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.

Case Report: Functional Analysis and Neuropsychological Evaluation of Dyshormonogenetic Fetal Goiter in Siblings Caused by Novel Compound Hyterozygous TPO Gene Mutations.

Introduction: It is rare for a euthyroid mother to carry a child with a fetal goiter. However, cases of congenital hypothyroidism (CH) caused by thyroid dyshormonogenesis have been reported. Even though gene mutations associated with fetal goiter have been reported in a few studies, the effects on intellectual development have not been investigated. This study aimed to characterize and investigate the underlying genetic mechanism of CH and neuropsychological development and growth of two siblings with CH-induced fetal goiters. Case report: Two male siblings from a non-consanguineous marriage with CH and fetal goiter were diagnosed by ultrasonography at 32- and 26-weeks of gestation. This condition was confirmed by cordocentesis in the first pregnancy (TSH: 135 µIU/ml). The mother was euthyroid, and no intra-amniotic levothyroxine treatment was performed. Peripheral blood DNA was screened for TPO mutations. The new deletion p.Cys296Alafs*21 and the p.Arg665Trp mutation, inherited from heterozygous parents, were identified in both patients. Functional analysis showed both mutations reduced the TPO enzyme activity and impaired the membrane localization. The p.Cys296Alafs*21 mutation produces a protein product with a drastically reduced molecular weight. Additionally, a complete clinical and neuropsychological evaluation was also performed. The WISC IV test was employed to provide an overall measure of the siblings' cognitive and intellectual abilities. No growth retardation was detected in either child. In general, both children showed normal neuropsychological development; however, they exhibited slight reduction of Processing Speed Index scores, which are sensitive to neurological and attentional factors and motor maturation activity. Notably, the younger sibling obtained significantly low scores in the Operational Memory Index, a measure of attention capacity and psychoneurological immaturity. Conclusion: We described a new TPO compound heterozygosity that severely impaired the TPO activity and membrane localization leading to severe CH and fetal goiter. This is the first report showing the neuropsychological evaluation in patients with dyshormonogenetic fetal goiter. More studies are needed to understand the neurodevelopmental outcomes of neonates with CH-induced fetal goiters.

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.

Mutation screening in the genes PAX-8, NKX2-5, TSH-R, HES-1 in cohort of 63 Brazilian children with thyroid dysgenesis.

OBJECTIVE: To evaluate the candidate genes PAX-8, NKX2-5, TSH-R and HES-1 in 63 confirmed cases of thyroid dysgenesis. SUBJECTS AND METHODS: Characterization of patients with congenital hypothyroidism into specific subtypes of thyroid dysgenesis with hormone levels (TT4 and TSH), thyroid ultrasound and scintigraphy. DNA was extracted from peripheral blood leukocytes and the genetic analysis was realized by investigating the presence of mutations in the transcription factor genes involved in thyroid development. RESULTS: No mutations were detected in any of the candidate genes. In situ thyroid gland represented 71.1% of all cases of permanent primary congenital hypothyroidism, followed by hypoplasia (9.6%), ectopia (78%), hemiagenesis (6.0%) and agenesis (5.5%). The highest neonatal screening TSH levels were in the agenesis group (p < 0.001). CONCLUSIONS: Thyroid dysgenesis is possibly a polygenic disorder and epigenetic factors could to be implicated in these pathogeneses.

Mutation screening in the genes PAX-8, NKX2-5, TSH-R, HES-1 in cohort of 63 Brazilian children with thyroid dysgenesis

ABSTRACT Objective: To evaluate the candidate genes PAX-8, NKX2-5, TSH-R and HES-1 in 63 confirmed cases of thyroid dysgenesis. Subjects and methods: Characterization of patients with congenital hypothyroidism into specific subtypes of thyroid dysgenesis with hormone levels (TT4 and TSH), thyroid ultrasound and scintigraphy. DNA was extracted from peripheral blood leukocytes and the genetic analysis was realized by investigating the presence of mutations in the transcription factor genes involved in thyroid development. Results: No mutations were detected in any of the candidate genes. In situ thyroid gland represented 71.1% of all cases of permanent primary congenital hypothyroidism, followed by hypoplasia (9.6%), ectopia (78%), hemiagenesis (6.0%) and agenesis (5.5%). The highest neonatal screening TSH levels were in the agenesis group (p < 0.001). Conclusions: Thyroid dysgenesis is possibly a polygenic disorder and epigenetic factors could to be implicated in these pathogeneses.

Molecular analysis of thyroglobulin mutations found in patients with goiter and hypothyroidism.

