Iodine plays a critical role in producing thyroid hormones essential for brain development. An imbalance of iodine, whether deficiency or excess, can disrupt thyroid function. Iodine-induced hypothyroidism is rare but has been reported, particularly in premature infants exposed to excess iodine. Currently, iohexol, a nonionic radiocontrast agent, has limited data but is considered compatible with breastfeeding. A small for gestation African American male neonate was born at 36 weeks and 3 days of gestation and admitted to the neonatal intensive care unit for respiratory distress and prematurity in the United States. Samples for Illinois newborn screens done at admission and repeated after 48 h of life were negative for thyroid abnormalities. On the infant's fifth day of life, the mother underwent a contrast-enhanced imaging study using iohexol, after which the infant received breast milk from days 5-11. On day 11, the neonate had an elevated thyroid-stimulating hormone (TSH) and low free thyroxine (T4) levels, consistent with hypothyroidism. Urine iodine level in the infant was checked and found to be elevated, prompting concern for the exposure to iodine in breastmilk. However, the need to increase the levothyroxine dose to achieve normal thyroid levels was not consistent with a transient effect such as iodine exposure. Genetic testing revealed a likely pathogenic intragenic deletion in the gene RPS6KA3, consistent with Coffin-Lowry syndrome, as well as two variants of unknown significance (VUS) in IYD. This case highlights the complex interplay between genetic factors and environmental influences in the development of neonatal hypothyroidism. While iodine contrast exposure through breast milk is generally considered safe, this case underscores the potential risks in preterm infants. Initially, iodine exposure through breastmilk was considered a likely contributor to thyroid dysfunction, but with further time and evaluation, congenital thyroid dysgenesis with underlying genetic findings complicated the diagnosis. This case demonstrates the importance of a comprehensive evaluation when working up thyroid dysfunction to exclude other potential etiologies before interrupting breastfeeding.

Congenital hypothyroidism (CH) may lead to irreversible neurological dysfunction of offspring by affecting hippocampal morphogenesis. The dentate gyrus (DG) is primarily the affected tissue by the CH, in which the dendritic spine density of gyrus granule cells (DGCs) is significantly reduced, thereby resulting in the cognitive impairment. The CaMKIV/CREB signaling pathway has been shown to mediate the deficient growth of DGCs dendritic spines, but the mechanism of CH in modulating the Ca2+-dependent CaMKIV is still elusive. CH model of rat pups was prepared by the supply of 0.02% methimazole in the drinking water of pregnant dams from the 9th day of gestation. The dendritic spine density of hippocampal DGCs was detected by Golgi staining before or after administration of drugs. Additionally, the expression of CH-mediated effectors in the hippocampus or primary neurons was determined by Western blot or RT-PCR, and the immunofluorescence or subcellular fractionation was used to examine the distribution of these factors. In the present study, the calcium influx-related channel TRPC6 was identified under the regulation of T3, which was significantly downregulated in the DGCs of CH pups. TRPC6 deficiency has been revealed to decrease the dendritic spine density by affecting intracellular calcium transients and the CaMKIV/CREB signaling pathway. Pharmacological activation of TRPC6 with hyperforin was shown to be efficient in the rescue of DGCs dendritic spines and in improving the cognitive function of CH pups. CH of the neonates leads to downregulation of TRPC6 in hippocampal dentate gyrus neurons, which affects calcium influx and decreases activation of CaMKIV and downstream signaling, thereby causing abnormal growth of DGCs' dendritic spines and impaired cognitive function in the offspring. This study provides a new target for CH-mediated developmental abnormality of the hippocampus in the offspring.

Transient congenital hypothyroidism (TCH) refers to temporary deficiency of thyroid hormone identified after birth which later recovers to improved thyroxine production. Its prevalence in the Philippines has not been reported in a large-scale study. Its diagnosis remains difficult due to its numerous possible etiologies. Identifying the predictive factors of TCH may aid in earlier diagnosis and decreased risk of overtreatment. This study aimed to determine the predictive factors for TCH in children with congenital hypothyroidism (CH) detected by newborn screening (NBS) in the Philippines from January 2010 to December 2017. In this multicenter retrospective cohort study involving 15 NBS continuity clinics in the Philippines, medical records were reviewed, and clinical and laboratory factors were compared between children with TCH and those with permanent congenital hypothyroidism (PCH). Of the 2,913 children diagnosed with CH in the Philippines from 2010 to 2017, 1,163 (39.92%) were excluded from the study due to an unrecalled or lost to follow-up status, or a concomitant diagnosis of Down Syndrome. Among the 1,750 patients included in analysis, 6.97% were diagnosed with TCH, 60.80% were female, mean gestational age at birth was 38 weeks, and mean birth weight was 2,841 grams. Confirmatory thyrotropin (TSH) was lower and confirmatory free thyroxine (FT4) was higher in the TCH group compared to those with PCH (TSH 32.80 vs 86.65 µIU/mL [p <0.0001]; FT4 9.90 vs 7.37 pmol/L [p 0.001]). The TCH group required lower L-thyroxine doses compared to the PCH group at treatment initiation and at 1, 2, and 3 years of age (initial 6.98 vs 12.08 µg/ kg/day [p <0.0001]; at 1 year 1.89 vs 4.11 µg/kg/day [p <0.0001]; at 2 years 1.21 vs 3.72 µg/kg/day [p <0.0001]; at 3 years 0.83 vs 3.45 µg/kg/day [p <0.0001]). Among those with TCH, mean serum TSH decreased significantly after treatment with L-thyroxine (32.80 vs. 6.55 µIU/ mL, p 0.0001). Other factors associated with TCH were results of thyroid ultrasonography (p 0.007), gestational age at birth (p 0.02), and maternal history of thyroid illness (p <0.0001). Of all the patients with confirmed congenital hypothyroidism via the newborn screening, 6.97% were diagnosed with transient CH. Factors associated with TCH are confirmatory TSH and FT4, L-thyroxine dose requirements, thyroid ultrasound findings, gestational age at birth, and a maternal history of thyroid illness.

