Residual Thyroid Tissue After Thyroidectomy in a Patient With TSH Receptor-Activating Mutation Presenting as a Neck Mass


Nonautoimmune neonatal thyrotoxicosis is a rare condition due to either familial or sporadic mutations in the TSH receptor (TSHR) (1). Recent reviews of the literature have cited 15 reported cases of de novo mutations (2, 3). Clinical and biochemical hyperthyroidism results from activating mutations in either the G protein or the TSHR-activating mutation (4). Treatment of infants with hyperthyroidism due to activating mutations is complex, involving rapid medical control of neonatal thyrotoxicosis followed by surgical intervention (total thyroidectomy) for removing the source of unregulated excessive thyroid hormone production. Initial treatment has been well described, but given the limited number of cases, the follow-up care of such patients and potential unexpected complications have not been well documented. We have previously described this case of neonatal nonautoimmune thyrotoxicosis due to de novo germline mutation Ile568Thr in exon 10 of TSHR (5). In this report, we present the clinical, biochemical, and imaging findings during long-term follow-up of this patient who presented with a clinically palpable neck mass after initial total thyroidectomy, consistent with autonomous enlarging residual thyroid tissue within the thyroglossal duct remnant.

Clinical Case

The patient is a 6-year-old boy with TSHR-activating mutation; he was born at 35 weeks with a birth weight of 2557 g (third percentile), height of 50.1 cm (25th percentile), and head circumference of 33.8 cm (10th percentile). He was the firstborn son of a 35-year-old white woman and a 42-year-old man of Hispanic and white ethnicity, not related, and without family history of thyroid disease. At birth, he had meconium aspiration and was admitted to the neonatal intensive care. He was monitored for respiratory status but was also found to have hepatomegaly with elevated transaminases (alanine aminotransferase of 54–62 U/L, reference range, 2–45 U/L; aspartate aminotransferase of 133–160 U/L, reference range, 0–120 U/L) along with direct bilirubinemia of 4.9–5.6 mg/dL (reference range, 0.2–0.3 mg/dL). He was treated with ursodiol and phenobarbital.

At day 9 of life, he was found to have hyperthyroidism with a free T4 of 5.26 ng/dL (reference range, 0.9–2.6 ng/dL) and TSH suppressed at 0.12 mIU/L (reference range, 0.35–5.5 mIU/L). Monitoring of thyroid function tests established persistent hyperthyroidism, and on day 44 of life, he had jitteriness, disturbed sleep, poor weight gain—now at 3660 g (third percentile)—and length of 54 cm (5th–10th percentile). Clinical examination showed fusion of posterior fontanelle and decreased anterior fontanelle (size, 1 × 1 cm) consistent with accelerated bone maturation. Laboratory tests revealed free T4 of 6.9 ng/dL and TSH < 0.01 mIU/L. Technetium pertechnetate (99m-TcO4) images were obtained showing normal thyroid configuration with intense homogenous distribution of radionuclide throughout bilateral thyroid lobes (Figure 1). He was started on Lugol’s solution, propanolol, and propylthiouracil.

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DNA analysis from peripheral blood was obtained from the patient and his parents. As previously described, the patient’s DNA revealed a de novo heterozygous point mutation (Ile568Thr) in exon 10 of TSHR resulting from a T to C substitution (5). To enable definite treatment for the hyperthyroidism, a total thyroidectomy was performed at 2 years, resulting in iatrogenic hypothyroidism and hypoparathyroidism. Surgical pathology showed a right lobe of 4.0 × 2.0 × 0.8 cm, left lobe of 3.5 × 2.0 × 0.8 cm, and isthmus of 2.0 × 0.5 × 0.3 cm (total thyroid volume, 6 cm3). Following the surgery, he was treated with levothyroxine, remained euthyroid, and received adequate treatment with calcitriol and calcium supplementation. Resolution of thyrotoxicosis resulted in normalization of liver function tests.

Postoperative otolaryngology evaluation with flexible fiberoptic laryngoscopy revealed paralysis of the left true vocal cord, which was well compensated by the right true vocal cord. Subsequent clinical evaluation after total thyroidectomy documented normal growth and development; the only intervening clinical events were frequent ear infections. Approximately 1 year after total thyroidectomy, the patient underwent bilateral tympanostomy tube placement. At the time of tube placement in the right ear, profuse bleeding was reported, and dehiscence of the jugular bulb was diagnosed (Figure 2). The patient had no external malformation of the auricles or external auditory canals. Subsequently, the right tube extruded, and the right tympanic membrane developed retraction without middle ear effusion.

