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Background: Congenital hypothyroidism (CH) is one of the most prevalent endocrine disorders in children. According to the literature, there is a high prevalence of other anomalies and syndromes in infants diagnosed with CH. Objectives: This study finds the prevalence of concurrent anomalies and the prevalence of each one. Methods: This was a systematic review study based on the preferred reporting items for systematic reviews and meta-analysis (PRISMA). The research question was the comparison of children with and without CH in terms of having extra-thyroidal congenital anomalies. A systematic literature search through PubMed, Science Direct, Scopus, and the Web of Science databases was done using the following key words: Congenital hypothyroidism, birth defects, congenital anomalies. Results: From the 655 initially retrieved articles, 24 articles remained, and 4 additional references were found by reviewing the references of the final articles. Finally, 28 articles were selected. The prevalence of extra-thyroidal anomalies ranged from 5% to 50% in girls and from 4% to 80% in boys. Meanwhile, 20% of the permanent CH patients and 13% of the patients with transient CH had extra-thyroidal congenital malformations. Cardiac anomalies were more prevalent in girls (female to male ratio=1.6 [0.7 to 5.5]), and urogenital anomalies were more reported in boys. Most of the studies did not report the association between non-thyroidal anomalies and thyroid stimulating hormone, gender, etiology of CH, and transient and permanent CH. Conclusions: Congenital anomalies are more common in CH patients compared with the general population, even in the absence of congenital syndromes or chromosomal abnormalities. The most common anomalies are cardiac, craniofacial, urogenital, and nervous system.

Congenital hypothyroidism (CH) is the most common cause of endocrinopathy in the newborn Its incidence lies between 1 in 3,000 and 1 in 2,000, However, congenital goiter is a rare form of presentation. Hypothyroidism secondary to autoimmune etiology is extremely rare, with an incidence of 1:84.700–1:31.000 newborns. Anti-thyroid peroxidase antibodies (TPOAb) are able to cross the placenta but rarely induce hypothyroidism in the newborn, much less goiter. A case of congenital goiter in a male newborn secondary to maternal high TPOAb levels is reported. The mother was diagnosed of Hashimoto thyroiditis prior to the pregnancy. At birth, a grade 3 goiter was detected in the newborn. Laboratory testings revealed hypothyroidism with free thyroxine of 7.6 pmol/L, thyroid-stimulating hormone of 108 mUI/L and high TPOAb levels. Treatment with Levothyroxine was started the second day of life with progressive thyroid function normalization. Neurological development has been normal until the date.

Introduction: Maternal thyroid disease is considered as a risk factor for abnormal thyroid function at birth, as well as for long-term morbidity in offspring. The potential harmful effects on the neonate had led to the clinical practice of thyroid function assessment in infants born to mothers with thyroid disease during pregnancy. In this study, we evaluated the usefulness of routine thyroid function tests for every newborn of a mother with thyroid dysfunction. Methods: Data were collected retrospectively from the medical files of mothers diagnosed with thyroid disease and their infants (496 mother–neonate pairs). All mothers with diagnosed thyroid disease who gave birth in the years 2016–2019 at our medical center were included. Results: Hypothyroidism was the most common maternal diagnosis (91.4%), among which 48.7% had Hashimoto’s thyroiditis. Hyperthyroidism was diagnosed in 8.6% of the cohort – 71.6% of them with Graves’ disease. None of the newborns was diagnosed with congenital hypothyroidism in the screening program. Thyroid-stimulating hormone was >10 mIU/L in 14.6% and >20 mUI/L in 2.2%; all had free thyroxine within normal range. Serum thyroid function test identified four infants with thyroid disease; two had congenital hypothyroidism not related to maternal thyroid disease, one had transient familial congenital hypothyroidism and one had neonatal Graves’ disease. Conclusions: Thyroid function testing for all newborns of mothers with thyroid dysfunction seems redundant. However, in cases of congenital hypothyroidism in siblings, thyroid function test, in addition to newborn thyroid screening, is recommended, and more careful follow-up is indicated. In maternal Graves’ disease, thyroid function test on days 2–3 of life is recommended.

Newborn screening (NBS) for congenital hypothyroidism (CH) was introduced in Switzerland in 1977, which allowed for the preclinical, biochemical diagnosis. The aim of this study was to evaluate the prevalence of transient CH (tCH) in the canton of Zurich. In this analytical cohort study, all newborns born in the canton of Zurich, between the 1st of January 2000 and the 30st of June 2016, with a TSH value above 15 mU/L (whole blood) were included. There were 115 cases out of 247,918 babies born during the study period. However, 23 cases had to be excluded due to missing data. The definite diagnosis was made after a thyroxine withdrawal at 2 years of age. The total prevalence of confirmed CH and the female to male ratio (f/m) were 1:2695 and 2.17:1; for permanent CH (pCH), 1:3443 and 2.8:1; and for tCH, 1:12,396 and 1:1, respectively. The TSH value was significantly higher in pCH compared to tCH, at 130.3 (62.9–171.9) and 36.4 (26.5–53.3) (median and interquartile range), respectively (p < 0.001). The prevalences found for congenital hypothyroidism and its transient form are comparable to previous studies. TSH concentration at birth was predictive for the further course of the disease. Low birth weight correlated with a tCH, whereas low gestational age did not. The dominance of the female sex in congenital hypothyroidism is supported by a gender ratio of 2.17:1. [ABSTRACT FROM AUTHOR]

