Search

Objective: To assess clinical variables, including early thyroid scintigraphy, in predicting the outcome (permanent vs transient) in term infants with congenital hypothyroidism (CH)., Methods: In a retrospective study, 142 full-term infants with CH diagnosed between 2000 and 2012 were categorized into three groups: agenesis/ectopic thyroid and permanent CH; eutopic thyroid and permanent CH; and eutopic thyroid and transient CH. All underwent early thyroid scintigraphy and were under regular follow-up in our tertiary Pediatric Endocrine Institute., Results: Thyroid scan showed agenesis/ectopic thyroid in 58 (41%) and eutopic thyroid in 84 (59%) infants. Imaging findings were similar in eutopic-permanent and eutopic-transient groups. At initial evaluation, TSH levels were higher in the agenesis/ectopic group than in the eutopic-permanent and eutopic-transient groups (71.5 ± 11.2 mIU/L vs 49.1 ± 27.9 mIU/L and 42.5 ± 29.1 mIU/L, respectively; P < 0.001). Higher l-T4 doses were required from the third month in the agenesis/ectopic than in the eutopic-permanent group (P < 0.001) and from the sixth month in the eutopic-permanent than in the eutopic-transient group (P < 0.01). Initial TSH >63.5 mU/L (P < 0.001) and l-T4 dose >4.6 μg/kg/d at age >6 months (P < 0.001) were found to be predictors for an agenesis/ectopic gland using receiver operating characteristic analysis, as was an l-T4 dose >2.2 μg/kg/d at age >6 months (P < 0.01) for permanent CH in patients with a eutopic gland., Conclusions: Although early thyroid scintigraphy is reliable in predicting permanent CH when detecting agenesis or ectopic gland, it cannot differentiate between permanent and transient CH in cases with a eutopic thyroid. Confirmatory TSH at diagnosis and the l-T4 dose through treatment may better distinguish between permanent and transient CH.

Context: Congenital hypothyroidism (CH) may arise from dual foci thyroid ectopia., Objective: To ascertain the incidence of dual ectopia in CH and compare the phenotype to single ectopia or thyroid agenesis., Design and Setting: Single center, retrospective study of babies referred through UK Newborn Bloodspot Screening between 2006 and 2012., Patients: A total of 837 377 babies were screened for CH, with 730 referred for diagnostic confirmation (134 thyroid ectopia, 73 thyroid agenesis)., Intervention: Thyroid isotope scans were classified as single or dual ectopia. Biochemical, clinical, and sociodemographic data were collected., Main Outcome Measures: The incidence of thyroid dual ectopia and comparison of clinical parameters with single ectopia and agenesis., Results: Thyroid ectopia occurs with an incidence of 16 per 100 000 births. Twenty-one of 134 (15.7%) babies with thyroid ectopia had dual foci, an incidence of 2.5 per 100 000 births. Dual ectopia infants had lower mean bloodspot TSH compared to single ectopia and agenesis groups (P < .001). On venous sampling, the ectopia group differences were absent, but the difference with the agenesis group remained (TSH, P < .001; free T4, P < .001). There were no between-group differences for gestation, ethnicity, maternal age, or levothyroxine requirements at 12 months., Conclusions: Thyroid dual ectopia has an incidence of 2.5 per 100 000 births. Early functional activity in the ectopia groups with detectable serum free T4 concentrations is lost at 12 months when T4 requirements are the same as the agenesis group.

Context: Adequate thyroid hormone availability during fetal and early life is crucial for normal child growth and development. Fetal growth heavily depends on angiogenesis. Placental growth factor (PlGF) is a proangiogenic factor sharing high homology with vascular endothelial growth factor, whereas soluble FMS-like tyrosine kinase-1 (sFlt1) is a potent antagonist of vascular endothelial growth factor and PlGF signaling. Because the thyroid is a highly vascularized organ, we hypothesized that fetal angiogenic factors influence in utero thyrogenesis and impair newborn thyroid function. Therefore, we investigated the association between sFlt1 and PlGF on newborn thyroid function., Design, Setting, and Participants: sFlt1, PlGF, TSH, and free T4 (FT4) were determined in cord serum of 3525 newborns from a large prospective cohort study. Analyses were adjusted for relevant maternal and child covariates., Results: sFlt1 levels were positively associated with TSH (β 0.07 ± 0.02 mU/L; P < .001) and inversely with FT4 (β -0.58 ± 0.11; P < .001). PlGF showed a positive association with FT4 (β 0.19 ± 0.02; P < .001). Elevated levels of sFlt1 were associated with a 2.8-fold increased risk of hypothyroxinemia (P = .04). Decreased levels of PlGF were associated with a 6.7-fold increased risk of hypothyroxinemia (P < .001). Within the normal range, a dose-dependent effect of sFlt1 on thyroid dysfunction was observed: high-normal sFlt1 levels were associated with a 17.7-fold increased risk of hypothyroxinemia (P < .001) and a 2.7-fold increased risk of hyperthyrotropinemia (P = .01)., Conclusion: Fetal angiogenic factors sFlt1 and PlGF are associated with newborn thyroid function. Possible effects are most likely mediated through effects on in utero thyrogenesis. Abnormal as well as normal-range fetal sFlt1 and PlGF levels influence the risk of impaired newborn thyroid function, which has been associated with adverse neurodevelopmental effects. These data provide important novel insights into the physiology of thyrogenesis and into the etiology of newborn thyroid (dys)function.

