Genetic Variability of the Paired Box Transcription Factor; PAX8 Gene: Guidance Towards Treatment Strategies in a Cohort of Congenital Hypothyroidism.

The contribution of PAX8 genetic variants to congenital hypothyroidism (CH) is not well understood. We aimed to study the genetic variability of exons 3 and 5 of PAX8 gene among a cohort of children with congenital hypothyroidism in correspondence to their clinical aspect. Blood samples were collected from 117 children (63 girls and 54 boys) with CH and enrolled as cases (Group I). All cases underwent biochemical confirmation with low FT4 and high TSH levels and thyroid gland imaging, along with equal number of matched apparently healthy individuals who served as controls (Group II). Genomic materials for exons 3 and 5 of PAX8 gene were extracted, amplified by PCR, detected by electrophoresis, purified, and sequenced by the Sanger technique through the application of ABI 3730x1 DNA Sequencer. Out of 117 cases, eight different effective PAX8 mutations were detected in exon 3 (G23D, V35I, I34T, Q40P, p.R31C, p.R31H, p.R31A, and p.I47T) in 14 patients with their sonographic findings ranged from normal, hypoplastic to thyroid agenesis. Besides the reported mutations, one novel mutation; R31A was detected in 1 euotopic case. Exon 5 analysis revealed no detected mutations elsewhere. In contrast, all healthy control children showed no mutation and normal sonographic findings. Mutations in exon 3 of PAX8 gene, implies its important role in thyroid development and function, as a first estimate of PA8 mutation rate in Egyptian patients with CH having normal and dysgenetic gland. Using ultrasound is mandatory for diagnosis and guiding the treatment of children with CH.

Sonography of the distal femoral epiphysis in the etiological diagnosis of congenital hypothyroidism.

The etiology of congenital hypothyroidism (CH) is often difficult to identify, owing mainly to limitations in currently available diagnostic tests. Characteristics of the distal femoral epiphyseal (DFE) ossification center may provide important information and help identify some causes of CH. We analyzed the contribution of DFE ultrasonography in the investigation of 11 young infants with positive screening for CH. DFE ultrasonography emerged as a simple test that helped indicate the period of onset of CH and, when associated with clinical history, hormone levels, and thyroid ultrasonography, contributed to suggest the etiology of CH.

Cardiac malformations in children with congenital hypothyroidism.

Congenital hypothyroidism (CH) is the most common endocrine disease in children, according to literature, infants with CH have an increased risk of associated congenital malformations (CM), especially cardiac defects (CD), compared to the general population. We retrospectively analyzed medical records of 255 patients with a positive screening result for CH in the period 1991-2016 followed at our Center. At the time of enrollment, the clinical examination included looking for the presence of heart murmurs and dysmorphic features. In all patients an echocardiography with cardiological evaluation were performed. Of all patients, 191 were included in the final analysis. Of these, 51.3% (98/191) presented an eutopic normally sized thyroid gland while 48.7% (93/191) showed a thyroid dysgenesis. Among the studied infants, 13.6% (26/191) presented CD. The most frequent cardiac anomaly was atrial septal defect (ASD) which was found in 65.4% (17/26) of patients with CD. Other defects were ventricular septal defect (VSD), patent ductus arteriosus (PDA), pulmonary valve stenosis (PvS), transposition of the great vessels (TGV), aortic valve stenosis (AvS). Six patients had multiple defects. In the analysed group, there was no significant relation with sex, type of CH, median blood-TSH (b-TSH) and serum-TSH (s-TSH) values and frequency of CD. There is a high prevalence of CD in CH, indicating the need of routine echocardiography in these patients to achieve an early diagnosis and management of CD.

Evaluating Ultrasound Determined Thyroid Volume as a Predictor of Newborn Thyroid Hormone Function.

BACKGROUND AND OBJECTIVES: Congenital hypo-thyroidism is a cause of intellectual and developmental disabilities in the newborn. Early screening and prompt treatment can prevent the devastating outcomes of congenital hypothyroidism. The disease burden of congenital hypothyroidism in Nigeria is higher than in many parts of the world. Using ultrasound, the authors sought to determine the normal mean thyroid gland volume in newborns and establish the thyroid gland volume as a predictor of thyroid hormone function in the newborn. METHODS: This was a descriptive cross-sectional study. Healthy newborns had their length and weight measured, thyroid ultrasound scan performed, and a blood sample taken for thyroid-stimulating hormone values. RESULTS: The mean total thyroid volume was 0.51cm3 ± 0.25. The thyroid volume of the right lobe (mean volume= 0.27cm3 ± 0.13) was significantly larger than the volume of the left lobe (mean volume =0.24cm3 ± 0.12) (p<0.001). The thyroid-stimulating hormone (TSH) values ranged from 1.36µIU/ml to 35.03µIU/ml with a mean value of 7.73µIU/ml ± 7.04. There was no significant correlation between the thyroid volumes and the TSH of the newborns. CONCLUSION: This study determined the mean thyroid volume in newborns. There was no significant correlation between the thyroid volumes and the TSH values of the newborns implying that the thyroid gland volume is not a reliable predictor of thyroid hormone function. Newborn, Ultrasound.

