ESPEYB20 1. Thyroid Genetics (3 abstracts)
1.8. The severity of congenital hypothyroidism with gland-in-situ predicts molecular yield by targeted NGS
Levaillant L , Bouhours-Nouet N , Illouz F , Jager JA , Bachelot A , Barat P , Baron S , Bensignor C , De La Perriere AB , Djellas YB , Caillot M , Caldagues E , Campas MN , Caquard M , Cartault A , Cheignon J , Decrequy A , Delemer B , Dieckmann K , Donzeau A , Doye E , Fradin M , Gaudillière M , Gatelais F , Gorce M , Hazart I , Houcinat N , Houdon L , Ister-Salome M , Jozwiak L , Jeannoel P , Labarthe F , Lacombe D , Lambert AS , Lefevre C , Leheup B , Leroy C , Maisonneuve B , Marchand I , Marquant E , Muszlak M , Pantalone L , Pochelu S , Quelin C , Radet C , Renoult-Pierre P , Reynaud R , Rouleau S , Teinturier C , Thevenon J , Turlotte C , Valle A , Vierge M , Villanueva C , Ziegler A , Dieu X , Bouzamondo N , Rodien P , Prunier-Mirebeau D & Coutant R
J Clin Endocrinol Metab. 2023 Mar 8:dgad119. doi: 10.1210/clinem/dgad119. Online ahead of print. PMID: 36884306
Brief summary: Over the recent years several publications reported on next generation sequencing (NGS) in cohorts of patients with congenital hypothyroidism (1). Based on these data, diagnostic yield was higher in patients with gland-in-situ, than with thyroid dysgenesis. Further studies performed NGS only in cohorts of patients with gland-in-situ, excluding thyroid dysgenesis forms such as athyreosis, ectopy, or hypoplasia (2). The publication of Levaillant et al. is so far the largest genetic study of patients with congenital hypothyroidism with gland-in-situ comparing for the first time diagnostic yield with disease severity of congenital hypothyroidism.
This genetic monocenter study presents systematic NGS results in n=103 patients with congenital hypothyroidism with gland-in-situ. Detailed clinical and laboratory phenotyping of all patients was performed. The used NGS panel covered n=48 genes either known to be associated with congenital hypothyroidism or known to be involved in thyroid physiology. In total in 42/103 (42%) patients a genetic cause of congenital hypothyroidism was identified. This diagnostic yield in the complete cohort is comparable to earlier results of previous studies. However, for the first time, this study analyzed the relationship between biochemical severity of congenital hypothyroidism based on TSH values at screening and at diagnosis and FT4 at diagnosis with diagnostic yield and found a higher diagnostic yield in patients with more severe hypothyroidism: the diagnostic yield in patients with TSH at screening of > 80 mU/L, with TSH at diagnosis of > 100 mU/L, or FT4 at diagnosis of <5 pmol/L was 73%, 60%, and 69% respectively compared to the diagnostic yield in patients with TSH and FT4 values below these cut-offs (25%, 30%, 29%).
In summary, this innovative study not only confirms earlier results of diagnostic yield in the so far largest cohort of patients with congenital hypothyroidism with gland-in-situ, but shows that a genetic diagnosis is far more probable in severe cases of congenital hypothyroidism than in milder forms. This observation is of importance in the context of increasing incidence of congenital hypothyroidism, especially of milder degree over the last decades, suggesting other than genetic causes for the increased incidence, such as e.g. lowering of screening cut-offs, mild iodine deficiency, or epigenetic effects.
References: 1. A frequent oligogenic involvement in congenital hypothyroidism. de Filippis T, Gelmini G, Paraboschi E, Vigone MC, Di Frenna M, Marelli F, Bonomi M, Cassio A, Larizza D, Moro M, Radetti G, Salerno M, Ardissino D, Weber G, Gentilini D, Guizzardi F, Duga S, Persani L. A frequent oligogenic involvement in congenital hypothyroidism. Hum Mol Genet. 2017 Jul 1;26(13):2507–2514. doi: 10.1093/hmg/ddx145. PMID: 28444304. 2. Comprehensive Screening of Eight Known Causative Genes in Congenital Hypothyroidism With Gland-in-Situ. Nicholas AK, Serra EG, Cangul H, Alyaarubi S, Ullah I, Schoenmakers E, Deeb A, Habeb AM, Almaghamsi M, Peters C, Nathwani N, Aycan Z, Saglam H, Bober E, Dattani M, Shenoy S, Murray PG, Babiker A, Willemsen R, Thankamony A, Lyons G, Irwin R, Padidela R, Tharian K, Davies JH, Puthi V, Park SM, Massoud AF, Gregory JW, Albanese A, Pease-Gevers E, Martin H, Brugger K, Maher ER, Chatterjee VK, Anderson CA, Schoenmakers N. Comprehensive Screening of Eight Known Causative Genes in Congenital Hypothyroidism With Gland-in-Situ. J Clin Endocrinol Metab. 2016 Dec;101(12):4521–4531. doi: 10.1210/jc.2016-1879. Epub 2016 Aug 15. PMID: 27525530.
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ESPE Yearbook of Paediatric Endocrinology
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