|Year : 2020 | Volume
| Issue : 2 | Page : 105-108
Iso-sexual precocious puberty associated with primary hypothyroidism–Van Wyk–Grumbach syndrome: An uncommon presentation of a common disorder
Sonalika Mehta, Prashant K Verma, Swathi Chacham, Nowneet Kumar Bhat
Department of Paediatrics, AIIMS, Rishikesh, Uttarakhand, India
|Date of Submission||06-May-2020|
|Date of Decision||20-Jun-2020|
|Date of Acceptance||29-Jun-2020|
|Date of Web Publication||15-Dec-2020|
Dr. Prashant K Verma
Department of Paediatrics, AIIMS, Rishikesh, Uttarakhand
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Mehta S, Verma PK, Chacham S, Bhat NK. Iso-sexual precocious puberty associated with primary hypothyroidism–Van Wyk–Grumbach syndrome: An uncommon presentation of a common disorder. J Med Evid 2020;1:105-8
|How to cite this URL:|
Mehta S, Verma PK, Chacham S, Bhat NK. Iso-sexual precocious puberty associated with primary hypothyroidism–Van Wyk–Grumbach syndrome: An uncommon presentation of a common disorder. J Med Evid [serial online] 2020 [cited 2021 Apr 13];1:105-8. Available from: http://www.journaljme.org/text.asp?2020/1/2/105/303569
| Introduction|| |
Primary hypothyroidism most frequently presents with a delayed sexual development and late-onset puberty, however long-standing hypothyroidism can rarely manifest as precocious puberty. The association of premature pubertal onset with bilateral ovarian cyst, pituitary hyperplasia and prolonged untreated hypothyroidism was first described by Van Wyk and Grumbach. The clinical manifestations associated with the syndrome are postulated to be secondary to the hormonal overlap in the pituitary feedback circuit secondary to molecular mimicry between the hormonal subunits. The association of early puberty with a delayed bone age and short stature strongly suggests the presence of the underlying hypothyroidism, which needs a meticulous evaluation. Complete regression of pituitary hyperplasia, ovarian cyst and cessation of vaginal bleeding has been documented with medical therapy alone without any surgical intervention. Here, we present a case of an 8-year-old female, who presented with precocious puberty associated with hypothyroidism and had features suggestive of Van Wyk–Grumbach syndrome. Through this case, we wish to highlight the importance of knowing about the rare presentations of thyroid insufficiency, which might prevent unnecessary delay in medical management or surgical explorations.
| Case Report|| |
An 8-year-old female presented to the endocrine outpatient department with progressive breast enlargement and episodes of irregular vaginal bleeding for the past 6 months. She was full-term delivered vaginally, was born of non-consanguineous marriage and was first in the birth order. Her birth weight was 2.5 kg (between 3rd and 15th centiles; WHO growth chart). Her development was normal for the age with a significant history of linear growth failure for the past 5–6 years. Her scholastic performance had been declining for the past 3 years. There was a history of constipation, which occasionally was associated with bleeding per rectum. There was no history of vomiting, headache or visual symptoms. There was no other significant past history. There was no history of autoimmune disorder in the family.
Her height was 104 cm (<3rd centile; IAP growth chart), weight was 25 kg (between 25th and 50th centiles; IAP growth chart) and height age was 4.5 years [Figure 1] with a delayed bone age [Figure 2]. Her pulse rate was 66/min and blood pressure was 96/58 mmHg (50th centile). She had dry skin, pallor and depressed nasal bridge. There were no café au lait spots. There was no goitre on palpation. As per Tanner's staging, her sexual maturation score was B4 and P1 for breast and pubic hair, respectively, and there were no axillary hair. Her intelligent quotient was 74 (low average) with a verbal IQ of 70 and a performance IQ of 75. Visual acuity and fields were normal. Her evaluation is summarised in [Table 1].
