Familial Congenital Hypothyroidism due to Compound Heterozygous Variants in the TPO Gene: Neonatal Diagnosis, Phenotypic Variability, and Lessons From Long‐Term Follow‐Up in Three Brothers

Dyshormonogenesis accounts for 15%–20% of permanent congenital hypothyroidism (CH), and pathogenic variants in the thyroid peroxidase (TPO) gene are its most frequent cause. We report three brothers, all diagnosed with severe CH in the neonatal period and referred to our Medical Genetics Unit in 2021 for molecular characterization and genetic counseling. Whole‐exome sequencing, followed by a targeted thyroid gene panel, identified the same compound heterozygous TPO genotype in all three: NM_000547.6:c.1297G > A, p.(Val433Met), inherited from the carrier mother, and NM_000547.6:c.1964G > C, p.(Cys655Ser), inherited from the carrier father, confirming autosomal recessive dyshormonogenetic CH. At neonatal diagnosis, initial TSH exceeded 100 mIU/L in all three brothers (reference range approximately 1–20 mIU/L beyond the first days of life (Wassner 2018 and Léger et al. 2014)). Despite this identical genetic cause and comparable neonatal severity, the three brothers (hereafter Patient 1, Patient 2, and Patient 3, the index case) went on to show markedly divergent clinical trajectories. Patient 1 was treated continuously from birth. Patient 2 was correctly identified neonatally through a proactive family thyroid screening, prompted by his elder brother’s pre‐existing diagnosis, but was then lost to adequate endocrine follow‐up: his levothyroxine dose stayed static and unadjusted for several years while his TSH remained persistently elevated. Patient 3, the index case, was diagnosed at Day 3 through Guthrie neonatal screening, and it was his diagnosis that prompted the family‐wide reassessment which ultimately confirmed the genotype in all three brothers. He additionally carries a heterozygous SLC26A4 variant of uncertain significance. Together, these three cases show that the prognosis of treated neonatal CH depends as much on the quality of postdiagnosis monitoring as on how quickly the initial diagnosis is made. They also make the case for systematic family thyroid screening once a sibling is known to carry dyshormonogenetic CH, and for the value molecular diagnosis adds to parental counseling and reproductive planning.