Thyroid dyshormonogenesis due to thyroglobulin (TG) gene mutations have an estimated incidence of approximately 1 in 100,000 newborns. The clinical spectrum ranges from euthyroid to mild or severe hypothyroidism. Up to now, one hundred seventeen deleterious mutations in the TG gene have been identified and characterized. The purpose of the present study was to identify and characterize new mutations in the TG gene. We report eight patients from seven unrelated families with goiter, hypothyroidism and low levels of serum TG. All patients underwent clinical, biochemical and image evaluation. Sequencing of DNA, genotyping, as well as bioinformatics analysis were performed. Molecular analyses revealed three novel inactivating TG mutations: c.5560G>T [p.E1835*], c.7084G>C [p.A2343P] and c.7093T>C [p.W2346R], and four previously reported mutations: c.378C>A [p.Y107*], c.886C>T [p.R277*], c.1351C>T [p.R432*] and c.7007G>A [p.R2317Q]. Two patients carried homozygous mutations (p.R277*/p.R277*, p.W2346R/p.W2346R), four were compound heterozygous mutations (p.Y107*/p.R277* (two unrelated patients), p.R432*/p.A2343P, p.Y107*/p.R2317Q) and two siblings from another family had a single p.E1835* mutated allele. Additionally, we include the analysis of 48 patients from 31 unrelated families with TG mutations identified in our present and previous studies. Our observation shows that mutations in both TG alleles were found in 27 families (9 as homozygote and 18 as heterozygote compound), whereas in the remaining four families only one mutated allele was detected. The majority of the detected mutations occur in exons 4, 7, 38 and 40. 28 different mutations were identified, 33 of the 96 TG alleles encoded the change p.R277*. In conclusion, our results confirm the genetic heterogeneity of TG defects and the pathophysiological importance of the predicted TG misfolding and therefore thyroid hormone formation as a consequence of truncated TG proteins and/or missense mutations located within its ACHE-like domain.

Timing of thyroid ultrasonography in the etiological investigation of congenital hypothyroidism

ABSTRACT Objectives To describe the findings of thyroid ultrasonography (T-US), its contribution to diagnose congenital hypothyroidism (CH) and the best time to perform it. Subjects and methods Forty-four patients with CH were invited to undergo T-US and 41 accepted. Age ranged from 2 months to 45 years; 23 patients were females. All were treated with L-thyroxine; 16 had previously undergone scintigraphy and 30 had previous T-US, which were compared to current ones. Results At the current T-US, the thyroid gland was not visualized in its normal topography in 10 patients (24.5%); 31 T-US showed topic thyroid, 17 with normal or increased volume due to probable dyshormonogenesis, 13 cases of hypoplasia and one case of left-lobe hemiagenesis. One patient had decreased volume due to central hypothyroidism. Scintigraphy scans performed 3-4 years earlier showed 100% agreement with current results. Comparisons with previous T-US showed concordant results regarding thyroid location, but a decrease in current volume was observed in eight due to the use of L-thyroxine, calling the diagnosis of hypoplasia into question. Conclusions The role of T-US goes beyond complementing scintigraphy results. It allows inferring the etiology of CH, but it must be performed in the first months of life. An accurate diagnosis of CH will be attained with molecular study and the T-US can guide this early assessment, without therapy withdrawal.

Timing of thyroid ultrasonography in the etiological investigation of congenital hypothyroidism.

OBJECTIVES: To describe the findings of thyroid ultrasonography (T-US), its contribution to diagnose congenital hypothyroidism (CH) and the best time to perform it. SUBJECTS AND METHODS: Forty-four patients with CH were invited to undergo T-US and 41 accepted. Age ranged from 2 months to 45 years; 23 patients were females. All were treated with L-thyroxine; 16 had previously undergone scintigraphy and 30 had previous T-US, which were compared to current ones. RESULTS: At the current T-US, the thyroid gland was not visualized in its normal topography in 10 patients (24.5%); 31 T-US showed topic thyroid, 17 with normal or increased volume due to probable dyshormonogenesis, 13 cases of hypoplasia and one case of left-lobe hemiagenesis. One patient had decreased volume due to central hypothyroidism. Scintigraphy scans performed 3-4 years earlier showed 100% agreement with current results. Comparisons with previous T-US showed concordant results regarding thyroid location, but a decrease in current volume was observed in eight due to the use of L-thyroxine, calling the diagnosis of hypoplasia into question. CONCLUSIONS: The role of T-US goes beyond complementing scintigraphy results. It allows inferring the etiology of CH, but it must be performed in the first months of life. An accurate diagnosis of CH will be attained with molecular study and the T-US can guide this early assessment, without therapy withdrawal.

[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.

Subcutaneous injection of 99mTc-pertechnetate for neonatal thyroid scintigraphy.

