Hypothyroidism is regarded as the most prevalent pediatric endocrine disorder, and studies reveal that the prevalence of childhood hypothyroidism is increasing in some parts of the world [1]. Although sexual development is delayed in the majority of hypothyroid children, hypothyroidism in pediatric patients that has been present for a long time rarely displays signs of early puberty, the Van Wyk-Grumbach syndrome (VWGS) [2].This syndrome is regarded as one of the most perplexing pediatric syndromes, which is a rare kind of sexual precocity linked to hypothyroidism in children [3].

In this syndrome, breast enlargement, multicystic ovaries, and menstrual bleeding in girls, and testicular enlargement with little penile development in boys, are all signs of sexual precocity [4]. This uncommon condition was first observed by Kendle in 1905 but was later characterized by Van Wyk and Grumbach in 1960, and now Van Wyk -Grumbach syndrome is the name given to this condition [5] It’s well known that this condition is more commonly seen in females [6-9]. However, there were an increasing number of case reports describing the occurrence of the syndrome in boys [10-11]. Rising awareness among physicians to this syndrome is of paramount importance as early diagnosis and establishment of replacement therapy with thyroxine can alleviate the already developed symptoms [12]., and avoid patients being exposed to unnecessary surgical interventions [13-14]. This article aims to review the recently published studies on Van Wyk-Grumbach Syndrome to raise awareness of such an important, rare presentation of childhood hypothyroidism.        

Pathophysiology

The complex interactions within the hypothalamic-pituitary axis are assumed to be the cause of Van Wyck-Grumbach syndrome. Ovarian hyperstimulation can occur as a result of increased FSH levels; thus, multicystic ovaries might be a symptom of this syndrome [15].

There are numerous theories for the paradoxical precocious puberty seen in primary hypothyroidism. First, the pituitary hypothalamic axis overproduces gonadotropins and other hormones, including estradiol, according to Van Wyk and Grumbach, due to the feedback system's lack of specificity [5]. Second, TSH has the ability to weakly stimulate the FSH receptor without simultaneously stimulating LH receptors, which explains the low level (pre-pubertal level) of LH, according to in vitro tests. As a result, excessive levels of TSH may trigger gonadal stimulation and early sexual changes via the FSH receptor [16]. Third, FSH secretion is stimulated by a constant high level of thyrotropin-releasing hormone (TRH) [17].

Isosexual precocious puberty with enlargement of the testicles but still no virilization is associated with primary hypothyroidism in males and the cause of this distinctive sexual precocity is unclear.; Jannini et al., found that severe hypothyroidism has a direct effect on the prepubertal testis, causing overproliferation of Sertoli cells and increased testicular size in boys; furthermore, the longer hypothyroidism lasts, the worse the testicular damage becomes [18].

Short stature associated with delayed bone age are distinguishing characteristics of VWGS precocious puberty, as opposed to other forms of premature puberty in which growth acceleration is the norm. This is due to the direct and indirect actions of thyroid hormone on bone maturation. Directly by promotion of chondrocyte differentiation and endochondral ossification in the growth plate and indirectly by insulin-like growth factor (IGF) system and the regulation of growth hormone gene expression [19].

Long-term hypothyroidism can cause thyrotroph hyperplasia, which causes the sella turcica to expand and enlargement of the pituitary gland [20]. 

The discordance between FSH and luteinizing hormone (LH) in this disease is elucidated by the role of prolactin theory [4]. Hyperprolactinemia is caused by the unopposed production of prolactin as a result of high TRH, and prolactin can increase the ovaries' sensitivity to gonadotropins while reducing the pulse frequency of gonadotropin-releasing hormone (GnRH) [8]. Slow GnRH pulses, on the other hand, decrease LH while generating FSH, this results in an unique FSH response [21].

Diagnosis

The condition is usually suspected in children with a long history of hypothyroidism who present with sexual precocity, decreased growth velocity and delayed bone age. 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 [3].

Clinical Characteristics

Children who were diagnosed with this problem had long-term hypothyroidism with all of the symptoms that come with it. Hypothyroidism caused by Hashimoto thyroiditis is a common cause of this type of hypothyroidism [22]. Although it is classically seen in prepubertal children, multiple cases of older patients in their late teens have been reported, indicating that the illness is not limited to the prepubertal age group [23-24].