Context: In recent years changes in screening strategies for congenital hypothyroidism (CH) led to an increased detection of mild forms of CH, associated with eutopic thyroid gland., Objectives: We aimed to determine the clinical evolution of CH with eutopic thyroid gland and to find out prognostic factors at diagnosis and follow-up., Patients and Methods: We retrospectively analyzed a group of 84 children with CH and eutopic thyroid gland treated at our institution. They all underwent clinical re-evaluation after the age of 3, based on thyroid function testing after l-thyroxine therapy withdrawal, thyroid ultrasonography, and (123)I scintigraphy with perchlorate discharge test. Genetic analysis was performed in selected cases., Results: At re-evaluation, 34.5% of patients showed permanent hypothyroidism and needed l-thyroxine reintroduction, 27.4% had persistent hyperthyrotropinemia (TSH 5-10 mU/L), and 38.1% had transient hypothyroidism. Major risk factors for permanent CH were prematurity, first-degree familial history of goiter/nodules, thyroid hypoplasia at diagnosis, and high l-thyroxine requirements at follow-up. Iodine organification defects were found in 29.7% of patients, 30% of whom harbored DUOX2 mutations. TSH receptor gene mutations were found in 8.7% of patients with persistent thyroid dysfunction and negative perchlorate discharge test., Conclusions: Only one-third of patients with CH and eutopic thyroid gland needed to continue l-thyroxine therapy after re-evaluation. A frequent finding was the persistence of mild hyperthyrotropinemia. The evolution of CH remains difficult to predict, although different clinical features might suggest different outcomes. Mutations in the genes commonly linked to mild forms of CH were documented in a minority of cases.

Context: Over the years lower TSH cutoffs have been adopted in some screening programs for congenital hypothyroidism (CH) worldwide. This has resulted in a progressive increase in detecting additional mild forms of the disease, essentially with normally located and shaped thyroid. However, the question of whether such additional mild CH cases can benefit from detection by newborn screening and early thyroid hormone treatment is still open., Objective: The aim of this study was to estimate the frequency of cases with mild increase of TSH at screening in the Italian population of babies with permanent CH and to characterize these babies in terms of diagnosis classification and neonatal features., Methods: Data recorded in the Italian National Registry of infants with CH were analyzed., Results: Between 2000 and 2006, 17 of the 25 Italian screening centers adopted a TSH cutoff at screening of <15.0 μU/mL. It was found that 21.6% of babies with permanent CH had TSH at screening of 15.0 μU/mL or less, whereas this percentage was 54% in infants with transient hypothyroidism. Among the babies with permanent CH and mild increase of TSH at screening (≤15 μU/mL), 19.6% had thyroid dysgenesis with serum TSH levels at confirmation of the diagnosis ranging from 9.9 to 708 μU/mL. These babies would have been missed at screening if the cutoff had been higher., Conclusions: Lowering TSH cutoff in our country has enabled us to detect additional cases of permanent CH, a number of which had defects of thyroid development and severe hypothyroidism at confirmation of the diagnosis.

Background: Thyroid ectopy results from the failure of the thyroid precursor cells to migrate from the primordial pharynx to the anterior part of the neck. Most ectopic thyroids are revealed by congenital hypothyroidism and present as a single round mass at the base of the tongue, with no other thyroid tissue. However, some cases have dual ectopy, with part of the tissue having partially migrated. We hypothesized that this occurs more frequently than previously reported., Methods: To determine the prevalence of dual ectopy, we reviewed the pertechnetate scintigraphies of 81 patients with congenital hypothyroidism from thyroid ectopy diagnosed between 2002 and 2011 at our institution., Results: We report a series of seven cases (9%) of dual ectopy, representing an incidence ranging from 1:50,000 to 1:70,000., Conclusions: Almost one in 10 cases with congenital hypothyroidism due to thyroid ectopy has dual ectopy. This suggests that two populations of cells diverged at an early stage of development, which may arise from insufficient signaling gradients in surrounding tissues during early organogenesis or may indirectly support the polyclonal nature of the thyroid.