A 9-day-old female infant with congenital hypothyroidism presented for thyroid scintigraphy. Multiple attempts including the "intravenous team" failed to establish peripheral access for administration of 99mTc-pertechnetate. We administered 99mTc-pertechnetate subcutaneously into the upper arm. Rapid absorption (85% of the dose in 20 minutes) was documented on dynamic images with physiological uptake, allowing diagnostic thyroid scintigraphy at 35 minutes that revealed ectopic sublingual thyroid. Subcutaneous injection allowed us to avoid traumatic and risky central vascular access procedure. When peripheral intravenous access cannot be obtained, 99mTc-pertechnetate can be administered subcutaneously for diagnostic thyroid scintigraphy, which is particularly useful in neonates.

Two novel mutations in the thyroglobulin gene as cause of congenital hypothyroidism: identification a cryptic donor splice site in the exon 19.

Thyroglobulin (TG) is a homodimeric glycoprotein synthesized by the thyroid gland. To date, 52 mutations of the TG gene have been identified in humans. The purpose of the present study was to identify and characterize new mutations in the TG gene. We report a French patient with congenital hypothyroidism, mild enlarged thyroid gland and low levels of serum TG. Sequencing of DNA, genotyping, expression of chimeric minigenes as well as bioinformatics analysis were performed. DNA sequencing identified the presence of compound heterozygous mutations in the TG gene: the paternal mutation consists of a c.3788-3789insT or c.3788dupT, whereas the maternal mutation consists of g.IVS19+3_+4delAT. Minigene analysis of the g.IVS19+3_+4delAT mutant showed that the exon 19 is skipped during pre-mRNA splicing or partially included by use of cryptic 5' splice site located to 100 nucleotides downstream of the wild type exon-intron junction. The c.3788-3789insT mutation results in a putative truncated protein of 1245 amino acids, whereas g.IVS19+3_4delAT mutation originates two putative truncated proteins of 1330 and 1349 amino acids. In conclusion, we show that the g.IVS19+3_+4delAT mutation promotes the activation of a cryptic donor splice site in the exon 19 of the TG gene. These results open up new perspectives in the knowledge of the mechanism of splicing for the TG pre-mRNA.

Non-immune goiter and hypothyroidism in a 19-week fetus: a plea for conservative treatment.

Hypothyroidism was documented by cordocentesis at 19 weeks in a fetus with non-immune goiter. Intra-amniotic thyroxine was injected at 25 weeks when amniotic fluid volume increased. Psychomotor outcome was normal. We argue that intra-amniotic thyroxine should not be used to treat the hypothyroidism but only to correct the development of polyhydramnios.

Ultrasound appearance of thyroid tissue in hypothyroid infants.

OBJECTIVE: To identify those infants who need a higher starting dose of levothyroxine (l-T4) for early normalization of thyroid-stimulating hormone (TSH) level. STUDY DESIGN: TSH levels at 2 time points (1 to 3 weeks and 3 to 5 weeks) after l-T4 therapy at a starting dose of 8 to 12 microg/kg/day were evaluated retrospectively in 22 hypothyroid infants screened for congenital hypothyroidism (CH) in terms of etiology as determined by ultrasonography (US), the size of distal femoral epiphysis (DFE), and initial thyroid function. RESULTS: The infants with a noneutopic thyroid or small DFE exhibited significantly higher posttherapeutic TSH levels compared with the other infants. Eight of the 9 infants who failed to achieve normalized TSH values at 1 to 3 weeks had noneutopic thyroid. All of the infants with eutopic thyroid exhibited normalized TSH at 3 to 5 weeks, and a significantly greater proportion of the infants with eutopic thyroid exhibited normalized TSH at 1 to 3 weeks compared with those with noneutopic thyroid. Stepwise regression analysis demonstrated that US etiology was a significant independent variable for normalization of TSH at 1 to 3 weeks. CONCLUSIONS: US examination to identify eutopic or noneutopic thyroid provides useful information for determining the starting dose of l-T4 in hypothyroid infants.

Craniofacial malformation among endemic cretins in Ecuador.

Nearly 6% of the inhabitants of two villages in Ecuador are deaf-mute and mentally retarded cretins. These communities are situated in the Andean highlands where environmental and dietary stores of iodine are extremely scarce. Endemic goiter and cretinism are widespread, and 10% of the cretins are additionally burdened with dwarfism and facial dysmorphia. Those with obvious involvement of the skeletal system were selected in order to study the extent of craniofacial malformation. Their appearance is characterized by midface hypoplasia, a broad nose with a depressed bridge, and a conspicuous circumoral prominence. Radiographic evaluation demonstrates a vertical displacement of the cranial base with an associated upward tilt of the midface. The flattened frontal bone, reduced frontal sinus pneumatization, and diminutive nasal bones collectively create a backward sloping face. The defect in the craniofacial skeleton of these Ecuadorian cretins is characteristic, and it readily sets them apart from the dysmorphism of those cretins with myxedema.