|Figure 1: The growth of the child before (left) and after (right) treatment with L-thyroxine. HA: Height age, CA: Height at chronological age, MPH: Mid-parental height|
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|Figure 2: (a) X-ray of the left hand and wrist of the female patient depicting bone age of 6 years at a chronological age of 8 years, (b) standard reference X-ray of the patient at 6 years, (c) standard reference X-ray of the patient at 8 years. Thyroxine mediates differentiation of chondrocytes by its direct action on growth plate, which is responsible for the growth of long bones. Deficiency states, as seen in the patient, (a) are therefore characterised by a delayed bone age, as compared to the bone age at a chronological age of 8 years (c)|
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|Table 1: Overview of the major laboratory examination results at admission and at 6 weeks' follow-up|
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Ultrasonography (USG) of the pelvis suggested a pubertal uterus and enlarged multicystic ovaries. Magnetic resonance imaging (MRI) scan of the brain revealed a well-defined sellar mass with suprasellar extension measuring 1.7 cm × 1.6 cm × 1.4 cm [Figure 3]. Levels of anti-thyroid peroxidase antibodies (anti-TPO) were documented to be normal on two different occasions. Her initial functional scan of the thyroid (Tc-99m pertechnetate) revealed absent tracer uptake, however USG of the neck suggested presence of the thyroid gland. A repeat tracer scan was done after withholding L-thyroxine therapy, which then showed a normal tracer uptake and no evidence of ectopic functional thyroid tissue. The child was managed with thyroid replacement therapy and was started on tablet L-thyroxine at a dose of 25 μg, which was escalated weekly to a daily dose of 100 μg, given in the early morning on an empty stomach. Thyroid-stimulating hormone (TSH) and free Thyroxine (T4) levels were monitored every 6th weekly initially for 1 year, after any dose change and subsequently every 3rd monthly. Her T4 levels were targeted at the upper limit of the normal range. Within a month of starting the therapy, her bleeding cycles stopped. Follow-up USG scan was done after 7 months of the start of treatment, which showed regression of cysts. She was followed with yearly USG scans thereafter, which persisted to be normal. Complete stabilisation of TSH and prolactin hormone levels was documented after 12 months of starting the therapy. Her final height was 143 cm (10th–50th centile; IAP growth charts) against the target height of 153 cm [Figure 1]. Repeat MRI of the brain done a year later showed regression of the suprasellar mass [Figure 3]. Her bone age was equal to the chronological age (12 years) at follow-up visit [Figure 4]. She was continued with L-thyroxine in a daily dose of 100 μg alternating with 75 μg. The onset of normal menstrual cycle was documented at 13 years of age.
|Figure 3: Magnetic resonance imaging brain of the child before treatment (left) suggesting pituitary hyperplasia while after treatment there is complete resolution of the lesion|
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| Discussion|| |
Our patient presented with features of linear growth retardation and a delayed bone age with iso-sexual peripheral precocious puberty. The most common differentials of growth failure were juvenile hypothyroidism, Cushing's disease and panhypopituitarism. Short stature with obesity initially pointed towards Cushing's syndrome as the diagnosis, which can be associated with early puberty as seen with endogenous cortisol-secreting adrenocortical tumours. Peripheral precocious puberty with adnexal masses is always associated with an advanced bone age with an elevated basal cortisol level, which was not seen in the index case. Severe growth retardation is also observed in patients with panhypopituitarism (due to the combined deficiency of growth hormone and TSH). It is associated with secondary hypothyroidism and delayed puberty, which was not seen in the index patient. Hence, we narrowed the diagnosis as primary hypothyroidism in view of the linear growth failure with a delayed bone age and features of thyroid hormone insufficiency.