Context: A modern approach to congenital hypothyroidism requires a definitive diagnosis of the underlying mechanisms; this can be achieved within the first weeks of life. When uncertainty persists, treatment is commenced, and the definitive diagnosis of congenital hypothyroidism is deferred to the age of 3 yr., Objectives: The interruption of thyroid replacement treatment is perceived as risky by parents and physicians. The aim of this pilot study was to test the possibility of a definitive diagnosis during thyroid replacement treatment, using stimulation of thyroid tissue by recombinant human (rh)TSH., Subjects: Eight patients, three boys and five girls, age 5-15 yr (mean, 9.5+/-3.7 yr), with congenital hypothyroidism that had been diagnosed by the neonatal screening program, and having their diagnosis verified between the ages of 3-4 yr, were reevaluated while on thyroid replacement therapy., Interventions: Patients received im 0.6 mg/m2 rhTSH on two consecutive days., Results: rhTSH pharmacokinetics, maximal concentration, t1/2, and area under the curve in children were different as compared with adults. In the patients with intact TSH receptors, free T4 levels decreased after the first and the second injection of rhTSH (P=0.0137 and P=0.0149, respectively). All eight children showed identical scintigraphy after rhTSH administration as compared with thyroid replacement withdrawal., Conclusions: The use of rhTSH is effective for definitive diagnosis of congenital hypothyroidism during thyroid replacement treatment, and no safety issues were encountered.

Background: Thyroid dysgenesis is the most frequent cause of congenital hypothyroidism (CH), and its genetic basis is largely unknown. Hitherto, two mutations in the human thyroid transcription factor 2 (TTF-2) gene have been described in unrelated cases of CH with cleft palate, spiky hair, variable choanal atresia, and complete thyroid agenesis. Here, we describe a novel TTF-2 mutation in a female child resulting in syndromic CH in the absence of thyroid agenesis., Results: The index case is homozygous for an arginine to cysteine mutation (R102C) of a highly conserved residue within the forkhead, DNA binding domain of TTF-2. Her consanguineous, heterozygous parents are unaffected, and the mutation was not detected in 100 control chromosomes. Consonant with its location, the R102C mutant TTF-2 protein showed loss of DNA binding and was transcriptionally inactive. CH in the proposita was associated with cleft palate, spiky hair, and bilateral choanal atresia. However, radiological studies showed the presence of thyroid tissue in a eutopic location., Conclusion: Our findings indicate that human thyroid development can occur despite loss of TTF-2 function and suggest that TTF-2 gene defects should also be considered in cases of syndromic CH without total athyreosis.

Thyroid dysgenesis (TD) is responsible for most cases of congenital hypothyroidism, a condition that affects about one in 4000 newborns. Mutations in PAX8, TITF1, or FOXE1 may account for congenital hypothyroidism in patients with either isolated TD or TD with associated malformations involving kidney, lung, forebrain, and palate. Pax8, titf1, and foxe1 are expressed in the mouse thyroid bud as soon as it differentiates on the pharyngeal floor. Because the spatio-temporal expression of these genes is unknown in humans, we decided to study them at different stages of human embryonic and fetal development. PAX8 and TITF1 were first expressed in the median thyroid primordium. Interestingly, PAX8 was also expressed in the thyroglossal duct and the ultimobranchial bodies. Human FOXE1 expression was detected later than in the mouse. PAX8 was also expressed in the developing central nervous system and kidney, including the ureteric bud and the main collecting ducts. TITF1 was expressed in the ventral forebrain and lung. FOXE1 expression was detected in the oropharyngeal epithelium and thymus. In conclusion, the expression patterns described here show some differences from those reported in the mouse. They explain the malformations associated with TD in patients carrying PAX8, TITF1, and FOXE1 gene mutations.

The PAX8 gene, mapped on 2q12-q14, encodes for a transcription factor involved in thyroid cell proliferation and differentiation. Five mutations in PAX8 have been so far described in both sporadic and rare familial forms of thyroid dysgenesis with proposed autosomal dominant inheritance, all associated with thyroid hypoplasia and/or dysfunction. Fifty-four subjects with congenital hypothyroidism detected during neonatal screening and associated with an ultrasound or scintiscan picture of thyroid dysgenesis were investigated for PAX8 mutations. The entire PAX8 coding region with exon-intron boundaries was amplified from genomic DNA, and a mutational screening was performed by denaturing HPLC followed by direct sequencing when denaturing HPLC elution abnormalities appeared. A new heterozygous deletion (c.989&#95;992delACCC) in exon 7 causing a frameshift with premature stop codon after codon 277 was identified in a subject with thyroid hypoplasia. This mutation is the only one so far identified that lies outside the paired domain. The predicted mutant protein completely lacks the C-terminal region but contains the paired box, octapeptide, and homeodomain. It retains the ability to bind a paired-domain sequence in vitro but is transcriptionally inactive. These results provide evidence that the C-terminal region is essential for transcriptional activity. The new mutation has been inherited from the completely euthyroid mother. It was also present in a brother with slightly elevated TSH only. Thus, it is associated with thyroid dysgenesis in the proband and both euthyroidism and compensated hypothyroidism in her family. This suggests that other factors/genes may modulate phenotypic expression.

