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Van Wyk and Grumbach Syndrome: An Unusual Case and Review of the Literature
Abstract
The syndrome consisting of primary hypothyroidism, precocious puberty, and massive ovarian cysts was termed Van Wyk and Grumbach syndrome in 1960. Little is known about the effect of the cysts on ovarian tumor markers.
A 12-year-old Caucasian female presented with headaches and fatigue. Imaging to evaluate her headaches revealed a pituitary macroadenoma. Soon after her macroadenoma was discovered, she presented to the emergency room with abdominal pain. Imaging at that time revealed massive bilateral ovarian masses with the left measuring 17 × 13 × 8.5 cm and the right measuring 18 × 11 × 10 cm. Ovarian tumor markers were drawn at this time, most of which were highly elevated. Subsequent evaluation revealed extreme hypothyroidism. Given these findings of a pituitary macroadenoma, bilateral ovarian masses, and severe hypothyroidism, the patient was diagnosed with Van Wyk and Grumbach syndrome. We followed the cyst conservatively and the ovaries and tumor markers returned to normal after adequate thyroid replacement.
This case supports conservative treatment as the first-line approach to massive ovarian cysts caused by hypothyroidism. In addition this case shows that tumor markers can be abnormal in the absence of a malignancy in this setting. Before proceeding with surgical evaluation, exclusion of hypothyroidism to exclude this rare but treatable syndrome should be undertaken. The most important diagnostic clue that the cyst may be caused by an endocrine source is the finding of bilateral ovarian cysts rather than one ovary affected as seen in most ovarian malignancies in this age group.
... Now termed VWGS, the characteristic clinical presentation is a discordant combination of precocious puberty and delayed growth. 3 The pathogenesis of VWGS involves complex hormonal interactions, with various hypotheses suggested to explain the pathogenesis. The most widely accepted theory is that the high levels of TSH, seen in profound hypothyroidism, interact with the FSH receptors. ...
... masses mimicking a tumour.3 Lack of thyroid hormonal feedback leads to thyrotrophic hyperplasia, causing pituitary hyperplasia. ...
... In contrast, our patients were markedly underweight, most likely related to their poor diet due to their lower socioeconomic backgrounds and syndromic diagnoses.Due to its rare presentation, patients with VWGS often comprise a diagnostic dilemma. Pubertal delay is the well-known consequence of prolonged untreated hypothyroidism.3 Diagnosis of VWGS is important, since the pubertal precocity can be reversible and a patient's genetic height potential can be achieved. ...
Van Wyk–Grumbach syndrome is a rare, female juvenile hypothyroidism disorder that is characterized by precocious puberty with clinical, radiological and hormonal pathologies. We present a case series of three patients with this unusual condition who were evaluated and followed up over a 3-year period between January 2017 and June 2020. All three patients presented with short stature (<3rd centile), low weight (<3rd centile), absence of goitre, no axillary or pubic hair, delayed bone age by more than 2 years, elevated thyroid-stimulating hormone with low T3 and T4 (primary hypothyroidism), and raised follicle-stimulating hormone with pre-pubertal levels of luteinizing hormone. Abdominal ultrasonography showed bilateral multi-cystic ovaries in two patients and a right-sided bulky ovary in the third patient. One of the patients also had a pituitary ‘macroadenoma’. All the patients were successfully managed with levothyroxine. We discuss the pathophysiological mechanisms with a brief literature review.
... The reduced circulating thyroid hormone stimulated hyperplasia of TSH-secreting pituitary cells, leading to compression of the pituitary stalk, disrupted inhibition of prolactin secretion, elevated prolactin levels, and eventual elevation in TRH levels in response to high prolactin levels [22,29]. The cross-sensitivity between TSH and prolactin pituitary cells to TRH stimulation may further contribute to elevated prolactin levels [21]. The elevated levels of prolactin also can increase ovarian sensitivity to circulating LH and FSH and decrease the frequency of gonadotropin-releasing hormone(GnRH) pulses, thereby increasing FSH levels, reducing LH levels, and increasing the risk of precocious puberty [30,31]. ...
... Some VWGS patients present with elevated tumor markers. Our case and several others report an elevated CA-125 level [21,24,27]. Importantly, CA-125 can be non-specific and elevated in endometriosis, uterine fibroids, and tubo-ovarian masses, which would fit the clinical picture of VWGS [21]. ...
... Our case and several others report an elevated CA-125 level [21,24,27]. Importantly, CA-125 can be non-specific and elevated in endometriosis, uterine fibroids, and tubo-ovarian masses, which would fit the clinical picture of VWGS [21]. Our patient also presented with elevated AFP, which has been related to dysgerminomas and other germ cell tumors. ...
Van Wyk-Grumbach Syndrome (VWGS) is a constellation of symptoms including precocious puberty without adrenarche, delayed bone age, ovarian cysts, and hypothyroidism. We report here a four-year-old Down Syndrome patient who presented for evaluation of abdominal distension, vaginal bleeding, and bilateral ovarian cysts. Her work-up and management demonstrates the importance of screening for hypothyroidism in Down Syndrome, as well as considering the diagnosis of VWGS when evaluating a patient with precocious puberty and an apparent intra-abdominal surgical process. Given the presence of ovarian masses, a surgical emergency such as ovarian torsion or rupture must be ruled out. Even when the diagnosis of VWGS is confirmed, practitioners must be vigilant to consider surgical intervention in the presence of uncontrolled vaginal bleeding, hemodynamic instability, or failure of regression of ovarian cysts with exogenous thyroid hormone replacement.
... (3) Congenital cytomegalovirus hepatitis (Patient no. 11 in Table 1). (4) Congenital listerial infection (Patient no. 12 in Table 1). ...
... The chief presenting complaints are nonspecific, and patient may present with acute abdominal pain, vomiting, and reduced consciousness. (9) Hypothyroidism is another rare cause of acute abdomen [11]. It is known to cause bilateral ovarian cysts which can present as abdominal lump. ...
Background We present our experience with children landing up in our pediatric surgery emergency with potentially confounding medical conditions that evade diagnosis. It is imperative to apply sound clinical judgement in the evaluation of these patients so that an unnecessary laparotomy can be avoided but, at the same time, a lifesaving intervention is not denied. Patients and methods This is a retrospective descriptive analysis pertaining to all patients who were admitted in our department from 1 January 2014 to 31 July 2017. A total of 27867 patients presented to our out-patient department of these, 3034 were admitted to our ward. A total of 1531 surgeries were performed, of which 288 were for various abdominal surgical conditions. A total of 16 patients, representing 0.5 % of the admissions, were eventually found to have an acute abdomen secondary to a medical cause. Results Out of the above 16 patients, 10 had to undergo exploratory laparotomy (62.5%). Eight patients of the 10 operated had a negative laparotomy. Two of the 10 operated were found to have a surgically correctable cause, one with ovarian torsion and one with severe colonic edema secondary to Kawasaki's disease causing intestinal obstruction. Conclusion Although eight patients with negative laparotomy result constitute only 0.5% of all the surgeries and 2.7% of all the laparotomies, it still forms the bulk (i.e. 8/16=50%) of the patients with underlying medical cause of the surgical abdomen. There were two deaths, representing a mortality of 12.5% (2/16=12.5%), with one in the operated group and one in the nonoperated group. This is why we want to stress the importance of caution and sound clinical judgement in evaluating this subset of patients.
... Rarely, children with longstanding untreated hypothyroidism may present with Isosexual Precocious Puberty, known as " Van Wyk Grumbach syndrome " (VWGS) [1]. Most cases of the syndrome have been reported in girls, [2,3] including its first ever description by Van Wyk and Grumbach. ...
... This syndrome is known as Van Wyk Grumbach syndrome (VWGS) [1]. This phenomenon has mostly been described in girls [3], and care reports of boys affected with this syndrome are rare [5,6]. Girls usually present with bilateral breast enlargement, development of multicystic ovaries and menstrual bleeding. ...
