Autoimmune Hyperthyroidism in Prepubertal Children (IPER6)

Autoimmune Hyperthyroidism in Prepubertal Children With Onset Before 6 Years of Age: Characteristics at Diagnosis and Follow-Up Trends.

The investigators propose a multicenter retrospective study to assess clinical, biochemical, and auxological characteristics at diagnosis and during follow-up in a cohort of Caucasian pediatric patients diagnosed with autoimmune hyperthyroidism before puberty. These prepubertal patients will be compared with a control group of post-pubertal patients with Graves' disease.

This study aims to enhance the understanding of autoimmune hyperthyroidism in prepubertal patients by providing a detailed evaluation of disease onset, therapeutic response, and growth-related outcomes. The inclusion of a carefully matched post-pubertal control group will allow for robust comparative analysis and identification of age-dependent clinical patterns and prognostic indicators, ultimately supporting more tailored and effective management strategies in pediatric populations at this particular age.

Study Overview

• Status: Enrolling by invitation
• Conditions: Children; Autoimmune Hyperthyroidism
• Intervention / Treatment: Other: restrospective observational study

Detailed Description

There are only few studies in literature focusing on the analysis of cohorts of patients with autoimmune hyperthyroidism with onset exclusively in early childhood. The investigators therefore propose this study with the aim of retrospectively assessing characteristics at onset and during follow-up in a cohort of Caucasian hyperthyroid subjects diagnosed with the disease before puberty.

OBJECTIVES AND ENDPOINTS

• Primary Objective To evaluate the clinical and biochemical features at the onset of autoimmune hyperthyroidism in patients diagnosed in prepubertal age Secondary Objectives

  1. To evaluate of biochemical parameters during medical therapy
  2. To evaluate of auxological parameters at diagnosis and during follow-up

  3. To compare the previous data with the clinical and biochemical features at diagnosis and during the follow-up in patients diagnosed with Graves during the pubertal age (> Tanner 2)

     Inclusion Criteria 1. Subjects with autoimmune hyperthyroidism 2. Prepubertal stage (Tanner 1) at diagnosis Exclusion Criteria 3. Subjects with hyperthyroidism not of autoimmune aetiology 4. Pubertal stage (>Tanner 2) at diagnosis

     Sample size:

• 50 hyperthyroid subjects diagnosed with the disease before puberty
• 50 hyperthyroid subjects diagnosed with the disease during and post puberty

The data will then be analyzed using PRISM software. The principal investigator will verify the completeness, correctness, consistency and congruence of the reported data.

• Study Type: Observational
• Enrollment (Estimated): 100

Contacts and Locations

Study Locations

• Italy
  • Italy
    • Milan, Italy, Italy, 20132
      • Irccs Ospedale San Raffaele

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

We enrolled all patients affected by autoimmune hyperthyroidism in prepubertal age and pubertal age to compare 2 groups

Description

Inclusion Criteria:

-Subjects with autoimmune hyperthyroidism

Exclusion Criteria:

• Subjects with hyperthyroidism not of autoimmune aetiology

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
50 patients affected by autoimmune hyperthyroidism in prepubertal age	Other: restrospective observational study; we collect clinical, hormonal and follow up data and compare data in prepubertal and pubertal patients affected by autoimmune hyperthyroidism
50 patients affected by autoimmune hyperthyroidism in pubertal age	Other: restrospective observational study; we collect clinical, hormonal and follow up data and compare data in prepubertal and pubertal patients affected by autoimmune hyperthyroidism

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of clinical signs of hyperthyroidism at diagnosis	Total number of clinical signs (including goiter, exophthalmos, and tachycardia) present at diagnosis, recorded as a count per patient.	Day 0 (retrospective assessment at diagnosis)
Number of clinical symptoms at diagnosis	Total number of symptoms per patient, categorized as none (0), mild (1-2), moderate (3-5), or severe (>5).	Day 0
Serum free triiodothyronine (FT3) levels at diagnosis	Measurement of serum FT3 (pmol/L) at diagnosis.	Day 0
Serum free thyroxine (FT4) levels at diagnosis	Measurement of serum FT4 (pmol/L) at diagnosis.	Day 0
Serum thyroid-stimulating hormone (TSH) levels at diagnosis	Measurement of serum TSH (mIU/L) at diagnosis.	Day 0
Serum TSH receptor antibody (TRAb) levels at diagnosis	Measurement of TRAb levels (IU/L) at diagnosis.	Day 0
Thyroid autoantibody positivity at diagnosis (TPOAb and TgAb)	Presence or absence of thyroid autoantibodies (TPOAb and TgAb), reported as positive/negative.	Day 0