Newborns with severe congenital hypothyroidism (often defined by the absence of knee epiphyses at diagnosis) are still at risk of loss of intellectual potential despite early treatment. Although there is no significant sexual dimorphism in the age at appearance and size of the knee epiphyses in normal newborns, it was our clinical impression that these epiphyses were more often absent in hypothyroid newborn males than in affected females. Using the large French database of congenital hypothyroidism, we studied the presence or absence of knee epiphyses at diagnosis, as well as the length of gestation and the birth weight of 1827 term newborns with athyreosis or ectopic thyroid. Boys were twice as likely as girls to have absent epiphyses [odds ratio, 2.1 (95% confidence interval, 1.6-2.7), P < 0.001, after adjustment for etiology, plasma free T(4) concentration, and presence or absence of clinical signs at diagnosis, gestational age and birth weight]. Compared with the general population of French newborns, those with congenital hypothyroidism were more often born after a prolonged gestation (> or =42 wk) and with a high birth weight (9% were above the 95th centile, as opposed to the expected 5%), regardless of sex. We conclude that the impact of congenital hypothyroidism on fetal skeletal maturation is sexually dimorphic. This may result from less efficient conversion of T(4) to T(3) by growth plate chondrocytes in males.

Thyroid hemiagenesis prevalence was studied by neck ultrasound examination in 24,032 unselected 11- to 14-yr-old schoolchildren from southeastern Sicily. Twelve cases of thyroid hemiagenesis were identified, with a prevalence of 0.05%. The female to male ratio was 1:1.4. Thyroid hemiagenesis was always due to the absence (11 cases) or severe hypoplasia (1 case) of the left lobe. The hemiagenetic thyroid volume was within the normal total thyroid volume range normalized to age in 4 of 12 cases, enlarged in 3, and significantly reduced in 5. Thyroid function (thyroid hormones and TSH, both basal and 30 min after administration of 200 micro g TRH, iv) was evaluated in 9 of 12 children and was always within the normal range. However, children with thyroid hemiagenesis had an average serum TSH significantly higher than that of 18 matched controls (2.8 +/- 0.6 vs. 1.9 +/- 0.5 mU/liter; P < 0.001). This study confirms that thyroid hemiagenesis is nearly always due to left lobe defect, and that its prevalence is similar to the cumulative prevalence of thyroid agenesis and ectopia. Compensatory hypertrophy of the residual thyroid lobe occurs in most, but not all, cases and is due to thyroid tissue overstimulation by TSH. The high risk of goiter and hypothyroidism suggests systematic follow-up of all identified cases of thyroid hemiagenesis.

Congenital hypothyroidism (CH) is most frequently caused by thyroid developmental abnormalities, and it has recently been shown to have a familial component with members affected by either CH or asymptomatic thyroid developmental abnormalities. The pathogenesis of the disease is unknown, but it seems possible that a common genetic mechanism underlies these heterogeneous phenotypic expressions. Associations among these anomalies in the same individuals have occasionally been described. The aim of this study was to investigate whether cysts of the thyroglossal duct could be shown by ultrasonography in patients with CH caused by thyroid dysgenesis. Children with CH (n = 57) who were diagnosed by newborn TSH screening were prospectively evaluated by ultrasonography at the age of 10.5 +/- 4.5 yr. The etiology of CH (ectopic thyroid tissue, n = 42; athyreosis, n = 15) was established before treatment initiation on the basis of thyroid radioiodine scanning and the absence of any thyroid tissue in the normal location confirmed by ultrasonography. Cysts were found in 39 patients (68% of cases) with either ectopic thyroid tissue (n = 29) or athyreosis (n = 10). All cysts were located in the empty thyroid area in the left (57%) or right (43%) side and were mostly closer to the midline. Patients had either a single cyst (n = 16 patients) or multiple cysts (n = 23 patients). The cysts were bilateral in 17 of the 39 patients. Most of them were vertically oval or round, with a size ranging in diameter from 2-21 mm (mean, 3.5 +/- 2). In conclusion, the presence of cysts within the empty thyroid area in 68% of patients with CH due to thyroid dysgenesis is a novel observation that is part of the developmental anomaly of this disease. Several explanations can be put forward to explain the presence of these cysts. They might be due to the persistence of the ultimobranchial bodies as a cystic structure or part of the thyroid-forming material, which may migrate along the normal pathway of the usual course of the thyroglossal duct, giving rise to cell residues within the empty thyroid area.

