Search Results (6)

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. Full article

In recent years, variants in immunoglobulin superfamily member 1 (IGSF1) have been associated with congenital hypopituitarism. Initially, IGSF1 variants were only reported in patients with central hypothyroidism (CeH) and macroorchidism. Later on, IGSF1 variants were also reported in patients with additional endocrinopathies, sometimes without macroorchidism. We studied IGSF1 as a new candidate gene for patients with combined CeH and growth hormone deficiency (GHD). We screened 80 male and 14 female Dutch patients with combined CeH and GHD for variants in the extracellular region of IGSF1, and we report detailed biomedical and clinical data of index cases and relatives. We identified three variants in our patient cohort, of which two were novel variants of unknown significance (p.L570I and c.1765+37C>A). In conclusion, we screened 94 patients with CeH and GHD and found variants in IGSF1 of which p.L570I could be of functional relevance. We provide detailed phenotypic data of two boys with the p.C947R variant and their large family. The remarkable phenotype of some of the relatives sheds new light on the phenotypic spectrum of IGSF1 variants. Full article

Newborn screening (NBS) for congenital hypothyroidism (CH) started in the 1970s, with the introduction of radioimmuno assays (RIA) for the measurement of thyroxine (T4), and thyroid stimulating hormone (TSH). With the development of sensitive enzyme immune assays (EIA, FIA, FEIA), RIAs were replaced in the newborn screening laboratories. With the increasing number of analytes and centralization of NBS, there is a growing demand of total automation. In the course of method validation, two fully automated platforms for the determination of TSH in dried blood samples (DBS) were compared. The GSP from PerkinElmer (PE), and the NS2400 from Labsystems (LDx), together with the recommended test kits from both manufacturers. Both systems showed good performance, with recoveries, of 103.0% (LDx) and 98.5% (PE), and CVs for intra and interassay variations at various concentrations, between 4.3 and 15.7. Both assays had a good correlation (r² = 0.8814). With LDx/NS2400 platform, TSH values were in the mean 2.09 mU/L higher; however, the difference of both results from the mean was within ±2 SD, up to 30 mU/L, and only for values above 50 mU/L did the difference become bigger. However, this has no influence on the clinical interpretation. No false negative results were observed with either of the two platforms. TSH results obtained with the LDx/NS2400 were slightly higher than those obtained with the PE/GSP; however, the recall rate was lower: 0.059% compared to 0.063%. This can be explained by the much narrower distribution of TSH values. In conclusion, both platforms are equally suitable for medium and large NBS laboratories. However, due to the more open structure the LDx/NS2400 platform has a lot of advantages compared to the totally closed PE/GSP platform. Full article

Hypothyroxinemia of prematurity increases the rate of false-positive results in total thyroxine (tT4)-based screening programs for congenital hypothyroidism. The use of specific cutoff values for preterm infants has been proposed, but data on tT4 reference ranges in this population are limited. The primary aim was to establish reference percentiles for tT4 in dried blood spots among Mexican preterm infants. Secondary aims included a comparison of the change of tT4 concentrations over time according to gestational age and to discuss its impact on tT4-based screening programs. This was a retrospective cohort study; 1561 preterm infants were included. Percentile 10th for tT4 concentration at 24–27, 28–30, 31–34, and 35–36 weeks of gestational age, measured in the first week of life was: 47.6, 56.6, 82.3, and 117.1 nmol/L, respectively. tT4 concentrations were compared in three different time points: first week of life, 2–3 weeks of life, and term-corrected gestational age (38 weeks of gestation), progressively increased in infants below 30 weeks, remained stable in infants from 31 to 34 weeks, and decreased in late preterm newborns (35–36 weeks). This study suggests that preterm infants may require the use of lower tT4 cutoff values in newborn screening. Full article

Background: Congenital hypothyroidism (CH) is an endocrine disease with a precocious significant impairment of growth and neuromotor development. Thyroid hormones are essential for central nervous system development, maturation, and myelination. Furthermore, thyroid hormone deficiency affects the function of several systems, including the musculoskeletal system. The disease has a significant incidence in the general population (1:3000–1:2000 newborns in Italy). The aim of the present study was to evaluate any differences in upper and lower limb strength, body sway, and plantar loading distribution in children with CH compared to healthy children. Methods: In this study, the case group was composed of children with CH (CHG), while the control group included healthy children (CG). Both groups comprised 19 children (CHG: female = 12; CG: female = 9). The maximum isometric handgrip strength and explosive-elastic lower limb strength were assessed with the handgrip test and the Sargent test, respectively. The stabilometric and baropodometric analyses were used to measure the Center of Pressure displacements and the plantar loading distribution between feet, respectively. The differences between groups were analyzed by a univariate analysis of covariance using as covariates weight and height with the significant level set at < 0.05. Results: We found that CHG children were shorter and thinner than CG ones (p < 0.05). No significant difference in the upper and lower limb strength was found between groups. CHG exhibited a significant greater Sway Path Length (p < 0.01) and Ellipse Surface (p < 0.05) than CG. Moreover, CHG displayed an asymmetric plantar loading distribution with a significant lower percentage in the right than in the left foot (p < 0.05). Moreover, a significant lower plantar loading percentage in the right foot of CHG than in the right foot of CG was observed (p < 0.05). Conclusions: These findings seem to suggest that CH does not affect muscle strength in early treated children. However, these patients show poor postural control ability and asymmetric plantar loading distribution. Increasing the physical activity in these children could improve their body posture. Full article

(1) Background: Central congenital hypothyroidism (CCH) is a rare endocrine disorder that can be caused by mutations in the β-subunit of thyrotropin (TSHB). The TSHB mutation C105Vfs114X leads to isolated thyroid-stimulating-hormone-(TSH)-deficiency and results in a severe phenotype. The aim of this study was to gain more insight into the underlying molecular mechanism and the functional effects of this mutation based on two assumptions: a) the three-dimensional (3D) structure of TSH should be modified with the C105V substitution, and/or b) whether the C-terminal modifications lead to signaling differences. (2) Methods: wild-type (WT) and different mutants of hTSH were generated in human embryonic kidney 293 cells (HEK293 cells) and TSH preparations were used to stimulate thyrotropin receptor (TSHR) stably transfected into follicular thyroid cancer cells (FTC133-TSHR cells) and transiently transfected into HEK293 cells. Functional characterization was performed by determination of Gs, mitogen activated protein kinase (MAPK) and Gq/11 activation. (3) Results: The patient mutation C105Vfs114X and further designed TSH mutants diminished cyclic adenosine monophosphate (cAMP) signaling activity. Surprisingly, MAPK signaling for all mutants was comparable to WT, while none of the mutants induced PLC activation. (4) Conclusion: We characterized the patient mutation C105Vfs114X concerning different signaling pathways. We identified a strong decrease of cAMP signaling induction and speculate that this could, in combination with diverse signaling regarding the other pathways, accounting for the patient’s severe phenotype. Full article