Advanced Bone Age Present in a Neonatal Case of Sporadic Non-Autoimmune Hyperthyroidism before Onset of Symptoms: A Case Report and Review of Literature

Case Report

J Pediatri Endocrinol. 2020; 5(2): 1037.

Advanced Bone Age Present in a Neonatal Case of Sporadic Non-Autoimmune Hyperthyroidism before Onset of Symptoms: A Case Report and Review of Literature

Alexandra Stephenson1, Zoya Punjwani2, Markus Eszlinger3, Sana Ghaznavi4, Pawel Matusik5, Aneta Gawlik5 and Ralf Paschke6*

1Department of Biochemistry and Molecular Biology & Arnie Charbonneau Cancer Institute, University of Calgary, Canada

2Department of Medical Sciences, University of Calgary, Canada

3Department of Oncology, University of Calgary, Canada

4Section of Endocrinology and Metabolism, Department of Medicine, University of Calgary, Canada

5Department of Pediatrics and Pediatric Endocrinology, Medical University of Silesia, Poland

6Departments of Medicine, Oncology, Pathology and Laboratory Medicine, and Biochemistry and Molecular Biology & Arnie Charbonneau Cancer Institute, University of Calgary, Canada

*Corresponding author: Ralf Paschke, Division of Endocrinology, Departments of Medicine, Biochemistry & Molecular Biology, and Oncology, and Arnie Charbonneau Cancer Institute, Heritage Medical Research Building, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Room 387, Canada

Received: September 03, 2020; Accepted: September 29, 2020; Published: October 06, 2020

Abstract

Familial and sporadic nonautoimmune hyperthyroidism are caused by TSHR mutations. 20 sporadic cases in children and 22 families with 25 well described children with have been described with nonautoimmune hyperthyroidism. 26 of these children presented with advanced bone age, indicative of untreated hyperthyroidism. We report a case of sporadic nonautoimmune hyperthyroidism for which the diagnosis of hyperthyroidism was established by chance prior to the onset of symptoms due to thyroxine treatment of the mother during pregnancy. Although the child was diagnosed based on suppressed TSH and increased free T3 and T4 at 4 months of age, an advanced bone age of 1.5 years was already present. There were no dysmorphic features present, her heart rate was in the upper normal range. She showed an enlarged thyroid as assessed by ultrasound. The thiamazole dose had to be increased repeatedly. At 13 months of age the patient had a further increase in thyroid gland volume and a further increase in bone age of 2.5 years. Using high resolution melting PCR followed by Sanger sequencing of peripheral blood DNA, a heterozygous Thyroid Stimulating Hormone Receptor (TSHR) c.1895C >T mutation, resulting in a T632I amino acid change was detected, it has previously been functionally characterized as constitutively activating. This case demonstrates that premature bone aging can be present even without the onset of hyperthyroidism symptoms. Detection of germline TSHR mutation is important to direct therapy as nonautoimmune hyperthyroidism does not generally respond well to antithyroid drug treatment and total thyroidectomy is necessary for these patients.

Keywords: Thyroid stimulating hormone receptor; Thyrotropin receptor

Introduction

Nonautoimmune Hyperthyroidism (NAH) can occur due to an inherited germline mutation (familial, FNAH) or a sporadic mutation (SNAH). To date, there are 20 cases of SNAH and 22 families with 25 well described children (<18 years of age) with FNAH [1]. In 15 reports (8 cases of SNAH and 7 cases of FNAH) with a documented range of time between onset of symptoms and treatment of 0 to 10 months, advanced bone age was present at 1.3-8.8 times the chronological age (Table 1). Untreated hyperthyroidism, indicated by advanced bone age, can lead to complications in children and neonates such as craniosynostosis, tachycardia, mental retardation [41]. We present a case of SNAH with premature bone aging present before the onset of hyperthyroidism symptoms.

Table 1: Summary of all 15 previous NAH cases and this case where advanced bone age was quantified and onset of symptoms was documented.



TABLECREATED







Table 1: Summary of all 15 previous NAH cases and this case where advanced bone age was quantified and onset of symptoms was documented.

Case Report/Case Presentation

The patient was a female born in the 37th week of gestation in Katowice, Poland. Birth weight was 2600g and birth length was 50cm. APGAR score was 8 points at the first minute, and 9 points after five minutes. The patient’s mother was diagnosed with transient gestational hypothyroidism at 19 weeks gestation and treated with levothyroxine during pregnancy. She had no symptoms of thyroid dysfunction, but was treated due to a TSH of >2.5 uIU/ml based on the standard procedure for pregnant women at the time.

