MCT8 deficiency in females

Groeneweg S; van Geest  FS; van der Most  F; Abela L; Alfieri P; Bauer AJ; Bertini E; Cappa M; Celik N; de Coo IFM; Dolcetta-Capuzzo A; Dubinski I; Granadillo JL; Hoefsloot LH; Kalscheuer VM; van der Knoop MM; Krude H; McNerney KP; Paone L; Peeters RP; Peters C; Schuelke M; Schweizer U; Sprague JE; van Trotsenburg  ASP; Wilpert NM; Zanni G; van Zutven LJCM; Visser WE

doi:10.1530/ey.22.3.6

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ESPE Yearbook of Paediatric Endocrinology (2025) 22 3.6 | DOI: 10.1530/ey.22.3.6

ESPEYB25 3. Thyroid Disorders of Thyroid Hormone Transport, Metabolism and Action (3 abstracts)

3.6. MCT8 deficiency in females

Groeneweg S , van Geest FS , van der Most F , Abela L , Alfieri P , Bauer AJ , Bertini E , Cappa M , Çelik N , de Coo IFM , Dolcetta-Capuzzo A , Dubinski I , Granadillo JL , Hoefsloot LH , Kalscheuer VM , van der Knoop MM , Krude H , McNerney KP , Paone L , Peeters RP , Peters C , Schuelke M , Schweizer U , Sprague JE , van Trotsenburg ASP , Wilpert NM , Zanni G , van Zutven LJCM & Visser WE

J Clin Endocrinol Metab. 2025 May 27:dgaf311. Online ahead of print. doi: 10.1210/clinem/dgaf311. PMID: 40420837

Brief Summary: This clinical study describes8 female patients with heterozygous pathogenic variants in SLC16A2, the gene causing MCT8 deficiency (Allan-Herndon-Dudley syndrome), previously thought to affect only males. All patients had variable neurocognitive impairment, behavioral problems and abnormal thyroid function abnormalities but, in contrast to male patients, only 2 had dystonia or spasticity, and hypotonia. 7 of the 8 studied women showed skewed X-chromosome inactivation, and in 5 of these 7 women functional studies showed impaired thyroid hormone transport in patient-derived fibroblasts. Compared to asymptomatic carriers, patients had higher (total) T3/rT3 and (total) T3/FT4 ratios.

This study highlights that MCT8 deficiency should be considered in females presenting with mild to moderate neurocognitive impairment, whether or not accompanied by psychiatric symptoms, and abnormal thyroid function tests, specifically low FT4 or T4 and elevated FT3 or T3.