Hypothyroidism commonly results in a delayed sexual development in most of the affected children. The rare association of Isosexual Precocious Puberty with delayed bone age in children with longstanding untreated hypothyroidism is called Van Wyk-Grumbach syndrome (VWGS). Most cases of the syndrome have been reported in girls, including its first ever description by Van Wyk and Grumbach. We describe a case of an adolescent boy who presented with the above syndrome and its classical features.
... The association in young females of longstanding primary hypothyroidism, isosexual precocious pseudopuberty and multicystic enlarged ovaries was first described in 1960 by Van Wyk and Grumbach (29). Since then, sporadic case reports have contributed to clarifying the features of this syndrome (30). Clinically this syndrome is a diagnostic challenge, because long-standing primary hypothyroidism usually causes both pubertal and growth delay. ...
... It is important to recognize this syndrome because all signs and symptoms regress with treatment of underlying hypothyroidism, avoiding unnecessary investigations for malignancy and/or surgical intervention. The pathophysiology of Van Wyk-Grumbach syndrome involves a complex mechanism, hormone overlap in the pituitary feedback, mediated by the direct action of TSH on FSH receptors (29,30). Our case fits the description of Van Wyk-Grumbach syndrome; however it is still unique since despite the hypothyroidism associated with an ovarian cyst, no symptoms of precocious puberty were present. ...
Pituitary hyperplasia secondary to primary longstanding hypothyroidism has been reported in the literature in adults and rarely in children.
Here we present the clinical presentation and diagnostic procedures in eight children with pituitary hyperplasia due to autoimmune thyroiditis, highlighting common findings, such as growth delay, fatigue or gaining weight, but also exceptional findings such as pericardial effusion, rhabdomyolysis, isolated hypertrichosis, and Van Wyk-Grumbach syndrome, which have rarely or never been described.
Surprisingly no thyroid enlargement was detected. We discuss the unusual presenting signs of autoimmune thyroiditis that should raise the suspicion of pituitary hyperplasia. We suggest that a more elaborate clinical assessment and even modification of the diagnostic approach to autoimmune thyroiditis is needed in order to avoid its serious complications.
... Hyperprolactinemia is a common feature in children with this syndrome and is TRH-mediated. Increased TRH production stimulates both thyrotrophic and lactotrophic pituitary cells, resulting in pituitary enlargement and hyperprolactinemia (due to the crosssensitivity between TSH and prolactin-producing pituitary cells to TRH stimulation) [20]. Estrogens may also be involved in this process [21]. ...
The primary manifestations of chronic hypothyroidism in children include growth arrest, delayed skeletal maturity, and delayed puberty. In 1960, Van Wyk and Grumbach reported three girls with hypothyroidism and a combination of incomplete isosexual precocious puberty (early breast development, menstruation, and absence of pubic hair), galactorrhea, delayed bone age, and pituitary enlargement. All abnormalities regressed after appropriate thyroid hormone replacement therapy. Over the years, an increasing number of reported cases has allowed for a more precise understanding of the clinical, biochemical, and radiological phenotypes of the Van Wyk–Grumbach syndrome (VWGS). These varying clinical manifestations are thought to result from a unique pathophysiological process where the thyroid-stimulating hormone (TSH) is a key element. We describe the cases of two patients (a boy and a girl) with severe autoimmune thyroiditis and VWGS. The clinical, biochemical, and radiological imaging characteristics were similar in both patients and included growth failure, absence of clinical goiter, markedly elevated TSH concentrations >100 mIU/L, undetectable free thyroxine levels, “normal” thyroglobulin levels, high follicle-stimulating hormone (FSH) and prolactin levels, prepubertal levels of luteinizing hormone (LH), delayed bone age, and hyperplasia of the pituitary gland. The two patients displayed differences, especially in the absence of clinical pubertal development, moderate anemia, abnormal renal function, and moderate goiter detected via ultrasonography (in the female patient). Thyroxine replacement therapy reversed the VWGS phenotype and hypothyroidism, with satisfactory growth velocity, strictly normal thyroid function, and normal pituitary size detected via magnetic resonance imaging at the 6-month follow-up visit.
... 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. ...
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.
... Laboratory tests showed normochromic normocytic anemia, elevated Ca 15.3 (75.5 IU/mL, normal value < 35 UI/mL [41]), that we have not found in the clinical cases reviewed, and normal levels of CA125. In some published cases [42,43] CA125 levels were initially elevated and they normalized after regression of ovarian cysts. ...
Severe hypothyroidism can affect different organs and can develop atypical manifestations. Peripheral precocious puberty may be secondary to other endocrinological diseases, which must be taken into account in the differential diagnosis to avoid unnecessary additional tests.
Van Wyk-Grumbach Syndrome is an infrequent manifestation characterized by severe hypothyroidism and incomplete precocious puberty. Diagnosis is made by clinical and complementary tests and the main treatment goal is to achieve euthyroidism through hormone replacement. Prognosis is good once the treatment is established.
The aim of this study is to review the available literature about Van Wyk-Grumbach syndrome following the PRISMA statement, and to present the first clinical case published in Spain. We have included the articles published between the period from 1905 to week 40 of 2022.
A total of 68 articles have been selected for study and analysis, in which there are 99 published clinical cases. Girls accounted for 92,1% of cases (median age at the diagnosis 8,5 years). Metorrhagia was the most prevalent symptom in 80,5% of the girls. Abdominal ultrasound was performed in 93,3% of the girls and 97,8% of them had at least one ovarian cyst. All cases were treated with levothyroxine, responding satisfactorily after the first doses of treatment.
To conclude, Van Wyk-Grumbach Syndrome is characterized by severe hypothyroidism and incomplete precocious puberty, that is important to keep it in mind in order to avoid complementary exams and unnecessary surgical interventions.
... Imaging typically reveals delayed bone maturation, multicystic enlarged ovaries, and an enlarged pituitary gland. Biochemically, serum T4 levels are low with often extremely elevated TSH levels [4][5][6][17][18][19][20]. ...
Context
Prolonged hypothyroidism in children commonly causes short stature with delayed bone maturation, and delayed puberty. However, a paradoxical occurrence of peripheral precocious puberty and pituitary enlargement in chronically untreated juvenile hypothyroidism was first reported by Van Wyk and Grumbach in 1960.
Objective
To create increased awareness and a better understanding of this clinical entity among emergency room physicians, pediatricians, surgeons, gynecologists and oncologists.
Methods
Case records of children diagnosed with Van Wyk–Grumbach syndrome (VWGS) were analyzed retrospectively.
Results
Twenty-six girls and 4 boys were identified (2005-2020). All had profound primary hypothyroidism (total thyroxine [T4]: 2.5-33.5 nmol/L, thyrotropin: > 75-3744 μIU/mL). Hypothyroidism was not the referral diagnosis in any of the girls. Among them, 17 were referred for precocious puberty, 5 with a diagnosis of pituitary tumor on magnetic resonance imaging, and others for acute surgical abdomen in 7 girls (painful abdominal mass—2, ovarian tumor—2, ovarian torsion—2, ruptured ovarian cyst—1), acute myelopathy in 1, and menorrhagia with headache in another. All girls were successfully managed with levothyroxine replacement alone, except for the 2 with ovarian torsion, who required surgery. Menstruation ceased promptly with T4 therapy in all girls, occurring at an age-appropriate later date. All boys had testicular enlargement at presentation that regressed partially after T4 treatment. Catch-up growth was remarkable during the first treatment year, but the final height was compromised in all.
Conclusion
Increased awareness of varied presentations of VWGS is vital among pediatricians to facilitate early diagnosis and targeted investigations, and to help in the initiation of the simple yet highly rewarding T4 replacement therapy to avoid all possible complications.
... Van Wyk Grumbach syndrome is described as isosexual precocious psuedopuberty, multicystic enlarged ovaries, hypothyroidism, and delayed bone age. In addition, it is not uncommon to see enlarged pituitary glands [1,22,23]. This pituitary hyperplasia is secondary to hyperstimulation by TRH due to the loss of negative feedback from thyroid hormone [24]. ...