Two endocrine disorders, congenital hypothyroidism (CH) and congenital adrenal hyperplasia (CAH), when untreated, can have devastating, irreversible and fatal outcomes. Permanent cognitive impairment, growth failure and dysmorphic appearance are seen in congenital hypothyroidism (CH) and early infant death in males with salt wasting CAH (as most females are discovered by presence of atypical genital appearance, while males appeared normal). Newborn screening (NBS) for CH was developed with broader engagement of centers, and was more rapidly adopted throughout the US and other large or developed countries, while NBS for CAH was pioneered by relatively few and was not fully adopted in the US until the initiation of Universal Expanded Newborn Screening Panel in 2005. Advances in genetic understanding of CH and CAH continue with NBS. Cost–benefit analysis, showing CH NBS as more successful than CAH NBS, may not fully recognize the cost of a life saved with CAH NBS. Early treatment of CH is much simpler with taking a pill a day unlike CAH requiring multiple medication doses, and possibly surgery apart from enteral and parenteral stress doses during adrenal crisis. CAH management outcomes with gender identity matters in persons with atypical genital appearance and androgen effects are still being studied.

The aim of the current prospective randomized control study was to assess efficacy, safety, and non-inferiority of a new liquid L-thyroxine formulation dissolved in glycerol and water (T4® drops, produced by a Greek pharmaceutical Company, Uni-Pharma, Athens, Greece) in comparison to the standard Tablets form (T4® tablets, Uni-Pharma, Athens, Greece) in the substitutive treatment of children with congenital hypothyroidism (CH). Thirty-nine children with CH, aged 3–12 years old, were enrolled in the study, after parental Informed Consent has been obtained, while three patients were lost from follow-up. At baseline, all participants had normal thyroid-stimulating hormone (TSH) and Free T4 values. Patients were randomly subdivided according to the assigned treatment in Group A (n=17)-Tablet Form and Group B (n=19)-Liquid Form. TSH and Free T4 levels were evaluated at 0, 2, 4, and 6 months. TSH values showed a statistically significant difference (p=0.017) between groups only at six months (Group A having higher TSH levels than Group B, albeit within the normal range), while Free T4 levels had no statistical difference throughout the six month study period and were always within the normal range. Moreover, dose adjustments were more frequent in Group A (p=0.038) during the six months. Liquid L-thyroxine substitutive treatment exhibited no statistically significant adverse effects in comparison to the widely used tablets. Levothyroxine (LT4) as liquid solution formulation is safe and noninferior to the widely used L-thyroxine Tablets, with less need for dose adjustment, and can therefore be safely used in the treatment of children with CH. [ABSTRACT FROM AUTHOR]

Backgrounds: As a crucial enzyme in thyroid hormone synthesis, the genetic defective thyroid peroxidase (TPO) was one of the main genetic factors leading to congenital hypothyroidism (CH). Methods: Mutations in the TPO gene were screened and identified in 219 patients with CH from northwest China by using high-throughput sequencing and bioinformatics analysis. The biological function of detected variants was studied by in vitro experiments and homology modeling. Results: Nineteen rare variants, including seven novel ones, were detected in 17 of 219 patients (7.8%). Most cases were detected with one single heterozygous variant, and only two patients were detected with multiple variants, i.e., compounds for (1) IVS7-1G>A, p.Ala443Val, and p.Arg769Trp and (2) p.Asn592Ser and p.Asn798Lys. The biological function of the four missense mutations (i.e., p.Ala443Val, p.Arg769Trp, p.Asn592Ser, and p.Asn798Lys) they carried were further studied. Experimental data showed that these four mutations did not affect the protein expression level of the TPO gene but remarkably reduced the peroxidase activity toward guaiacol oxidation, retaining 8–32% of activity of the wild-type protein. The comparison of the predicted 3-D structures of wild-type and mutant TPO proteins showed that these four amino acid substitutions changed the non-covalent interactions of studied residues that might alter the structure and function of the TPO protein. Conclusion: This study was the first to analyze the TPO mutation spectrum of patients with CH in northwest China. Our data indicated that the TPO mutation was not a common reason to cause CH in China. The functional data may help to clarify the structure-function relationship of the TPO protein and provide further evidence for the elucidation of the genetic etiology of CH. [ABSTRACT FROM AUTHOR]

