Diagnostic challenges of Allan-Herndon-Dudley syndrome: a case of hypothyroidism and developmental delay

To the editor, Allan-Herndon-Dudley syndrome (AHDS, MIM#300523) is an X-linked recessive disorder by in SLC16A2 gene.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 (252.2ng/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 g/dL; peak, 39 g/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 g/ 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 (213.9ng/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 >