Functional non-coding variants in a TTTG microsatellite on chromosome 15q26.1 are a common genetic etiology of congenital hypothyroidism, and present with a mild phenotype

Hirohito Shima; Tomohiro Nakagawa; Kanako Kojima-Ishii; Akinobu Miura; Ikuma Fujiwara; Satoshi Narumi; Atsuo Kikuchi; Junko Kanno

doi:10.1530/endoabs.110.OC11.2

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Endocrine Abstracts (2025) 110 OC11.2 | DOI: 10.1530/endoabs.110.OC11.2

ECEESPE2025 Oral Communications Oral Communications 11: Thyroid Part 1 (6 abstracts)

Functional non-coding variants in a TTTG microsatellite on chromosome 15q26.1 are a common genetic etiology of congenital hypothyroidism, and present with a mild phenotype

Hirohito Shima ¹ , Tomohiro Nakagawa ¹ , Kanako Kojima-Ishii ^1,2 , Akinobu Miura ¹ , Ikuma Fujiwara ^1,3 , Satoshi Narumi ⁴ , Atsuo Kikuchi ¹ & Junko Kanno ¹

Author affiliations

¹Tohoku University Graduate School of Medicine, Department of Pediatrics, Sendai, Japan; ²Fukuoka Children’s Hospital, Department of Endocrinology and Metabolism, Fukuoka, Japan; ³Sendai City Hospital, Department of Pediatrics, Sendai, Japan; ⁴Keio University School of Medicine, Department of Pediatrics, Tokyo, Japan

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Introduction: Variants affecting a microsatellite on the non-coding region of chromosome 15q26.1 are associated with familial non-autoimmune thyroid abnormalities that are characterized by mild congenital hypothyroidism (CH) with elevated thyroglobulin (Tg) levels. Individuals harboring these variants may develop multinodular goiter (MNG) in the absence of treatment. Although these variants have been recognized as genetic etiologies of CH, nongoitrous, 3 (CHNG3), the associated severity of CH remains unclear.

Methods: A cohort of 63 participants diagnosed with CH at Tohoku University underwent screening for genetic variants on 15q26.1. We subsequently analyzed the clinical phenotypes of the variant-carrying participants.

Results: We identified five 15q26.1 variant carriers from four families among the cohort. Family histories of thyroid abnormalities were documented in three particpants of these two families. The variant carriers exhibited mild CH phenotypes, with two discontinuing levothyroxine treatment and the others requiring relatively low doses (1.33–1.89 µg/ kg/day) at their final visit. Notably, the patients’ elevated neonatal TSH levels decreased spontaneously within weeks. This suggests that congenital thyroid hormone synthesis capacities are compensated for during early infancy in a subgroup of patients with CHNG3. All the variant carriers presented with ectopic and normal-sized thyroid glands. During levothyroxine treatment, serum thyroglobulin and thyroid-stimulating hormone (TSH) levels were within the reference ranges at the majority of the evaluation points. Three of the five participants continued treatment into adulthood, whereas the other two discontinued treatment and maintained their serum TSH levels within the reference range. All five participants demonstrated normal intellectual development and stature. Notably, in our sister participants who discontinued their treatments at puberty after 5 and 13 years of levothyroxine treatment, respectively, one of them with a short treatment period exhibited significantly higher Tg levels following treatment. This observation may be attributed to the fact that levothyroxine replacement can prevent thyroid gland enlargement resulting elevation in serum Tg levels, suggesting that levothyroxine treatment may prevent thyroid enlargement and lead to MNG requiring surgical intervention.

Conclusion: These findings provide further evidence supporting the role of 15q26.1 variants as a common genetic etiology of CH, with clinical phenotypes including transient CH. Early genetic evaluation may facilitate the identification of 15q26.1 variant carriers among patients who are diagnosed with CH.