BackgroundsAs a crucial enzyme in thyroid hormone synthesis, the genetic defective thyroid peroxidase (TPO) was one of the main genetic factors leading to congenital hypothyroidism (CH).MethodsMutations in the TPO gene were screened and identified in 219 patients with CH from northwest China by using high-throughput sequencing and bioinformatics analysis. The biological function of detected variants was studied by in vitro experiments and homology modeling.ResultsNineteen rare variants, including seven novel ones, were detected in 17 of 219 patients (7.8%). Most cases were detected with one single heterozygous variant, and only two patients were detected with multiple variants, i.e., compounds for (1) IVS7-1G>A, p.Ala443Val, and p.Arg769Trp and (2) p.Asn592Ser and p.Asn798Lys. The biological function of the four missense mutations (i.e., p.Ala443Val, p.Arg769Trp, p.Asn592Ser, and p.Asn798Lys) they carried were further studied. Experimental data showed that these four mutations did not affect the protein expression level of the TPO gene but remarkably reduced the peroxidase activity toward guaiacol oxidation, retaining 8–32% of activity of the wild-type protein. The comparison of the predicted 3-D structures of wild-type and mutant TPO proteins showed that these four amino acid substitutions changed the non-covalent interactions of studied residues that might alter the structure and function of the TPO protein.ConclusionThis study was the first to analyze the TPO mutation spectrum of patients with CH in northwest China. Our data indicated that the TPO mutation was not a common reason to cause CH in China. The functional data may help to clarify the structure-function relationship of the TPO protein and provide further evidence for the elucidation of the genetic etiology of CH.

Background: Mutations in DUOX2 are the frequent cause of congenital hypothyroidism (CH), a common neonatal metabolic disorder characterized by great phenotypic variability. CH can be traditionally subclassified into two subtypes: thyroid dysgenesis (TD) and thyroid dyshormonogenesis. The objectives of this study were to analyze the genetic data of two familial CH cases, to elucidate the pathogenesis from the perspective of genetics and to review and summarize the previous findings. Methods: Targeted regions sequencing (TRS) technology covering all exons and intron-exon boundaries of 35 known and potential CH-related candidate target genes in combination with Sanger sequencing were performed to identify the likely pathogenic mutations of the six patients with familial CH. Results: In family 1, two DUOX2 missense mutations, namely, c.1060C>T/p.R354W in exon 10 and c.3200C>T/p.S1067L in exon 25, were found. Patient 1 (P1), P2 and P3 were transient CH (TCH) patients with eutopic thyroid glands of normal size and function. In family 2, only the mutation c.3200C>T/p.S1067L was identified. P4, P5, and P6 were diagnosed with permanent CH (PCH), which requires lifelong levothyroxine (L-T4) treatment. Furthermore, both P4 and P5 harbored properly located thyroid glands, whereas P6 had a mildly reduced gland. P1, P3, P6, and other family members carrying monoallelic or biallelic DUOX2 mutations showed no obvious abnormal clinical symptoms or signs, while P2, P4, and P5 showed umbilical hernias. Conclusions: The present study suggests that the phenotypic features resulting from DUOX2 mutations vary greatly. The p.R354W and p.S1067L alterations or the combination of the two alterations in DUOX2 are probably only predisposing to CH and DUOX2 may be involved in the morphogenesis of the human thyroid gland. Simultaneously, the compensation of DUOX1 for the loss of DUOX2, undetectable pathogenic mutations, the effects of environmental factors, epigenetic mechanisms and the involvement of multiple genes cannot be excluded in the explanation of these genetic results. [ABSTRACT FROM AUTHOR]

Congenital hypothyroidism (CH) is the most common cause of endocrinopathy in the newborn Its incidence lies between 1 in 3,000 and 1 in 2,000, However, congenital goiter is a rare form of presentation. Hypothyroidism secondary to autoimmune etiology is extremely rare, with an incidence of 1:84.700-1:31.000 newborns. Anti-thyroid peroxidase antibodies (TPOAb) are able to cross the placenta but rarely induce hypothyroidism in the newborn, much less goiter. A case of congenital goiter in a male newborn secondary to maternal high TPOAb levels is reported. The mother was diagnosed of Hashimoto thyroiditis prior to the pregnancy. At birth, a grade 3 goiter was detected in the newborn. Laboratory testings revealed hypothyroidism with free thyroxine of 7.6 pmol/L, thyroid-stimulating hormone of 108 mUI/L and high TPOAb levels. Treatment with Levothyroxine was started the second day of life with progressive thyroid function normalization. Neurological development has been normal until the date., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Català, Casas, Yeh, Josa-Eritja, Tirado-Capistros, Moliner and Carreras.)

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.

The purpose of this study was to define reference intervals for total thyroxine (tT4) in dried blood samples (DBSs) obtained for newborn screening. The aim of our study was to assess the possible benefit of measuring tT4 concentrations directly in DBSs obtained for newborn screening in premature and term-born infants. In order to have a sufficient number of samples for the extremely premature infants (4 stability in DBSs. We found that tT4 strongly correlated with gestational age (GA) in premature infants, highlighting the need for age-specific reference ranges. For term-born infants, the tT4 ranges did not vary significantly among different gestational ages, allowing for the use of one single reference range.

