Thyroid dyshormonogenesis (THD) is a heterogeneous group of genetic diseases caused by the total or partial defect in the synthesis or secretion of thyroid hormones. Genetic variants in DUOX2 can cause partial to total iodination organification defects and clinical heterogeneity, from transient to permanent congenital hypothyroidism. The aim of this study was to undertake a molecular characterization and genotype-phenotype correlation in patients with THD and candidate variants in DUOX2. A total of 31 (19.38%) patients from the Catalan Neonatal Screening Program presented with variants in DUOX2 that could explain their phenotype. Fifteen (48.39%) patients were compound heterozygous, 10 (32.26%) heterozygous, and 4 (12.90%) homozygous. In addition, 8 (26.67%) of these patients presented variants in other genes. A total of 35 variants were described, 10 (28.57%) of these variants have not been previously reported in literature. The most frequent variant in our cohort was c.2895_2898del/p.(Phe966SerfsTer29), classified as pathogenic according to reported functional studies. The final diagnosis of this cohort was permanent THD in 21 patients and transient THD in 10, according to reevaluation and/or need for treatment with levothyroxine. A clear genotype-phenotype correlation could not be identified; therefore, functional studies are necessary to confirm the pathogenicity of the variants.

OBJECTIVE: To carry out clinical and genetic analysis for a child featuring Brain-Lung-Thyroid syndrome (BLTS).
METHODS: A child who had presented at the Children\'s Hospital Affiliated to Shandong University on May 27, 2022 was selected as the study subject. Clinical data was collected. Trio-whole exome sequencing (Trio-WES) was carried out for the child and his parents, and candidate variant was verified by Sanger sequencing and bioinformatic analysis. The child was given individualized treatment following the diagnosis.
RESULTS: The child, a two-year-and-seven-month-old boy, had presented with global developmental delay, ataxia and hypothyroidism. WES revealed that he has harbored a heterozygous c.674C>T variant of the NKX2-1 gene, based on which he was diagnosed with BLTS. CT scan revealed interstitial and parenchymal inflammation in his lungs, which was reduced by budesonide aerosol inhalation.
CONCLUSIONS: Discovery of the novel c.674C>T variant has enriched the mutational spectrum of the NKX2-1 gene. Budesonide aerosol may be used to treat lung inflammation associated with BLTS.

OBJECTIVE: To assess the incidence of congenital hypothyroidism (CH) and acquired hypothyroidism (AH) between 2014 and 2019 in continental France.
METHODS: New cases of CH and AH were identified using the French National Health Data System (Système Nationale des Données de Santé, SNDS). Temporal trends were studied using linear regression models. Spatial distributions were studied using Moran\'s global index (I) and the statistical method and local indicators of spatial association.
RESULTS: The incidence of permanent CH in females increased by 8.9% per year (2014: 36.9 [31.1-43.7] per 100,000 birth-years vs. 2019: 51 [43.9-59.3] per 100,000 birth-years, p < 0.01). The incidence of AH decreased between 2014 and 2019 for both females (2014: 535.7 [533.2-538.2] per 100,000 person-years vs 2019: 335.5 [333.6-337.4] per 100,000 person-years, p < 0.01) and males (2014: 197.5 [195.9-199] per 100,000 person-years vs 2019: 141.7 [140.4-142.9] per 100,000 person-years, p<0.01). The incidence of hypothyroidism was high in the Nord-Pas-De-Calais and Lorraine regions (CH and AH).
CONCLUSIONS: The incidence of permanent CH in females has increased over time. AH incidence decreased. It seems necessary to investigate environmental factors in the disparity of incidence distribution.

