An endoplasmic reticulum storage disease causing congenital goiter with hypothyroidism

In humans, deficient thyroglobulin (Tg, the thyroid prohormone) is an important cause of congenital hypothyroid goiter; further, homozygous mice expressing two cog/cog alleles (linked to the Tg locus) exhibit the same phenotype. Tg mutations might affect multiple different steps in thyroid hormone synthesis; however, the microscopic and biochemical phenotype tends to involve enlargement of the thyroid ER and accumulation of protein bands of M(r) < 100. To explore further the cell biology of this autosomal recessive illness, we have examined the folding and intracellular transport of newly synthesized Tg in cog/cog thyroid tissue. We find that mutant mice synthesize a full-length Tg, which appears to undergo normal N-linked glycosylation and glucose trimming. Nevertheless, in the mutant, Tg is deficient in the folding that leads to homodimerization, and there is a deficiency in the quantity of intracellular Tg transported to the distal portion of the secretory pathway. Indeed, we find that the underlying disorder in cog/cog mice is a thyroid ER storage disease, in which a temperature- sensitive Tg folding defect, in conjunction with normal ER quality control mechanisms, leads to defective Tg export. In relation to quality control, we find that the physiological response in this illness includes the specific induction of five molecular chaperones in the thyroid ER. Based on the pattern of chaperone binding, different potential roles for individual chaperones are suggested in glycoprotein folding, retention, and degradation in this ER storage disease.     

Multivariate analysis on factors affecting suppression of thyroid-stimulating hormone in treated congenital hypothyroidism

AIMS: To determine the factors which influence the suppression of thyroid-stimulating hormone (TSH) in infants with congenital hypothyroidism (CH) following treatment. METHODS: We examined retrospectively the patterns of thyroid function tests from diagnosis to 3 years of age in 140 infants diagnosed with CH from screening. Patients were classified into 3 groups: athyreosis, ectopia and presumed dyshormonogenesis on the basis of thyroid scans. Adequate TSH suppression was defined as plasma TSH concentration <6 mU/l. The factors affecting the suppression of TSH at 6 months and 1 year of age which were evaluated were: initial confirmatory plasma TSH, initial plasma thyroxine (T4), mean age of starting treatment with L-T4, dose of L-T4 at diagnosis, 6 weeks, 3 months and 6 months, and aetiology of the congenital hypothyroidism. Variables were then entered in a stepwise logistic regression model for TSH suppression at 6 months and 1 year of age. RESULTS: All infants had radionuclide scans prior to treatment: athyreosis (n = 39), ectopia (n = 78) and dyshormonogenesis (n = 23). 58% of patients had persistently raised TSH at 6 months of age while 31% of patients had a persistently raised TSH at 1 year of age. There was a significant delay in the normalisation of plasma TSH in athyreosis and ectopia groups compared with dyshormonogenesis. Multiple regression analysis for TSH suppression at 6 months of age found plasma T4 levels and aetiology of CH as independent factors affecting the timing of TSH suppression. Aetiology of CH was the only independent factor affecting TSH suppression at 1 year of age. CONCLUSION: At 6 months of age, plasma T4 levels at 6 weeks and 3 months, and aetiology of CH were independent factors affecting timing of TSH suppression. However, by 1 year of age, the aetiology of CH was the only independent factor affecting suppression of TSH.     

Screening for congenital hypothyroidism in the Republic of Ireland.

A national pilot study for detecting congenital hypothyroidism by radioimmunoassay of thyroid-stimulating hormone concentrations in dried blood was incorporated into the newborn screening programme in Ireland on 1 August 1979. The programme has been monitored by a steering committee and follows the guidelines set by the European Society of Paediatric Endocrinologists. During the first 12 months 76 224 infants were screened and 19 cases confirmed, giving an incidence of 1:4012. Fifty infants (0.07%) were recalled for a serum sample, though most of the recalls (31; 0.04%) occurred during the first three months, before the methodology had become established. No case was detected clinically. At recall only three of the 19 affected infants had obvious features, and nine inconspicuous features. Organisation was directed at early diagnosis and treatment, the mean age at beginning treatment being 15 days. These results confirm the efficacy of screening for congenital hypothyroidism and suggest that capital and running costs will be offset by savings in maintenance treatment of untreated patients. Screening does not, however, remove the need for continued vigilance, and clinicians should request thyroid-function tests in any suspected case.     

Management of patients with congenital hypothyroidism.

The biochemical state and treatment of 73 children and 44 adults up to the age of 40 with proved congenital hypothyroidism were assessed in a regional study in the north of England. The findings showed that a substantial proportion of the patients were having inappropriate treatment or were not taking their treatment regularly and that in some of these there were clinical effects.     