Congenital central hypothyroidism (C-CH) is a rare disease in which thyroid hormone deficiency is caused by insufficient thyrotropin (TSH) stimulation of a normally-located thyroid gland. Most patients with C-CH have low free thyroxine levels and inappropriately low or normal TSH levels, although a few have slightly elevated TSH levels. Autosomal recessive TSH deficiency and thyrotropin-releasing hormone receptor-inactivating mutations are known to be genetic causes of C-CH presenting in the absence of other syndromes. Recently, deficiency of the immunoglobulin superfamily member 1 (IGSF1) has also been demonstrated to cause C-CH. IGSF1 is a plasma membrane glycoprotein highly expressed in the pituitary. Its physiological role in humans remains unknown. IGSF1 deficiency causes TSH deficiency, leading to hypothyroidism. In addition, approximately 60% of patients also suffer a prolactin deficiency. Moreover, macroorchidism and delayed puberty are characteristic features. Thus, although the precise pathophysiology of IGSF1 deficiency is not established, IGSF1 is considered to be a new factor controlling growth and puberty in children.

Congenital hypothyroidism (CH) is the most common preventable cause of mental retardation in children. Diagnosis is difficult at birth without neonatal screening. Neonatal thyroid screening was established in Prilep, Republic of Macedonia as an integral part of the nationwide screening program. To estimate the prevalence of CH in this region, neonatal thyroid screening was performed on 9757 newborns, during the period 2002-2011. The DELFIA method was applied to measure the thyroid-stimulating hormone (TSH) concentration in dried blood spot samples on standard filter paper taken 48 hours after birth by heel-stick. The TSH cut-off level was 10 mU/L.

Objective Mutations in TSH receptor ( TSHR) are associated with TSH resistance, a genetic defect characterized by a heterogeneous phenotype ranging from severe hypothyroidism to subclinical hypothyroidism ( SCH). We assessed the clinical and hormonal pattern of TSHR variants in a series of pediatric patients, and the long-term outcome of growth, biochemical measurements of metabolism, and neuropsychological functions in TSHR mutations carriers. Design Observational, retrospective study. Patients Thirty four children (age 7 days to 11 years) and 18 adult carriers of TSHR variants. Measurements The TSHR gene was sequenced by PCR-amplified direct sequencing in 111 pediatric patients with slight to moderate elevation of TSH and normal FT4 levels. The study focused on the: auxological and biochemical parameters, thyroid ultrasound, bone age, bone mineral density ( BMD), and intellectual outcome ( IQ) were collected during the long follow-up (1-15 years). Results Seventeen different TSHR variants (eight novel) were identified in 34 of the 111 pediatric patients, with a high prevalence of familial cases (27/34). Neonatal screening for congenital hypothyroidism was positive in half of the TSHR carriers. Growth, IQ, BMD, and biochemical parameters were normal in all subjects. Twenty patients received L-T4 replacement therapy, in all cases before genetic analysis. After re-evaluation, six patients resumed L-T4 therapy: they were compound heterozygous, or single heterozygous and with associated conditions at risk of thyroid impairment ( SGA). No adults presented clinical features consistent with impaired thyroid function. Conclusions Children carriers of TSHR variants, regardless of L-T4 treatment, show regular growth and neuropsychological development, with no evident biochemical and US alterations. [ABSTRACT FROM AUTHOR]

The aim of the work was to assess the prevalence of cardiac anomalies in primary congenital hypothyroidism (PCH) patients. Fifty patients with PCH recruited after diagnosis by ultrasonography or scintigraphy (64% Dysgenesis, 36% Dyshormonogenesis). The prevalence of cardiac anomalies was 18%, with renal anomalies being 8%. There was no significant difference in the longitudinal follow-up of growth and sexual maturation between a hypothyroid with and without anomalies. Statistically significant difference was found with replacement therapy of both groups. Hence, echocardiography should be done to screen this birth defect as soon as possible so as to prevent or delay the possible complications. [Arch Clin Exp Surg 2013; 2(2.000): 85-91]

