the roles of folliclestimulating hormone receptor polymorphisms in gonadal hyperstimulation associated with severe juvenile primary hypothyroidism. J Clin Endocrinol Metab 2007;92:2312–17. 5. Yin F, Omran A, Peng J, et al. Male child with Van Wyk Grumbach Syndrome and other complications of long standing primary hypoyhyroidism: a case report. Case Rep Pediatr 2012:352751. 6. Brudes JM, Samuels MH, Brenner WJ, et al. Hypothyroidisminduced macroorchidism: use of a gonadotropin-releasing hormone agonist to understand its mechanism and augment adult stature. J Clin Metab 1995;80:11–16. 7. Esen I, Demirel F. Hypothyroidism-associated testicular enlargement: is it a form of precocious puberty or not? A case report. Turkish J Pediatr 2011;53:210–12. 8. Gordon CM, Austin DJ, Radovick S, Laufer MR. Primary hypothyroidism presenting as severe vaginal bleeding in a prepubertal girl. J Pediatr Adolesc Gynecol 1997;10:35–38. 9. Jannini EA, Ulisse S, D’Armiento M. Macroorchidism in juvenile hypothyroidism. J Clin Endocrinol Metab 1995;80:2543–4.
Gynecol Endocrinol, 2014; 30(4): 272–276
10. Laron Z, Karp M, Dolberg L. Juvenile hypothyroidism with testicular enlargement. Acta Paediatr Scand 1970;59:317–22. 11. Patni N, Cervantes LF, Diaz A. Elevated a-fetoprotein levels in Van Wyk-Grumbach syndrome: a case report and review of literature. J Pediatr Endocr Met 2012;25:761–7. 12. Riddlesberger MM, Kuhn JP, Munschauer RW. The association of juvenile hypothyroidism and cystic ovaries. Radiology 1981;139: 77–80. 13. Baranowski E, Ho¨gler W. An unusual presentation of acquired hypothyroidism: the Van Wyk-Grumbach syndrome. Eur J Endocrinol 2012;166:537–42. 14. Campaner AB, Scapinelli A, Machado R, et al. Primary hypothyroidism presenting as ovarian tumor and precocious puberty in a prepubertal girl. Gynecol Endocrinol 2006;22:395–8. 15. Chattopadhyay A, Kumar V, Marulaiah K. Polycystic ovaries, precocious puberty and acquired hypothyroidism: the Van Wyk and Grumbach syndrome. J Pediatr Surg 2003;38:1390–2. 16. Durbin K, Diaz-Montes T, Loveless M. Van Wyk and Grumbach syndrome: an unusual case and review of the literature. J Pediatr Adolesc Gynecol 2011;24:93–6. 17. Chemaitilly W, Thalassinos C, Emond S, Thibaud E. Metrorrhagia and precocious puberty revealing hypothyroidism in a child with Down’s syndrome. Arch Dis Child 2003;88:330–1. 18. Hunold A, Alzen G, Wudy SA, et al. Ovarian tumor in a 12 year old female with severe hypothyroidism: a case of Van Wyk and Grumbach syndrome. Pediatr Blood Cancer 2009;52:677–9. 19. Krishnamurthy S, Seth A, Puri A, et al. Ovarian tumors with elevated CA-125 levels and severe juvenile hypothyroidism: a need for increased awareness. Indian J Pediatr 2010;77:693–4. 20. Orgen T, Gu¨ven A, Aydin M. Precocious puberty in a girl with Down syndrome due to primary hypothyroidism. Turkish J Pediatr 2009;51:381–3. 21. Rastogi A, Bhadada SK, Bhansali A. An unusual presentation of a usual disorder: Van Wyk-Grumbach syndrome. Indian J Endocrinol Metab 2011;15:141–3. 22. Singh BM, Ammini AC, Kriplani A. Ovarian cysts in juvenile hypothyroidism. Arch Gynecol Obstet 2005;271:262–3. 23. Tran S, Kim EE, Chin AC. Severe menorrhagia, unilateral ovarian mass, elevated inhibin levels, and severe hypothyroidism: an unusual presentation of Van Wyk and Grumbach syndrome. J Pediatr Surgery 2013;48:E51–4. 24. Indumathi CK, Bantwal G, Patil M. Primary hypothyroidism with precocious puberty and bilateral cystic ovaries. Indian J Pediatr 2007;74:781–3. 25. Lim HH, Kil HR, Kim JY. Unusual presentations of a girl with Down syndrome: Van Wyk-Grumbach syndrome. J Pediatr Endocr Met 2012;25:1209–12. 26. Rakover Y, Weiner E, Shalev E, Luboshitsky R. Vaginal bleeding: presenting symptom of acquired primary hypothyroidism in a seven year-old girl. J Pediatr Endocrinol 1993;6:197–200. 27. Advis JP, Richards JS, Ojeda SR. Hyperprolactinemia induced precocious puberty: studies on the mechanism(s) by which prolactin enhances ovarian progesterone responsiveness to gonadotrophins in prepubertal rats. Endocrinology 1981;108:1333–42. 28. Radaideh AM, Nusier M, El-Akawi Z, Jaradat D. Precocious puberty with congenital hypothyroidism. Neuro Endocrinol Lett 2005;26: 253–6. 29. Mandl AM. Factors influencing ovarian sensitivity to gonadotropins. J Endocrinol 1957;15:448–57. 30. Dobozy O, Csaba G, Hetenyi G. Investigation of gonadotropinthyrotropin overlapping and hormonal imprinting in the rat testis. Acta Physiol Hung 1985;66:169–75. 31. Anasti JN, Flack MR, Froehlich J, et al. A potential novel mechanism for precocious puberty in juvenile hypothyroidism. J Clin Endocrinol Metab 1995;80:276–9. 32. Ryan RJ, Charlesworth MC, McCormick DJ, et al. The glycoprotein hormones: recent studies of structure-function relationships. FASEB J 1988;2:2661–9. 33. Sanjeevaiah AR, Sanjay S, Deepak T, et al. Precocious puberty and large multicystic ovaries in young girls with primary hypothyroidism. Endocr Pract 2007;13:652–5.