Imaging in congenital hypothyroidism.

PURPOSE OF REVIEW: Congenital hypothyroidism is a common worldwide condition. Due in part to increasingly widespread newborn screening, the number of patients with this diagnosis is increasing. In this review, we discuss currently available imaging techniques and the benefits and limitations of these techniques in evaluating congenital hypothyroidism. RECENT FINDINGS: Recent work has demonstrated an increasing diagnosis of congenital hypothyroidism with normally located glands and mildly decreased thyroid function. Increasingly more genetic abnormalities have been recognized in the hormone synthesis pathways. These cases may have lower or shorter term treatment requirements than the more common severe forms of congenital hypothyroidism, and the ability to distinguish between these situations may become increasingly more important to management and counseling. SUMMARY: Imaging studies for congenital hypothyroidism may be unlikely to change immediate management in the majority of cases. The common modalities of imaging include thyroid ultrasound and radionuclide uptake scanning with either technetium or iodine. These can help establish an etiology for the condition, and in less-common causes of congenital hypothyroidism may have implications on treatment decisions, prognosis, and counseling.

High-resolution computed tomography findings of thyroid transcription factor 1 deficiency (NKX2-1 mutations).

BACKGROUND: The expression of the NKX2-1 gene and its encoded protein, thyroid transcription factor 1 (TTF-1), plays a role in pulmonary surfactant homeostasis and lung development. NKX2-1 mutations have been associated with neonatal respiratory distress, hypotonia, choreoathetosis and congenital hypothyroidism. These clinical findings have been coined brain-lung-thyroid syndrome, although not all three organs are always involved. While many of these children develop interstitial lung disease, no systematic review of chest high-resolution CT (HRCT) findings has been reported. OBJECTIVE: To summarize the clinical presentations, pathology and HRCT imaging findings of children with NKX2-1 mutations. MATERIALS AND METHODS: We identified six children with NKX2-1 mutations, deletions or duplications confirmed via genetic testing at our institution. Three pediatric radiologists reviewed the children's HRCT imaging findings and ranked the dominant findings in order of prevalence via consensus. We then correlated the imaging findings with histopathology and clinical course. RESULTS: All children in the study were heterozygous for NKX2-1 mutations, deletions or duplications. Ground-glass opacities were the most common imaging feature, present in all but one child. Consolidation was also a prevalent finding in 4/6 of the children. Architectural distortion was less common. CONCLUSION: HRCT findings of TTF-1 deficiency are heterogeneous and evolve over time. There is significant overlap between the HRCT findings of TTF-1 deficiency, other surfactant dysfunction mutations, and pulmonary interstitial glycogenosis. TTF-1 deficiency should be considered in term infants presenting with interstitial lung disease, especially if hypotonia or hypothyroidism is present.

Prenatal diagnosis and successful intrauterine treatment of severe congenital hypothyroidism associated with fetal goiter.

Congenital hypothyroidism with fetal goiter is a rare condition associated with severe, but possibly preventable, intrauterine and postnatal complications. Ultrasound examination after 20 weeks of pregnancy enables prenatal diagnosis and early treatment. Due to limited transplacental transport of thyroid hormones, direct intrauterine treatment is needed. So far, only a few reports of fetal goitrous hypothyroidism have been published and no consensus on adequate management exists. We present a case of severe fetal goitrous hypothyroidism diagnosed at 23 gestational weeks treated by sequential intra-amniotic administration of L-thyroxin. Treatment resulted in significant goiter reduction and normalization of amniotic hormone levels, and enabled uncomplicated vaginal delivery at term. Current knowledge regarding prenatal diagnosis and intrauterine treatment were unified and applied within this case and a recommendation for clinical practice is provided in this report.

[Clinical and ultrasound features of congenital hypothyroidism]. / Hipotiroidismo congénito: aspectos clínicos y ultrasonográficos.