Sanjad-Sakati syndrome (SSS) (Online Mendelian Inheritance in Man 241410) is a rare autosomal recessive disorder also known as hypoparathyroidism-retardation-dysmorphism syndrome. It is characterized by congenital hypoparathyroidism, growth retardation, typical facial features, and variable developmental delay. SSS is caused due to mutations of the tubulin-specific chaperone E ( TBCE ) gene. In this article, we reported the first Libyan child of first parental consanguinity with SSS and whole exome sequencing results identified the homozygous missense variant c.155-166del and it encodes p.(Ser52-Gly55del) (chr1:235564867) located in the TBCE gene , chromosome 1q42.3. In addition, the patient was also diagnosed with congenital hypothyroidism and presented with acquired bilateral cataract in the first year of life. Most likely, all Arab patients with SSS syndrome have the same TBCE gene mutation.

The spectrum of thyroid disorders presenting to paediatricians is different to that seen by adult physicians. Referrals reflect cases detected by the neonatal screening programme for congenital hypothyroidism and many of the inherited defects of thyroid hormone generation or action will be manifest in early life. Autoimmune thyroid disease can be particularly challenging to manage in the young and the potential impact of thyroid status on neurodevelopment and schooling are key considerations throughout childhood and adolescence.

Pseudohypoparathyroidism (PHP) type 1a (PHP 1a) is a rare hereditary disorder characterized by target organ resistance to hormonal signaling and the Albright hereditary osteodystrophy (AHO) phenotype, which features round facial features, short fingers, subcutaneous calcifications, short stature, obesity, and intellectual disability. Progressive osseous heteroplasia (POH) is another rare disorder characterized by heterotopic ossification (HO) that progressively affects skin, subcutaneous tissues, and deep skeletal muscle. PHP 1a is inherited maternally due to a GNAS mutation, while pure POH is inherited paternally. This case study presented a Chinese boy with congenital hypothyroidism, tonic-clonic seizures, hypoparathyroidism, AHO, POH, and joint fixation deformity. Sequencing analysis of GNAS-Gsα revealed a heterozygous C.432+2T>C(P.?) variant (NM_000516.7) affecting the canonical splice donor site of intron 5 in the boy and his mother, indicating maternal inheritance of a GNAS mutation. The patient was diagnosed with POH overlap syndrome (POH/PHP 1a). Following calcium and calcitriol supplementation, he experienced a reduction in seizures, and surgery was performed to correct the joint fixation deformity caused by HO. This case report provided valuable insights into the genotype-phenotype correlations of POH overlap syndrome and underscored the significance of genetic testing in diagnosing rare diseases.

Background and Objectives: Congenital thyroid dyshormonogenesis is caused by alterations in the synthesis of thyroid hormones in a newborn. Additionally, 10 to 20% of these cases are hereditary, caused by defects in proteins involved in hormonal synthesis. One of the most common causes is mutations in the thyroid peroxidase (TPO) enzyme gene, an autosomal recessive disease. We aimed to detect mutations of the TPO gene in 12 Chilean patients with congenital hypothyroidism due to dyshormonogenesis (CHD) and to characterize these patients clinically and molecularly. Materials and Methods: Twelve patients under 20 years of age with CHD, controlled at San Juan de Dios Hospital in Santiago, Chile, were selected according to the inclusion criteria: elevated neonatal TSH, persistent hypothyroidism, and thyroid normotopic by imaging study. Those with deafness, Down syndrome, and central or transient congenital hypothyroidism were excluded. Blood samples were taken for DNA extraction, and the 17 exons and exon-intron junctions of the TPO gene were amplified by PCR. The PCR products were sequenced by Sanger. Results: Two possibly pathogenic mutations of the TPO gene were detected: c.2242G>A (p.Val748Met) and c.1103C>T (p.Pro368Leu). These mutations were detected in 2 of 12 patients (16.6%): 1 was compound heterozygous c.1103C>T/c.2242G>A, and the other was heterozygous for c.2242G>A. In the diagnostic confirmation test, both patients presented diffuse hyper-uptake goiter on thyroid scintigraphy and high TSH in venous blood (>190 uIU/mL). Conclusions: The frequency of patients with possibly pathogenic mutations in TPO with CHD was 16.6%. Its study would allow for genetic counseling to be offered to the families of affected patients.