• In girls:Breast development and menstruation are common in females, with the latter occurring even in those with minor breast development [22]

Some females may have non spontaneous galactorrhea so that when "milking" the subareolar ductal tissue, a few drops of milky fluid may become visible [3]. Headache as a presenting symptom of pituitary hyperplasia was reported [25] although it was asymptomatic in the majority [10]. In one case report, oligosyndactyly was reported in a girl with this condition [13].

• In boys: the only clinical characteristic is testicular enlargement with minimal or no penile enlargement [22] 

• In both genders: precocious puberty is always isosexual. No pubic hair development occurs in either females or males and all had decreased growth velocity and delayed bone age [26].

Laboratory and Imaging Characteristics

Thyroid-stimulating hormone (TSH) levels are considerably high, typically exceeding 500 U/mL, and prolactin and estrogen levels are marginally elevated. When assessed by particular assays, the enormously high quantities of TSH, causing FSH-like effects in the absence of LH effects on the gonads, despite the fact that blood FSH is low and LH is undetectable. The FSH-like impact is sufficient to cause ovaries to secrete estradiol, but testicular enlargement occurs in males without significant testosterone secretion [22].

In several case reports of Van Wyk-Grumbach syndrome, increased tumor markers such as alpha fetoprotein have been seen (AFP). Both patients and professionals may experience severe anxiety as a result of an increased tumor marker. However, with medical treatment, AFP levels returned to normal after 2 months in one study [26].

Skull film or MRI can reveal enlargement of the Sella, which is indicative of long-term primary hypothyroidism [14]. Ultrasonography can typically reveal multicystic ovaries [3]. These cysts can grow to enormous proportions [5].

Treatment

The main steps in the treatment of patients with VWGS are early detection and the start of thyroid hormone replacement. These steps will help to alleviate the symptoms and increase the height gained. In addition, following the appropriate treatment, reversal to the prepubertal condition is common [13].

The biochemical and clinical signs of hypothyroidism revert to normal quickly after treatment. The probability of escalation to central puberty with faster bone age progression in the months following the start of levothyroxine is an issue that might justify delaying puberty with GnRH analogs. A remarkable finding in male patients is the persistence of macroorchidism (testicular volume >30 mL) in adult male patients despite sufficient medical therapy [22].

Elevated tumor markers (such as AFP [27], CA-125 [28], LDH, and Inhibin) have been identified in case reports of Van Wyk-Grumbach syndrome. Both patients and professionals may experience severe anxiety as a result of an increased tumor marker. Jyotsna Gupta reported a 4-year-old female patient with trisomy 21, who is originally from Guyana complaining of recurrent vaginal bleeding. Laboratory evaluation revealed picture of long-term untreated hypothyroidism with severely elevated TSH level and low free thyroxin levels.an elevated levels of Estradiol and AFP, while her bone age was delayed. The patient was diagnosed with Van Wyk-Grumbach syndrome and was prescribed levothyroxine, which allowed the vaginal bleeding to cease and estradiol level returned to normal. Within two months of treatment, the AFP levels had returned to normal. As a result, it's critical to understand that high tumor markers should be checked again during treatment, and that an MRI may not be required [29].

Furthermore, early commencement of thyroid hormone replacement not only results in corrected hormonal profile, but it also prevents unnecessary surgery. In Nepal, Vivek Panta and Suman Baralb [14] documented a case report in which a 5-year-old girl was referred to a higher center for intervention after her caregivers being recommended to have her ovaries surgically removed in a primary health care center. Her serum TSH level was over 100 microIU/mL, Serum LH was low, with very high levels of FSH, estrogen and Prolactin. Thyroid peroxidase antibody was about 15 times the normal range, Bilateral multiloculated cystic ovaries were identified on magnetic resonance imaging (MRI) of the abdomen and pelvis and an X-ray of the left wrist indicated delayed bone age. Van Wyk Grumbach Syndrome (VWGS) was diagnosed as ovarian hyperstimulation caused by severe hypothyroidism. based on these elevated TSH values and radiological findings. Her ovarian cyst operation was cancelled. She was then started on oral levothyroxine 25 μg daily. She had no vaginal bleeding after two months of levothyroxine medication and was more active than previously. Her height and weight climbed by 5 cm and 3 kg, respectively, over the next four months. Her ovarian cyst had shrunk in size, according to ultrasonography of her abdomen and pelvis [14].