Background: Nurses have a major role in caring for congenital hypothyroidism (CH) neonates in the pre-analytic phase of the Newborn Screening Program (NSP) as well as at the post-analytic phase. Objectives: To assess performance of nurses working in the pre-analytic phase of the Egyptian NSP for CH at Kafr El-Dawar Health District, El-Behaira Governorate and to assess their knowledge regarding this program before and after implementation of educational sessions. Methods: Crosssectional and quasi-experimental designs were used to conduct the study in 39 health units, representing all health units in Kafr El-Dawar health district, and included 122 nurses working in these units. Observational checklist was used to assess their screening performance during collection of samples and their adherence to the program guidelines.The Knowledge was assessed before and after the application of an educational program using knowledge assessment sheet. Results: Adherent nurses' performance was observed at all heath centres (100%) regarding the following items: the use of appropriate filter paper in collecting the samples; the accuracy in writing cards information; disinfection of the heel; putting the used lancet in the safety box and sending sampling cards to lab in the same day (5 items out of 20 items). On the other hand, washing hands before every sampling was not done in 100% of observations. The lancet was used in the appropriate site in nearly two thirds of observations (74.6%).The sample cards were kept in its special rack in nearly 73.8% of observations. The screening cards were put in its envelope after drying in 81.1% of observations. Health education of mothers about CH in general and CH complications in particular were done with only 57.4% and 28.7% of cases respectively. It was not done about the symptoms of CH in 100% of the observations. There was a statistically significant improvement in nurses' Knowledge after the educational program. Recommendations: Continuous education programs should be mandatory for all nurses providing pre-analytical phase services of NSP for CH. In addition, adequate supervision, guidance and regular feedback by head nurses as well as availability of clinical protocols and guidelines are greatly needed to improve nurse's performance. To facilitate implementing the guidelines by nurses, adequate infection control materials should be available in units providing the service.

Thyroid dyshormonogenesis (DH) has recently been reported to be more frequently associated with mutations in the dual oxidase 2 (DUOX2) gene. The present study was aimed to investigate the prevalence, clinical, and molecular characteristics of congenital hypothyroidism (CH) caused by DUOX2 mutations in Guangzhou. A populationbased cohort of 156 patients with CH was recruited based on neonatal screening among 433 578 newborns born in Guangzhou from 2011 to 2012. Genetic analysis of DUOX2 was performed in 96 patients with suspected thyroid dyshormonogenesis (SDH) by PCR-amplified direct sequencing. Apart from 2 cases without ultrasonographic data, 118 (76.6 %) of the 156 patients were classified as SDH and 36 (23.4 %) as thyroid dysgenesis (TD) according to thyroid ultrasound at diagnosis. Genetic analysis revealed 23 different variants in 60 unrelated individuals (60/96, 62.5 %), including 13 novel variants that were absent from HGMD, dbSNP databases, and the 50 normal controls. The novel missense variants were predicted to be pathogenic by SIFT and Poly- Phen-2. The p.K530X was the most common mutation. Ninety-three percent of mutant alleles occurred in exons 5, 6, 9, 14, 17, 20, 25, 27, and 28. There were no significant differences in phenotypes between biallelic and monoallelic variants cases or between with-DUOX2 and non-DUOX2 variants cases. Most patients with DUOX2 defects (78.2 %) were transient CH. In conclusion, the prevalence of DUOX2 pathogenic variants was high (62.5 %) in this cohort. Thirteen novel probably pathologic variants were reported. The p. K530X was the most common mutation in the Chinese population. There was no correlation between DUOX2 genotypes and clinical phenotypes. [ABSTRACT FROM AUTHOR]

Background: In order to accurately interpret neonatal thyroid function tests (TFTs), it is necessary to have population specific reference intervals (RIs) as there is significant variation across different populations possibly due to genetic, environmental or analytical issues. Despite the importance of RIs, globally there are very few publications on RIs for neonatal TFTs primarily due to ethical and technical issues surrounding recruitment of neonates for a prospective study. To the best of our knowledge, this is the first report from Africa on neonatal RIs for TFTs. Methods: We used hospital based data largely derived from neonates attending the wellness clinic at the Aga Khan University Hospital Nairobi (AKUHN) where screening for congenital hypothyroidism is routinely done. Specifically we derived age and gender stratified RIs for free thyroxine (fT4) and thyroid stimulating hormone (TSH) which had been analyzed on a Roche e601 analyzer from 2011 to 2013. Determination of reference intervals was done using a non-parametric method. Results: A total of 1639 and 1329 non duplicate TSH and fT4 values respectively were used to derive RIs. There was a decline in TSH and fT4 levels with increase in age. Compared to the Roche RIs, the derived RIs for TSH in neonates aged 0-6 days and those aged 7-30 days had lower upper limits and narrower RIs. The fT4 lower limits for neonates less than 7 days and those aged 7-30 days were higher than those proposed by Roche. There was a significant difference in TSH RIs between male and female neonates aged less than 15 days. No gender differences were seen for all other age stratifications for both TSH and fT4. Appropriate age and gender specific RIs were subsequently determined. Conclusion: The AKUHN derived RIs for fT4 and TSH revealed similar age related trends to what has been published. However, the differences seen in upper and lower limits across different age stratifications when compared to the Roche RIs highlight the need for population specific RIs for TFTs especially when setting up a screening programme for congenital hypothyroidism. We subsequently recommend the adoption of the derived RIs by the AKUHN laboratory and hope that the RIs obtained can serve as a reference for the African population. [ABSTRACT FROM AUTHOR]

