The hypothyroidism in an inbred kindred with congenital thyroid hormone and glucocorticoid deficiency is due to a mutation producing a truncated thyrotropin receptor.

Growth and function of the thyroid and adrenal glands are maintained and controlled by thyrotropin (TSH) and adrenocorticotrophic hormone (ACTH), respectively. The action of these trophic hormones requires the presence of functional TSH and ACTH receptors. We describe a large inbred Bedouin kindred in which profound congenital hypothyroidism and hypoadrenocortisolism occurred alone or together in eight family members belonging to four nuclear families. The high serum TSH and ACTH levels in the presence of normal or hypoplastic thyroid glands and low glucocorticoid, but not mineralocorticoid concentrations, are characteristic of resistance to TSH and ACTH. Linkage analysis, using specific polymorphic markers, excluded the involvement of the ACTH receptor but not thyrotropin receptor (TSHR). A novel point mutation was identified in exon 10 of the TSHR that replaces the normal cytosine in nucleotide 2024 with a thymidine. As a result the normal arginine in codon 609 (CGA) is replaced with a stop codon (TGA). This mutation produces a truncated TSHR lacking the third intracellular and extracellular loops, the sixth and seventh transmembrane segments, and the intracytoplasmic tail. The presence of hypothyroidism did not affect the timing, severity, and manner of clinical manifestation of hypoadrenocortisolism.     

20例先天性甲状腺功能减退症患者甲状腺过氧化物酶基因突变分析

检测20例先天性甲状腺功能减退症患者甲状腺过氧化物酶(TPO)基因突变.发现1例患者在TPO基因第13外显子处存在c.2268insT纯合性突变,另1例为TPO基因c.2268insT突变和第9外显子c.1477G＞A突变复合杂合子.TPO基因可能是中国人群先天性甲状腺功能减退症发生的原因之一.

Abstract：

Thyroid peroxidase(TPO) gene was detected in 20 patients with congenital hypothyroidism. An insertion c. 2268insT of TPO gene was found in one of them, and c. 2268insT combined with c. 1477G＞C mutation in another. TPO gene mutation may be related to pathogenesis of congenital hypothyroidism in Chinese.     

Recombinant thyrotropin in the diagnosis of congenital hypothyroidism

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.     

Novel mutations of the thyroid peroxidase gene in patients with permanent congenital hypothyroidism.

OBJECTIVE: It is suggested that iodide organification defects account for 10% of all cases with congenital hypothyroidism (CH). One candidate gene for these defects is the thyroid peroxidase (TPO) gene. DESIGN: Exons 2, 8-10 and 14 of the TPO gene were examined in 30 patients with permanent CH without a family history of CH. This group was characterized by the presence of an orthotopic thyroid gland and elevated TSH levels. METHODS: The mutational screening was performed by single-strand conformational polymorphism followed by sequence analysis of fragments with abnormal migration patterns and by restriction enzyme analysis. RESULTS: In four patients we were able to identify mutations on both alleles which have not been described so far. One patient was a carrier of a new homozygous point mutation in exon 9 resulting in an exchange from Leu to Pro at codon 458. Another patient was found to be compound heterozygous for two mutations, a 20 bp duplication in exon 2 and a new mutation in exon 9 (Arg491His). Two brothers of consanguineous parents showed a homozygous T deletion in exon 14 at position 2512. CONCLUSIONS: Our findings confirm the genetic heterogeneity of TPO defects and support the suggested prevalence of organification defects.     

Free thyroid hormones in evaluating persistently elevated thyrotropin levels in children with congenital hypothyroidism on replacement therapy

Some children with congenital hypothyroidism receiving L-T4 therapy have elevated serum TSH levels despite having normal serum T4 concentrations, suggesting that they have a higher threshold for the feedback regulation of TSH release. To further study this possibility, we determined serum free T4 (FT4) and T3 (FT3) concentrations in two groups of L-T4-treated hypothyroid children. Group A consisted of 10 patients with high serum TSH levels; group B consisted of 10 patients with normal TSH levels. All patients were clinically euthyroid, and serum total T4 and T3 concentrations were similar in the two groups. A third (control) group (C) consisted of randomly selected normal children. The three groups were age matched. Serum FT3 and FT4 were significantly lower in group A compared to group B. Serum FT4 and T4 were higher and TSH was lower in group B compared to group C. The T4/T3 ratio wash higher in both groups of children with hypothyroidism than in group C. We conclude that in most patients a high serum TSH was due to inadequate L-T4 therapy, as shown by free hormone concentrations (low) but not by total hormone levels (normal). This suggests that L-T4 therapy should be monitored by measurement of TSH and free hormone concentrations. The latter also can be used to indicate moderate overdosage, not clinically detectable, as shown by the comparison between groups B and C. Measurement of serum total T4, as indicated by the lack of difference between groups A and B and also by T4/T3 ratio, cannot be considered a reliable index of therapeutic adequacy in such children.     