In fact several female patients with this syndrome who had unilateral and/or bilateral ovarian tumors, have had surgery given the risk of cancer. Despite the presence of increased tumor markers, pathologic examination of ovarian masses seen in the context of hypothyroidism reveals that these masses are nonmalignant [25]. Sanjeevaiah et al. reported a patient in which CA-125 and AFP levels were abnormally high, and the patient's left ovary was resected. The final pathology indicated a large number of cystic follicles with the occasional corpura albincantia and luteal cysts, as well as the lack of malignant cells. A biopsy of the right ovary in the same patient was also lack any evidence of malignant changes [30]. 

The response to treatment in both prepubertal and post pubertal girls with this syndrome is good .As mentioned previously in this article, this syndrome can affect individuals of different ages and isn't just a disease that affects prepubescent children. [23-24] have come to similar conclusions, reporting Hypothyroidism, oligomenorrhea, and bilateral enlarged ovarian masses in a 17-year-old girl, as well as hypothyroidism, stomach discomfort, distention, and ovarian masses in a 21-year-old woman. After their hypothyroidism was managed, both of these patients' symptoms faded away. In both, the basic pathogenic mechanism appears to be the same.

Furthermore, not only are ovarian cysts in VWGS misunderstood, exposing patients to unneeded procedures, but pituitary hyperplasia is also misinterpreted, as evidenced in two cases reported by HuiYing Zhang [12]. Pituitary growth was observed by MRI in both cases; however, it's hard to differentiate between pituitary hyperplasia and macroadenoma. One of the two patients had pituitary adenoma removal due to a lack of awareness of the condition, and the final pathology revealed pituitary prolactinoma and thyrotropin-secreting adenoma.When dealing with second patient, he refrained from surgery in view of evident VWGS and was treated with thyroid hormone resulted in the shrinkage of the enlarged pituitary gland. A decrease in the negative feedback exerted by circulating thyroid hormones has been associated to asymptomatic pituitary hyperplasia, which is caused by thyrotroph cell hyperplasia, the number of TSH-secreting cells reduces as the pituitary gland's size returns to normal after thyroid hormone therapy [31].

On the other hand, it is vital to notice the uncommon association of VWGS, such as the case of a 9-year-old female kid who arrived to the endocrine department with complaints of intermittent vaginal bleeding, difficult walking, and short stature. She was diagnosed with autoimmune hypothyroidism, FSH-dominated pseudoprecocious puberty, delayed relaxation of deep tendon reflexes, pseudohypertrophy of the calf muscles, and delayed bone age during her evaluation. The diagnosis of VWGS associated with Kocher-Debre-Semelaigne (KDSS) was made. The patient was started on a 25 μg thyroxin replacement and its dose modified as needed. All clinical and biochemical markers improved after 12 months of follow-up, including the remission of pseudohypertrophy of the calf muscles [31]. 

In 2015, Akman, A. O. et al. [32] reported an adolescent female with congenital hypothyroidism who presented with menstrual irregularities, multicystic ovaries, and muscle ache and made a link between VWGS and KDSS. CPK levels were elevated, and the calf muscles were pseudo hypertrophied. After a brief period of thyroxin medication, all the features were gone.

Another link to VWGS to be noted is the occurrence of café au-lait spots, as described by [33] in their case study. It's thought to be caused by the effect of melanocyte stimulating hormone (MSH) on the skin as a due to cross reaction between TSH and FSH. Despite the fact that there have never been any reports of café au lait spots in VWGS before. At this time, it is impossible to determine if the incidence was coincidental or not. 

Alberto Leonardi described an interesting case of a never-before-reported association of Van Wyk-Grumbach syndrome and acute rhabdomyolysis in a young girl with previously undiagnosed hypothyroidism, highlighting the significance of identifying the signs and symptoms of rare hypothyroidism complications in order to establish appropriate therapy. Levothroxin replacement treatment improved both incomplete precocious puberty and rhabdomyolysis promptly [34].

Thyroid hormone treatment in Van Wyk-Grumbach syndrome eliminates all symptoms and restores the hormonal profile to normal. This also eliminates the need for additional diagnostic tests, the worry of cancer, and unneeded surgery.

Acknowledgement

To our beloved University; Al Mustansiriyiah for continuous support

Disclaimer

None to declare. 

Funding

Self-funding.

Conflict of Interest

None to declare.

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