Resistance to thyroid hormone alpha (RTHα) due to a de novo THRA p.Asp268Asn variant: Early levothyroxine treatment and outcome

INTRODUCTION

Since the first reported case in 2012, resistance to thyroid hormone alpha (RTHα) has remained a rare diagnosis with only 41 cases described in the literature as of 2024.^[1] In contrast to resistance to thyroid hormone beta (RTHβ), which typically demonstrates a characteristic dissociation pattern between elevated serum thyroid hormone (TH) levels and inappropriately normal or raised thyroid-stimulating hormone (TSH), RTHα often presents with only marginally low or normal free thyroxine (FT4) and normal TSH levels. Its rarity, subtle biochemical abnormalities, limited clinician awareness, and variable symptom severity all contribute to under-recognition.

Here, we present a case of a 12-year-old boy with a heterozygous missense thyroid hormone receptor alpha (THRA) variant (c.802G>A, p.Asp268Asn) who received levothyroxine since the age of 14 months, representing only the second reported case of this variation. The first case was described by Yalçın et al. in a patient who also harbored a coexisting chromodomain helicase DNA-binding (CHD3) gene variation.^[2]

CASE REPORT

A 12-year 4-month-old boy, born to non-consanguineous healthy Chinese parents, was the second child in the family. He was delivered at full term with a birth weight of 3.55 kg. The newborn examination was unremarkable apart from a small umbilical hernia. Cord blood TSH screening was normal.

He was first noted to have pallor at 10 months of age during a routine health assessment. Subsequent blood testing revealed normocytic normochromic anemia, with borderline iron deficiency. His anemia did not resolve despite correction of iron deficiency. At 13 months, additional features became apparent, including persistent pallor, yellowish skin tone, coarsening of facial features, flat nasal bridge, hypertelorism, macroglossia, macrocephaly, and a wide anterior fontanelle. His fingers and toes appeared short and stubby with hyper-flexibility at the right first metacarpophalangeal joint. There was lumbar kyphosis and generalized hypotonia but no bradycardia. Gross motor delay was evident, as he was unable to stand with support or cruise at 13 months.

A skeletal survey demonstrated features suggestive of hypothyroidism or mucopolysaccharidosis (MPS), including a J-shaped sella, obtuse mandibular angle, thickened short long bones, and inferior beaking of the upper lumbar vertebrae. Wormian bones along the lambdoid sutures raised a greater suspicion of hypothyroidism. Thyroid function revealed a borderline low FT4 with an inappropriately normal TSH, while FT3 was within the reference range. Concomitant investigations revealed mildly elevated creatine kinase (CK) levels, with no hepatosplenomegaly on abdominal ultrasound, normal urinary glycosaminoglycans and oligosaccharides, and normal lysosomal enzymes, excluding MPS or lysosomal storage disease. He was therefore treated as central hypothyroidism and commenced on levothyroxine from 14 months of age. Baseline morning spot cortisol, adrenocorticotropic hormone, insulin-like growth factor-1 (IGF-1), and prolactin were within reference range. Magnetic resonance imaging of the pituitary was normal.

Following levothyroxine replacement, his parents observed improved motor strength and activity and catch-up of gross motor development. He cruised at 15 months, walked independently at 16 months, and was able to ascend and descend stairs using two feet per step by 18 months. Coarsening of facial features and umbilical hernia resolved, macroglossia improved, although lumbar kyphosis persisted.

At the age of 2 years, his expressive language remained markedly delayed. He used no meaningful words and could not identify body parts. Developmental assessment at 2 years and 8 months estimated his developmental age at 1 year and 9 months. He attended regular physiotherapy, occupational therapy, and speech therapy, with subsequent developmental improvement. Despite mild learning and handwriting difficulties as well as slow speech, he was able to attend mainstream schooling with average academic performance.

Over the years, he demonstrated delayed dental eruption and exfoliation of primary teeth, mild postural imbalance, and intermittent constipation, particularly when occasionally FT4 values were at the lower end of the normal range. He remained on levothyroxine since infancy, with occasional compliance lapses. His TSH levels had been consistently suppressed while FT4 was maintained mostly within the upper half of the reference intervals. Although no pre-treatment lipid profile was available, his low-density lipoprotein (LDL) cholesterol remained elevated at 4.0–4.4 mmol/L despite levothyroxine treatment. His pretreatment and latest biochemical profiles are listed in Table 1. Selected longitudinal thyroid function tests and weight-based levothyroxine doses from early childhood to 12 years are summarized in Table 2.

At 5 years of age, he was referred to clinical genetics, where a congenital hypothyroidism gene panel identified a THRA heterozygous missense variant c.802G>A p.Asp268Asn, initially classified as a variant of uncertain significance and later reinterpreted as likely pathogenic. Both parents tested negative for the variant.

At his latest review, at the age of 12 years 4 months, he was on levothyroxine 75 µg daily. His height tracked at the 50^th centile until 5 years old, followed by a gradual decline to the second centile by 12 years. His weight tracked between 75^th and 91^st centile throughout follow-up. He had entered early puberty with a testicular volume of 6 mL and Tanner genital stage 2.