Congenital hypothyroidism is a condition where a newborn has decreased or absent thyroid function and thyroid hormone production. It is the most common cause of preventable mental retardation and its early diagnosis can only be achieved through systematic neonatal screening because its clinical manifestations are usually late. The etiologic study of this condition relies heavily on nuclear medicine and ultrasound, describing various findings. This research analyzed the characteristics of the ultrasound patterns observed in these children and their correlation with the most common etiologies. The use of ultrasound allows selecting children that require scintigraphic studies, decreasing the use of radiation in neonates.

Clinical and magnetic resonance imaging findings in a French bulldog puppy with genetically confirmed congenital hypothyroidism.

A 7-month-old male French bulldog was referred for abnormal mentation and gait. Physical examination revealed a dome shaped calvarium and persistent bregmatic fontanelle. Neurological examination revealed proprioceptive ataxia, pelvic limb paraparesis and strabismus with moderate ventriculomegaly, thinning of the cerebral parenchyma, and widened cerebral sulci on magnetic resonance imaging. Masses were identified in the region of the thyroid, which appeared heterogeneous and hyperintense in T1-weighted and T2-weighted compared with the adjacent muscle signal masses were identified. Radiological diagnosis was hydrocephalus "ex vacuo" and goiter. Blood test revealed abnormally low total thyroxine (TT4), free thyroxine (FT4), and normal thyrotropin concentration. A diagnosis of congenital hypothyroidism was confirmed by positive genetic test for thyroid peroxidase mutation. Thyroxine supplementation treatment rapidly improved clinical signs.

A novel mutation in thyrotropin (thyroid-stimulating hormone) gene in congenital hypothyroidism.

A 3-year-old girl had global developmental delay with dysmorphic facies. In addition, she was found to have congenital hypothyroidism. In view of the associated dysmorphism, a karyotype analysis was done. It revealed a novel translocation mutation, 46XX t(1;14) (p22;q32). The association of this mutation with congenital hypothyroidism has been postulated in our case report. To the best of our knowledge, this mutation has never been described before in cases of congenital hypothyroidism.

Cerebral Cortical Thickness Morphometry and Neurocognitive Correlations in Adolescents With Congenital Hypothyroidism.

CONTEXT: Subtle cognitive impairments have been described in children with congenital hypothyroidism (CH) detected by neonatal screening (NS), even with early and adequate treatment. Patients with CH may present with brain cortical thickness (CT) abnormalities, which may be associated with neurocognitive impairments. OBJECTIVE: This work aimed to evaluate the CT in adolescents with CH detected by the NS Program (Paraná, Brazil), and to correlate possible abnormalities with cognitive level and variables of neurocognitive prognosis. METHODS: A review was conducted of medical records followed by psychometric evaluation of adolescents with CH. Brain magnetic resonance imaging with analysis of 33 brain areas of each hemisphere was performed in 41 patients (29 girls) and in a control group of 20 healthy adolescents. CT values were correlated with Full-scale Intelligence Quotient (FSIQ) scores, age at start of treatment, pretreatment thyroxine levels, and maternal schooling. RESULTS: No significant difference in CT between patients and controls were found. However, there was a trend toward thinning in the right lateral orbitofrontal cortex among patients and in the right postcentral gyrus cortex among controls. CT correlated significantly with FSIQ scores and with age at start of treatment in 1 area, and with hypothyroidism severity in 5 brain areas. Maternal schooling level did not correlate with CT but was significantly correlated with FSIQ. Cognitive level was within average in 44.7% of patients (13.2% had intellectual deficiency). CONCLUSION: There was a trend toward morphometric alterations in the cerebral cortex of adolescents with CH compared with healthy controls. The correlations between CT and variables of neurocognitive prognosis emphasize the influence of hypothyroidism on cortical development. Socioeconomic status exerts a limiting factor on cognitive outcome.

Ultrasound for primary imaging of congenital hypothyroidism.

OBJECTIVE: The purpose of this study was to retrospectively evaluate the use of sonography as the primary imaging modality for congenital hypothyroidism (CH). MATERIALS AND METHODS: From our regional registry, we reviewed the cases of patients for whom either sonography or (99m)Tc-pertechnetate scanning was performed for CH between 2003 and 2010. Ultrasound studies were reviewed for presence, size, echotexture, vascularity, and location of the thyroid gland. Technetium-99m-pertechnetate scans were evaluated for the presence and location of the thyroid gland. The ultrasound studies were compared with the (99m)Tc-pertechnetate scans. We assessed the use of ultrasound as the primary imaging modality for the evaluation of CH. RESULTS: We identified the cases of 124 patients (89 girls, 35 boys). Ultrasound studies were available for 121 patients, and (99m)Tc-pertechnetate studies for 62 patients. Three patients were examined only by (99m)Tc-pertechnetate scanning. The final imaging results were normal location with normal size or diffuse enlargement of the thyroid gland (n = 47), sublingual thyroid gland (n = 49), agenesis (n = 18), hypoplasia (n = 8), and hemiagenesis (n = 2). Compared with (99m)Tc-pertechnetate scanning, ultrasound had high (100%) specificity and low (44%) sensitivity for detection of sublingual thyroid gland. CONCLUSION: We suggest using ultrasound as the primary imaging modality for guiding the treatment of children with CH, potentially decreasing radiation exposure and cost.

