Allan-Herndon-Dudley syndrome associated with SLC16A2 c.1384G>A (p.Gly462Arg): A family case report with retrospective molecular diagnosis in a deceased sibling

RATIONALE: Allan-Herndon-Dudley syndrome (monocarboxylate transporter 8 deficiency) is an X-linked disorder caused by pathogenic variants in SLC16A2, with severe neurodevelopmental impairment and a characteristic high-triiodothyronine (T3)/low-thyroxine (T4) thyroid profile. SLC16A2 c.1384G> A (p.Gly462Arg; NM_006517.5) was reported previously. We describe a Chinese family with the same variant, including retrospective molecular confirmation in a deceased maternal half brother. PATIENT CONCERNS: The proband was evaluated at 4.3 years for profound developmental delay. He could not sit, stand, or walk independently and had an intelligence quotient of 36, axial hypotonia with peripheral hypertonia, dystonia, muscle atrophy, joint contractures, and bilateral cryptorchidism. DIAGNOSIS: Thyroid testing showed elevated free triiodothyronine and total triiodothyronine, decreased free thyroxine and total thyroxine, and mildly elevated thyroid-stimulating hormone. Brain magnetic resonance imaging showed delayed myelination, a thin corpus callosum, and widened frontal subarachnoid spaces. Whole-exome sequencing identified hemizygous SLC16A2 c.1384G> A (p.Gly462Arg); Sanger sequencing confirmed the variant in the proband and heterozygosity in his mother. The same hemizygous variant was detected in DNA from the archived neonatal dried blood spot of a maternal half brother who had severe developmental delay and died at 16 months. Thyroid tests, neuroimaging, and cause of death were not recorded for the deceased child. INTERVENTIONS: The proband received physical, occupational, and speech therapy and underwent bilateral orchiopexy. Triiodothyroacetic acid was not available at diagnosis. OUTCOMES: At the last documented follow-up at age 5 years, he remained unable to sit, stand, or walk independently. Clinical notes described improved head control, but no repeat standardized developmental score was available. Epileptiform electroencephalogram discharges persisted, but no clinical seizures were documented. LESSONS: This family provides additional clinical and segregation evidence for p.Gly462Arg. Testing an archived neonatal blood spot established the diagnosis in the deceased sibling and strengthened genetic counseling. SLC16A2 testing should be considered in boys with unexplained severe neurodevelopmental delay and a high-triiodothyronine/low-thyroxine pattern. Functional studies are still required to define the effect of p.Gly462Arg on monocarboxylate transporter 8 trafficking and thyroid hormone transport.