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of antithyroid drug therapy	Time in months from initiation of antithyroid drug therapy to treatment discontinuation or switch to definitive therapy, whichever occurs first.	Baseline (treatment initiation) to treatment discontinuation (up to 24 months)
Remission rate after antithyroid drug therapy	Proportion of patients achieving sustained normalization of thyroid function (TSH, FT3, FT4) for at least 12 months after discontinuation of therapy.	At 24 months after treatment initiation
Rate of definitive treatment (thyroidectomy or radioactive iodine therapy)	Proportion of patients requiring definitive treatment, defined as thyroidectomy or radioactive iodine therapy.	Baseline to 24 months
Serum TSH receptor antibody (TRAb) levels at time of the definitive treatment	Measurement of serum TRAb levels (IU/L) at the time of transition to definitive therapy.	At time of definitive treatment (up to 24 months)
Time to normalization of thyroid function	Time in weeks from initiation of antithyroid therapy to normalization of FT3, FT4, and TSH levels.	Baseline to normalization (up to 12 months)
Aauxological parameters at diagnosis and during follow-up	delta target height	day 0, diagnosis; at 6 months; at 12 months
Number of antithyroid drug discontinuation attempts	Number of attempts to discontinue antithyroid therapy per patient, categorized as successful or unsuccessful based on biochemical remission.	Baseline to 24 months
Annual growth velocity during follow-up	Change in height per year (cm/year).	Baseline to 24 months
Bone age during follow-up	Bone age assessed using Greulich and Pyle method.	At baseline, 12 months, and 24 months

Collaborators and Investigators

• Sponsor: IRCCS Ospedale San Raffaele
• Collaborators: IRCCS Azienda Ospedaliero-Universitaria di Bologna; Federico II University; Azienda Ospedaliera Universitaria Integrata Verona; Azienda Ospedaliero-Universitaria di Parma; University of Genova; Azienda Ospedaliera Universitaria Policlinico "G. Martino"; Azienda Ospedaliero-Universitaria Consorziale Policlinico di Bari; Azienda Ospedaliera SS. Antonio e Biagio e Cesare Arrigo di Alessandria; Arcispedale S. Anna, Ferrara; Fondazione IRCCS San Gerardo dei Tintori; Buzzi Children's Hospital; University of Campania Luigi Vanvitelli; Università di Torino, Torino

Publications and helpful links

General Publications

• Gu Y, Liang X, Liu M, Wu D, Li W, Cao B, Li Y, Su C, Chen J, Gong C. Clinical features and predictors of remission in children under the age of 7 years with Graves' disease. Pediatr Investig. 2020 Sep 27;4(3):198-203.
• Chen J, Eng L & Lam L. MON-263 Graves' disease presenting as chronic diarrhea in a toddler. Journal of the Endocrine Society 2019
• Jonak O, Polubok J, Barg E. Graves' disease in 2.5 years old girl - 6-years-long observation. Pediatr Endocrinol Diabetes Metab. 2016;22(2):76-79. doi: 10.18544/PEDM-22.02.0055.
• Azova S, Rajabi F, Modi BP, Mansfield L, Jonas MM, Drobysheva A, Boyd TK, Wassner AJ, Smith JR. Graves' disease in a five-month-old boy with an unusual treatment course. J Pediatr Endocrinol Metab. 2020 Dec 15;34(3):401-406. doi: 10.1515/jpem-2020-0549. Print 2021 Mar 26.
• Shulman DI, Muhar I, Jorgensen EV, Diamond FB, Bercu BB, Root AW. Autoimmune hyperthyroidism in prepubertal children and adolescents: comparison of clinical and biochemical features at diagnosis and responses to medical therapy. Thyroid. 1997 Oct;7(5):755-60. doi: 10.1089/thy.1997.7.755.
• Lazar L, Kalter-Leibovici O, Pertzelan A, Weintrob N, Josefsberg Z, Phillip M. Thyrotoxicosis in prepubertal children compared with pubertal and postpubertal patients. J Clin Endocrinol Metab. 2000 Oct;85(10):3678-82. doi: 10.1210/jcem.85.10.6922.
• Francis N, Francis T, Lazarus JH, et al. Current controversies in the management of Graves' hyperthyroidism. Expert Rev Endocrinol Metab 2020;15:159-69
• Mooij CF, Cheetham TD, Verburg FA, et al. 2022 European Thyroid Association Guideline for the Management of Pediatric Graves' Disease. Eur Thyroid J 2022;11:e210073.
• Kaplowitz PB, Vaidyanathan P. Update on pediatric hyperthyroidism. Curr Opin Endocrinol Diabetes Obes. 2020 Feb;27(1):70-76. doi: 10.1097/MED.0000000000000521.
• Léger J, Olivieri A, Donaldson M, et al.; ESPE-PES-SSLEP-JSPE-APEG-APPES-ISPAE;Congenital HHypothyroidism Consensus Conference GGroup European Society for Paediatric Endocrinology consensus guidelines on screening, diagnosis, and management of congenital hhypothyroidism Horm Res Paediatr 22014;81:80-10

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2026
• Primary Completion (Actual): January 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: February 26, 2026
• First Submitted That Met QC Criteria: April 15, 2026
• First Posted (Actual): April 22, 2026

Study Record Updates

• Last Update Posted (Actual): April 22, 2026
• Last Update Submitted That Met QC Criteria: April 15, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: antithyroid drugs; pubertal age; autoimmune hyperthyroidism; graves; prepubertal age
• Additional Relevant MeSH Terms: Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Eye Diseases; Exophthalmos; Orbital Diseases; Goiter; Hyperthyroidism; Thyroid Diseases; Graves Disease
• Other Study ID Numbers: CET 164-2025

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No