Delayed Diagnosis of Ectopic Thyroid Due to Ignored Borderline Result of Newborn Screening for Congenital Hypothyroidism

Introduction

Ectopic thyroid is a relatively rare condition that arises during embryogenesis when thyroid tissue fails to properly migrate to the paratracheal region [1]. Thyroid tissue migration occurs around the seventh week of fetal development, requiring appropriate molecular and cellular interactions [1]. The most common form of ectopic thyroid is lingual thyroid, in which thyroid tissue is located at the base of the tongue [2]. The incidence of lingual thyroid is 1 in 100 000 to 300 000 [3]. The transcription factor genes NKX2-1, FOXE1, and PAX-8 are essential for thyroid development and differentiation; mutations in these genes may lead to abnormal thyroid migration [4]. Individuals with lingual thyroid can present with a broad range of symptoms [5]. For example, a 5-year-old girl displayed progressive dysphagia to solid foods [5]; a 29-year-old woman presented with fatigue and depression of 3 months’ duration [6]; and a 70-year-old woman experienced a muffled voice, throat fullness, and intermittent shortness of breath [7]. Management of lingual thyroid depends on symptom severity and thyroid function. Conservative treatment with levothyroxine constitutes first-line therapy for hypothyroid or mildly symptomatic patients, aiming to restore euthyroidism, suppress thyroid-stimulating hormone (TSH), reduce gland size, and relieve symptoms [8]. Surgical intervention is reserved for severe obstruction, bleeding, dysphagia, airway compromise, or cases in which conservative therapy fails [9].

Newborn screening (NBS) is an important public health intervention that detects congenital conditions such as congenital hypothyroidism (CH), allowing early treatment to prevent neurodevelopmental deficits [10–12]. In some countries, including the Kingdom of Saudi Arabia, NBS for CH is performed via measurement of TSH and free thyroxine (fT4) in cord blood at birth [12]. Nonetheless, borderline or mildly elevated TSH values may be difficult to interpret – they may reflect transient hypothyroidism, thyroid dysgenesis, or the development of permanent CH [13]. TSH levels may also be influenced by prematurity, illness, or iodine exposure [13]. For these reasons, follow-up testing is critical to determine whether hypothyroidism is transient or permanent, given that these conditions require different management strategies [14,15].

In this report, we describe a girl who displayed a borderline NBS result for CH, was diagnosed with lingual thyroid–related CH at age 8, and has been followed to age 15. This case demonstrates that ectopic thyroid may present with borderline TSH levels on NBS and underscores the importance of oropharyngeal and neck examination during the neonatal period to identify the thyroid gland, followed by ongoing monitoring to detect underlying abnormalities.

Case Report

PATIENT INFORMATION:

A girl, now 15 years old, was first referred to the pediatric endocrine clinic for evaluation at age 8. She reported constipation and cold intolerance since age 5, and by school age she developed poor concentration that impaired her academic performance. She had no muscle weakness, hair loss, dry skin, neck pain, goiter, difficulty swallowing, tremors, palpitations, excessive sweating, anxiety, diarrhea, increased appetite, or eye bulging. She had been born at term after an uneventful pregnancy with regular antenatal follow-up. Her mother had no thyroid abnormalities, took no medications, and used a regular iodine supplement. The patient had no prolonged jaundice and did not require neonatal unit admission. There was a family history of hypothyroidism and hypercholesterolemia. At age 8, clinical assessment was consistent with hypothyroidism.

CLINICAL FINDINGS:

During the initial presentation at age 8, the patient was oriented, cooperative, and in no apparent distress. Her height and weight were appropriate for age, without signs of growth retardation. Skin was warm and of normal texture, without dryness or thickening. Hair was normal in distribution and texture, with no alopecia. There was no facial puffiness, periorbital edema, or macroglossia. No thyroid gland was palpable in the neck; a red, well-vascularized, mass measuring 3×5 cm, which moved with swallowing, was observed at the base of the tongue (Figure 1).

DIAGNOSTIC ASSESSMENT:

Upon initial presentation at age 8, laboratory evaluation confirmed subclinical hypothyroidism, with a TSH level of 13.87 mIU/L (reference: 0.35–4.94 mIU/L) and an fT4 level of 8.43 pmol/L (reference: 9.00–19.00 pmol/L). Her thyroid peroxidase antibody level was below 1.00 IU/mL (reference: <5.6 IU/mL), and thyroglobulin antibody level was below 5.00 IU/mL (reference: <4 IU/mL). She exhibited dyslipidemia, with an elevated low-density lipoprotein level of 3.86 mmol/L (optimal: 2.84 mmol/L) and a total cholesterol level of 5.86 mmol/L (desirable: <4.40 mmol/L).