DISCUSSION

TH receptors are encoded by two distinct genes, THRA and THRB, each undergoing alternative splicing to produce receptor isoforms (TRα1, TRβ1, and TRβ2) with tissue-specific expression patterns. TRα1 is predominantly expressed in bone, the gastrointestinal tract, cardiac and skeletal muscles, and the central nervous system. TRβ1 is most abundant in the liver and kidneys, whereas TRβ2 is mainly localized to the hypothalamus, pituitary, cochlea, and retina. THRA variants attenuate the functional response of TRα to TH, leading to selective hormone resistance in TRα-dominant organs. However, tissues that predominantly express TRβ, such as the hypothalamus and the pituitary, remain sensitive to TH. As a result, the hypothalamic– pituitary–thyroid feedback axis is preserved, with a thyroid function profile of normal or mildly reduced FT4 and inappropriately normal TSH.

Given the thyroid function pattern, it is common for patients with RTHα to be treated as central hypothyroidism before the definitive diagnosis becomes apparent.^[2-4] Clinicians should maintain a high index of suspicion when the severity of clinical hypothyroid features appears disproportionate to the degree of FT4 reduction. In such circumstances, measurement of FT3 can provide an important diagnostic clue, as a normal and occasionally elevated FT3 level in this context should prompt consideration of THRA mutation testing.

Diagnostic recognition of RTHα can be further complicated by the fact that a substantial proportion of patients displays entirely normal thyroid function profiles. In a 2020 review summarizing all reported cases of THRA variants,^[5] up to 61% of children had both FT4 and TSH levels within the reference range before treatment, although all FT4 values clustered in the lower half of normal. Awareness of this rare disorder is therefore crucial. Furthermore, cases are easily overlooked when thyroid screening relies solely on TSH measurement, as nearly all patients demonstrate normal TSH values despite clinical evidence of hypothyroidism,^[5]and RTHα cannot be detected when newborn screening programs use TSH-only protocols.

Identifying RTHα correctly is important, as appropriate treatment can lead to meaningful clinical improvement. In our patient, levothyroxine supplementation was associated with noticeable benefits, including enhanced energy level, increased motor strength, and striking progress in gross motor development shortly after initiation of therapy.

A similar pattern of rapid motor improvement after treatment has been observed in another case started on levothyroxine at a comparable age.^[4] Furthermore, our patient was able to attend mainstream schooling with average academic performance and demonstrated resolution of coarsened facial features and normalization of serum CK levels following hormone replacement. Although the levothyroxine doses used were not particularly high on a µg/kg basis compared with some reports of RTHα, they were sufficient to maintain FT4 mostly within the upper half of the reference interval, with lower values occurring mostly during periods of non-compliance. Even though his height centile gradually declined and weight tracked along a higher centile, his overall outcome of preserved mainstream schooling, absence of major neurocognitive impairment, and partial catch-up of motor milestones would still fall toward the milder clinical end.

Disease severity and treatment response among patients with RTHα are not uniform. A degree of genotype-phenotype correlation has been observed, with missense variants generally associated with a milder spectrum of disease.^[6] Differences in therapeutic response may also relate to the functional characteristics of the underlying mutant TRα protein.^[3] Most THRA variants reported in RTHα cluster within the ligand-binding domain of TRα1, including the variant in this case,^[2] a region critical for T3 binding and the switch from corepressor to co-activator complexes at TH response elements. Biochemical and structural studies indicate that such mutants often show reduced T3 affinity and impaired co-activator recruitment, and exert a dominant-negative effect on wild-type receptors at shared response elements, thereby amplifying tissue hypothyroidism despite heterozygosity.^[6-8] Across the literature, symptoms related to energy level and alertness,^[4,9,10] and constipation^[3,7-10] have shown fairly consistent improvement with levothyroxine supplementation, whereas anemia often persists despite treatment.^[3,4,8,9] Responses regarding growth and neurocognitive function are more variable, likely influenced by additional factors beyond the specific THRA variation, such as age of therapy initiation. Nonetheless, our case illustrates that patients with RTHα can potentially benefit from levothyroxine therapy, especially when commenced at a young age, concurring with observations in other reported cases.^[3,4]

Careful monitoring for potential adverse effects related to overactivation of TRβ-mediated pathways is warranted. One study reported alterations in bone turnover markers during levothyroxine therapy, raising concern about reduced bone mineral density.^[9] Additional studies are needed to define the optimal dosing strategy, establish reliable biomarkers of treatment response, and determine therapeutic targets. Several indicators of biochemical response have been proposed, including serum LDL, CK, IGF-1, and sex hormone-binding globulin.^[7]

CONCLUSION

This case illustrates the diagnostic challenge of RTHα, which may present with subtle biochemical changes despite significant clinical features. Children with disproportionate hypothyroid manifestations and only marginal reduction in FT4 should prompt testing of FT3 and consideration of RTHα. Our findings support that patients with RTHα due to THRA variation, especially when diagnosed at a young age, can experience meaningful clinical improvement with levothyroxine therapy.