Mild thyroid peroxidase deficiency caused by TPO mutations with residual activity: Correlation between clinical phenotypes and enzymatic activity

Endocrine journal

Tomonobu Hasegawa¹  Satoshi Narumi²  Zenichi Sakaguchi³  Kiyomi Abe⁴  Kaori Kameyama⁴  Keisuke Fukudome⁵  Chiho Sugisawa⁵  Larry A Fox⁶ 

[1] Department of Diagnostic Pathology, Keio University School of Medicine, Tokyo 160-8582, Japan;Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan;Department of Pediatric Cardiology, Shikoku Medical Center for Children and Adults, Zentsuji 765-8507, Japan;Department of Pediatrics, Keio University School of Medicine, Tokyo 160-8582, Japan;Department of Pediatrics, Takamatsu Red Cross Hospital, Takamatsu 760-0017, Japan;Division of Endocrinology, Nemours Children’s Specialty Care, Jacksonville, FL 32207, USA

关键词: Congenital hypothyroidism;    Newborn screening;    Thyroid peroxidase (TPO);    Mutation;    Genetics;   

DOI  :  10.1507/endocrj.EJ17-0194

学科分类：内分泌与代谢学

来源: Japan Endocrine Society

【 摘 要 】

Thyroid peroxidase (TPO) deficiency, caused by biallelic TPO mutations, is a well-established genetic form of congenital hypothyroidism (CH).More than 100 patients have been published, and the patients have been diagnosed mostly in the frame of newborn screening (NBS) programs. Correlation between clinical phenotypes and TPO activity remains unclear.Here, we report clinical and molecular findings of two unrelated TPO mutation-carrying mildly hypothyroid patients.The two patients were born at term after an uneventful pregnancy and delivery, and were NBS negative.They sought medical attention due to goiter at age 8 years.Evaluation of the thyroid showed mild elevation of serum TSH levels, normal or slightly low serum T4 levels, high serum T3 to T4 molar ratio, high serum thyroglobulin levels, and high thyroidal 123I uptake.We performed next-generation sequencing-based genetic screening, and found that one patient was compound heterozygous for two novel TPO mutations (p.Asp224del; c.820-2A>G), and the other was homozygous for a previously known mutation (p.Trp527Cys).In vitro functional analyses using HEK293 cells showed that the two amino acid-altering mutations (p.Asp224del and p.Trp527Cys) caused partial loss of the enzymatic activity.In conclusion, we report that TPO mutations with residual activity are associated with mild TPO deficiency, which is clinically characterized by marked goiter, mild TSH elevation, high serum T3 to T4 molar ratio, and high serum thyroglobulin levels.Our findings illuminate the hitherto under-recognized correlation between clinical phenotypes and residual enzymatic activity among patients with TPO deficiency.

【 授权许可】

Unknown