Since the advent of biochemical screening for congenital hypothyroidism, the majority of monozygotic twins reported with thyroid dysgenesis have been discordant, and most were missed on neonatal screening, presumably due to fetal blood mixing. We hypothesized that there may be bias leading to preferential reporting of discordant twins and/or of false negative screening results. Therefore, we performed a systematic search for twins in two congenital hypothyroidism screening centers, Quebec and Brussels, that use a primary TSH approach. In Quebec, 10 pairs of twins were identified, all discordant for congenital hypothyroidism due to thyroid dysgenesis (4 monozygotic and 4 dizygotic pairs) and dyshormonogenesis (2 dizygotic pairs). The 6 pairs identified in the Brussels database were also all discordant for congenital hypothyroidism due to thyroid dysgenesis (1 monozygotic and 3 dizygotic pairs) and dyshormonogenesis (2 dizygotic pairs). The median increase in TSH between screening and diagnosis was 7-fold in the monozygotic twins vs. 2-fold in matched singletons (P = 0.02), suggesting fetal blood mixing between the twins. In summary, discordance for thyroid dysgenesis is the rule in monozygotic twins, and fetal blood mixing may result in delayed or missed diagnoses. We therefore conclude that 1) a second sample for congenital hypothyroidism screening at 14 d of age should be considered for all same-sex twins; and 2) thyroid dysgenesis generally results from epigenetic phenomena, early somatic mutations, or postzygotic stochastic events.

Congenital hypothyroidism (CH) is most frequently caused by thyroid developmental abnormalities and it has recently been seen to have a familial component. The aim of this study was to investigate whether thyroid developmental abnormalities exist in first degree relatives of CH children with thyroid dysgenesis, an anomaly which, when present, is sometimes asymptomatic. Thyroid ultrasonography and function were evaluated among first degree relatives (n = 241) of 84 isolated CH children with thyroid dysgenesis. The results were compared with those of an unselected control population (n = 217). In 19 individuals (7.9% of cases) belonging to 18 families (21.4%), 21 cases of thyroid developmental abnormalities were detected, whereas only 2 subjects (0.9%) were affected in controls (P < 0.001). These 21 thyroid developmental abnormalities included thyroglossal duct cysts (n = 14), additional thyroid tissue with presence of a pyramidal lobe (n = 3), thyroid hemiagenesis (n = 3), and ectopic thyroid tissue (n = 1). All of these subjects showed normal thyroid function and belonged to nuclear families of CH children with athyreosis (n = 8), ectopic thyroid tissue (n = 9), or hemiagenesis (n = 1). A segregation analysis led to the conclusion that thyroid developmental abnormalities are compatible with an autosomal dominant mode of inheritance with a low penetrance estimated at 21% for asymptomatic thyroid developmental abnormalities and a probability of less than 7% of developing CH for a carrier of the susceptibility allele. In conclusion, these observations support the hypothesis of a common genetic component of the disorder with heterogeneous phenotypes.

Congenital hypothyroidism associated with thyroid hypoplasia can be caused by several genetic defects, including mutations in the TSHbeta-subunit, the TSH receptor, the G(s)alpha-subunit, and the transcription factor PAX8. Four girls with sporadic congenital hypothyroidism and hypoplastic thyroid glands were analyzed for mutations in PAX8 and TTF2 (FKHL15). Mutations in the coding region of the TSHbeta-subunit gene, the TSH receptor gene, and exons 8 and 9 of G(s)alpha had been excluded previously. Serum TSH concentrations were 150 mU/liter or more, TG levels were within normal limits, and thyroid autoantibodies were absent. Technetium scintigraphies did not reveal the presence of thyroid tissue, but ultrasonography documented hypoplastic, normally located glands. One patient was found to harbor a heterozygous transversion 119A-->C in exon 3 of PAX8 replacing a conserved glutamine by proline in the paired box domain (Q40P). Analysis of her family members revealed that her mother, who has a thyroid gland of normal size and mild, adult-onset autoimmune hypothyroidism, is also heterozygous for this mutation. Functional analyses of the PAX8 Q40P mutation showed impaired binding to a PAX8 response element and absent trans-activation of a thyroid peroxidase promoter luciferase reporter gene. These findings confirm the important role of PAX8 in the development of the thyroid, but they indicate that PAX8 gene mutations may have a variable penetrance or expressivity. The absence of mutations in the coding sequences of the analyzed genes in the three other patients supports the concept that the pathogenesis of congenital hypothyroidism associated with thyroid hypoplasia is diverse.

