Retrospective, multicentre evaluation of central congenital hypothyroidism in the UK

Objective: Central congenital hypothyroidism (incidence ∼1:13,000) occurs in isolation (40% cases) or with additional pituitary hormone deficiencies. T4±TSH-based neonatal screening detects central congenital hypothyroidism within the first two weeks of life, permitting prompt treatment, but the UK TSH-based screening programme will not detect these cases. We delineated clinical characteristics, time-frame and pathway to diagnosis in clinically-diagnosed individuals. Methods: Records were reviewed for 118 cases diagnosed from 1996-2022, in 4 tertiary centres. Results: Median age at diagnosis was 68 days (range 1-5056). 96% had combined pituitary hormone deficiencies. Non-specific neonatal concerns (hypoglycaemia/jaundice/weight concerns, 83%) and significant neurodevelopmental defects (34%) occurred frequently. Compared with cases diagnosed late (>1year, n=42), early diagnosis (≤14 days n=23) was associated with neonatal intensive care admission (78% vs 29%, p<0.001) and ACTH deficiency (96% vs 40% p<0.0001). Mean FT4 was moderately low at diagnosis, (-2.7±0.9 SDS) but initial thyroid function was within reported reference ranges in 31 cases. Treatment delays could be substantial, even following detection of subnormal FT4, especially in late-diagnosed cases (mean 208±486 days). Conclusion: UK Central congenital hypothyroidism cases are diagnosed later than screening-detected cases, and isolated TSH deficiency may evade detection entirely. 'Sicker' neonates are diagnosed earlier, but late diagnosis frequently occurs despite neonatal/childhood morbidity attributable to combined pituitary hormone deficiencies. Challenges include non-specific neonatal signs, requirement for bespoke age-specific FT4 reference ranges, lack of biomarkers for alternative diagnoses and masking by concomitant GH deficiency. Our findings mandate further studies to assess practicalities, costs and justification for introducing UK-wide central congenital hypothyroidism screening.