Abstract:
We describe a case of a 7-year-old female who presented to the emergency department (ED) with a three-day history of vaginal bleeding, progressive abdominal pain, and dehydration. Ini-tial computerized tomography (CT) scan of the abdomen followed by a transabdominal ultra-sound of the pelvis identified bilateral, symmetric adnexal cysts and proliferative-phase endo-metrium with no evidence of inflammatory or malignancy-related findings. A gynecologic on-cology consult led to surgical exploration diagnosing the child with an acute surgical abdomen. Surgery was performed through a vertical infra-umbilical, mini-laparotomy (4 cm) incision. Both intra-operative and final pathology confirmed bilateral ovarian, low malignant potential (LMP), granulosa cell tumors. Post-operative bone age was over 18 months less than the pa-tient’s age. The discrepant bone age prompted investigation into pediatric syndromes character-ized by juvenile hypothyroidism, isosexual precocious puberty, and granulosa cell tumors with delayed bone age. A rare diagnosis matching all criteria was identified as Van WykGrumbach Syndrome (VW-GS). This syndrome was originally reported in 1960 by Drs. Van Wyk and Grumbach. They identified the discrepancies in bone age and how simple thyroid replacement results in complete resolution of this unique syndrome. Our literature review found few reports related to VW-GS in the gynecologic oncology case studies. We hope this report will further assist in the appropriate diagnosis and management of similar cases to avoid unnecessary and invasive interventions and treatment. Keywords: Van Wyk-Grumbach Syndrome; Precocious Puberty; Hypothyroidism; Ovarian Cyst; Pediatric Syndrome
... Feedback adenoma or hyperplasia of the pituitary can occur (as in our patient) due to excessive stimulation of thyrotrophs by TRH. Thyroxine replacement therapy can lead to regression of pubertal changes and ovarian size, and gain in height [7]. It can also reduce pituitary hyperplasia, although the time taken for the shrinkage of the hyperplastic pituitary is variable. ...
Not required for Clinical Vignette.
... The etiology has been thought to be related to complex interactions within the hypothalamicpituitary axis and high levels of TSH acting on FSH receptors due to molecular similarities between the glycoprotein receptors of these two hormones, which share a common subunit. 1 Girls with Van Wyck-Grumbach syndrome can have varying degrees of pubertal development as well as multi-cystic ovaries, vaginal bleeding, galactorrhea and delayed bone age. Boys usually present with testicular enlargement without virilization. ...
A thirteen years old female child, who was recently diagnosed with hypothyroidism and polycystic ovary and under thyroid supplements, presented with acute abdominal pain of one day duration. Examination showed pallor with rough skin, hypotension (70/40 mmHg) and distended abdomen. Abdomen was tense with tenderness and guarding. Urgent contrast CT abdomen showed bilateral polycystic ovaries with left ovarian torsion and hemo-peritoneum. Blood investigations showed anemia (6.0 g/dL) and TSH >100 microIU/ml. She was stabilized with Intravenous fluids, packed red blood cells and taken up for surgery. Laparoscopy confirmed the diagnosis and detorsion with deroofing of cysts was done. A post-operative diagnosis of Van Wyk Grumbach syndrome - Hypothyroidsm with ovarian hyper stimulation syndrome with hemorrhagic torsion of left ovary was made. She withstood procedure well and was stable. She was discharged to a local hospital after 2 days of surgery. She is on thyroid supplements and doing well.
... In 2011, Durbin and colleagues exemplified VWGS in a 12-year-old Caucasian girl who also had a pituitary macroadenoma and bilateral ovarian masses mimicking a tumor [14]. Another typical phenotype of VWGS with coexisting TSH-secreting adenoma and hyperprolactinemia was described in an 8-year-old girl with autoimmune thyroiditis by Baranowski and Högler in 2012 [5]. ...
Background:
Van Wyk-Grumbach syndrome refers to the development of isosexual precocious pseudopuberty and multicystic enlarged ovaries in the presence of hypothyroidism and delayed bone age. It is a rare presentation of untreated hypothyroidism. The prepubertal response in Van Wyk-Grumbach syndrome is always isosexual and mediated by very high thyroid-stimulating hormone levels acting through the follicle-stimulating hormone receptors inducing a follicle-stimulating hormonal effect. Early recognition and thyroid hormone replacement can completely regress precocious puberty and ovarian enlargement, while improving the final height achievement. Oligosyndactly is a congenital bony abnormality and can manifest either as an isolated malformation or as a component of a syndromic diagnosis. However, development of hypothyroidism in children with this peculiar bony deformity has rarely been described in the medical literature, with the exception of Cenani-Lenz Syndactyly syndrome.
Case presentation:
We report the case of a 6-year-old Sri Lankan girl who presented with a 2-day history of vaginal bleeding and exertional dyspnea. She had marked short stature (well below -3 standard deviations) with an upper segment to lower segment ratio of 1.47. This girl had isolated breast development of Tanner stage 2. She was diagnosed to have acquired hypothyroidism secondary to autoimmune thyroiditis and also had macrocytic anemia, pericardial effusion, gonadotropin-releasing hormone-independent precocious puberty with radiological evidence of pubertal changes in the uterus, and multicystic ovaries. Interestingly, she also had post-axial oligosyndactyly in both feet and right-sided clubfoot. The diagnosis of Van Wyk-Grumbach syndrome was made based on the clinical and laboratory features. Her symptoms were successfully managed with L-thyroxine therapy.
Conclusions:
Acquired hypothyroidism is a relatively common endocrine disorder among children and early recognition is important to prevent serious complications like Van Wyk-Grumbach syndrome. Sexual precocity with delayed bone age and stunting should direct our minds toward this unique diagnosis. It is always necessary to identify the other associated anomalies in addition to the primary diagnosis since these features may direct to a syndromic diagnosis.
... Type III is related to hypothyroidism. Even though hypothyroidism induced Van Wyk and Grumbach syndrome is well recognised in the paediatric population, its parallel amongst women in the reproductive age group is uncommon (Durbin et al., 2011). Suggested pathways for stimulation of the FSH receptors in Type III spontaneous OHSS include the direct action of TSH on FSHR, and via the hypothalamic production of TRH (Fig. 6). ...
We report a case of a 22-year-old single female with spontaneous ovarian hyperstimulation syndrome (s-OHSS) referred for transvaginal aspiration of follicles. Investigations revealed primary hypothyroidism, mild hyperprolactinaemia and unelevated levels of both follicle stimulating hormone (FSH) and estradiol. Supplementation with L-thyroxine lead to euthyroid status and gradual resolution of signs and symptoms of ovarian hyperstimulation syndrome (OHSS) over 4 months.
... This presentation was described by Van Wyk and Grumbach in 1960 and is called Van Wyk-Grumbach syndrome. The etiology has been thought to be related to high levels of TSH acting on FSH receptors due to molecular similarities between the glycoprotein receptors of these two hormones, which share a common subunit [1]. ...
Background:
Children with hypothyroidism typically present with delayed growth and development, but on rare occasions can present with signs of precocious puberty. This presentation is called Van Wyk-Grumbach syndrome. Van Wyk-Grumbach syndrome has seldom been described in patients with trisomy 21.
Case presentation:
We present the case of a 4-year-old girl with trisomy 21, who recently moved to the United States from Guyana, and presented to the emergency room with recurrent vaginal bleeding. She was eventually diagnosed with hypothyroidism and Van Wyk-Grumbach syndrome. She was noted to have Tanner I breasts and pubic hair. A pelvic ultrasound was performed, which showed a simple cyst in the right adnexa. Subsequent laboratory evaluation revealed a thyroid stimulating hormone (TSH) of > 150 mIU/ml along with low free thyroxine of 0.3 ng/dl, suggesting longstanding untreated hypothyroidism. Estradiol and alpha-fetoprotein (AFP) levels were elevated. Bone age was delayed. The patient was diagnosed with Van Wyk-Grumbach syndrome and was started on levothyroxine therapy with subsequent resolution of vaginal bleeding. Estradiol and AFP both normalized after initiating levothyroxine therapy.
Conclusion:
This case emphasizes the importance of recognizing the presence of precocious puberty, delayed bone age and ovarian cyst as a manifestation of primary hypothyroidism. In addition, it highlights the need for thyroid function screening in patients with Trisomy 21. Tumor markers may be elevated in Van Wyk-Grumbach syndrome with subsequent normalization after treatment.
