Coexisting ADAR and TSHB Mutations in an Infant With Retinal Detachment and Transient Cardiomyopathy

Central congenital hypothyroidism (C-CH) due to thyroid-stimulating hormone beta (TSHB) variants is rare and often missed by thyroid-stimulating hormone (TSH)-based neonatal screening. Adenosine deaminase acting on RNA (ADAR)-related Aicardi-Goutières syndrome type 6 (AGS6) is an interferonopathy with early-onset encephalopathy.

A term small-for-gestational-age male infant of consanguineous parents presented at 3 months with failure to thrive, generalized edema, transient hyperinsulinemic hypoglycemia and biventricular hypertrophy on echocardiography. Biochemistry showed profoundly low free thyroxine (FT4) and free triiodothyronine with inappropriately low TSH, consistent with central hypothyroidism, together with hypoalbuminemia and elevated liver enzymes. L-thyroxine replacement and nutritional rehabilitation corrected hypoglycemia and were followed by complete normalization of cardiac structure and function on repeat echocardiography. Persistent global developmental delay, hypotonia and abnormal eye movements prompted neuro-ophthalmological assessment, which demonstrated bilaterally small globes with peripheral retinal/choroidal detachment. Whole-exome sequencing identified a homozygous pathogenic ADAR frameshift variant (NM_001111.5:c.2433_2434del) and a homozygous likely pathogenic TSHB variant (NM_000549.5:c.313T >C; p.Cys105Arg), confirming combined ADAR-related encephalopathy and isolated C-CH. At 8 months the child remained growth-restricted with marked developmental delay but stable cardiorespiratory status.

This case underscores the value of early genetic evaluation in infants with central hypothyroidism and syndromic features and of systematic cardiac surveillance in severe neonatal hypoglycemia to detect potentially reversible cardiomyopathy. To our knowledge, this is the first reported case of coexisting TSHB-related C-CH and ADAR-related AGS6 in the same infant.