The natural history of the hyperthyrotropinemia of children born prematurely.

OBJECTIVE: Non-autoimmune hyperthyrotropinemia has been previously reported among children born prematurely. The aim of this study was to follow up their thyroid function, volume, and structure and to investigate the relationship with growth, IGF-I, lipid profile, and insulin sensitivity. METHODS: Seventy-two children born prematurely (33.2±2.2 weeks), 26 appropriate (AGA) and 46 small for gestational age (SGA), were evaluated at the age of 7.6±2.3 yr (time 1) and at the age of 11.4±2.3 yr (time 2). We also measured TSH, free T(3) (fT(3)), free T(4) (fT(4)), thyroperoxidase antibodies (TPO-Ab), thyroglobulin antibodies (TG-Ab), thyroid ultrasound, auxological parameters, lipid profile, glucose, and insulin level. RESULTS: In the AGA group TSH was similar in both times (2.7±1.0 vs 3.0±0.9 mU/l) and above the upper normal limit in 4 (15.4%) subjects at time 1 and in 6 (23.7%) subjects at time 2 (ns). In the SGA group, TSH was similar in both times (2.8±1.2 vs 2.5±1.0 mU/l) and above the upper normal limit in 11 (23.9%) subjects at time 1 and 5 (10.8%) subjects at time 2 (ns). fT(4) and fT(3) were always normal and TPO- and TG-Ab absent. Thyroid volume increased progressively, but significantly only in the AGA group (p=0.0005). The thyroid structure was always normal and there was no influence on the growth and the biochemical profile. CONCLUSIONS: Some ex-premature babies show a mild and variable thyroid dysfunction, which does not seem to evolve toward an overt thyroid dysfunction.

Thyroid developmental anomalies among first-degree relatives of children with thyroid dysgenesis and congenital hypothyroidism.

BACKGROUND: Thyroid dysgenesis (TD) is usually sporadic. In approximately 2%-8% of TD cases, familial TD has been identified. AIMS: The aim of this study is to define the prevalence of thyroid developmental anomalies in first-degree relatives of children with TD-caused congenital hypothyroidism (CH). METHODS: The investigation included 102 relatives of 33 children with CH and TD (study group) and 27 relatives of 12 normal children (comparative group). All the individuals were subjected to thyroid ultrasound and serum thyroid stimulating hormone (TSH) and free T4 (FT4) determinations. Statistical analysis was based on Fisher's exact test. RESULTS: TD-caused familial CH was noted in 2 of 33 (6%) children with CH. Asymptomatic thyroid developmental anomaly was seen in 1 of 102 (1%) relatives - left thyroid lobe hypoplasia in the mother of a girl with CH and thyroid severe hypoplasia. Familial prevalence of asymptomatic TD in the study group was observed in 1 of 32 families (3.13%). None of the comparative group members demonstrated any thyroid developmental anomalies. CONCLUSIONS: The prevalence rate of thyroid developmental anomalies in the study group is slightly higher than in the comparative group. These disturbances are asymptomatic.

A case of congenital hypothyroidism in PHACE syndrome.

Although hemangiomas, benign tumors of vascular origin, are very common among children and represent the most frequent benign tumor at that age, their association with other malformations constitutes a rare neurocutaneous disorder called PHACE syndrome. This condition is characterized by posterior fossa anomalies, hemangioma of the face, arterial alterations, cardiac defects, and eye anomalies (as represented by the acronym PHACE); sternum defects, endocrinopathies, and thyreopathies may be present as well. In this report, we describe a case of congenital hypothyroidism due to an empty thyroid site, as demonstrated by ultrasound, in an Italian child.

Congenital hypothyroidism: analysis of discordant US and scintigraphic findings.