Linkage analysis identifies the thyroglobulin gene region as a major locus for familial congenital hypothyroidism

Congenital hypothyroidism affects 1/3000-4000 newborns and it has been estimated that 10-20% are familial cases with an autosomal recessive mode of inheritance. Previous studies of mostly individual cases have led to the identification of mutations in a number of genes, indicating that it is a genetically heterogeneous disease, but no major gene has been identified. In the present investigation, a population-based sample of 23 families with autosomal recessive congenital hypothyroidism, but no signs of goitre, were subject to linkage analysis. When markers located close to the thyroglobulin gene on chromosome 8q24 were used in a two-point analysis allowing for heterogeneity, a Z(max) of 4.10 was obtained with the microsatellite marker D8S557, indicating heterogeneity with 43% of the families being linked. A multipoint analysis using the markers D8S557 and D8S1835 gave a Z(max) of 3.51, assuming homogeneity. There was significant evidence of heterogeneity with 44.5% of the families being linked. The results indicate that a gene in 8q24 is a common cause of familial congenital hypothyroidism. Since thyroglobulin is essential for thyroid physiology, the gene encoding this protein is the obvious candidate for mutation analysis in the linked families.     

Genetic and linkage analysis of familial congenital hypothyroidism: exclusion of linkage to the TSH receptor gene

Congenital hypothyroidism affects 1/3000– 4000 newborns. The causes of this group of disorders are still largely unknown. Although most cases are sporadic, some families have several affected children and/or consanguineous parents, suggesting autosomal recessive inheritance. Furthermore, there is a murine strain (hyt) with congenital hypothyroidism and autosomal recessive inheritance, whose phenotype appears to be identical with the corresponding human disease. In the hyt mouse, the disease is caused by a mutation in the thyroid-stimulating hormone receptor (TSHR) gene, making this gene a likely candidate also for the human disease. The human TSHR gene was mapped on radiation hybrid panels and closely linked flanking markers D14S287 and D14S616 were identified. On the Genebridge 4 panel, D14S287 was found to be located 8.5 cR (corresponding to 2.3 cM) proximal to the TSHR gene, and D14S616 was found to be located 4.4 cR (1.2 cM) distal to the TSHR gene. These markers were analyzed in 23 families, most of them with two or more children affected by congenital hypothyroidism and some with appreciable consanguinity of the parents. Assuming homogeneity, the two-point lod score at θ = 0.1 was –4.8 for D14S287 and –5.8 for D14S616, and thus linkage to the TSHR gene was excluded. Even when the data were analyzed with allowance for heterogeneity, there was no evidence of linkage. Our conclusion is that if mutation of the TSHR gene causes familial congenital hypothyroidism in humans, it affects only a small proportion of the cases. Received: 8 July 1996     

Prevalence of minor musculoskeletal anomalies in children with congenital hypothyroidism

In the last decade a high frequency of extrathyroidal congenital anomalies has been reported in infants with congenital hypothyroidism (CH) detected by neonatal screening. In the present study the occurrence of additional congenital malformations (CM) in a cohort of children with confirmed primary CH due to thyroid dysgenesis was investigated. A high prevalence of extrathyroidal major congenital anomalies (15.9%), more than 5-fold higher than that reported in the Egyptian population (2.7%), was found. The cardiac and musculoskeletal systems were the most commonly involved, comprising 9.09 and 47.72% of all anomalies, respectively. The high prevalence of musculoskeletal anomalies in this study was mostly due to minor anomalies as brachydactyly and digitalization of thumbs. The type of dysgenesis (i.e. aplastic, ectopic or hypoplastic) as well as the severity of hypothyroidism, as assessed by TSH and T(4) levels at diagnosis, had no relation with the occurrence of extrathyroidal abnormalities.     

Seasonal variation in the incidence of peptic ulcera perforations

A series of 986 cases of peptic ulcer perforation during 1958–1972 admitted to Sassoon Hospitals in Poona has been studied. The meteorological factors and their relationship to the incidence of cases were determined. It has been shown by correlation studies that water vapour pressure plays a dominant role in the incidence of perforated peptic ulcer. Combinations of high vapour pressure with small range of diurnal temperature or diurnal vapour pressure are associated with an increase in the incidence of peptic ulcer perforations.     

Evaluation of the incidence of congenital rubella in GDR]

Annual number of congenital rubellas in GDR was evaluated by means of a mathematic model. Dates of inmunity rate of rubella in L. and P. districts obtained by means of haemagglutination inhibition reaction were taken into account. From these dates of a number of possible primary cases of rubella infection in wifes in the first 3 months of pregnancy as well as literary dates on mean number of monsters determined after the infection, i.e. 10--15--25% cases, were evaluated. There were obtained in relation with different mean numbers of monsters 37--56--93 cases of congenital rubellas for live born children from mothers at the age of 14 to 45 years. It results in total that the incidence of disease for live born children from mothers up to 45 years, is 0,2--0,5%, i.e. 2--5 children with congenital rubella on 10 000 live born children. Compared with literary data, it results a good correlation between proper evaluations and numbers of congenital rubella incidence quoted by other authors. In view of these evaluations, a conclusion to introduce protective rubella vaccination, is fully justified.     