Due to this, the neonate’s thyroid function was investigated at 2 and 4 months of age, and hyperthyroidism was diagnosed at 4 months based on suppressed TSH and increased free T3 and T4 (fT3 and fT4) (Table 2). The general pediatrician initially believed suppressed TSH to be laboratory bias as the patient did not show any signs of hyperthyroidism which delayed specialist referral.

Table 2: Patient measurements, notes on Bone Age (BA) and thyroid ultrasound measurements (USG) of Right Lobe (RL) and Left Lobe (LL).



TABLECREATED







Table 2: Patient measurements, notes on Bone Age (BA) and thyroid ultrasound measurements (USG) of Right Lobe (RL) and Left Lobe (LL).

After diagnosis, the patient was hospitalized to normalize thyroid hormone levels. Physical examination revealed no dysmorphic features and the resting heart rate was within the normal range, although it was borderline high (heart rate 140/min; normal range: 100-180 [42]). Anti-thyroid antibodies were negative both for anti-TPO and anti-TSH receptor. Thyroid ultrasound showed her thyroid to be enlarged, with heterogenous echogenicity, some areas of hypoechogenicity, increased vascular flow, and no presence of nodules (Figure 1). The thyroid volume was 3.38mL at 17 weeks (Table 2) as compared to the average size of 1.1mL for European newborns [43]. The volume of each lobe was calculated by the formula: V (ml)=0.479*d*w*l (cm). [44]. An X-ray of the patient’s hand and wrist revealed an advanced bone age of 1.5 years at a chronological age of 4 months, using Greulich and Pyle’s bone age assessment.

Figure 1: Ultrasound results for the patient on December 12, 2017 at 16 months of age with thyroid lobe measurements noted in the upper images. Lower images represent corresponding arterial vascularization for each thyroid lobe.

    

    
    

    

    Figure 1: Ultrasound results for the patient on December 12, 2017 at 16
months of age with thyroid lobe measurements noted in the upper images.
Lower images represent corresponding arterial vascularization for each
thyroid lobe.

The patient was treated with 5 mg/day of thiamazole and was discharged 3 weeks later with test results showing TSH <0.005 μIU/mL (N: 0.270-4.20 μIU/mL; Elecsys TSH assay by Cobas); fT4 –2.69 (N: 0.65-2.3Elecsys fT4 III assay by Cobas); fT3–6.74 (N: 2.15-5.83Elecsys fT3 III assay by Cobas).

After several dose increases with transient periods of normalization of thyroid function, the patient failed to go into remission with antithyroidal medications alone (Figure 2). Bone age was measured again at a chronological age of 1 year; at this time, the patient had a bone age of 2.5 years and exhibited a further increase in thyroid gland volume shown by ultrasound (Table 1). Bone age was measured twice more at 21 months and 25 months and continued to increase disproportionately to chronological age (Table 2). No clinical or biochemical adverse events were observed during the treatment period.

Figure 2: Patient thyroid hormone measurements and thiamazole dose following diagnosis and onset of treatment at 6 and 16 weeks of age respectively. Units of measurement are as follows: fT4 [ng/dl]; fT3 [pg/ml]; TSH [uIU/ml].

    

    
    

    

    Figure 2: Patient thyroid hormone measurements and thiamazole dose
following diagnosis and onset of treatment at 6 and 16 weeks of age
respectively. Units of measurement are as follows: fT4 [ng/dl]; fT3 [pg/ml];
TSH [uIU/ml].

Genomic DNA was extracted from EDTA blood samples obtained from the index patient (child) and her parents. High resolution melting PCR [45] followed by Sanger sequencing detected a c.1895C >T mutation leading to threonine being substituted by isoleucine (p.T632I) in the index patient but not in the parents; therefore, this mutation is categorized as a sporadic germline mutation.

During the course of her treatment, the patient remained within the normal range for weight, height and head circumference according to the Polish guidelines [46] (Table 1; (Supplementary Figures1-3); mid-parental height/target height for the patient is 169 cm, 75th percentile). As the patient’s psycho-physical development is normal thus far, the parents and treating physician agreed to delay total thyroidectomy and continue to discuss the patient’s parents’ concerns regarding anesthesia and post-operative complications. The primary physician continues to monitor the patient’s psychological, neurological and anthropometrical state and treat with antithyroid drugs.