PURPOSE: To retrospectively review discordant cases of congenital hypothyroidism according to a comparison of findings of ultrasonography (US) and scintigraphy. MATERIALS AND METHODS: Institutional review board approval was obtained for this retrospective study with a waiver of informed consent. Data of 300 pediatric patients (mean age, 4.7 weeks; range, 1-48 weeks; male-to-female ratio, 169:131) with congenital hypothyroidism who underwent technetium 99m radioisotope scintigraphy and US were reviewed. Scintigraphic scans were analyzed for location and range of the radioisotope uptake. US images were analyzed for location and thyroid volume. If a normal thyroid was not detected, ectopic thyroid was evaluated. Detection of focal thyroid abnormalities was recorded. Correlation between radioisotope uptake at scintigraphy and volume of normally located glands measured at US was analyzed by using the Pearson correlation test. Differences between results of thyroid function testing and radiologic data among subtypes of congenital hypothyroidism were analyzed with analysis of variance and Scheffe multiple comparison test. RESULTS: Among 55 patients with no radioisotope uptake, the appearance of the thyroid gland on US scans was normal in 42 patients (76%). This finding was attributed to hypopituitarism (n = 3), maternal antibody-induced hypothyroidism (n = 4), transient elevated thyrotropin (n = 5), and unknown causes (n = 30). Ectopic tissue was not detected at US (sensitivity, 78%; specificity, 100%) in six patients with a diagnosis of ectopy based on scintigraphic findings. Correlation between radioisotope uptake and US thyroid volume was statistically significant (P < .001). Correlation of results from thyroid function testing (thyrotropin, thyroxine, thyroglobulin) and radiologic data (radioisotope uptake, US measurement of volume) with subtypes of congenital hypothyroidism was significant (P < .001). Solid thyroid nodules were present in the thyroid gland in 0.7% (two of 300) of cases. CONCLUSION: Use of both scintigraphy and US results in a more complete depiction of neonatal congenital hypothyroidism than either test alone.

Bone maturity and thyroidal status at birth: role of the ultrasonographic evaluation of the distal femoral epiphysis.

PURPOSE: Thyroidal hormones are important for bone development, and ultrasonographic (US) evaluation of the distal femoral epiphysis (DFE) has recently been suggested as a new method for the assessment of skeletal maturity in infants. A delayed bone maturation, expressed by a smaller or absent DFE nucleus (in terms of DFE surface area, sum of the epiphyseal diameters, or DFE height and acetabular size), has been largely demonstrated in diagnosed hypothyroid infants, while no data analyze the role and meaning of the DFE dimensions (in terms of volume) in newborn before knowledge of the congenital neonatal screening results. The aims of the present study were to ultrasonographically evaluate the volume of DFE in newborns, and to determine whether it has any predictive role for the thyroidal status at birth. MATERIALS AND METHODS: 238 newborns (M/F: 121 /117) were evaluated. The gestational age, body weight and length at birth were registered. Neonatal screening for congenital hypothyroidism (CH), based on TSH levels on blood spot, was performed in all on the 3 rd day of life. The DFE volume was ultrasonographically evaluated, taking into account the three diameters of the DFE nucleus, within 48 hours of birth. RESULTS: No newborn was found to have CH on neonatal screening. The DFE volume ranged between 0.00 cm and 0.61 cm (mean 0.14 ± 0.10 cm, median 0.13 cm). The DFE volume did not differ between males and females, while it was significantly greater in at term babies than in preterm babies. No differences in TSH values at screening were noted among the groups. The DFE volume was significantly related to gestational age, birth weight and length. A significant relationship was found between the DFE volume and TSH concentrations at screening. CONCLUSION: US evaluation of DFE volume provides a simple method for assessing bone maturity at birth, which is related to gestational age, body weight and length at birth. Nonetheless, it has any predictive role for thyroidal status at birth, being not related to TSH levels on neonatal screening for CH.

Thyroid scintigraphy differentiates subtypes of congenital hypothyroidism.

INTRODUCTION: UK screening for congenital hypothyroidism (CH) is based on dried blood spot Thyroid Stimulating Hormone (TSH). Scintigraphy may identify CH subtypes classified as dysplasia, gland in situ (GIS) and ectopia, but is not performed in all centres. We retrospectively investigated the role of scintigraphy to identify CH subtypes in a single tertiary centre cohort. METHODS: Babies who screened positive for CH between 2007 and 2017 were studied (n=418 of 534 783). Scintigraphy outcomes were correlated with TSH and levothyroxine dose. GIS patients were analysed for 3-year outcomes. RESULTS: 303 patients started levothyroxine. Scintigraphy demonstrated three subtypes: GIS (n=139, 46%) ectopia (n=84, 28%) and dysplasia (n=80, 26%). Three-year follow up demonstrated permanence in 54% of 37 GIS cases. DISCUSSION: Thyroid scintigraphy differentiates subtypes of CH and suggests a higher than expected proportion of patients with GIS and ectopia. CH is permanent in half of those with GIS.