先天性甲状腺功能减退症致病基因的研究进展

先天性甲状腺功能减退症(congenital hypothyroidism,CH)是由于甲状腺发育不良或甲状腺激素合成障碍所造成的一种疾病。现已证实有多个基因的遗传变异可导致甲状腺发育不良或甲状腺激素合成障碍。这一结果提示,甲状腺发育不良和甲状腺激素合成障碍与遗传密切相关。该文简单阐述了近年来有关甲状腺激素合成障碍相关基因的研究状况,并对该领域发展做了展望。     

Epidermal growth factor receptor ontogeny in mice with congenital hypothyroidism

To assess the effect of endogenous thyroid hormone on hepatic EGF receptors in developing mice we measured EGF binding to plasma membrane receptors in liver and brain of mice with congenital hypothyroidism and in euthyroid controls at 20, 30 and 40 days of age. At 20 days hepatic EGF receptor binding was low in both hypothyroid and control animals. Between 20 and 30 days the hepatic binding increased dramatically in the euthyroid animals, an increase that was greater in males than females. The increase in binding was due to an increase in the high affinity receptor population. Among hypothyroid animals there were no changes in hepatic EGF receptor binding with increasing age. In cerebral cortex EGF binding was similar in euthyroid and hypothyroid animals at all ages. These results suggest that thyroxine has regulatory effects on the postnatal ontogeny of hepatic EGF receptors.     

The costs and benefits of screening for congenital hypothyroidism in Wisconsin

Abstract

A comprehensive benefit‐cost analysis of the screening program to detect newborns with congenital hypothyroidism in Wisconsin is presented. Congenital hypothyroidism, if left undetected and untreated at an early age, can have serious irreversible effects on the growth and development of the brain. The monetary costs of the detection and treatment program for congenital hypothyroidism were compared with the projected benefits (avoided costs) that result from the prevention of the mental retardation associated with the disorder. Future costs and benefits were determined using a 4 per cent, 7 per cent, and 10 per cent rate of discount. Net benefits (benefits minus costs) for detecting and treating one individual with congenital hypothyroidism were approximately $98,200 ($141,700 ‐ $43,500) using the 7 per cent rate of discount. Net benefits for detecting the 13 individuals with congenital hypothyroidism in 1981–1982 totaled $1,277,000.     

Factors in the incidence of childlessness in Canada: An analysis of census data

The impact of the 1918 influenza pandemic on human fertility has been subject to significant scholarly debate. The current study characterizes the inter-temporal association between excess deaths during the pandemic and the subsequent birth deficit by identifying the length of time between these two phenomena using cross-correlations of monthly death and birth data from Taiwan from 1906 to 1943. The analysis demonstrates a strong and negative correlation between deaths (d) at time t and births (b) at time t + 9 (r_db(9) = –0.68, p < .0001). In other words, a significant drop in births was observed nine months after pandemic mortality peaked. The findings suggest that the 1918 influenza pandemic impacted subsequent births primarily through the mechanism of reduced conceptions and embryonic loss during the first month of pregnancy rather than through late-first-trimester embryonic loss.     

Newborn screening and single nucleotide variation profiling of TSHR,TPO, TG and DUOX2 candidate genes for congenital hypothyroidism

Molecular Biology Reports - High prevalence of congenital hypothyroidism (CH) among Indian newborns prompted us to establish population-specific reference ranges of TSH and to explore the...     

Thyroid function tests in children with congenital hypothyroidism on L-thyroxine treatment

The plasma levels of thyroxine (T4), triiodothyronine (T3), free T4 (FT4), free T3 (FT3), reverse T3 (rT3) and immunoradiometrically assayed thyrotropin (IRMA TSH) have been measured in 28 L-T4-treated children with congenital hypothyroidism as well as in a control group (group C). The patients were subdivided into 2 groups according to the nonsuppressed (group A) or suppressed (group B) TSH response to TSH-releasing hormone (TRH). Basal IRMA TSH correlated with the TSH increment after TRH and it was significantly lower in group B vs. groups A and C, while no difference was present between groups A and B in regard to T4, FT4 and rT3, all higher than in group C. FT3 levels were similar in the 3 groups. In children, as in adults, basal IRMA TSH seems to be a reliable index in monitoring overtreatment.