Delayed Presentation With Atypical Extrathyroidal Manifestations of Sporadic Non-autoimmune Congenital...

Sporadic non-autoimmune congenital hyperthyroidism (SNAH) is a rare form of persistent thyrotoxicosis caused by germline activating mutations in the thyroid-stimulating hormone (TSH) receptor (TSHR) gene, distinct from the more common autoimmune neonatal hyperthyroidism. SNAH typically presents early with variable severity but often lacks the overt autoimmune features, leading to diagnostic delays. Extrathyroidal manifestations remain underrecognized in the sporadic form. We report a case of SNAH from India in a 15-year-old male with a heterozygous activating mutation in exon 10 of the TSHR gene: p.Asp633Glu, caused by a de novo pathogenic nucleotide variant (c.1899C>G). To the best of our knowledge, this is the first documented case of SNAH from the Indian subcontinent. The patient initially presented at seven years of age with mild thyrotoxic features, dysmorphic facies (ocular telecanthus, flat nasal bridge), bilateral brachydactyly (short 3rd-5th metacarpals/metatarsals), and mitral valve prolapse. While some of such extra-thyroidal phenotypic features have been previously reported in familial non-autoimmune hyperthyroidism (FNAH), particularly those associated with TSHR mutation syndrome, they have not been described in any published case of sporadic non-autoimmune congenital hyperthyroidism, thereby expanding the phenotypic spectrum of SNAH. Despite initial biochemical control with carbimazole, the patient experienced disease progression requiring two radioiodine ablations. This case uniquely demonstrated delayed onset, persistently uncontrolled disease, delayed bone age despite thyrotoxicosis, and extra-thyroidal features as described above novel to SNAH. This report expands the phenotypic spectrum of SNAH, highlighting atypical extrathyroidal manifestations such as facial dysmorphism and skeletal abnormalities. The identified Asp633Glu mutation has previously been reported in toxic adenomas as well as in one case of SNAH; however, the pathologic variant (c.1899C>G) is newly documented in this case report. A comprehensive review of 19 published SNAH cases emphasizes the clinical heterogeneity and lack of consistent genotype-phenotype correlation. Our case reinforces the importance of early genetic testing in persistent, antibody-negative thyrotoxicosis and underscores the role of definitive therapy in severe or refractory disease. Additionally, while most reported cases of SNAH present in the neonatal period or early infancy, this case was notable for its delayed presentation at seven years of age, further contributing to its diagnostic uniqueness.  This is the first Indian case of genetically confirmed SNAH associated with the Asp633Glu TSHR mutation, presenting with previously undescribed extrathyroidal features (e.g., brachydactyly, ocular telecanthus, flat nasal bridge, mitral valve prolapse). The delayed clinical onset in this case, compared to the typically early presentation in SNAH, underscores the importance of considering this diagnosis even beyond infancy in cases of persistent thyrotoxicosis. Early recognition of atypical phenotypes and consideration of SNAH in differential diagnosis can prompt timely intervention, improving developmental and metabolic outcomes.