Although a few familial forms of congenital hypothyroidism (CH) due to thyroid dysgenesis (TD) have been reported, this disorder is usually considered to be sporadic. Recently, we reported that 2% of CH patients with TD have a positive familial history. The aim of this study was to describe the clinical characteristics of these familial cases and to compare them with sporadic cases. We used the French national population-based registry of the first 19-yr screening program, which included 14,416,428 screened neonates with a 100% recovery rate. Familial history of CH with TD was investigated by means of a questionnaire sent to the pediatricians (n = 592) who provided ongoing clinical care for the 4049 CH patients detected during this period, including 2863 CH cases due to TD. Information was obtained from 73% of these pediatricians who were following up 2472 CH patients with TD (86%). In all, 67 patients with a positive family history of CH with TD were referred, belonging to 32 multiplex families (i.e. including at least 2 affected members). Families were identified with ectopic gland (n = 12), athyreosis (n = 7), or both (n = 13). Comparison of familial with isolated cases showed a similar etiological diagnosis distribution of CH (40% vs. 33% for athyreosis and 60% vs. 67% for ectopic thyroid gland, respectively), whereas a significantly lower predominance of females was found in familial than in isolated cases (1.4 vs. 2.7; P < 0.03). Extrathyroidal congenital malformations were found with a similarly higher incidence in familial and isolated CH populations compared with the general population (respectively, 9% and 8.2% vs. 2.5%). In conclusion, although familial cases represent a minority of cases of congenital hypothyroidism caused by thyroid dysgenesis, they were observed in a significantly higher proportion (>15-fold) than would be expected from chance alone. This familial clustering, including athyreosis and ectopic thyroid gland, strongly suggests that genetic factors could be involved in thyroid dysgenesis with a common underlying mechanism for both etiological groups. Moreover, the high proportion of extrathyroidal congenital malformations in a population affected by CH due to TD suggests that the potential genetic factors involved in thyroid gland organogenesis are also involved in the development of other organs.

We examined the patterns of TSH, T(4), and treatment schedules from diagnosis to 4 yr of age in 125 children (50 males anf 75 females) with congenital hypothyroidism (CH). Subjects were divided into 3 groups based on their thyroid scans: 1) athyreosis (n = 31), 2) dysgenesis (n = 54; 49 lingual and 5 hypoplastic), and 3) dyshormonogenesis (n = 40). Follow-up evaluation was carried out at 2-4 wk and 3, 6, 9, 12, 24, 36, and 48 months of age. Median gestational age, age at onset of therapy, and starting L-T(4) dose were similar in the three groups. In infants with athyreosis median screening TSH levels were higher (P < 0.02) and confirmatory T(4) levels were lower than in the other two groups (P < 0.01 vs. dysgenetic; P < 0.05 vs. dyshormonogenetic CH). During the first 6 months of therapy, mean TSH levels were highest in the athyrotic group, intermediate in the dysgenetic group, and lowest in the dyshormonogenetic group. In children with athyreosis, TSH levels normalized by 12 months of age. At 12 months dysgenetic patients had the highest TSH levels (P < 0.05). During the entire study period, TSH levels were lowest in patients with dyshormonogenesis (except at 48 months) and normalized earlier. Mean T(4) levels normalized by 2-4 weeks in all groups. At 3 and 6 months, the percentage of patients who required dose changes was highest in the athyrotic group, and at 12 months it was highest in the dysgenetic group. The athyrotic group received the highest dose of L-T(4), and dyshormonogenetic group received the lowest dose. We conclude that treatment and follow-up schedules for CH may differ in the three etiological categories based on the different hormonal patterns and responses to therapy. Children with athyreosis need close monitoring particularly early in life, whereas those with dysgenesis and dyshormonogenesis require more attention later in life.

Congenital hypothyroidism (CH) is a relatively frequent and potentially severe disease. It is classically subdivided into: 1) thyroid dysgenesis (TD), a defect in the organogenesis of the gland leading to hypoplastic, ectopic, or absent thyroid gland; or 2) thyroid dyshormonogenesis, a defect in one of the biochemical mechanisms responsible for thyroid hormone synthesis. Most cases of TD are sporadic, although familial occurrences have occasionally been described. Recently, several genes have been implicated in a small proportion of TD, but, in the majority of the cases, the etiology remains unknown. PAX8 is a transcription factor involved in thyroid development. So far, three loss-of-function mutations of PAX8 have been described, two in sporadic cases and one in familial thyroid hypoplasia. Here, we describe a novel mutation of PAX8 causing autosomal dominant transmission of CH with thyroid hypoplasia. The mutation consists of the substitution of a tyrosine for cysteine 57 in the paired domain of PAX8. When tested in cotransfection experiments with a thyroid peroxidasse promoter construct, the mutant allele was unable to exert its normal transactivation effect on transcription. Our results give further evidence that, contrary to the situation in knockout mice, haplo-insufficiency of PAX8 is a cause of CH in humans.

