Mild TPO deficiency characterized by progressive goiter and normal serum TSH level



Mild thyroid peroxidase (TPO) deficiency is rare and can be extremely occult. This study aimed to replenish the phenotypic and genetic spectrum of mild TPO deficiency.


Four unrelated patients with progressive goiter were described in this study. Genes associated with congenital hypothyroidism were analyzed and in vitro functional experiments were conducted to evaluate the residual TPO enzyme activities of each mutant.


The four patients (age: 5–27 years old) were characterized by progressive goiter, discordant alteration in thyroid hormones with free triiodothyronine (FT3) to free thyroxine (FT4) ratio ranging from 0.557 to 1.012, two with slightly elevated TSH level and two with normal TSH level. Six different mutations of TPO gene were identified including three novel mutations (p.Glu337Lys, p.Ala544Val, and p.Glu641Lysfs∗21). Two mutants (p.Asp224del and p.Ala544Val) with residual TPO activity of 41 and 65% may explain the mild TPO-deficient picture in our study. After levothyroxine (L-T4) therapy, three patients showed gradual decline of FT3 to FT4 ratio and two patients showed reduced thyroid size.


Patients with mild TPO deficiency can present with progressive goiter, normal TSH level, and largely reserved TPO activities.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3


  1. 1.

    M.V. Rastogi, S.H. LaFranchi, Congenital hypothyroidism. Orphanet J. Rare Dis. 5, 17 (2010)

    Article  Google Scholar 

  2. 2.

    H.M. Targovnik, C.E. Citterio, C.M. Rivolta, Iodide handling disorders (NIS, TPO, TG, IYD). Best. Pract. Res. Clin. Endocrinol. Metab. 31(2), 195–212 (2017)

    CAS  Article  Google Scholar 

  3. 3.

    A. Grüters, H. Krude, Detection and treatment of congenital hypothyroidism. Nat. Rev. Endocrinol. 8(2), 104–113 (2011)

    Article  Google Scholar 

  4. 4.

    E.G. Lever, G.A. Medeiros-Neto, L.J. DeGroot, Inherited disorders of thyroid metabolism. Endocr. Rev. 4(3), 213–239 (1983)

    CAS  Article  Google Scholar 

  5. 5.

    M. Morrison, G.R. Schonbaum, Peroxidase-catalyzed halogenation. Annu Rev. Biochem. 45, 861–888 (1976)

    CAS  Article  Google Scholar 

  6. 6.

    S. Pannain, R.E. Weiss, C.E. Jackson, D. Dian, J.C. Beck, V.C. Sheffield, N. Cox, S. Refetoff, Two different mutations in the thyroid peroxidase gene of a large inbred Amish kindred: power and limits of homozygosity mapping. J. Clin. Endocrinol. Metab. 84(3), 1061–1071 (1999)

    CAS  PubMed  Google Scholar 

  7. 7.

    A.C. Nascimento, D.R. Guedes, C.S. Santos, M. Knobel, I.G. Rubio, G. Medeiros-Neto, Thyroperoxidase gene mutations in congenital goitrous hypothyroidism with total and partial iodide organification defect. Thyroid 13(12), 1145–1151 (2003)

    CAS  Article  Google Scholar 

  8. 8.

    B. Bakker, H. Bikker, T. Vulsma, J.S. de Randamie, B.M. Wiedijk, J.J. De Vijlder, Two decades of screening for congenital hypothyroidism in The Netherlands: TPO gene mutations in total iodide organification defects (an update). J. Clin. Endocrinol. Metab. 85(10), 3708–3712 (2000)

    CAS  Article  Google Scholar 

  9. 9.

    C. Ris-Stalpers, H. Bikker, Genetics and phenomics of hypothyroidism and goiter due to TPO mutations. Mol. Cell Endocrinol. 322, 38–43 (2010)

    CAS  Article  Google Scholar 

  10. 10.

    S. Narumi, L.A. Fox, K. Fukudome, Z. Sakaguchi, C. Sugisawa, K. Abe, K. Kameyama, T. Hasegawa, Mild thyroid peroxidase deficiency caused by TPO mutations with residual activity: Correlation between clinical phenotypes and enzymatic activity. Endocr. J. 64(11), 1087–1097 (2017)

    CAS  Article  Google Scholar 

  11. 11.

    T. Kotani, K. Umeki, J. Kawano, T. Suganuma, A. Hishinuma, T. Ieiri, S. Harada, Partial iodide organification defect caused by a novel mutation of the thyroid peroxidase gene in three siblings. Clin. Endocrinol. 59(2), 198–206 (2003)

    CAS  Article  Google Scholar 

  12. 12.