Discussion/Conclusion

In this study, we describe the case of an asymptomatic neonate with biochemical hyperthyroidism where molecular analysis revealed a sporadic gain-of function TSHR mutation, p.T632I. This mutation has previously been described as a somatic mutation in hot thyroid nodules as well as in both a hot follicular thyroid carcinoma and a hot papillary thyroid carcinoma [45,47,49].

The same nucleotide substitution has been previously described in a case of SNAH with a severe phenotype [2]. However, at variance with the case described by Kopp et al. (1), here we describe a patient with the same TSHR mutation in whom hyperthyroidism was diagnosed without any symptoms. Very different clinical manifestations with regards to severity of symptoms and age of onset for hyperthyroidism have previously been described for the same TSHR germline mutations causing neonatal NAH [8,25,26].

This case is distinguished from all other cases of neonatal NAH by the documented presence of advanced bone age before onset of symptoms. In previously documented cases of neonatal NAH, patients presented with a spectrum of symptoms, the most common of which were tachycardia, restlessness, poor weight gain and diarrhea. Children with biochemical hyperthyroidism are nearly always frankly symptomatic, especially with adrenergic symptoms [50,51]. Had her mother not been treated with levothyroxine during her pregnancy, our asymptomatic patient would not have been evaluated for hyperthyroidism based on heart rate (within normal range) and lack of other symptoms of hyperthyroidism, despite her advanced bone age, which may have gone undetected.

Advanced bone age is thought to be characteristic of children with untreated hyperthyroidism. Advanced bone age is an important concern for children with hyperthyroidism as it impacts adult height and the effects of untreated SNAH hyperthyroidism are not reversible [52-54]. It is not known if the induction of advanced bone age or the induction of craniosynostosis is dependent on the duration of hyperthyroidism.

There are 26 published cases of children with NAH and advanced bone age in 10 families and 13 sporadic cases. Only 15 cases have quantified advanced bone age and documented time of symptoms prior to treatment (Table 2). The correlation coefficient of symptom duration before the start of antithyroid treatment and bone age/ chronological age, excluding patients untreated for >1 year, is 0.1135. Although these data are anecdotal, this suggests an absence of correlation between these variables shown in (Figure 3).

Figure 3: Linear regression analysis of bone age/chronological age and duration of symptoms of patients from Table 1 including present case (represented as a square) with correlation coefficient of 0.1135.

    

    
    

    

    Figure 3: Linear regression analysis of bone age/chronological age and
duration of symptoms of patients from Table 1 including present case
(represented as a square) with correlation coefficient of 0.1135.

Although there is considerable inter and intra-rater variability in bone age determination and different methods for the evaluation of bone age were used, these findings argue that neither the duration of symptoms prior to treatment nor the age at onset of symptoms, two factors which are likely to be the best possible indicators for the duration of untreated hyperthyroidism, explain the degree to which advanced bone age is present. These findings are in line with the finding of this case report with advanced bone age despite a presumed short duration of hyperthyroidism.

TSHR has been demonstrated to be expressed in both osteoblasts and osteoclasts, albeit with cAMP independent pathways [55]. While some studies have proposed that the effect of thyrotoxicosis on the bone is due to increased thyroid hormone rather than decreased TSH, the role of the TSHR in bone is still uncertain [56-58]. The degree of hyperthyroidism may be indicative of one aspect of TSHR signaling whereas the advanced bone age/bone phenotype could also be the result of an alternative pathway based on coupling of TSHR to all four G protein subfamilies [59], some of which are yet to be fully explored, particularly in bone.

NAH patients do not respond well to antithyroid drug treatment and remission of hyperthyroidism is rarely achieved. This was demonstrated early in our case as the patient needed several dose increases which resulted only in transient periods of normalization of thyroid function. For this reason, thyroidectomy is the treatment of choice for NAH [60]. Detection of a TSHR germline mutation and verification of the diagnosis of NAH provides a justification for early total thyroidectomy. Less complete surgeries are associated with frequent relapses [60].

In summary, we report a case of SNAH due to a previously characterized constitutively activating TSHR mutation. This case is unique in that NAH was detected prior to the onset of symptoms, yet bone age was already advanced. Our report demonstrates the importance of early detection and treatment of NAH as hyperthyroidism can impact bone development very early and even before the onset of symptoms.

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Citation: Stephenson A, Punjwani Z, Eszlinger M, Ghaznavi S, Matusik P, Gawlik A, et al. Advanced Bone Age Present in a Neonatal Case of Sporadic Non-Autoimmune Hyperthyroidism before Onset of Symptoms: A Case Report and Review of Literature. J Pediatri Endocrinol. 2020; 5(2): 1037.