Measurements of serum concentrations of free T4, T3, TSH, and thyroglobulin (Tg) were conducted in 42 infants (2-9 months of age) detected and treated through the Northwest Newborn Regional Screening Program and 63 children and adolescents (1-18 yr of age) with congenital hypothyroidism (CH) detected and managed in the Northern California Kaiser Permanente Medical Care Program. Normal feedback control axis data were developed by Quest Diagnostics, Inc. - Nichols Institute Diagnostics and Loma Linda University, from free T4 and TSH measurements in 589 healthy subjects, 2 months to 54 yr of age; 83 untreated hypothyroid patients; and 116 untreated hyperthyroid patients. Twenty-four of the 42 CH infants and 57 of the 63 CH children manifested serum TSH concentrations appropriate for the measured free T4 level. In the remaining 18 infants and 6 children, serum free T4 values were increased 0.2-1.4 ng/dL (2.6-18.0 pmol/L) for the prevailing TSH level, suggesting a state of mild to moderate pituitary-thyroid hormone resistance. In the treated children, the mean T3 concentration was lower (by 32%, 102 vs. 150 ng/dL; 1.57 vs. 2.31 nmol/L) than in normal children, in agreement with earlier data in hypothyroid adults treated with exogenous T4. Serum Tg concentrations were normal or elevated in 90% of the 19 children with ectopic glands and 93% of 27 children with eutopic glands in whom measurements were available. There was a positive correlation between serum TSH and Tg concentrations (P < 0.001), suggesting significant endogenous thyroid hormone production in these children. Our results suggest that the majority of infants and children with CH have a normal hypothalamic-pituitary-thyroid negative feedback control axis during treatment and that the measurement of serum TSH is a useful marker complementing the free T4 measurement in the management of children with CH. A minority have variable pituitary-thyroid hormone resistance, with relatively elevated serum TSH levels for their prevailing serum free T4 concentration. The prevalence of resistance is greater (43%) in young infants (< 1 yr of age) than in older children (10%), indicating that, in most children, the resistance improves with age.

Permanent primary congenital hypothyroidism (CH) can be caused by abnormal thyroid differentiation (athyreosis), migration (ectopy), or function (leading to goiter). Goiters follow an autosomal recessive pattern of inheritance, whereas ectopy and athyreosis are considered as a single sporadic entity with a female preponderance. On the other hand, a high prevalence of extrathyroidal malformations has been reported in CH, but without linking specific defects to specific types of CH. On the basis of TSH screening, 273 newborns were referred to an academic pediatric endocrinology clinic in the province of Quebec between 1988 and 1997. Of 230 patients with permanent primary CH who had scintigraphy at diagnosis, 141 had ectopy (104 girls), 36 had athyreosis (21 girls), 42 had goiter (18 girls), 10 (3 girls) had a normal scan, and 1 girl had hemiagenesis. Only in the ectopies was the proportion of girls significantly higher than 0.5 (P<0.001). Isolated cardiac malformations were observed in 7 patients (3.0%), a prevalence 5-fold higher than that in the general population; this was largely due to atrial and ventricular septal defects, which were only observed in ectopy and athyreosis. Our data suggest that the molecular mechanisms that lead to complete absence of thyroid differentiation or defective thyroid migration 1) may be similar, but are modulated by the genetic makeup of the embryo and/or the hormonal milieu of the fetus; and 2) may also be involved in septation of the embryonic heart.

The pathogenesis of congenital hypothyroidism due to thyroid dysgenesis is still unknown. A point mutation in the TSH receptor (TSHR) of the hypothyroid hyt/hyt mouse invoked the TSHR as a candidate gene for congenital hypothyroidism. Therefore, we screened for mutations in the TSHR gene in patients with congenital hypothyroidism and hypoplasia of the gland. In one girl detected in neonatal screening with the confirmed diagnosis of permanent congenital hypothyroidism with reduced thyroid volume, two novel mutations in the TSHR gene were identified. Single strand conformational polymorphism and subsequent DNA sequencing studies of a fragment of the TSHR gene showed that the patient is a compound heterozygote for 2 loss of function mutations in exon 10 of the TSHR gene. In the mutant maternal allele, 18 nucleotides (positions 1217-1234) are deleted, and 4 novel bp are inserted, resulting in a frame-shift and premature termination of the coding sequence. Transfection studies showed that this truncated TSHR was trapped intracellularly and completely lacked cell surface expression. The paternal gene harbors a missense mutation at nucleotide position 1170, leading to the exchange of the highly conserved C-390 for a W residue. This alteration resulted in a drastic loss of affinity and potency of TSH acting at the mutant compared to the wild-type receptor. In contrast to the published loss of function mutations of the TSHR leading to euthyroid hyperthyrotropinemia, the two new mutations lead to persistent congenital hypothyroidism and defective organ development. Further studies will have to analyze to what extent TSHR mutations are involved in the pathogenesis of congenital hypothyroidism as opposed to other genetic or environmental factors.

