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 to 2022, in four tertiary centres.

RESULTS: Median age at diagnosis was 68 days (range: 1-5,056). 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 ( > 1 year, 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.