... Additional features associated with pseudoprecocious puberty (designated Van Wyk-Grumbach syndrome) include galactorrhea, vaginal bleeding, and ovarian cysts associated with elevated prolactin, normal to high estradiol, elevated follicle stimulating hormone (FSH) with suppressed luteinizing hormone (LH) [70]. The ovarian cysts may be large with an increased risk of torsion and may be associated with elevated tumor markers including CA-125, lactate dehydrogenase (LDH) and inhibin, all of which normalize with LT4 therapy [74]. Prolonged elevation in TRH may also lead to anterior pituitary enlargement with expansion of the sella turcica caused by marked thyrotroph hyperplasia, which may be mistaken for a pituitary macroadenoma [75,76]. ...
The evaluation and management of hypothyroidism in children are similar to adults, but there are important differences based on the dependence on normal thyroid function for neurocognitive and physical development. In the pediatric population, hypothyroidism is frequently categorized as congenital or acquired hypothyroidism, depending on the age of presentation and the underlying etiology. The evaluation and management of children and adolescents with hypothyroidism are determined by the etiology as well as by the age at diagnosis, severity of the hypothyroidism, and the response to thyroid hormone replacement therapy. Children and adolescents require higher weight-based doses for thyroid hormone replacement than do adults, likely due to a shorter half-life of thyroxine (T4) and triiodothyronine (T3) in children, but weight-based dose requirements decrease as the child advances into adulthood. Multiple gaps in knowledge remains regarding how to optimize the treatment of hypothyroidism in pediatric patients, including (but not limited to) the selection of patients with subclinical hypothyroidism for treatment, and the potential benefit of combined LT3/LT4 therapy for patients with persistent symptoms and/or low T3 on LT4 monotherapy. The life-long impact on growth and development, and potentially on long-term cardiovascular and psychosocial health, are significant and highlight the importance of future prospective studies in pediatric patients to explore these areas of uncertainty.
... Only sporadic cases are reported. Clinically VWGS is often a diagnostic challenge, because long-standing primary hypothyroidism in children is known to cause delayed puberty as well as growth delay, whereas, in this rare syndrome, hypothyroidism leads to growth delay with paradoxical precocious puberty 5, 6 . ...
p>Van Wyk- Grumbach syndrome (VWGS) is characterized by juvenile hypothyroidism, delayed bone age, and precocious puberty with a complete reversal to the pre-pubertal state following thyroid hormone replacement therapy. In this study, a 7 years and 1 month old girl presented with precocity having premature menarche, short stature, constipation, delayed bone age and enlarged bilateral multicystic ovaries. She presented with acute abdomen due to torsion of left ovary and had to undergo left sided oophorectomy and right ovarian cystectomy. High serum TSH, low FT4 with high FSH but low LH within pre-pubertal range suggestive of ‘severe hypothyroidism with FSH dominant precocious pseudopuberty’ confirmed the diagnosis of VWGS.
Journal of Armed Forces Medical College Bangladesh Vol.11(1) 2015: 85-88</p
... Van Wyk-Grumbach syndrome (VWGS) is characterized by juvenile hypothyroidism, delayed bone age, isosexual precocious puberty and massive ovarian cysts, with reversal to aprepubertal state following thyroid hormone replacement therapy [1]. This syndrome has been described since 1905, but the term Van Wyk and Grumbach syndrome was coined in 1960 [2]. In this entity, the hypothyroidism leads to growth delay with paradoxi-cally and precocious puberty, while the primary hypothyroidism traditionally leads to both pubertal and growth delay. ...
... Met het lijstje van mogelijke etiologieën bij de mens in het achterhoofd (Tabel 1), lijkt abdominale echografie het meest aangewezen als diagnostisch hulpmiddel. Gezien zowel de ovaria als de bijnieren van de pup met deze beoordelingstechniek als normaal werden beoordeeld en de genetische oorzaken en primaire hypothyroïdie -Van Wyk and Grumbach Syndrome bij de mens (Durbin et al., 2011) -buiten beschouwing gelaten, blijft nog slechts één mogelijke oorzaak over, namelijk de exogene opname van oes-Tabel 1. Etiologie van gonadotropineonafhankelijke (perifere) vroegtijdige puberteit bij de mens (classificatie volgens Brito et al., 2008;Eugster, 2009 trogenen. In deze casus betreft het hoogstwaarschijnlijk een secundaire blootstelling via de huid van de eigenares. ...
A female intact Chihuahua pup was presented at the age of four months with complaints of vulvar swelling and precocious sexual behaviour. Both complaints started to develop at the age of 9-10 weeks. During clinical examination, inspection revealed swollen mammary glands. The differential diagnosis was gonadotrophin-independent (peripheral) precocious puberty (or precocious pseudopuberty) as a result of the exogenous intake of estrogens, or intersexuality. The first diagnosis was the most probable one since the female owner of the dog applied an estrogen gel on face and shoulders on a daily basis. The owner was advised to avoid contact of the pup with the gel. This resulted in a positive evaluation after two months, with a complete disappearance of the complaints four months after the first examination.
... 15 CA-125, LDH, AFP, Inhibin were also elevated in few reported cases. 16 All of the tumor markers, including inhibin, returned to normal values after treatment of hypothyroidism. 17 Urinary and vaginal bleeding in young children must be clearly differentiated, and hypothyroidism must be investigated in children who have precocious puberty to avoid inappropriate surgical treatment in these young girls. ...
... Rastogi et al. and Durbin et al reported pituitary macroadenoma with Van Wyk and Grumbach syndrome (VWGS). [9,10] Our patient of severe juvenile hypothyroidism of autoimmune etiology presented with a slightly different, reversible syndrome-like presentation of hypertrichosis, multicystic ovaries, and pituitary adenoma; the main difference was that in our case there was no evidence of isosexual precocity; instead there was a very unusual presentation with hypertrichosis. ...
Primary hypothyroidism may present with atypical features in children. Here we report a 6-year-old female child with primary hypothyroidism presenting with a combination of several atypical features in the form of hypertrichosis, bilateral cystic ovaries, and feedback pituitary adenoma.
... Where bilateral ovarian enlargement exists, hypothyroidism must be definitively excluded because strong evidence exists that the ovaries return to normal with simple levothyroxine replacement. 12,13 However, when left untreated or unrecognized, ovarian torsion can occur. ...
A 12-year-old girl presented with acute abdominal pain due to an acute ovarian torsion. She required an oophorectomy. Clinical and laboratory assessment confirmed severe primary hypothyroidism. In this report, we review this rare complication of untreated primary hypothyroidism and the physiologic mechanisms proposed to explain this phenomenon.
Van Wyk–Grumbach syndrome (VWGS) refers to the development of peripheral precocious puberty, long-standing hypothyroidism, and gonadal masses; when not diagnosed, an unnecessary gonadectomy may be performed. Herein, we present a case of a 10-year-old girl with Down’s syndrome, short stature, and vitiligo who presented to our hospital with vaginal bleeding and a palpable pelvic mass. Upon ultrasound and topographical examination, bilateral ovarian masses with negative tumor markers were detected. After bilateral gonadectomy, endocrine studies revealed profound hypothyroidism and peripheral puberty that led to the VWGS syndrome diagnosis (TSH 367.3 mUI/mL, isolated menstruation, indetectable LH, and elevated estradiol). Levothyroxine treatment improved obesity and short stature, and sexual hormone replacement began at 13 years of age. The literature on Van Wyk–Grumbach syndrome shows that it presents most often in women, and classic hypothyroidism symptoms always precede the diagnosis. Approximately 11% of patients have Down’s syndrome, sometimes tumor markers are elevated, and some develop severe symptoms (myopathy, short stature, mental delay, ascites, pericardial effusion, Cullen’s sign, pituitary hyperplasia, and severe anemia) that respond to levothyroxine treatment. Conclusions: Children with peripheral precocious puberty and gonadal masses must be studied for hypothyroidism before any radical decision is made.