A familial case of congenital hypothyroidism caused by a homozygous mutation of the thyrotropin receptor gene.

Most of the time congenital hypothyroidism appears as a sporadic disease. In addition to the rare defects in hormonosynthesis associated with goiters, the causes of congenital hypothyroidism include agenesis and ectopy of the thyroid gland. The study of some familial cases has allowed the identification of a few genes responsible for congenital hypothyroidism. We report here a familial case of congenital hypothyroidism, transmitted as a recessive trait, and caused by a homozygous mutation in the thyrotropin receptor (TSH-R). The initial diagnosis of thyroid agenesis, based on the absence of tracer uptake on scintiscan, was incorrect, because ultrasound examination identified severely hypoplastic thyroid tissue in the cervical region.     

Changes in the sialylation and sulfation of secreted thyrotropin in congenital hypothyroidism.

We have examined the oligosaccharide structure of secreted thyrotropin (TSH) in perinatal and mature rats with congenital primary hypothyroidism. Rat pituitaries from euthyroid control animals and those rendered hypothyroid by methimazole treatment were incubated with [3H]glucosamine in vitro. Secreted TSH was purified, and oligosaccharides were enzymatically released and characterized by anion-exchange HPLC. In perinatal hypothyroid animals compared with control animals, oligosaccharides from TSH alpha and beta subunits contained more species with three or more negative charges. Moreover, perinatal hypothyroid animals demonstrated a dramatic increase in the ratio of sialylated to sulfated species within oligosaccharides of the same negative charge (2.9- to 7.4-fold increase for TSH-alpha; 15.1- to 25.5-fold increase for TSH-beta). In mature hypothyroid 9-week-old animals compared with control animals, changes were less pronounced, suggesting that endocrine regulation of oligosaccharide structure is dependent upon the maturational state of the animal. These changes were specific for TSH because glycosylation of free alpha subunit (synthesized by the thyrotroph and gonadotroph) and of total glycoproteins was minimally altered by hypothyroidism. Together, these data provide direct evidence and characterization of specific changes in the structure of a secreted pituitary glycoprotein hormone occurring as a result of in vivo endocrine alterations during early development. Moreover, they provide a potential structural basis to explain the delayed clearance of both TSH and the gonadotropins with end-organ deficiency, which may have important implications for the in vivo biological activities of these hormones. Specifically, such posttranslational changes may be an important adaptive response to prevent the consequences of endocrine deficiency during early development.     

Sex-specific impact of congenital hypothyroidism due to thyroid dysgenesis on skeletal maturation in term newborns

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.     

A novel mutation in the thyrotropin (thyroid-stimulating hormone) receptor gene in a case of congenital hypothyroidism.

Congenital hypothyroidism (CH) occurs approximately with a frequency of 1 in 3000-4000 births, being a disease caused by defects in thyroid hormone synthesis associated either with goiter presence or with agenesis or ectopy of the thyroid gland. A study of some familial cases has allowed identification of mutations in several known genes, including that encode the thyroid-stimulating hormone receptor (TSHR). We report a familial case of CH that transmitted as a recessive trait and caused by a novel homozygous nonsense mutation in TSHR with an initial diagnosis of thyroid agenesis hypoplasia. Genomic DNA was obtained from two siblings and their parents; TSHR was amplified using pairs of overlapping exonic primers; and polymerase chain reaction products were automatically sequenced. The propositus was homozygous (genotype: M/M) for a novel C to G transversion (1431C>G), producing a nonsense mutation, Y444X, in the first intracellular loop of TSHR, rendering a truncated receptor. Thus, the observed unresponsiveness to TSHR may be due to absent insertion of the truncated receptor into the cell membrane (if it gets translated at all) or the truncation may lead to nonsense-mediated mRNA degradation (its unresponsive to TSH). Both parents were heterozygous (wWt/M) and unrelated, as known from family history. The other daughter was homozygous for both wild-type alleles (wWt/wWt).     