Background: The morphological and biochemical phenotype of PAX8 mutation in patients with congenital hypothyroidism (CH) is variable. The contribution of mutations in PAX8 gene in children with CH and dysgenetic thyroid glands still remains a subject of interest for researchers. Patients and methods: Some 48 children (37 girls and 11 boys) with CH associated with thyroid ectopy (n=22), agenesis (n=10), hypoplasia (n=6), or thyroid dysgenesis of unknown cause (n=10) were enrolled. The study participants were born in south-eastern Poland in the years 1993-2012 and were selected for neonatal mass screening for CH. DNA was extracted from peripheral blood samples using Master Pure DNA Purification Kit (Epicentre Biotechnologies, Madison, WI, USA). The 12 exons of the PAX8 gene along with their exon-intron boundaries were amplified and sequenced by the Sanger method. Capillary electrophoresis was run on ABI 3500 (Applied Biosystems, Carlsbad, CA, USA). Results: Novel heterozygous transition in exon 3 (c.68G>A) was detected in a 3-year-old girl with a thyroid hypoplasia. This substitution was not identified in the patient's parents (de novo event). Additionally, a novel genetic variant in 3′UTR region of exon 12 (c.*416C>T) occurred in a 3-year-old boy with ectopic thyroid tissue and concomitant congenital urogenital malformation. This heterozygous variant was also detected in other healthy family members. Thirteen well-described single nucleotide polymorphisms were revealed in the PAX8 gene. Conclusions: The study reports on the occurrence of two novel heterozygous substitutions in the PAX8 gene. Estimation of the contribution of the revealed c.68G>A variant to the etiology of CH in a girl with hypoplastic thyroid requires further functional analysis. [ABSTRACT FROM AUTHOR]

Introduction: Among endocrine disorders commonly encountered in pediatric age group, thyroid diseases are more frequent. Congenital hypothyroidism is one of the major problems in this age with worldwide incidence of 1:3000-4000 live birth and in India it is 1:2500-2800. Objectives: The aim of this study is to know the prevalence of thyroid diseases in newborn and children by hormonal evaluation. Methodology: We have studied 50 children suspected of having signs and symptoms of thyroid diseases. Hormonal evaluation was done by the estimation of serum TSH, T3 and T4. Results: Out of total 50 children, 16 were detected with abnormal hormone level and diagnosed having thyroid diseases. Out of 16 affected children, 4 had congenital hypothyroidism (25%), 6 had subclinical or acquired hypothyroidism (37.5%), 3 had autoimmune thyroiditis (18.75%) and 3 had goiter with graves disease (18.75%). Conclusion: Congenital hypothyroidism is one of the major preventable thyroid disease if diagnosed early. Other thyroid diseases commonly seen in pediatric age are subclinical hypothyroidism, autoimmune thyroiditis, goiter and rarely hyperthyroidism.

Objective: To determine the diagnostic and predictive value of ultrasound and radioisotope scans of the thyroid, alone and in combination, during a single visit after initial referral by the screening laboratory with thyroid-stimulating hormone (TSH) elevation. Study design: Retrospective blind review of ultrasound and radioisotope images followed by final diagnosis based on clinical features, biochemistry, imaging, and molecular genetic study. Results: Infants (n = 97; 61 female) with median birthweight 3.38 kg (range 2.04-4.86) and gestation 40 weeks (range 33-42), underwent successful dual thyroid ultrasound and technetium-99m pertechnetate radioisotope scan in a single center. Combined scanning at the initial visit resulted in a correct final diagnosis in 79 of 97 (81%) cases. One patient was misdiagnosed initially as having athyreosis as the result of delayed radioisotope scan and the diagnosis of ectopia made later on diagnostic challenge. The specificity/sensitivity for radioisotope scan and for ultrasound was as follows: 100%/97% and 100%/55% for ectopia (n = 39); 81%/100% and 54%/100% for athyreosis (n = 18); and 89%/90% and 80%/95% for dyshormonogenesis (n = 20). Neither modality, alone or in combination, predicted final diagnosis in eutopic glands due to hypoplasia (n = 4), transient TSH elevation (n = 12), and status still uncertain (n = 4). Conclusion: More than 80% of newborn infants with TSH elevation can be diagnosed correctly on initial imaging with combined radioisotope scan and ultrasound. Ultrasound cannot reliably detect thyroid ectopia. Radioisotope scan, especially if performed late, may show no uptake despite the presence of a eutopic gland. [Copyright &y& Elsevier]