Van Wyk Grumbach syndrome refers to the development of peripheral precocious puberty, long-standing hypothyroidism, and gonadal masses; when not diagnosed, an unnecessary gonadectomy may be done; Here we present a case of a 10-year-old girl with Down syndrome, short stature, and vitiligo presented with vaginal bleeding, and a pelvic mass, in whom bilateral gonadectomy was performed. Most cases of Van Wyk Grumbach syndrome present in women, and classic hypothyroidism symptoms always precede the diagnosis; 11% of patients have Down Syndrome, sometimes tumor markers get elevated, and some develop severe symptoms (myopathy, short stature, mental delay, ascites, pericardial effusion, Cullen sign, pituitary hyperplasia, and severe anemia), that respond to levothyroxine treatment; Conclusions: Children with peripheral precocious puberty and gonadal masses, must be studied for hypothyroidism before any radical decision is made. Keywords: Puberty, Precocious; Ovarian Cysts, gonadectomy, Van Wyk Grumbach Syndrome
Introdução: Este artigo de revisão explora a patogênese, epidemiologia e manifestações clínicas de cistos ovarianos em crianças, uma condição ginecológica complexa com implicações significativas para o diagnóstico e manejo clínico. A incidência desses cistos varia significativamente com a idade, sendo mais baixa em crianças pré-púberes em comparação com neonatos e adolescentes, devido às flutuações na atividade gonadotrópica. Objetivo: aprofundar a compreensão das causas e apresentações clínicas dos cistos ovarianos em pacientes pediátricos, destacando a necessidade de estratégias diagnósticas e terapêuticas precisas. Metodologia: Essa revisão integrativa da literatura, foi realizada por busca em base de dados de artigos que correspondessem ao tema proposto. Incluiu-se avaliação dos artigos elegíveis na íntegra, excluindo aqueles que não se enquadram nos objetivos do estudo, teses e dissertações, sem contabilizar duplicatas. Resultados e Discussão: a maioria dos cistos em infantes e crianças está relacionada à falha no processo de involução folicular. Além disso, alguns cistos são hormonais e podem induzir puberdade precoce, enquanto outros, como os tumores de células de Sertoli-Leydig, podem causar virilização. As manifestações clínicas variam de massas abdominais assintomáticas a sintomas agudos que simulam condições como apendicite, complicando significativamente o diagnóstico clínico. Conclusão: Cistos ovarianos em crianças representam um desafio diagnóstico devido à sua diversidade de apresentações. O diagnóstico preciso é vital para um manejo eficaz, que pode variar de observação vigilante a intervenções cirúrgicas. Ainda, sublinha a importância de uma abordagem clínica informada e sensível à idade para melhorar os resultados de saúde e qualidade de vida das jovens pacientes. Este trabalho também ressalta a necessidade de mais pesquisas para otimizar as abordagens de diagnóstico e tratamento para esta condição.
Van Wyk Grumbach syndrome (VWGS) is characterized by untreated severe hypothyroidism, isosexual precocious puberty, multiple ovarian cysts and delayed bone age. Although it is extremely rare, it is important to recognize before the unnecessary ovarian surgeries because of its curability with a simple thyroid hormone replacement. Here, we reported a 5-year-and-3-months old female patient presented with precocious menarche and diagnosed as VWGS with primary hypothyroidism, isosexual precocious puberty and multiple ovarian cysts. Following L-thyroxine replacement therapy, all complaints and hormonal abnormalities resolved and finally, the multicystic mass structure in the ovaries disappeared completely. The diagnosis of VWGS should be kept in mind because simple L-thyroxine replacement completely resolves symptoms and abnormalities and prevents unnecessary investigations for malignancies and surgeries.
Keywords: Van Wyk Grumbach syndrome, hypothyroidism, precocious puberty
An 11-year-old girl presented to the pediatric gastroenterology outpatient department of our institution with gradually increasing painless abdominal distention. The distention started 2 years earlier and was not associated with any other constitutional symptoms, vomiting, diarrhea, jaundice, hematemesis, or melaena. She reported early satiety and heaviness in the lower abdomen. The abdominal swelling was predominantly in the infraumbilical region and was soft at palpation. She was the first child of nonconsanguineous parents and had an uneventful perinatal course after a normal vaginal delivery. Her developmental milestones were normal. She had an average scholastic performance at school. There was no history of visual problems, seizures, or inappropriate behaviors. She had an early menarche 2 years previously. Her menstrual cycles were regular, and there was no abnormal vaginal discharge. Her breast development was normal (Tanner stage III), while pubic and axillary hair were absent (Tanner stage I). She was short for her age (104 cm; normal range, 120-154 cm). There was no history of short stature among her siblings or parents. Laboratory investigations were performed to measure thyroid-stimulating hormone (1354.34 µIU/mL; normal range, 0.35-5.5 µIU/mL), triiodothyronine (<2.5 ng/dL [0.0385 pmol/L]; normal range, 100-200 ng/dL [1.54-3.08 pmol/L]), thyroxine (1.35 µg/dL [17.37 nmol/L]; normal range, 5-12 µg/dL [64.35-154.44 nmol/L]), β-human chorionic gonadotropin (<1.2 mIU/mL; normal, <5 mIU/mL), luteinizing hormone (0.08 mIU/mL; normal range, 0.1-6.0 mIU/mL), and follicle-stimulating hormone (6.93 mIU/mL; normal range, 0.3-2.0 mIU/mL) levels. Complete blood count was normal. An abdominal mass was suspected, and abdominopelvic CT was performed and followed by US; these examinations revealed multiple large cysts in both ovaries. The uterus was pubertal in shape, and endometrial thickness was 9 mm, representing normal follicular phase measurement. Serum CA-125 and inhibin levels were normal. To evaluate short stature, radiographs of the hand and pelvis were obtained as part of a limited skeletal survey, keeping in mind the possible skeletal changes associated with hypothyroidism. In view of the hypothyroidism, US of the neck was also performed. Treatment was started based on the clinical and radiologic parameters, and the child's condition improved with medical treatment.
Puberty is the stage of development leading to sexual maturation and reproductive potential. Normal puberty is regulated by the hypothalamic–pituitary–gonadal (HPG) axis which is activated at the onset of puberty from the quiescent prepubertal state. Precocious puberty is the onset of pubertal changes at an earlier age than is expected for the population. Precocious pubertal development may occur by either premature activation of the HPG axis (central precocious puberty) or exposure to endogenous or exogenous sex steroids independent of HPG axis activation (peripheral precocious puberty). Although some children evaluated for precocious puberty will have variants of normal development such as premature thelarche (breast development), others will need evaluation to rule out pathologic causes.KeywordsPrecocious pubertyPremature adrenarchePubarcheMenarcheThelarcheGnRH agonistLeuprolide
Van Wyk-Grumbach syndrome (VWGS) is one of the most perplexing pediatric syndromes, which is a rare kind of sexual precocity linked to hypothyroidism in children. This condition represents an aberration from the usual norm that a delayed growth pattern is associated with delayed puberty, which is followed by the majority of children with long-lasting hypothyroid. Early diagnosis and establishment of replacement therapy with thyroxine can alleviate the already developed symptoms and avoid patients being exposed to unnecessary surgical interventions .we reviewed studies and case reports recently published on this subject in which patient with this syndrome have different presentations and discussed the benefit of early establishment of thyroxine therapy in reversing the clinical and laboratory changes.This paper critically discussed the importance of being aware of this syndrome to avoid subjecting the patients to unnecessary laboratory tests and/or surgical interventions.
Precocious puberty is defined as the presence of any sign of puberty in a child at a chronologic age two standard deviations below the mean age of pubertal development for a given population. Similarly, delayed puberty is defined as lack of signs of puberty at an age two standard deviations above the mean age. Normal puberty is initiated by the onset of pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus. These pulses cause release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gland. These pituitary gonadotropins then circulate to the gonads and stimulate production of sex steroids. Precocious puberty can result from early activation of this pulse, termed central or gonadotropin-dependent precocious puberty, but also from production of testosterone and/or estrogen that is not controlled by the hypothalamic-pituitary-gonadal axis, referred to as peripheral or gonadotropin-independent precocious puberty. Treatment with GnRH agonists may be indicated for central precocious puberty while treatment for peripheral puberty is focused on the underlying source. For pubertal delay, the differential diagnosis is extensive but can most easily be divided into four categories: variants of normal puberty timing, functional disorders, such as chronic illness, hypogonadotropic hypogonadism, in which hypothalamic or pituitary failure results in deficiency of circulating gonadotropins and hypergonadotropic hypogonadism which results from primary gonadal failure, resulting in elevated serum gonadotropin levels. Sex hormone replacement with testosterone and estrogen in boys and girls, respectively, remains the first line treatment in hypogonadism.