    Y. Tenenbaum-Rakover, S. Mamanasiri, C. Ris-Stalpers, A. German, J. Sack, S. Allon-Shalev, J. Pohlenz, S. Refetoff, Clinical and genetic characteristics of congenital hypothyroidism due to mutations in the thyroid peroxidase (TPO) gene in Israelis. Clin. Endocrinol. 66(5), 695–702 (2007)

    CAS  Article  Google Scholar 

  13. 13.

    D. Turkkahraman, O.M. Alper, S. Pehlivanoglu, F. Aydin, A. Yildiz, G. Luleci, S. Akcurin, I. Bircan, Analysis of TPO gene in Turkish children with iodide organification defect: identification of a novel mutation. Endocrine 37(1), 124–128 (2010)

    CAS  Article  Google Scholar 

  14. 14.

    M.J. Abramowicz, H.M. Targovnik, V. Varela, P. Cochaux, L. Krawiec, M.A. Pisarev, F.V. Propato, G. Juvenal, H.A. Chester, G. Vassart, Identification of a mutation in the coding sequence of the human thyroid peroxidase gene causing congenital goiter. J. Clin. Invest. 90(4), 1200–1204 (1992)

    CAS  Article  Google Scholar 

  15. 15.

    R. Santos-Silva, M. Rosário, A. Grangeia, C. Costa, C. Castro-Correia, I. Alonso, M. Leão, M. Fontoura, Genetic analyses in a cohort of Portuguese pediatric patients with congenital hypothyroidism. J. Pediatr. Endocrinol. Metab. 32(11), 1265–1273 (2019)

    CAS  Article  Google Scholar 

  16. 16.

    H. Bikker, F. Baas, J.J. De Vijlder, Molecular analysis of mutated thyroid peroxidase detected in patients with total iodide organification defects. J. Clin. Endocrinol. Metab. 82(2), 649–653 (1997)

    CAS  PubMed  Google Scholar 

  17. 17.

    H. Bikker, M.T. den Hartog, F. Baas, M.H. Gons, T. Vulsma, J.J. de Vijlder, A 20-basepair duplication in the human thyroid peroxidase gene results in a total iodide organification defect and congenital hypothyroidism. J. Clin. Endocrinol. Metab. 79(1), 248–252 (1994)

    CAS  PubMed  Google Scholar 

  18. 18.

    T. Kotani, K. Umeki, I. Yamamoto, H. Maesaka, K. Tachibana, S. Ohtaki, A novel mutation in the human thyroid peroxidase gene resulting in a total iodide organification defect. J. Endocrinol. 160(2), 267–273 (1999)

    CAS  Article  Google Scholar 

  19. 19.

    M. Godlewska, P.J. Banga, Thyroid peroxidase as a dual active site enzyme: Focus on biosynthesis, hormonogenesis and thyroid disorders of autoimmunity and cancer. Biochimie 160, 34–45 (2019)

    CAS  Article  Google Scholar 

  20. 20.

    C.C. Lee, F. Harun, M.Y. Jalaludin, C.H. Heh, R. Othman, S.M. Junit, Prevalence of c.2268dup and detection of two novel alterations, c.670_672del and c.1186C > T, in the TPO gene in a cohort of Malaysian-Chinese with thyroid dyshormonogenesis. BMJ Open. 5(1), e006121 (2015)

    Article  Google Scholar 

  21. 21.

    C. Sriphrapradang, Y. Thewjitcharoen, S. Chanprasertyothin, S. Nakasatien, T. Himathongkam, O. Trachoo, A novel mutation in thyroid peroxidase gene causing congenital goitrous hypothyroidism in a German-Thai patient. J. Clin. Res. Pediatr. Endocrinol. 8(2), 241–245 (2016)

    Article  Google Scholar 

  22. 22.

    D. Simm, N. Pfarr, J. Pohlenz, D. Prawitt, H.G. Dörr, Two novel mutations in the human thyroid peroxidase (TPO) gene: genetics and clinical findings in four children. Acta Paediatr. 98(6), 1057–1061 (2009)

    CAS  Article  Google Scholar 

Download references


This study was supported by the grants from the National Key Research and Development Program of China (2016YFC0901503), Foundation of Health and Family planning Commission of Shanghai (20174Y0204), National Science Foundation of China (81570702, 81400772, 81700686), and Foundation of Guangci Distinguished Young Scholars Training Program (GCQN-2019-A13).

Author information



Corresponding author

Correspondence to Lei Ye.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This study was approved by the board of medical ethics of Ruijin Hospital, Shanghai Jiaotong University.

Informed consent

Written informed consents were obtained from all patients included in the study.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Zhang, J., Han, R., Shen, L. et al. Mild TPO deficiency characterized by progressive goiter and normal serum TSH level. Endocrine 68, 599–606 (2020).

Download citation


  • Congenital hypothyroidism
  • TPO deficiency
  • Gene mutation
  • Thyroid dyshormonogenesis