The patient was followed with twice-yearly examinations in the Pediatric Otolaryngology Clinic without evidence of neck mass until 6 |${}^{4}!!diagup!!{}_{12};$| years of age, at which time neck examination revealed a mobile, well-circumscribed, nontender superficial midline neck mass approximately 1 centimeter in size (Figure 3A). Neck ultrasound demonstrated a 1.4 × 0.9 × 0.6-centimeter homogeneously hyperechoic solid mass with significant internal vascularity. No cystic components were identified within the midline neck mass; in addition, no thyroid tissue was sonographically visible in the thyroid bed. Further evaluation with 123-I thyroid scan (Figure 3, B and C) revealed two foci of activity in the neck: a superior focus of activity corresponded to the clinically palpable anterior neck nodule measuring 0.5 × 0.8 cm, consistent with ectopic functional thyroid tissue in the thyroglossal duct remnant; the second focus depicted residual functional thyroid tissue in the left tracheoesophageal groove (left thyroid bed remnant). At the time of these studies, the patient remained on levothyroxine 50 μg daily and was euthyroid with a free T4 of 0.99 ng/dL (reference range, 0.76–1.7 ng/dL) and TSH of 1.00 mIU/L (reference range, 0.3–5.5 mIU/L).

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Treatment options including surgical excision vs radionuclide ablation or observation were discussed. Given the patient’s young age and likelihood of increased nodule growth due to constitutive TSHR-activating mutation resulting in persistent TSH stimulation, and with the intention of minimizing whole body radiation exposure in childhood, surgical excision of the nodule was considered the best treatment approach. Although the risk of papillary thyroid carcinoma was small, surgery had the added advantage of obtaining a definitive tissue diagnosis. Therapeutic surgical resection of this subcutaneous midline neck nodule was performed at the time of elective adenotonsillectomy for treatment of obstructive sleep apnea related to adenotonsillar hypertrophy.

At the time of surgery, a soft, superficial, mobile mass was encountered, with a gross appearance consistent with thyroid tissue. There was no evidence of a tract or connection to the hyoid bone. A simple excision was performed; a Sistrunk procedure (resection of midportion of hyoid) was not deemed necessary. Pathological analysis revealed benign thyroid tissue (Figure 4). The tissue in the left tracheoesophageal groove was not removed, given the very small amount of tissue involved and the increased surgical risks, including injury to the recurrent laryngeal nerves, esophageal perforation, and airway edema.


This report highlights the unexpected clinical course during long-term follow-up after thyroid resection for an unusual case of nonautoimmune neonatal thyrotoxicosis due to a sporadic activating TSHR mutation. This case study demonstrates that any residual thyroid tissue remaining after total thyroidectomy may continue to enlarge due to the intrinsic TSHR-activating mutation conferring autonomy independent of TSH stimulation. In this case, 4 years after thyroid resection, an enlarging palpable subcutaneous nodule in the anterior neck was characterized on radioiodine anatomic-functional fusion imaging as ectopic thyroid tissue in the thyroglossal duct. This tissue clearly expresses NaI symporter, with trapping and organification of iodine as demonstrated on delayed 123-I images obtained at 24 hours after 123-I NaI ingestion, and it very likely maintains thyroid hormone production. Our patient remained euthyroid on a modest dose of thyroid hormone (L-T4, 50 μg daily), which supplemented his endogenous thyroid hormone production from residual functional thyroid tissue in the neck (the predicted full L-T4 replacement dose of 3–5 μg/kg/d for this patient body mass is 66–110 μg/d). Due to the superficial nature of the palpable neck mass, the patient was identified early during clinical follow-up, before significant enlargement of the mass and clinical hyperthyroidism developed. For this patient, continued clinical surveillance with active monitoring of thyroid function tests has been considered the best management strategy for addressing the presence of a small amount of residual functional tissue in the left thyroidectomy bed. If hyperthyroidism related to left thyroid bed remnant hypertrophy develops at any time in the future, then administration of 131-I for remnant ablation represents a simple, noninvasive, and effective therapeutic intervention.

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Since the initial report of germline mutations for TSHR (6), there have been 15 reported cases of sporadic germline TSHR mutations described in the literature (615), including the report on the initial presentation of the current patient (5). However, there is limited information regarding long-term follow-up in these cases. There has been one case report of recurrent hyperthyroidism after subtotal thyroidectomy (16) but no reports of recurrence after total thyroidectomy. Given the variety of mutations that have been identified, it is clear that even among activating TSHR mutations there may be variation in the degree of receptor activation, and it is important that the functional significance of the specific mutation be taken into account when evaluating treatment and follow-up options.

Thyroid hormone is essential for the normal development of the cochlea, and congenital hypothyroidism is a known cause of congenital deafness (17). Less is known about the effects of congenital hyperthyroidism on auditory development; studies of T4-injected rat pups have demonstrated earlier onset of hearing and accelerated development of the inner ear (18). It is interesting that our patient with neonatal thyrotoxicosis also had dehiscence of the right jugular bulb, an association that has not been previously described. In this condition, the bone that normally covers the jugular bulb is absent, and the vein is exposed, bulging into the middle ear space, where it may be injured during middle ear surgical procedures (19).

This case demonstrates that in the context of thyroidectomy, residual thyroid cells in the thyroglossal duct and in the thyroidectomy bed remain autonomously active and may hypertrophy due to the presence of activating TSHR mutation. Whereas new palpable cervical masses generally raise concerns for malignancy, in cases of TSHR activation, prompt functional imaging evaluation with radioiodine 123-I or 99m-TcO4 will establish the thyroidal origin of such tissue and help guide the clinical management.


Disclosure Summary: The authors have nothing to declare.





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About the Author: Tung Chi