A review of her neonatal records showed that NBS for CH, performed using a cord blood sample, had revealed a TSH level of 43.647 mIU/L, within the borderline range of 30–60 mIU/L according to Saudi NBS criteria (TSH <30 mIU/L is considered normal; >60 mIU/L is abnormal). Her fT4 at that time was 13.7 pmol/L (reference: 9–22 pmol/L). Despite the borderline TSH level, she was discharged without further follow-up.

Because a mass was present in conjunction with the laboratory abnormalities at age 8, thyroid scintigraphy was performed. The scintigraphy demonstrated radiotracer uptake at the base of the tongue; no thyroid tissue was identified in the usual cervical location, confirming a diagnosis of lingual thyroid (Figure 2).

Intelligence quotient testing revealed a score of 90 points, and all domains were within normal limits: fluid reasoning 40%, quantitative reasoning 34%, visual-spatial 30%, and working memory 50%. Knowledge was borderline delayed with a score of 5%. This intelligence quotient score corresponded to a mild level of impairment.

At age 15, follow-up laboratory monitoring of TSH levels, fT4 levels, and lipid profile was performed as part of ongoing endocrine and metabolic evaluation.

DIFFERENTIAL DIAGNOSIS:

The patient’s progressive TSH elevation with normal fT4 and symptoms of hypothyroidism placed her within the subclinical hypothyroidism category. Exclusion of several potential diagnoses was necessary to establish the final diagnosis.

Based on these findings, autoimmune thyroiditis, a common cause of hypothyroidism in children, was unlikely – the patient had no goiter and both thyroid peroxidase and thyroglobulin antibodies were absent. Thyroid hormone resistance, a rare genetic disorder characterized by decreased tissue sensitivity to thyroid hormones and associated with elevated levels of TSH, triiodothyronine (T3), and T4, was excluded because the patient’s fT4 level remained normal. Iodine deficiency was also unlikely, given that insufficient iodine intake is rare in the patient’s region, and there were no signs of inadequate dietary intake. Central hypothyroidism due to pituitary or hypothalamic dysfunction was considered; however, this diagnosis was ruled out because it typically presents with low or inappropriately normal TSH and low fT4, inconsistent with our patient’s results.

Thyroid agenesis was another possible diagnosis, but it was considered unlikely given the normal TSH and fT4 levels until age 8. Agenesis was further excluded clinically and radiologically by the identification of ectopic thyroid tissue. Dyshormonogenesis was also considered; however, it was deemed less likely because the patient had normal TSH levels for 5 years and no family history of CH or goiter, both of which are commonly associated with this condition.

The presence of a lingual mass and absence of a thyroid gland in the usual cervical location suggested thyroid dysgenesis, including aplasia, hypoplasia, or ectopic thyroid tissue. An isotope thyroid scan demonstrated uptake at the base of the tongue without uptake in the neck, establishing the diagnosis of lingual thyroid with CH, which explained the laboratory findings and clinical symptoms.

THERAPEUTIC INTERVENTION:

Levothyroxine therapy was initiated at age 8 at a starting dose of 25 μg/day, which was gradually increased to 100 μg/day (25 μg until month 8, then 50 μg until year 2, then 75 μg until year 4, and 100 μg thereafter). As the patient adhered to her medication regimen, her symptoms improved and her TSH level normalized.

FOLLOW-UP AND OUTCOMES:

With continuous treatment, the child showed improvement in her symptoms and TSH levels. However, inconsistent adherence to the prescribed medication regimen – she admitted to missing some doses – led to fluctuations in TSH levels (Figure 3). At age 15, laboratory monitoring of TSH, fT4, and lipid profile continued as part of routine follow-up. Despite hormonal replacement, dyslipidemia persisted, likely due to the patient’s family history of hypercholesterolemia and her lifestyle. Comprehensive dietary counseling, behavior modification, and lipid-regulating therapy were initiated. Regular follow-up visits were scheduled to monitor thyroid function, lipid levels, and overall well-being.

Discussion

Borderline TSH levels on NBS can contribute to missed diagnoses of ectopic thyroid. Accordingly, close clinical follow-up and thorough oral cavity and neck examinations during the neonatal period are essential to identify the thyroid gland, with continued oral cavity assessment to detect underlying abnormalities.