Introduction: Maternal thyroid disease is considered as a risk factor for abnormal thyroid function at birth, as well as for long-term morbidity in offspring. The potential harmful effects on the neonate had led to the clinical practice of thyroid function assessment in infants born to mothers with thyroid disease during pregnancy. In this study, we evaluated the usefulness of routine thyroid function tests for every newborn of a mother with thyroid dysfunction., Methods: Data were collected retrospectively from the medical files of mothers diagnosed with thyroid disease and their infants (496 mother-neonate pairs). All mothers with diagnosed thyroid disease who gave birth in the years 2016-2019 at our medical center were included., Results: Hypothyroidism was the most common maternal diagnosis (91.4%), among which 48.7% had Hashimoto's thyroiditis. Hyperthyroidism was diagnosed in 8.6% of the cohort - 71.6% of them with Graves' disease. None of the newborns was diagnosed with congenital hypothyroidism in the screening program. Thyroid-stimulating hormone was >10 mIU/L in 14.6% and >20 mUI/L in 2.2%; all had free thyroxine within normal range. Serum thyroid function test identified four infants with thyroid disease; two had congenital hypothyroidism not related to maternal thyroid disease, one had transient familial congenital hypothyroidism and one had neonatal Graves' disease., Conclusions: Thyroid function testing for all newborns of mothers with thyroid dysfunction seems redundant. However, in cases of congenital hypothyroidism in siblings, thyroid function test, in addition to newborn thyroid screening, is recommended, and more careful follow-up is indicated. In maternal Graves' disease, thyroid function test on days 2-3 of life is recommended.

Medications administered during the neonatal period may mask the diagnosis of congenital hypothyroidism. Herein, we report a case of undiagnosed congenital hypothyroidism while the infant was on treatment with dopamine. Given the inhibitory effect of dopamine on thyroid-stimulating hormone, a high index of suspicion for potential congenital hypothyroidism is needed in such neonates. [ABSTRACT FROM AUTHOR]

Objectives: The aim of the current prospective randomized control study was to assess efficacy, safety, and non-inferiority of a new liquid L-thyroxine formulation dissolved in glycerol and water (T4 ® drops, produced by a Greek pharmaceutical Company, Uni-Pharma, Athens, Greece) in comparison to the standard Tablets form (T4 ® tablets, Uni-Pharma, Athens, Greece) in the substitutive treatment of children with congenital hypothyroidism (CH)., Methods: Thirty-nine children with CH, aged 3-12 years old, were enrolled in the study, after parental Informed Consent has been obtained, while three patients were lost from follow-up. At baseline, all participants had normal thyroid-stimulating hormone (TSH) and Free T4 values. Patients were randomly subdivided according to the assigned treatment in Group A (n=17)-Tablet Form and Group B (n=19)-Liquid Form. TSH and Free T4 levels were evaluated at 0, 2, 4, and 6 months., Results: TSH values showed a statistically significant difference (p=0.017) between groups only at six months (Group A having higher TSH levels than Group B, albeit within the normal range), while Free T4 levels had no statistical difference throughout the six month study period and were always within the normal range. Moreover, dose adjustments were more frequent in Group A (p=0.038) during the six months. Liquid L-thyroxine substitutive treatment exhibited no statistically significant adverse effects in comparison to the widely used tablets., Conclusions: Levothyroxine (LT4) as liquid solution formulation is safe and noninferior to the widely used L-thyroxine Tablets, with less need for dose adjustment, and can therefore be safely used in the treatment of children with CH., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

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 (r 2 = 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.

Background: This study aimed to explore the relationship between the phenotype and genotype of congenital hypothyroidism (CH) caused by dual oxidase 2 (DUOX2) mutation in Chinese children, and to investigate the genetic causes of permanent and transient hypothyroidism through next-generation genetic testing technology and long-term clinical follow-up data., Methods: We recruited 61 patients with thyroid stimulating hormone (TSH) levels of >10 mIU/mL during newborn screening, clinical diagnosis of CH, and L-thyroxine (L-T4) oral treatment within 1 month of birth; they were followed up until the present. All CH infants and their parents were genotyped using whole-exome sequencing (WES); DUOX2 variants were detected in 20 infants, and the longitudinal prognosis, genotype, and phenotype correlations were analyzed., Results: Biallelic DUOX2 mutations were detected in 20 participants. All of them were born full term. All patients were treated with L-T4 when diagnosed with CH; 9 of them stopped L-T4 eventually before 3 years old; and 2 were treated with a reduced dose of L-T4 (12.5 µg per day). The others were still treated with L-T4 at a dose of 37.5-87.5 µg per day. Of these 20 participants, 5 carried an R1110Q variant and 5 carried K530X variants. A total of 7 novel variants were discovered in our cohort. The variants carried in transient CH patients were located extracellularly and not near the functional domain., Conclusions: Most CH patients with DUOX2 mutations were those with transient or subclinical CH. The R1110Q, R885L, and K530X were the most common variants in our Chinese cohort. The R1110Q and K530X variants may play a founder effect in the transient CH. The R885L variant may play a benign role in transient CH. Intracellular variants or those near the functional domain may cause permanent CH., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-7165). The authors have no conflicts of interest to declare., (2020 Annals of Translational Medicine. All rights reserved.)