Puberty, which in humans is considered to include both gonadarche and adrenarche, is the period of becoming capable of reproducing sexually and is recognized by maturation of the gonads and development of secondary sex characteristics. Gonadarche referring to growth and maturation of the gonads is fundamental to puberty since it encompasses increased gonadal steroid secretion and initiation of gametogenesis resulting from enhanced pituitary gonadotropin secretion, triggered in turn by robust pulsatile GnRH release from the hypothalamus. This chapter reviews the development of GnRH pulsatility from before birth until the onset of puberty. In humans, GnRH pulse generation is restrained during childhood and juvenile development. This prepubertal hiatus in hypothalamic activity is considered to result from a neurobiological brake imposed upon the GnRH pulse generator resident in the infundibular nucleus. Reactivation of the GnRH pulse generator initiates pubertal development. Current understanding of the genetics and physiology of the brake will be discussed, as will hypotheses proposed to account for timing the resurgence in pulsatile GnRH and initiation of puberty. The chapter ends with a discussion of disorders associated with precocious or delayed puberty with a focus on those with etiologies attributed to aberrant GnRH neuron anatomy or function. A pediatric approach to patients with pubertal disorders is provided and contemporary treatments for both precocious and delayed puberty outlined.
In this chapter we discuss the development of the hypothalamic-pituitary-gonadal (HPG) axis followed by a description of the physiology of the HPG axis, with a focus on its dynamic function across development from the in utero period into adolescence. Factors that lead to the relative quiescence of the HPG axis during childhood, as well as the activation of the axis at puberty, are described. Regulation and disorders of pubertal timing are a major focus with detailed information provided regarding the etiology, evaluation, and treatment of precocious and delayed puberty in the male. Other conditions that often present during puberty, such as Klinefelter syndrome and gynecomastia, are also discussed.
Van Wyk Grumbach syndrome is well known for protracted hypothyroidism, characterised by multicystic ovaries (normal size ovaries contain many follicles of various sizes), isosexual precocious puberty and delayed skeletal growth. A series of ten children with Van Wyk Grumbach syndrome is been presented with their clinical features, biochemical and radiological profile and management. Patients showed a noteworthy improvement upon thyroxine therapy. It is vital to keep this entity in consideration and; hence, should investigate for thyroid status during the evaluation of ovarian cysts. Thyroxin replacement after establishing the diagnosis early can prevent the patient from going through extensive workup and surgeries.
Primary hypothyroidism can lead to delayed growth and pseudoprecocious puberty in juvenile patients, which was known as Van Wyk–Grumbach's syndrome (VWGS). There have been very few clinical case reports of primary juvenile hypothyroidism presenting with concurrent huge bilateral cystic ovaries. Here, we report the case of a 14-year-old female patient suffering from primary hypothyroidism in combination with bilateral cystic ovaries. Remarkable improvement of symptoms was observed after one month of hormone replacement therapy and an unnecessary surgical treatment was avoided. A comprehensive literature review of VWGS is summarised here to illustrate the presentation, diagnosis, and treatment of VWGS in pediatric patients. The present study aims to improve the current clinical knowledge of VWGS.
Ovarian cysts are one of the most common gynecologic affections for females. The most effective therapy is surgery, but not for all conditions. An 18‐year‐old woman was referred to our hospital because of menstruation disorder and abdominal distension. Ultrasound and computer tomography of the abdomen revealed a giant ovarian cyst. Magnetic resonance imaging revealed profound pituitary enlargement. Laboratory studies showed severe hypothyroidism, mild anemia, hyperlipidemia, hyperprolactinemia and an elevated level of cancer antigen‐125. Regression of the giant ovarian cyst and pituitary enlargement was observed after a 5‐month levothyroxine replacement therapy. Thus, for patients with ovarian cysts, hypothyroidism should be taken into account. Making correct diagnosis would avoid unnecessary surgery.
Isosexual precocious puberty in a girl child is defined as thelarche before 6 years in African–Americans and 7 years in Caucasians and menarche before the age of 9 years. In 1960, Van Wyk and Grumbach first described a syndrome characterised by breast development, uterine bleeding and multicystic ovaries in the presence of long standing primary hypothyroidism. We describe an interesting case of 8 year old girl presented with the complaint of abdominal mass with history of premature menarche and breast development. She is found to have gross hypothyroidism, hyperprolactinemia, prepubertal LH levels, multicystic ovaries and delayed bone age. Thyroid replacement amazingly settled her problems bringing her to normalcy.
Pediatric and adolescent patients may present to the emergency room with vulvovaginal bleeding, pruritus, or lesions. This chapter presents a broad differential diagnosis for vulvovaginal complaints in this population, subdivided by conditions presenting with bleeding, vesicles, ulcers or masses, and infectious versus noninfectious etiologies. Diagnostic approaches are provided for specific presenting complaints, as well as management methods for a range of conditions, including but not limited to vaginal foreign bodies, vulvovaginitis, lichen sclerosis, infections (bacterial, protozoan, fungal, and viral), Lipschutz ulcers, labial adhesions and urethral prolapse.
Puberty is the stage of development leading to sexual maturation and reproductive potential. Normal puberty is regulated by the hypothalamic-pituitary-gonadal (HPG) axis which is activated at the onset of puberty from the quiescent prepubertal state. Precocious puberty is the onset of pubertal changes at an earlier age than is expected for the population. Precocious pubertal development may occur by either premature activation of the HPG axis (central precocious puberty) or exposure to endogenous or exogenous sex steroids independent of HPG axis activation (peripheral precocious puberty). Although some children evaluated for precocious puberty will have variants of normal development such as premature thelarche (breast development), pathologic causes will need to be ruled out in others (Kaplowitz, J Clin Endocrinol Metab 89(8):3644-3650, 2004). © 2014 Springer Science+Business Media New York. All rights are reserved.
A female intact Chihuahua pup was presented at the age of four months with complaints of vulvar swelling and precocious sexual behaviour. Both complaints started to develop at the age of 9-10 weeks. During clinical examination, inspection revealed swollen mammary glands. The differential diagnosis was gonadotrophinindependent (peripheral) precocious puberty (or precocious pseudopuberty) as a result of the exogenous intake of estrogens, or intersexuality. The first diagnosis was the most probable one since the female owner of the dog applied an estrogen gel on face and shoulders on a daily basis. The owner was advised to avoid contact of the pup with the gel. This resulted in a positive evaluation after two months, with a complete disappearance of the complaints four months after the first examination.
This chapter describes pituitary disorders in the pediatric population, including panhypopituitarism, pituitary tumors, growth hormone deficiency, precocious puberty, and delayed puberty. While adults can develop panhypopituitarism, pituitary tumors, and/or growth hormone deficiency, the etiology and management of these problems in children are significantly different. New causes (with improvements in genetic diagnosis) and treatment approaches for precocious and delayed puberty continue to evolve.
Abstract 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.
Van Wyk and Grumbach syndrome is characterized by a long-standing history of hypothyroidism, high levels of thyroid-stimulating hormone, uni- or bilateral ovarian cysts, isosexual precocity and a delayed bone age. All of the features can be reversed with treatment of the underlying hypothyroidism. Here, we describe two cases of Van Wyk and Grumbach syndrome presenting with bilateral multicystic ovaries and enlargement of the pituitary gland. One patient suffered from ovarian cyst and hypophysoma resection, the other patient promptly responded to L-thyroxine with complete regression of the ovarian cyst and other symptoms.