Identification and functional analysis of novel inactivating thyrotropin receptor mutations in patients with thyrotropin resistance.

OBJECTIVE: We identified and analyzed novel thyrotropin (TSH) receptor mutations in three Japanese families with resistance to TSH. DESIGN: The TSH receptor gene was sequenced and the mutations were determined. The mutant TSH receptors were transfected into COS-7 cells, and their functions were analyzed. PATIENTS: The patients were compound-heterozygotes for the R450H mutation and novel mutations in the TSH receptor gene. The first patient was a compound-heterozygote for R450H and V473I. The second sibling possessed R450H and R519C. The third sibling had R450H and R519G. RESULTS: The R450H mutant exhibited moderately impaired receptor functions and a moderately decreased cell surface expression in agreement with previous results. The V473I mutant exhibited an almost normal TSH binding, a slightly decreased cyclic adenosine monophosphate (cAMP) response, a moderately decreased inositolphosphate (IP) response, and an almost normal cell surface expression. TSH binding and TSH stimulation of cAMP and IPs were markedly decreased in the R519C and R519G mutants. Cell surface expression was decreased in the R519C mutant and negligible in the R519G mutant. All of these mutants showed normal intracellular synthesis of TSH receptors. CONCLUSIONS: These novel inactivating mutations contribute to understanding of the structure-function relationship of the TSH receptor. To date, all of the patients with TSH resistance resulting from TSH receptor mutations identified in Japan possessed the R450H mutation at least in one allele. These observations suggest that the R450H mutation is a commonly observed TSH receptor mutation in patients with TSH resistance in Japan.     

Additional phenotypic abnormalities with presence of cysts within the empty thyroid area in patients with congenital hypothyroidism with thyroid dysgenesis

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.     

Transient neonatal hypothyroidism: characterization of maternal antibodies to the thyrotropin receptor

Transient neonatal thyroid disease is known to occur as a result of transplacental passage of maternal immunoglobulin G (IgG) that contains antibodies to the TSH receptor (TRAb). Thyroid-stimulating antibody (TSAb) produces hyperthyroidism, and antibody that blocks TSH binding (TBIAb) results in hypothyroidism. We have analyzed in detail the IgG from four women who gave birth to children with transient neonatal hypothyroidism and have shown stimulating and inhibiting antibodies to coexist in three. Human and/or rat thyroid (FRTL5) cells were used to show stimulatory effects in vitro. Inhibition was assessed as prevention of stimulation of these cells (by TSH or TSAb) or by the blocking of binding of [125I] TSH to its receptor. The IgG from two mothers was tested to identify whether the inhibitory and stimulating bioactivities resided in molecules characterized by either or both kappa- or lambda-light chains. Evidence for restricted heterogeneity (implying oligoclonality) was obtained, in that with one, purely inhibitory IgG all activity was with IgG kappa. With the other, stimulating and inhibitory activities were predominantly in IgG kappa and IgG lambda, respectively. In addition, the latter IgG contained a second stimulator that was not suppressed by either its own or other inhibitory IgG. Despite the presence of stimulatory antibodies in these IgG, the clinical effect was neonatal hypothyroidism, reflecting the greater potency of the inhibitory IgG in all instances. Based on the histories of these four women and their offspring it is apparent that TRAb, and in particular TBIAb, can develop at any point in the course of autoimmune thyroid disease, i.e. either at the onset or long after the autoimmune process has been established.     

Primary hypothyroidism due to leukemic infiltration of the thyroid gland

We describe a patient with acute B-lymphocyte lymphoblastic leukemia who developed laboratory changes (not detectable free thyroxine, TSH 66 microIU/ml) suggesting severe primary hypothyroidism. Histological examination at autopsy showed massive leukemic infiltration of the thyroid gland: the progressive reduction of thyroid hormone levels with concomitant increase in TSH levels observed over a three-month period from the onset of the hemopathy suggests a cause-effect relationship between leukemic infiltration of the thyroid gland and hypothyroidism.     