The purpose of this study was to define reference intervals for total thyroxine (tT 4 ) in dried blood samples (DBSs) obtained for newborn screening. The aim of our study was to assess the possible benefit of measuring tT 4 concentrations directly in DBSs obtained for newborn screening in premature and term-born infants. In order to have a sufficient number of samples for the extremely premature infants (<30 weeks), we set up a retrospective study, measuring the concentrations in DBSs collected over the previous 21 weeks. This time frame was a result of the included miniature study of tT 4 stability in DBSs. We found that tT 4 strongly correlated with gestational age (GA) in premature infants, highlighting the need for age-specific reference ranges. For term-born infants, the tT 4 ranges did not vary significantly among different gestational ages, allowing for the use of one single reference range., Competing Interests: Conflicts of InterestThe authors declare no conflict of interest., (© 2020 by the authors.)

Transient congenital hypothyroidism (CH) refers to a temporary deficiency of thyroid hormone identified after birth, with low thyroxine (T4) and elevated thyrotropin (TSH), which later recovers to improved thyroxine production, typically in first few months of infancy. Approximately 17% to 40% of children diagnosed with CH by newborn screening (NBS) programs were later determined to have transient hypothyroidism. Causes of transient CH are prematurity, iodine deficiency, maternal thyrotropin receptor blocking antibodies, maternal intake of anti-thyroid drugs, maternal or neonatal iodine exposure, loss of function mutations and hepatic hemangiomas. The classic clinical symptoms and signs of CH are usually absent immediately after birth in vast majority of infants due to temporary protection from maternal thyroxine. NBS has been largely successful in preventing intellectual disability by early detection of CH by performing thyroid function tests in infants with abnormal screening results. In this review we present the evidence for decision making regarding treatment vs. withholding treatment in infants with transient CH and present a rational approach to identifying transient CH based on American Academy of Pediatrics (AAP) recommendation., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Medications administered during the neonatal period may mask the diagnosis of congenital hypothyroidism. Herein, we report a case of undiagnosed congenital hypothyroidism while the infant was on treatment with dopamine. Given the inhibitory effect of dopamine on thyroid-stimulating hormone, a high index of suspicion for potential congenital hypothyroidism is needed in such neonates., (© The Author [2015]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Congenital central hypothyroidism (C-CH) is a rare disease in which thyroid hormone deficiency is caused by insufficient thyrotropin (TSH) stimulation of a normally-located thyroid gland. Most patients with C-CH have low free thyroxine levels and inappropriately low or normal TSH levels, although a few have slightly elevated TSH levels. Autosomal recessive TSH deficiency and thyrotropin-releasing hormone receptor-inactivating mutations are known to be genetic causes of C-CH presenting in the absence of other syndromes. Recently, deficiency of the immunoglobulin superfamily member 1 (IGSF1) has also been demonstrated to cause C-CH. IGSF1 is a plasma membrane glycoprotein highly expressed in the pituitary. Its physiological role in humans remains unknown. IGSF1 deficiency causes TSH deficiency, leading to hypothyroidism. In addition, approximately 60% of patients also suffer a prolactin deficiency. Moreover, macroorchidism and delayed puberty are characteristic features. Thus, although the precise pathophysiology of IGSF1 deficiency is not established, IGSF1 is considered to be a new factor controlling growth and puberty in children.

Over 50 years after the introduction of a blood-spot newborn screening test using the bacterial-inhibition assay (BIA), blood-spot newborn screening has evolved into complex public service scientific programmes. For several decades, many patients with phenylketonuria (PKU), congenital hypothyroidism (CH), cystic fibrosis (CF) and hemoglobinopathy disorders have benefited from early intervention across the world. In the last 20 years, there have been great changes in laboratory techniques and high-throughput data handling meaning that a huge spectrum of disorders can be identified from an increasing population. This coupled with the fact that there are an increasing number of therapies for specific rare disorders mean that health services may become inundated with complex and expensive demands in the future. Some of these issues have been realised in the implementation of multiplex assay such as electrospray tandem mass spectrometry (MSMS) programmes but will be much more exaggerated if genomic sequencing screening becomes a reality. In this context, the core-principles for implementation of newborn screening tests remain as important today as they have in the past when new tests are considered as part of the blood-spot screening programme.

In Sapporo, Japan, a neonatal screening program for congenital hypothyroidism (CH) has employed measurement of free thyroxine (T4) and TSH in the same filter-paper blood spot. This system has enabled us to identify primary CH and central CH during the neonatal period. The aim of this study was to clarify the prevalence and clinical characteristics of central CH. For this purpose, the screening program requested serum from infants with free T4 concentrations below the cut off value regardless of the TSH levels. Between January 2000 and December 2004, 83,232 newborns were screened and six central CH patients were detected as a result of follow-up of low free T4 and non-elevated TSH screening (1:13,872). This frequency is higher than in other studies. Four patients showed multiple pituitary hormone deficiency with pituitary malformations on magnetic resonance imaging. One patient was diagnosed as having Prader-Willie syndrome. The remaining patient was considered to have isolated central CH. Our study demonstrated that the frequency of central CH is 1:13,872. Free T4 measurement would also be advantageous in early recognition of multiple pituitary hormone deficiency.