The term 'precocious puberty' signifies the onset of secondary sexual characters before the age of 9 y in boys and 8 y in girls. Menarche before 9.5 y is also considered precocious. These definitions are constantly evolving due to the secular trends observed all over the world. It is crucial to decide whether the child has central (gonadotropin-dependent, GDPP) or peripheral (gonadotropin-independent, GIPP) form of precocious puberty. Some benign conditions such as premature thelarche and premature pubarche may mimic precocious puberty. A systematic approach with detailed history and clinical examination helps to arrive at a diagnosis in most cases. An underlying neurologic disorder is more likely in a very young boy. Basal LH level is the best screening test to diagnose GDPP. LH level less than 0.1 IU/L by a very sensitive assay indicates prepubertal stage. Stimulation tests using gonadotropin releasing hormone (GnRH) or its analog (GnRHa), leuprolide help to confirm the diagnosis of GDPP. High resolution MRI of brain helps to detect abnormalities in hypothalamus and pituitary region. GnRH analogs (GnRHa) are the only effective treatment for GDPP at present. In girls, breast size may regress; menses ceases and vaginal mucosa becomes non-estrogenized. In boys testicular volumes remain static or decrease and genital growth regresses. The effects of GnRH analogs are reversible on discontinuation of therapy, with restoration of normal function within 3 mo after stopping treatment. Treatment of GIPP however is far from satisfactory.
Although androgen resistance has been characterized in men with a normal chromosome complement and mutations in the androgen-receptor gene, a mutation in the gene encoding estrogen receptor α (ESR1) was previously described only in one man and not, to our knowledge, in a woman. We now describe an 18-year-old woman without breast development and with markedly elevated serum levels of estrogens and bilateral multicystic ovaries. She was found to have a homozygous loss-of-function ESR1 mutation in a completely conserved residue that interferes with estrogen signaling. Her clinical presentation was similar to that in the mouse orthologue knockout. This case shows that disruption of ESR1 causes profound estrogen resistance in women. (Funded by the National Institutes of Health.).
A syndrome associated with juvenile hypothyroidism is described, the cardinal feature of which is sexual development beyond that consistent with the bone age and other indices of maturity. The 3 girls described in this paper had precocious menstruation, galactorrhea, absence of public hair, and enlargement of the sella turcica. One patient was excessively pigmented. These abnormal signs disappeared promptly when the hypothyroid state was alleviated. Serial x-rays of the skull after treatment with thyroid was instituted revealed an initial period of further enlargement and demineralization of the pituitary fossa followed by a decrease in its size toward normal. A normal menarche later ensued in 2 of the girls when the level of maturity had progressed appropriately. The implications of the close similarity between the findings in this syndrome and in patients with pituitary tumors are discussed. A primary target gland deficiency is suggested as the etiologic factor in at least some patients with chromophobe adenomas.
It is postulated that the mechanism for the development of menorrhagia, galactorrhea, and pigmentation in these patients was an overlapping secretion of gonadotropin, mammotropic hormone, and (in 1 case) melanocyte-stimulating hormone along with the presumed high level of thyroid-stimulating hormone. A similar overlap in pituitary hormones occurs in experimental pituitary tumors induced by single target gland deficiencies and in certain clinical endocrine disorders. This lack of specificity in the pituitary feedback mechanism, so strikingly demonstrated in the present syndrome, is suggested as the mechanism responsible for a number of phenomena commonly observed in clinical endocrine disorders.
We report a 12-year-old female presenting with an abdominal tumor. Diagnostic workup revealed giant bilateral ovarian cysts, severe hypothyroidism as well as an elevation of CA 125. We refrained from ovariectomy, which would be necessary for a malignant tumor, in view of an evident Van Wyk and Grumbach syndrome. The patient promptly responded to L-thyroxine with complete regression of all symptoms. Hypothyroidism should be considered in the evaluation of ovarian cysts. Although the Van Wyk and Grumbach syndrome is rare, it is crucial to rule it out in order to avoid unnecessary ovarian surgery when thyroid replacement is completely sufficient.
A 21-year-old woman was referred because of abdominal pain. On physical examination, her abdomen was distended up to the umbilical region. Ultrasound and computer tomography of the abdomen revealed bilateral multiple ovarian cysts. Laboratory studies revealed increased liver function, total cholesterol and creatine phosphokinase. Further clinical investigations determined that the patient suffered from primary hypothyroidism due to autoimmune thyroiditis. The cysts resolved spontaneously after the simple replacement of a thyroid hormone. Some reports have been published of primary hypothyroidism presenting as ovarian cysts and precocious puberty in prepubertal girls. However, the case presented herein indicates that an ovarian tumor as a result of hypothyroidism may also occur in adult females. To avoid inadvertent surgery to remove an ovarian tumor, it is essential that a patient with multiple ovarian cysts and hypothyroidism be properly managed, as the simple replacement of a thyroid hormone could resolve the ovarian cysts.
Background
Primary hypothyroidism is a rare and unusual cause of precocious puberty in children. While delayed growth and pubertal development are more commonly seen in long-stading primary hypothyroidism, a few case reports have documented the rare occurrence of precocious puberty. Even more rare is the manifestation of multicystic ovaries with this endocrinopathy. Females may progress to have vaginal bleeding with the absence of a growth spurt or radiologic evidence of sexual maturation. We describe a unique case of enlarged ovaries, severe vaginal bleeding, and hemodynamic instability.
Case
A 6 year-old presented to her primary pediatrician with a 24 hour history of abdominal pain, and vaginal bleeding with the passage of clots. Increasing malaise had been noted over the previous year, as well as constipation, dry skin, cold intolerance, the development of breast buds, and no change in height in the previous year. During the initial evaluation, she had a spontaneous bradycardic episode to 20–30 beats/minute that subsequently self-resolved. A pelvic ultrasound revealed enlarged ovaries (right: 7.6 × 5.8 × 7.2 cm, left: 5.5 × 6.1 × 5.9 cm) with numerous simple cysts and a thickened endometrial stripe. A TSH level returned at 907 u/ml, thyroxine was <1 g/dl, and estradiol was 99 pg/ml. Aspiration of the cysts, in concert with L-thyroxine therapy resulted in decreased estradiol levels, halted vaginal bleeding, and led to prompt reωlution of cysts on follow up ultrasound.
Conclusion
This is the first reported case of percutaneous follicular cyst aspiration to treat ovarian hyperstimulation caused by severe hypothyroidism in a child. Health care providers should keep this diagnosis in mind as this constellation of symptoms can be completely reversed with the initiation of levothyroxine therapy. In a hemodynamically unstable patient, follicular aspiration may be a helpful intervention to decrease estradiol stimulation of the endometrium in order to lessen bleeding and stabilize a rapidly falling hematocrit.
A case of ectopic thyroid with congenital hypothyroidism presenting with bilateral multicystic ovaries without marked precocious puberty is reported. The cystic ovaries disappeared dramatically after thyroid hormone therapy.
Conclusion When ovarian cysts are found in prepubescent females, the possibility of associated hypothyroidism should be considered.
Long-standing acquired hypothyroidism can rarely be associated with precocious puberty and polycystic ovaries. The authors report such a case, which responded to the simple replacement of thyroid hormone. It is important to look for hypothyroidism in girls with ovarian masses and precocious puberty to avoid surgery on the ovaries.
Some children with profound and long-standing hypothyroidism present with signs of paradoxical sexual maturation. In females, it is characterized by breast development, vaginal bleeding, lack of pubic hair, and delayed bone age. A case of multiple ovarian cysts in a prepubertal girl with severe hypothyroidism due to autoimmune thyroiditis is reported. A 7-year, 8-month-old girl presented with precocious puberty and vaginal bleeding. A pelvic ultrasound revealed markedly enlarged ovaries with numerous cysts which disappeared dramatically after thyroid replacement. When large multiple ovarian cysts with vaginal bleeding are found in a prepubertal girl who has a retarded bone age, the possibility of associated hypothyroidism should be considered. Health care providers should keep this in mind because this constellation of symptoms can be completely reversed with the initiation of thyroid replacement.