Hyperthyroidism and goiter have been reported frequently in association with the McCune-Albright syndrome (MAS). To assess the prevalence and extent of thyroid abnormalities in girls with MAS, we studied 19 patients [mean age, 6.6 +/- 1 (+/- SE) yr; mean bone age, 9.5 +/- 1 yr] and 18 normal control girls (mean age, 10.3 +/- 0.5 yr). All patients appeared euthyroid when examined; 1 was taking antithyroid medication. Ultrasonography revealed thyroid abnormalities in 7 patients, including generalized inhomogeneity, small (2-4 mm) and large (greater than 10 mm) hypoechoic regions, and echogenic nodule-like regions. Repeat ultrasonography after intervals of 9-18 months showed enlargement of large hypoechoic regions in 2 patients. In the patients with abnormal ultrasound findings, serum TSH was uniformly low or suppressed both at baseline and after administration of 7 micrograms/kg TRH. The mean serum T3 level in this group was significantly higher than that in controls (2.9 +/- 0.2 vs. 2.3 +/- 0.1 nmol/L; P less than 0.05), whereas mean serum T4, free T4, and T4-binding globulin levels did not differ from those of controls. In the remaining 11 patients, thyroid ultrasonography was normal, and the serum levels of T3, T4, free T4, and TSH were normal. Bioassay showed no detectable thyroid-stimulating activity in the plasma of the MAS patients with suppressed TSH levels. None of the patients became overtly thyrotoxic over 3-6 yr of observation, and their serum iodothyronine levels remained stable. We conclude that thyroid dysfunction is common in girls with MAS, but that it may be clinically occult and not rapidly progressive. The thyroid dysfunction, like that of the ovaries, is associated with structural abnormalities in the gland itself, together with suppressed levels of the respective stimulating hormones.

A review of the available world literature revealed a total of 90 cases of thyroidal hemiagenesis. An additional 4 cases are reported, 3 of which also had absence of the isthmus. All 4 patients had the left lobe of the thyroid absent. As in previously reported cases, absence of the left lobe was more common. In this study, the left lobe was absent in 80% of the cases and the right lobe was absent in 20% of the cases (a left to right hemiagenesis ratio of 4:1). The isthmus was absent in 50% of the patients where the isthmus was specifically mentioned. Females accounted for 75% and males accounted for 25% of the cases, giving a female to male ratio of 3:1. Associated disease in the remaining thyroid lobe included adenocarcinoma, hyperthyroidism, primary and secondary hypothyroidism, benign adenoma, multinodular goiter, hyperparathyroidism, and chronic thyroiditis. Some patients were found to be in a euthyroid state without abnormalities. The most common disease of the remaining lobe was hyperthyroidism. Thyroidal hemiagenesis with an isthmus present has the appearance of a hockey stick.

Four patients with hemiaplasia of the thyroid gland presented with thyrotoxicosis. Each patient was noted to have unilateral goiter without palpable thyroid tissue on the contralateral side. Investigation of these patients included measurements of serum L-T4, T3, thyroglobulin, thyroid microsomal antibody, long acting thyroid stimulator (LATS), and long acting thyroid stimulator protector (LATS-P). In addition, an 131I thyroid scan was performed on each patient and was repeated after TSH administration (TSH stimulation test). Three patients underwent surgery; information from the remaining patient was obtained from postmortem examination. In three patients, LATS and LATS-P were undetected, and these subjects were found to have adenomas. LATS-P, without LATS, was detected in the remaining patient, and she was found to have diffuse hyperplasia. From our cases as well as a search of the world literature, three points arise. 1) Hemiaplasia is found only when attention is drawn to the thyroid gland through some other abnormality, e.g. thyrotoxicosis or goiter. The true incidence of hemiaplasia, therefore, is unknown. 2) A TSH stimulation test is essential to differentiate hemiaplasia from a hot nodule with contralateral thyroid suppression. 3) The measurement of thyroid-stimulating immunoglobulins may be helpful in distinguishing toxic adenoma from Graves' disease without exophthalmos.