Allan-Herndon-Dudley syndrome (AHDS, MIM#300523) is an X-linked recessive disorder caused by mutations in SLC16A2 gene. This gene encodes monocarboxylate transporter 8 (MCT8), located at Xq13.2 [1].

We report a male infant initially misdiagnosed with central hypothyroidism and treated with levothyroxine, which yielded no improvement. He was subsequently confirmed to have AHDS through genetic testing.

A 5-month-old boy presented with failure to thrive and neurodevelopmental delay including hypotonia. Despite being large for gestational age at birth (39⁺⁵ weeks, 4.46 kg, 98.1 percentile) and having an unremarkable perinatal history, he was significantly underweight (<3 percentile, 6 kg) with normal head circumference (42.6 cm, 50 percentile). Initial thyroid hormone profile revealed mild elevation in T3 (252.2 ng/mL; normal - <1 yr: 85–250), along with normal free thyroxine (free T4) (1.2 ng/dL) and thyroid-stimulating hormone (TSH, 2.46 mIU/L) (Table 1). At 10 months of age, he exhibited microcephaly (3 percentile, 43 cm), and showed spasticity and dystonia. Brain magnetic resonance imaging (MRI) results indicated cortical atrophy without demyelination. Neck ultrasound indicated no abnormalities, including the thyroid gland. Repeated thyroid hormone tests (TSH, 2.97 mIU/L; free T4, 0.64 ng/dL; T3 level was not measured) led to a diagnosis of central hypothyroidism. After confirming normal adrenal function by adrenocorticotropic hormone (ACTH) stimulation test (basal ACTH, 28.79 pg/ mL; cortisol basal, 9.34 μg/dL; peak, 39 μg/dL), levothyroxine treatment was initiated. After 2 months of treatment, the patient’s free T4 level normalized (1.12 ng/dL), and the T3 level increased (336.6 ng/dL), but his body weight did not increase.

The patient was lost to follow up and revisited at 3 years old. He was unable to control his head or say meaningful words. Primitive reflexes such as asymmetrical tonic neck reflex and Galant reflex remained intact. Global developmental delay (GDD) was confirmed by Bayley test, with an average developmental level assessed at 3 months of age. Levothyroxine (4 μg/kg/day) was readministered due to severe developmental delay, growth failure (height, 0.3 percentile; weight, 0.2 percentile), and hypothyroxinemia (TSH, 2.96 mIU/L; free T4, 0.64 ng/dL).

Similar to the results of previous treatment, six months of therapy did not improve the patient's condition, and thyroid function tests revealed low free T4 (0.66 ng/dL) and elevated T3 (283 ng/mL). We performed chromosomal microarray analysis (CMA) for GDD, but no abnormalities were detected. At 4.5 years old, AHDS was confirmed through trio whole genome sequencing (WGS), which identified Xq13.2 microdeletions (2.86 KB) in SLC16A2 gene, as found in the mother. After genetic diagnosis, levothyroxine treatment was discontinued. The patient's recent thyroid profiles demonstrated an elevated free T3 (7.70 pg/mL) and FT3/FT4 ratio of 8.95 (normal range, 2.2–2.9; FT3 in pg/mL and FT4 in ng/dL), normalized T3 (213.9 ng/mL) and TSH level (3.33 mIU/L), although free T4 remained low (0.86 ng/dL).

Like other thyroid hormone resistance syndromes, AHDS can only be diagnosed through genetic testing. Elevated T3, along with normal to low TSH and free T4, and free T3/T4 ratio > 6.28 (FT3 in pg/mL and FT4 in ng/dL) or >0.75 (mmol/mmol), are characteristic features of thyroid hormone profiles in AHDS [2,3]. MCT8 is essential for cerebral uptake of triiodothyronine (T3), whereas it is not the primary transporter for peripheral tissues. The mutation in the SLC16A2 gene impedes the entry of T3 into the brain, resulting in elevated levels of circulating T3. Peripheral tissues, utilizing alternative transporters, are exposed to these high levels of T3, which may induce symptoms characteristic of hyperthyroidism. The decreased levels of thyroxine (T4) are likely attributable to accelerated conversion of T4 to T3 in glial cells, a compensatory mechanism in response to restricted T3 access to neurons [1].

These functional disparities result in a unique thyroid profile and clinical symptoms of AHDS patients. Therefore, treatment with synthetic thyroxine (levothyroxine) may intensify symptoms of peripheral hyperthyroidism such as poor weight gain, tachycardia, and irritability [4,5]. Most patients with AHDS present with severe GDD, but their brain MRI findings are heterogeneous from normal to permanent hypomyelination [6]. To date, treatments for AHDS mostly focus on supportive care. Levothyroxine treatment may worsen dysthyroidism. Clinical trials attempting to treat AHDS patients with the T3 analogue TRIAC have reported normalizing T3 levels and improving hyperthyroidism symptoms, but not alleviating neurological symptoms [7].

In this case, there were no abnormal findings on CMA, but WGS was performed due to hypothyroxinemia that did not respond to levothyroxine treatment and severe GDD. Generally, CMA is more cost-effective and requires less time to find copy number variants (CNVs) than WGS. WGS provides higher resolution than CMA (WGS: 1 bp vs. CMA: 50–100 kb), and can detect genetic abnormalities beyond CNVs. In our patient, we detected a microdeletion using WGS that was not found in CMA. Therefore, for patients with GDD and hypothyroidism who do not respond to levothyroxine administration, confirmation of thyroid profiles including T3, free T3, and free T4 and early genetic testing should be considered.

This study was approved by the Institutional Review Board (IRB 2024-02-010-001) of the Inha University Hospital. Informed consent was obtained from the parent for the preparation and publication of this case report.