Case report
A case of primary hypothyroidism in a pre-pubertal girl presenting with vaginal bleeding and unilateral ovarian cyst is reported. The cyst resolved spontaneously after the institution of thyroid hormone therapy.
Conclusion
Watchful expectancy is recommended when an ovarian cyst is found in association with primary hypothyroidism and precocious puberty.
We report a case of a prepubertal girl with juvenile primary hypothyroidism presenting as ovarian cysts and precocious puberty. The 7-year-old female was referred to our clinic because of a pelvic/abdominal mass and vaginal bleeding. Besides these findings, on physical examination we noticed the thyroid gland globally increased and the presence of secondary sexual characteristics. Based upon the clinical profile and investigations, the patient was diagnosed with juvenile primary hypothyroidism due to autoimmune thyroiditis. The cysts and precocious puberty resolved spontaneously after the simple replacement of thyroid hormone. It is important to bear in mind hypothyroidism in cases of girls presenting ovarian cysts and precocious puberty in order to avoid unnecessary surgery on the ovaries.
Ovarian cysts have been reported in girls with longstanding uncompensated primary hypothyroidism. Restoration of euthyroid state has been associated with resolution of these cysts; long-term follow-up of these patients is however lacking. We evaluated the outcome in ten girls with ovarian cysts and hypothyroidism managed at our hospital with special emphasis on subsequent pubertal development and ovarian imaging. Patients were diagnosed at the age of 8.6 +/- 2.3 years (mean +/- SD) with severe uncompensated primary hypothyroidism (TSH levels >100 mIU/l in all; 509.3 +/- 651 mIU/l) and growth retardation (height SDS -4.1 +/- 1.8). Nine girls had vaginal bleeding at diagnosis; five also had thelarche. LH and FSH levels were prepubertal in all patients. Ovarian cysts were bilateral in eight girls (80%); internal septation was noted in six. Thyroxine replacement (4.1 +/- 0.7 microg/kg/day) led to normalization of TSH levels with reversal of pubertal changes and regression of ovarian cysts in all patients 2.2 +/- 1.0 months after treatment. At last follow-up 3.5 +/- 2.6 years after initiation of treatment at the age of 12.0 +/- 2.3 years, all patients had normal ovarian size in ultrasound evaluation with six girls progressing to normal puberty. Our study emphasizes the need to exclude hypothyroidism in young girls with ovarian cysts. Identification of hypothyroidism in these girls obviates the need for extensive investigations.
A seven year and ten months old girl presented with cyclic vaginal bleeding and a huge abdominopelvic mass. She had clinical features of hypothyroidism. The investigation results were consistent with the diagnosis of primary hypothyroidism with precocious puberty. She also had bilaterally enlarged cystic ovaries on CT scan of abdomen and CT scan of brain showed pituitary macroadenoma. After starting treatment with thyroxine, patient became euthyroid and her general condition improved. Treatment with thyroxine alone halted the cyclic vaginal bleeding, led to rapid resolution of the ovarian cysts and regression of the pituitary mass.
To describe 2 cases of primary hypothyroidism, precocious puberty, large multicystic ovaries, possible diagnostic dilemma, unilateral oophorectomies, and subsequent response to levothyroxine replacement therapy.
We present the clinical, biochemical, radiologic, and histopathologic findings in 2 patients with rare cases of Van Wyk-Grumbach syndrome and megaovaries, who underwent unilateral oophorectomy.
Two patients, an 8-year-old girl and a 3-year-old girl (cases 1 and 2, respectively), were referred to our center. Both patients presented with precocious puberty and vaginal bleeding and had undergone unilateral oophorectomy before referral. In the first patient (case 1), the surgical intervention was a consequence of torsion of the left megaovary, necessitating emergency oophorectomy. Oophorectomy in the second patient (case 2) was a result of initial diagnostic confusion, inasmuch as a sexcord stromal tumor was suspected. A detailed history, physical examination, and laboratory results pointed toward primary hypothyroidism due to Hashimoto's thyroiditis and thyroid dysgenesis, respectively. Serial ultrasound studies of the abdomen and pelvis revealed large multicystic ovaries, with progressive enlargement (including regrowth from an apparent ovarian "postsurgical remnant"). Both patients responded dramatically after initiation of levothyroxine replacement therapy, with no further vaginal bleeding and reversal of megaovary to normal size (in case 1).
In a highly selected minority of children with untreated primary hypothyroidism, there is development of precocious puberty and progressively enlarging multicystic ovaries. The precise endocrine, neuroanatomic, and neurophysiologic bases for this phenomenon are unclear. Nevertheless, the entire clinicopathologic picture, including giant ovaries, dramatically reverts to normal status with the restoration of a euthyroid state by means of simple levothyroxine replacement therapy.
Case study of a young female patient with severe hypothyroidism due to autoimmune thyroiditis and multiple ovarian cysts is reported. A 14-year 7-month-old girl presented with pelvic and abdominal pain and severe asthenia. Her last menstrual period was 10 months before presentation. Physical examination showed obesity; apathetic and flat expression; periorbital puffiness; pale, cold, dry skin and slow sustained reflexes; swelling in the hands and feet; no galactorrhea; a hardly palpable thyroid gland; and ovaries with a palpable irregular surface. Her heart rate was 90 bpm with a blood pressure within the normal range (110/70 mmHg). Laboratory findings showed severe hypothyroidism (thyroid-stimulating hormone [TSH]: 960 mIU/L), gravis macrocytic anemia, hyperfibrinogenemia, and hyperprolactinemia. Imaging examinations revealed a normal-size thyroid with irregular echogenicity, strongly hypoechogenous area at the neck ultrasonography, bilateral multilocular ovarian masses with cystic components at pelvic ultrasound and computed tomography, and both anterior and posterior pericardial effusion at echocardiography. As soon as thyroid replacement therapy was initiated, all symptoms progressively disappeared and biochemical and hormonal values normalized, while the right ovary did not decrease in size during the follow-up period. For this reason, our patient underwent right ovarian wedge resection 14 months after the initiation of medication replacement. Ovarian histological examination showed a benign ovarian cyst with extensive hemorrhage and myxedematous infiltration. It is concluded that it is important to recognize early in young girls the association between large multiple ovarian cysts and high elevated levels of TSH in order to resolve this disorder with substitutive therapy.
In 1960 Van Wyk and Grumbach described a syndrome of juvenile hypothyroidism, precocious puberty and ovarian enlargement. These findings undergo complete regression with thyroid hormone replacement therapy. This diagnosis can be made on the basis of imaging findings and thyroid function analysis, avoiding surgery.
To relate the distinctive clinical and imaging features and putative pathophysiological mechanism of a series of patients with Van Wyk and Grumbach syndrome (VWGS).
Patients with VWGS diagnosed at two large children's hospitals over a 6-year period beginning in 1999 were retrospectively reviewed. A literature review was also conducted.
Five female patients were diagnosed with cystic ovarian enlargement and hypothyroidism at ages ranging from 9 to 17 years. Isosexual precocious puberty was found in prepubescent patients. Associated findings included delayed bone age, ascites, and pleural and pericardial effusions. Ovarian cyst involution occurred following treatment of the hypothyroidism.
The association of primary hypothyroidism with cystic ovarian enlargement and precocious puberty is important to recognize. In the absence of suspected ovarian torsion, surgery is unnecessary, as cyst regression occurs after appropriate thyroid hormone replacement. Noncompliance with hormone replacement therapy should be considered when cystic ovarian enlargement is noted in patients with a history of hypothyroidism.
Case of precocious puberty in a female cretin:246 12. van Wyk JJ: Grumbach MM: Syndrome of precocious menstration and galactorrhea in juvenile hypothyroidism: an example of hormonal overlap in pituitary feedback
- Kendle
- Fw
Kendle FW: Case of precocious puberty in a female cretin. Br Med J 1905; 1:246 12. van Wyk JJ: Grumbach MM: Syndrome of precocious menstration and galactorrhea in juvenile hypothyroidism: an example of hormonal overlap in pituitary feedback. J Pediatr 1960; 57:416
Primary hypothyroidism presenting as severe vaginal bleeding in a prepubertal girl
- Gordon