Background/Objectives: Neonatal screening programmes for thyroid function testing, based on thyroid-stimulating hormone (TSH) assessment, detect both Permanent Congenital Hypothyroidism (PCH) and Transient Congenital Hypothyroidism (TCH). Maternal iodine-deficient dietary intake may result in compensatory neonatal TSH elevation; screening for Congenital Hypothyroidism (CH) is used as an indicator of the degree of iodine deficiency and of its control. In Greece, newborn screening for CH, using TSH measurement in dried blood spots (Guthrie card), began in 1979 through the Institute of Child Health (ICH). Although the general Greek population is considered iodine-replete, most pregnant Greek people are mildly iodine deficient according to the stricter WHO criteria. The aim of this retrospective study was to record the cases of TCH and the main causative factors over a 10-year period (2010-2019) in Greece, when the country was deemed to be iodine-replete. Methods: The number of births in Greece between 2010 and 2019 was retrieved from the Hellenic Statistical Authority (ELSTAT) archives: 952,109 births were recorded. The total number of newborns assessed through the ICH was 951,342 (99%). During this period, 22,391 newborns were identified to have TSH > 7 mIU/L after the second check on the initial card. Among those, 17,992 underwent retesting with a serum sample. Out of the retested newborns, 1979 were screened positive for CH and immediately began treatment with levothyroxine. We followed up with families, paediatricians, and paediatric endocrinologists to determine whether L-thyroxine therapy had been successfully discontinued for at least two months after the child's third birthday. Successful contact was achieved with 889 individuals. From this group, 329 children had successfully discontinued thyroxine, classified as TCH. Demographic data, including gender, gestational age, and birth weight, were collected from the archives of the ICH. Maternal data, including thyroid medication use and the presence of elevated thyroid autoantibodies during pregnancy and childbirth, were also recorded. Results: Logistic regression analysis revealed that, while controlling for all other predictor variables, the odds ratio of transient hypothyroidism was 2.078 (95% CI: 1.530 to 2.821) for prematurely born children compared to those born at term. The effects of other factors on TCH versus PCH were not significant. Conclusions: It seems that prematurity is the main factor contributing to Transient Congenital Hypothyroidism in Greece, a recently iodine-replete country.

Primary congenital hypothyroidism (CH) was classified into thyroid dysgenesis(TD) and thyroid dyshormonogenesis(TDH) based on pathophysiology, and into permanent CH (PCH) and transient CH (TCH) based on outcomes after age two. Despite progress in identifying pathogenic genes and genetic variants, the genetic characteristics and genotype-phenotype correlations remained insufficiently explored. This study aimed to identify novel variants, assess their pathogenicity, and analyze the correlation between genotype and phenotype. Clinical data from 97 pediatric patients with primary CH were collected (32 previously reported, 65 newly diagnosed). Next-generation sequencing was used to screen for variants, and statistical analysis was performed on the clinical data. Genetic etiologies were identified in 48% of patients, with 91% associated with TDH and 9% with TD. Six genes were involved: DUOX2 (68%), DUOXA2 (9%), TPO (9%), TG (6%), PAX8 (6%), and TSHR (2%). Seven novel variants were identified, including two pathogenic and five likely pathogenic. The TD-positive rate was significantly higher in the PCH group (43%) compared to the TCH group (0%). Genotype-phenotype analysis revealed that, at diagnosis, free thyroxine (FT4) levels were significantly lower in the genetic CH group compared to the carrier and wild-type groups. Additionally, the DUOX2 group had significantly higher free triiodothyronine (FT3) and FT4 levels at diagnosis compared to the non-DUOX2 group. This study highlighted the significant role of genetic factors in primary CH, with DUOX2 being the most common pathogenic gene. Seven novel variants were identified, expanding the genetic spectrum. TDH might have been the main pathogenic mechanism, and TD was closely linked to PCH. Genetic CH was associated with lower FT4 levels, while DUOX2 variants correlated with milder biochemical phenotypes, further supporting genotype-phenotype correlations.