In Saudi Arabia, a cord TSH value above 60 mIU/L in NBS for CH may signify hypothyroidism, whereas a value below 30 mIU/L is considered normal. However, some countries use a lower threshold of below 20 mIU/L to exclude CH [12]. Borderline TSH levels between 30 and 60 mIU/L require venous fT4 measurement for final interpretation [12]. Although an fT4 level below 9 pmol/L strongly indicates hypothyroidism, higher values suggest that thyroid dysfunction is less likely [16]. In the present case, NBS showed a borderline TSH level of 43.647 mIU/L and normal fT4 level of 13.7 pmol/L. Nevertheless, the patient was discharged without follow-up or neck and oropharyngeal examinations; she later presented with lingual thyroid and hypothyroidism. Before exclusion of CH, recently published Clinical Pediatric Endocrinology guidelines recommend performing a confirmatory test to measure serum TSH and T4 if the TSH level is high and fT4 level is normal according to NBS [15].

The age at diagnosis and clinical presentation of ectopic thyroid vary depending on the gland’s compensatory capacity [17]. Ectopic thyroid can be diagnosed at any age, from birth to 80 years [7]. Differences in compensatory ability among patients lead to a broad range of clinical manifestations [18]. Most patients have a normally functioning thyroid and present with asymptomatic ectopic tissue discovered incidentally on imaging or screening [3]. Some patients develop symptoms of hypothyroidism due to reduced hormone synthesis, as observed in the present case [18,19]. Others have mass effect symptoms, including foreign body sensation, dysphagia, and airway obstruction [18].

Reported cases include a 29-year-old woman with fatigue and depression of 3 months’ duration [6] and a 70-year-old woman with a muffled voice, throat fullness, and intermittent shortness of breath [7]. Another case involved a school-aged girl with substantial tongue-base enlargement that caused clinically significant dysphagia and poor oral intake, such that she sometimes only drank water (without eating) for many days [19]. In contrast, our patient’s lingual thyroid maintained sufficient function until late childhood, with only mild symptoms (e.g., constipation, cold intolerance, and concentration difficulties) and without local obstructive features – likely due to the small size of the ectopic gland. Nevertheless, she had an intelligence quotient score of 90, which falls within the mild impairment range. Her height was also within the normal range for Saudi girls and consistent with her mid-parental height centile, supporting the ability of the lingual thyroid to compensate during early life.

Thyroid scintigraphy uses technetium-99m or iodine-123 and aims to depict the functional activity and distribution of thyroid tissue. It is considered the gold standard modality for detecting ectopic thyroid [5,20]. In the present case, scintigraphy was useful in ruling out the presence of thyroid tissue in the expected paratracheal region and identifying a “hot spot” of radiotracer uptake at the base of the tongue, consistent with lingual thyroid [5]. Other imaging modalities, such as ultrasound and computed tomography, can delineate the size, shape, and position of ectopic thyroid tissue; however, they do not provide the functional information afforded by scintigraphy [20].

The management of ectopic thyroid depends on thyroid function and clinical features [5,20]. Asymptomatic individuals with preserved thyroid function (normal TSH and fT4) should be treated conservatively and monitored via regular follow-up [5,20]. Individuals with hypothyroidism, such as our patient, require thyroid hormone replacement therapy [5]. Levothyroxine is the drug of choice because it restores euthyroidism, suppresses TSH stimulation, and inhibits the growth of ectopic thyroid tissue [5,6,20]. Additionally, levothyroxine helps relieve symptoms related to gland enlargement, such as airway obstruction [5,6]. Our patient received levothyroxine, which improved her symptoms and normalized her TSH levels. Nonetheless, symptoms recurred and TSH levels rose due to variable medication adherence (Figure 3). This recurrence highlighted the need for education regarding the consequences of poor medication adherence in adolescent patients [21]. Some cases of lingual thyroid have required surgical management [6]. This intervention is reserved for specific situations, including respiratory difficulty, recurrent bleeding, or suspected malignancy [6]. However, the risk of malignancy in ectopic thyroid tissue is low, with reported rates of 1% to 3% [5,6].

Hyperlipidemia is a known consequence of untreated hypothyroidism [6]. Hypothyroidism decreases hepatic lipase activity and low-density lipoprotein receptor function, thereby impairing lipid clearance [6]. In our patient, dyslipidemia persisted despite adequate thyroid hormone replacement, possibly due to her family history of hypercholesterolemia and an unhealthy diet and lifestyle. To reduce cardiovascular risk, lifestyle modification was initiated and lipid-lowering agents were discussed.

Conclusions

This case emphasizes that borderline NBS results can lead to delayed diagnosis of CH; therefore, a thorough oropharyngeal and neck examination is necessary to confirm the location of the thyroid gland. Additionally, CH should be considered in the differential diagnosis of patients who present with thyroid-related symptoms, particularly those with a history of borderline NBS results. Early identification of ectopic thyroid tissue, such as lingual thyroid, allows clinicians to anticipate thyroid compensation failure and intervene early to minimize complications and improve outcomes.