The association of long-standing thyroid insufficiency with sexual precocity has been described in literature as Van Wyk and Grumbach syndrome (VWGS). The exact mechanism of the development of precocious puberty in VWGS remains undefined and has been explained with several theories. The most widely accepted of which is hormonal overlap in the pituitary feedback mechanism due to molecular mimicry between TSH and follicle-stimulating hormone (FSH) receptors. TSH in high concentrations leads to stimulation of gonadal FSH, as they share the common alpha subunit, which, in turn, increases the oestrogen levels, thereby manifesting as peripheral sexual precocity in females and macroorchidism in males. Pubic and axillary hairs are characteristically absent as there is no effect on adrenal hormone synthesis, thus it is also known as incomplete sexual precocity. Multiple cysts in the ovaries develop secondary to the enhanced production and decreased clearance of FSH due to hyperstimulation of its receptors by elevated thyrotropin-releasing hormone (TRH). In addition, high circulating TSH acts on the FSH receptors present on the ovarian follicle due to specificity-spillover, resulting in the follicular cyst formation. Pituitary adenoma reported on imaging is basically thyro-lactotrope hyperplasia, which is an indication of a long-standing, severe thyroid deficiency state. High circulating levels of TRH due to lack of thyroxine-mediated feedback inhibition result in hyperstimulation of thyro-lactotropes in the pituitary gland, thus presenting as a macroadenoma on imaging studies. The similar mechanism is also responsible for the stimulation of prolactin secretion, thereby leading to hyperprolactinaemia. Hyperplastic pituitary causes compression of the pituitary stalk that disrupts the hypothalamic inhibition of prolactin secretion, which further explains the presence of high prolactin levels with long-standing hypothyroidism.
The most common cause of thyroid insufficiency in an iodine-sufficient area in young females has been attributed to immune-mediated destruction of the thyroid gland (Hashimoto's thyroiditis). It is defined by the presence of high anti-TPO antibody titre. Our patient had no evidence of autoimmune thyroiditis due to the normal level of anti-TPO antibodies documented on two separate occasions. Thyroid dysgenesis could be ruled out due to the presence of normal thyroid gland on the USG and the presence of functional thyroid tissue seen in Tc-99m pertechnetate scan. Our patient underwent two functional scans: the first one was done at some other hospital which showed no uptake. At our hospital, confirmation of an intact thyroid gland was done by an USG following which a repeat scan was done after withholding L-thyroxine treatment, which revealed a normal uptake. This discrepancy in reports could be explained by L-thyroxine-mediated TSH suppression, during the first scan. Hypothyroidism in our patient could have been due to severe iodine deficiency or a delayed-onset dyshormogenesis .
Several methods have been devised for the estimation of bone age in children, of which the most frequently used and practically feasible is through Greulich and Pyle Atlas More Details. In females aged 3 years and above, assessment of the bone age is done through comparison between ossification centres of the epiphysis and metaphysis of proximal and intermediate phalangeal joints, in an X-ray of hand. This can also be done by comparison with age-matched standards derived from healthy children, published in the atlas.,, Our patient at presentation had a bone age of 6 years, which was delayed by 2 years from the chronological age. Thyroxine is needed for the secretion and action of growth hormone. It acts directly on the growth plate and promotes differentiation of chondrocytes to hypertrophic chondrocytes, which is required for the growth of long bones. Deficiency states as seen in primary hypothyroidism lead to growth failure and a delayed bone age, as was seen in the index patient.
Thyroid replacement therapy in VWGS leads to complete resolution of all the symptoms along with complete regression of ovarian cyst and pituitary hyperplasia, as was seen in our patient, without any need of surgical management.
| Conclusion|| |
Juvenile severe long-standing primary hypothyroidism can present with precocious puberty along with the presence of pituitary hyperplasia and ovarian cysts. Knowledge of uncommon presentation of this common disorder is essential as with therapy there is complete resolution of all the signs and symptoms. Management of precocious puberty in a protocol-based algorithm not only helps in early diagnosis and management but also prevents any invasive surgical interventions for associated ovarian cystic lesions and pituitary hyperplasia.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]