A higher incidence of primary congenital hypothyroidism (CH) has been related to increased sensitivity in neonatal screening tests. The benefit of treatment in mild cases remains a topic of debate. We evaluated the impact of reducing the blood-spot TSH cut-off (b-TSH) from 10 (Group 2) to 6 mIU/L (Group 1) in a public neonatal screening program. During the study period, 40% of 123 newborns with CH (n = 162,729; incidence = 1:1323) had b-TSH between 6 and 10 mIU/L. Group 1 patients had fewer clinical signs (p = 0.02), lower serum TSH (p < 0.01), and higher free T4 (p < 0.01) compared to those in Group 2 at diagnosis. Reducing the b-TSH cut-off from 10 to 6 mIU/L increased screening sensitivity, allowing a third of diagnoses, mainly mild cases, not being missed. However, when evaluating the performances of b-TSH cut-offs (6, 7, 8, 9, and 10 mIU/L), the lower values were associated with low positive predictive values (PPVs) and unacceptable increased recall rates (0.57%) for a public health care program. A proposed strategy is to adopt a higher b-TSH cut-off in the first sample and a lower one in the subsequent samples from the same child, which yields a greater number of diagnoses with an acceptable PPV.

UNASSIGNED: Defects in any thyroid hormone synthesis steps cause thyroid dyshormonogenesis (THD). THD due to thyroglobulin (TG) gene variants is a cause of congenital hypothyroidism (CH) with a wide clinical spectrum, ranging from mild to severe permanent hypothyroidism. We present high-throughput sequencing results of patients with TG variants.
UNASSIGNED: A CH high-throughput sequencing-panel of the main genes involved in the regulation of thyroid hormonogenesis was performed to identify those TG variants that may be related to patient THD phenotype.
UNASSIGNED: We identified 21 TG gene variants in 19 patients (11.8%) which could explain their phenotype. Ten of those (47.6%) were not previously described. CH was biochemically severe in these 19 patients. Eight of them were reevaluated after one month of discontinuing LT4 treatment and all had severe permanent hypothyroidism. We also identified another 16 patients who presented heterozygous TG variants, of whom, at reevaluation, five had mild permanent and only one had severe permanent hypothyroidisms.
UNASSIGNED: In this study, 10 novel and 11 previously reported variants in the TG gene have been identified that could explain the phenotype of 19 patients from non-consanguineous families from a large THD cohort. Although not all these TG gene variants can explain all the patients\' THD phenotypes, some of them had severe or mild permanent hypothyroidism at reevaluation.

Congenital hypothyroidism (CHT) is a diverse condition with various genetic etiologies. This study aimed to investigate the utility of next-generation sequencing (NGS) analysis in guiding treatment decisions and predicting prognosis for CHT patients with gland in situ (GIS). A retrospective analysis was conducted on 33 CHT patients with GIS who underwent NGS analysis at a single institution between 2018 and 2023. Patients were classified as having permanent (PCH), transient congenital hypothyroidism, or ambiguous congenital hypothyroidism (ACH) CHT based on their response to levothyroxine discontinuation at 3 years of age. Among the 33 patients, genetic variants were identified in 26, with the most prevalent variants found in DUOX2 (26.92%), TSHR (30.77%), TG (19.35%), and DUOXA2 (19.23%). Patients with high initial thyroid-stimulating hormone levels (>50 mIU/L) and low free thyroxine levels (<0.89 ng/dL) at diagnosis tended to have compound heterozygous or homozygous variants in DUOX2, DUOXA2, and TG, and were more likely to develop PCH. In contrast, patients with heterozygous variants in these genes often exhibited ACH. TSHR variants were associated with diverse clinical manifestations, ranging from PCH to ACH, and were more common in patients with initial thyroid-stimulating hormone levels <50 mIU/L. The study highlights the potential utility of NGS analysis in predicting the clinical course and guiding treatment decisions for CHT patients with GIS. Genetic analysis may aid in determining the appropriate duration of levothyroxine therapy and monitoring strategies, particularly in cases where traditional clinical indicators are inconclusive.