Congenital hypothyroidism (CH) is the most common congenital endocrine disorder and one of the most preventable causes of intellectual disability. The underlying etiology of CH can be thyroid dysgenesis or dyshormonogenesis, and in rare cases, CH can occur as part of a genetic syndrome. Sotos syndrome is a rare overgrowth disorder caused by pathogenic variants in the NSD1 gene, characterized by excessive growth in infancy, distinctive facial features, and developmental delay. We describe two unrelated children with permanent CH and genetically confirmed Sotos syndrome. Both children were referred to our Pediatric Endocrinology Centre due to abnormal thyroid-stimulating hormone (TSH) values detected through neonatal screening. A permanent CH was confirmed in both cases: one patient had thyroid hypoplasia with the presence of only the right thyroidal lobe; the other one had an in-situ thyroid gland. The diagnosis of Sotos syndrome was made later in infancy. In the first case, auxological parameters at birth were within normal ranges and overgrowth became apparent after six months of age; in the second case, overgrowth was already manifest at birth, but the diagnosis was guided primarily by the neurodevelopmental delay. We describe two cases in which CH occurred with Sotos syndrome, and we hypothesize that this association may not be coincidental. To our knowledge, these are among the few reported cases of genetically confirmed Sotos syndrome associated with permanent congenital hypothyroidism. Further studies are needed to determine whether CH is a clinical feature of Sotos syndrome or an unrelated finding. We recommend early thyroid function testing in patients with Sotos syndrome and suggest suspecting Sotos syndrome in children presenting with CH, cognitive delay and overgrowth or additional congenital anomalies.

Objective: Myxedema coma (MC) is a severe and rare clinical form of hypothyroidism that causes multiple organ failure and altered consciousness. The aim of reporting this case series is to evaluate the clinical presentation, diagnostic findings, and outcomes in pediatric patients diagnosed with MC. Materials and Methods: This article presents a case series of 8 patients diagnosed with MC between January 1, 2020, and October 31, 2024, at pediatric endocrinology department of the authors' hospital. The clinical and laboratory data of the cases were obtained from the hospital records system, and the cases were scored using the diagnostic scoring system for MC. Results: The mean age was 10.36 ± 3.56 years, with a male-to-female ratio of 1:3. Four of the patients were diagnosed with hypothyroidism upon admission with MC, while the remaining 4 had a history of hypothyroidism but presented with MC due to non-compliance with treatment. The majority of patients presented with edema, rapid weight gain, lethargy, and other symptoms of hypothyroidism. Six patients had Hashimoto's thyroiditis, 1 had thyroid hypoplasia, and 1 had thyroid aplasia. Laboratory tests revealed severely elevated thyroid-stimulating hormone (TSH) and low free thyroxine (fT4) and free triiodothyronine (fT3) levels. Six patients had elevated CK and myoglobin levels, indicating secondary rhabdomyolysis. Following levothyroxine (LT4) therapy, significant improvements were observed in muscle strength, thyroid function, and other clinical parameters. None of the patients required intensive care, and all recovered with 100% survival rate. Conclusion: Early diagnosis and appropriate thyroid hormone replacement therapy are crucial for reversing the metabolic abnormalities and preventing life-threatening complications. This study highlights the importance of timely intervention and emphasizes the need for strict adherence to thyroid hormone therapy in children with hypothyroidism.

Lower thyrotropin (TSH) cutoffs for Congenital Hypothyroidism (CH) during the neonatal period and childhood have led to increased detection of Mild Isolated Hyperthyrotropinemia (MIH) or Subclinical Hypothyroidism; however, genetic testing has been limited in this setting. We aimed to evaluate the contribution and molecular spectrum of genetic variants in MIH. Ten patients underwent targeted Next-Generation Sequencing (NGS). Data was analyzed for Single Nucleotide Variants (SNVs), short insertions/deletions, noncanonical splice site (NCSS) variants, and Copy Number Variants (CNVs) in 13 candidate genes associated with thyroid dyshormonogenesis and isolated thyroid hypoplasia. To provide an expanded view of the genes and variants associated with MIH, we performed a Systematic Review (SR) and variant reclassification. Eight monoallelic SNVs affecting 4 genes were identified in 5 subjects. A potential digenic or pseudo-digenic inheritance was identified in 3 infants. One novel variant was found in the TG gene. Genetic diagnosis, established based on the inheritance pattern, zygosity, pathogenicity of the variant, and genotype-phenotype correlation, was highly suggested in 4 patients. Through SR, we created a valuable database resource of 122 unique reclassified SNVs comprising 173 patients. Results provide further evidence for the elucidation of the genetic etiology of MIH and expand the phenotypic and variant spectrum of CH. Future, more extensive prospective studies are needed to investigate the utility of NGS in guiding treatment decisions and predicting prognosis for MIH patients.

Thyroid hypoplasia is described as a rare congenital anomaly. It is characterized by incomplete development of thyroid tissue, which can be differentiated from thyroid hemiagenesis, where a lobe is completely absent. These cases mostly present asymptomatically and are often found when imaged for unrelated conditions. In this report, we present a case of a 22-year-old euthyroid female who was incidentally discovered to have a hypoplastic left thyroid lobe during ultrasonography. After undergoing further investigations, the thyroid functioning tests were within a normal range (thyroid-stimulating hormone (TSH) 0.751 mIU/L, triiodothyronine (T3) 1.99 pg/mL, thyroxine (T4) 8.21 µg/dL). In addition, an isotope thyroid scan was done, confirming no functioning tissue in the hypoplastic lobe. This case study underlines the significance of differentiating between thyroid hemiagenesis and hypoplasia. In addition, it also highlights the importance of long-term follow-up for assessment of associated thyroid pathologies.

BOREALIN/CDCA8 mutations are associated with congenital hypothyroidism and thyroid dysgenesis. Borealin is involved in mitosis as part of the Chromosomal Passenger Complex. Although BOREALIN mutations decrease thyrocyte adhesion and migration, little is known about the specific role of Borealin in the thyroid. We characterized thyroid development and function in Borealin-deficient (Borealin +/-) mice using histology, transcriptomic analysis, and quantitative PCR. Thyroid development was impaired with a hyperplastic anlage on embryonic day E9.5 followed by thyroid hypoplasia from E11.5 onward. Adult Borealin +/- mice exhibited euthyroid goiter and defect in thyroid hormone synthesis. Borealin +/- aged mice had disorganized follicles and papillary-like structures in thyroids due to ERK pathway activation and a strong increase of Braf-like genes described by The Cancer Genome Atlas (TCGA) network of papillary thyroid carcinoma. Moreover, Borealin +/- thyroids exhibited structural and transcriptomic similarities with papillary thyroid carcinoma tissue from a human patient harboring a BOREALIN mutation, suggesting a role in thyroid tumor susceptibility. These findings demonstrate Borealin involvement in critical steps of thyroid structural development and function throughout life. They support a role for Borealin in thyroid dysgenesis with congenital hypothyroidism. Close monitoring for thyroid cancer seems warranted in patients carrying BOREALIN mutations.