Structural and functional alterations in the hippocampus due to hypothyroidism

Thyroid hormones (THs) exert a broad spectrum of effects on the central nervous system (CNS). Hypothyroidism, especially during CNS development, can lead to structural and functional changes (mostly resulting in mental retardation). The hippocampus is considered as one of the most important CNS structures, while the investigation and understanding of its direct and indirect interactions with the THs could provide crucial information on the neurobiological basis of the (frequently-faced in clinical practice) hypothyroidism-induced mental retardation and neurobehavioral dysfunction. THs-deficiency during the fetal and/or the neonatal period produces deleterious effects for neural growth and development (such as reduced synaptic connectivity, delayed myelination, disturbed neuronal migration, deranged axonal projections, decreased synaptogenesis and alterations in neurotransmitters’ levels). On the other hand, the adult-onset thyroid dysfunction is usually associated with neurological and behavioural abnormalities. In both cases, genomic and proteomic changes seem to occur. The aim of this review is to provide an up-to-date synopsis of the available knowledge regarding the aforementioned alterations that take place in the hippocampus due to fetal-, neonatal- or adult-onset hypothyroidism.     

Recombinant human thyrotropin in thyroid cancer and hypopituitarism due to sella metastasis.

We present a patient with thyroid cancer and hypopituitarism who required recombinant human thyrotropin (rhTSH) for 131I scanning with respect to subsequent therapy. The thyroid cancer had been unknown until central neurological symptoms developed, leading to the diagnosis of a huge metastasis to the sella that was the only manifestation of metastatic spread. The failure to generate endogenous thyrotropin (TSH) was overcome by the use of rhTSH for performing a 131I test. Unfortunately, the 131I uptake was not sufficient for therapy. This subject is the first reported case who required the application of rhTSH due to a single thyroid cancer metastasis in the sella region with secondary failure to generate endogenous TSH.     

Sexual dimorphism of thyroid function in newborns with congenital hypothyroidism

Several characteristics of congenital hypothyroidism (CH) from thyroid dysgenesis (ectopy and athyreosis) are sexually dimorphic: girls are more often affected, and boys are twice more likely than girls to have absent knee epiphysis at diagnosis, an indicator of severity of CH. Whether the biochemical severity of CH is sexually dimorphic is unknown. We therefore reviewed the charts of all newborns referred to our clinic from 1990 to 2004 because of a TSH greater than 15 mU/liter on newborn screening. In ectopy (24 boys, 78 girls) at screening, median TSH was lower in boys than girls (75 vs. 135 mU/liter, P = 0.017), whereas total T4 was higher (123 vs. 68 mmol/liter, P = 0.003); the same differences were present at diagnosis: TSH was 90 and 284 mU/liter (P = 0.001) and free T4 10 and 7 pmol/liter (P = 0.049) in boys and girls, respectively. The log-linear relationships between TSH and T4 at screening and diagnosis were similar in both sexes. In athyreosis (10 boys, 14 girls) at screening and diagnosis, TSH was higher in boys [308 vs. 207 (P = 0.053) and 712 vs. 555 mU/liter (P = 0.0057)]. In infants with an orthotopic gland (dyshormonogenesis, nine boys, 13 girls), there was no sex difference in biochemical severity of CH. In conclusion, sexual dimorphism in biochemical severity of CH from thyroid dysgenesis is apparent but differs according to etiology. These novel findings suggest that sexual dimorphism should be considered as a modulator of the mechanisms underlying the fate and function of ectopic thyroid cells.     

Spontaneous normalization of thyrotropin concentrations in patients with subclinical hypothyroidism

CONTEXT: Patients with subclinical hypothyroidism may revert to normal TSH values. OBJECTIVE: The objective of this study was to examine the time course of the normalization of TSH levels in subclinical hypothyroidism. DESIGN: This was a prospective, observational study with no intervention, with a duration of follow-up of 12-72 months. SETTING: Outpatients visited an endocrinology clinic of a general hospital. PATIENTS: Forty patients (32 women, mean age 62.8 +/- 8.2 yr) with spontaneous subclinical hypothyroidism (TSH > 5 mU/liter and normal free T(4)) participated in the study. Each patient normalized their TSH values without T(4) therapy throughout the follow-up. MEASUREMENTS: TSH and free T(4) levels were evaluated every 6 months. RESULTS: Normalization occurred at a median time of 18 months (range, 6-60 months). Fifteen patients normalized their TSH levels during the first year of follow-up and 27 during the first 2 yr. Ten patients normalized their TSH values at the fourth or fifth year. Only four patients reverted to TSH values less than 2 mU/liter. Final TSH levels achieved by the patients were significantly correlated with the time elapsed until normalizing these levels (r = 0.367; P = 0.020). CONCLUSIONS: There is no clear pattern of TSH normalization, although most patients normalize their TSH values early in the follow-up. The final TSH reached seems to be related to the time of normalization.