We propose a multicenter prospective study to define the prevalence and severity score of metabolic syndrome in a prepubertal pediatric cohort with congenital hypothyroidism, compared to a healthy and normal-weight pediatric population. These data will help to define whether hypothyroidism can be considered a risk factor for the metabolic health of the pediatric population. The possible identification of an at-risk metabolic profile will provide useful information to optimize the diagnostic and monitoring pathway for affected children.

Primary congenital hypothyroidism is the most common endocrine disorder in childhood and can present in either a permanent or transient form. Prolonged thyroid hormone deficiency can cause widespread damage affecting multiple organs and systems. Exposure to thyroid hormone deficiency during fetal and/or neonatal life has particularly severe consequences on the central nervous system, leading to neurocognitive delay. Appropriate and timely hormone replacement therapy (L-thyroxine) can prevent such outcomes, provided it is initiated early.

Thyroid hormones play a crucial role not only in growth and organ development but also in metabolic homeostasis. Thyroid function lies at the crossroads of multiple metabolic pathways. They have multiple effects on glucose and lipid metabolism, specifically by increasing glucose levels, fatty acid oxidation in muscle and liver, and lipolysis in adipose tissue. They also contribute to blood pressure regulation, thereby influencing the prevalence of metabolic syndrome, which is itself a key predictor of type 2 diabetes, cardiovascular diseases, and neurodegenerative conditions.Thyroid function plays a central regulatory role at the intersection of key metabolic pathways. Although, the role of thyroid hormones in metabolic processes is well established, and a bidirectional relationship between metabolic dysfunction and thyroid hypofunction has been reported in the adult population, data on metabolic risk in pediatric patients with congenital hypothyroidism are currently lacking.

The primary aim of this multicenter project is to assess the prevalence of metabolic syndrome in patients with congenital hypothyroidism and to determine whether this population presents a higher metabolic risk profile compared to the general population. As secondary objectives, this prospective study aims to:

1. Define the prevalence and severity score of metabolic syndrome in a prepubertal pediatric cohort with congenital hypothyroidism, compared to a pediatric population with obesity.
2. Evaluate the correlations between individual metabolic dysfunction parameters and the clinical and hormonal profile (including thyroid hormone levels and thyroid hormone sensitivity indices).
3. Assess the correlations between the metabolic profile and renal function.
4. Assess the correlations between the hormonal profile and renal function. To achieve these objectives, auxological parameters, vital signs (including blood pressure and heart rate), and metabolic profile data (glucose and lipid profiles, renal function, and hormonal status - FT3, FT4, TSH and thyroid hormone resistence indices TSHI, TT4RI, TT3RI, TFQI, PTFQI) will be collected for each enrolled subject. These parameters will be evaluated on peripheral blood samples collected during routine blood monitoring already scheduled according to established follow up. The potential presence of metabolic syndrome will be evaluated in each enrolled patient. The severity of the metabolic disorder will be evaluated using the Metabolic Score (MetS).

Data analysis will be performed using the statistical packages R 4.0.5 (R Core Team, 2021) and STATA (version 15.1, 2017, Stata Corporation, College Station, Texas, USA).

Inclusion Criteria:

• Pubertal stage Tanner 1
• Permanent congenital hypothyroidism
• All ethnic groups
• Informed consent signature

Exclusion Criteria:

• Age< 5 years
• Pubertal stage Tanner 2-5
• Transient congenital hypothyroidism or other type of hypothyroidism

We enrolled patients affected by permanent congenital hypothyroidism in prepubertal age and healthy childrens in prepubertal age to compare them with each other.