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G Van Vliet

Publications and source records attributed to G Van Vliet.

At least 19 recordsLinked to original sources
PubMed2006

Effects of early high-dose levothyroxine treatment on auditory brain event-related potentials at school entry in children with congenital hypothyroidism.

AIMS: We tested whether brain event-related potentials (ERPs) are normal in children with congenital hypothyroidism (CH) after early high-dose levothyroxine treatment. METHODS: Auditory ERPs were recorded in 33 normal controls and in 15 children with CH at 5 years 9/12. Based on bone maturation at diagnosis, the CH group was divided into severe (n = 8) and moderate (n = 7) subgroups. CH patients were treated at a median age of 14 days with a mean initial dose of levothyroxine of 11.6 microg/kgxday. Two ERP components (N100 and N200) were measured and clinical follow-up variables collected. RESULTS: The functional anatomical and cognitive organisation of the auditory system, as revealed by the analyses of ERP measures, did not differ between CH and controls, or between severe and moderate CH subjects. However, N200 latency was globally longer in the CH than in the control group (p = 0.01) and was positively correlated with the over-treatment index (r = 0.61; p < 0.05) and verbal IQ. N200 amplitude was negatively correlated with initial dose (r = -0.74; p < 0.005). CONCLUSION: These data suggest that sensitive tools such as ERPs can reveal differences between CH and controls and relate these differences to the adequacy of treatment of CH.

Child, Preschool↗
PubMed2006

[Congenital hypothyroidism].

Congenital hypothyroidism is the principle cause of preventable mental retardation, with a prevalence of 1 in 3,500 neonates. The disorder may be permanent or transitory. Permanent congenital hypothyroidism is caused principally by thyroid dysgenesis. In industrialized countries, mass screening allows the disorder to be diagnosed at birth. The severity is variable but is generally more pronounced in females. The majority of studies point to a genetic origin for the disease and no consistent evidence has been found to suggest a major role for environmental factors. The genetic factors have already been identified and involve several elements (mutations in the TTF-1, TTF-2, PAX8 and TSH receptor genes). The etiological diagnosis is based on scintigraphy, ultrasound and the level of circulating thyroglobulin. At present, treatment is administered at an adapted dose during the first two weeks of life and should allow the child to reach its full intellectual potential. However, minor anomalies have been reported in some treated children, suggesting that this treatment cannot compensate for a certain degree of foetal hypothyroidism.

Female↗
PubMed2003

Development of the thyroid gland: lessons from congenitally hypothyroid mice and men.

Congenital hypothyroidism is the most common congenital endocrine disorder (one newborn in 3000) and represents the most common cause of preventable mental retardation. In 10-20% of cases, it is due to autosomal recessive functional disorders leading to goiter formation (thyroid dyshormonogenesis). In the remainder, it is due to thyroid dysgenesis, which comprises usually isolated defects in: (1) migration of the median thyroid anlage, leading to a round cluster of ectopic cells (usually in a sublingual position) with no other thyroid tissue present; (2) differentiation or survival of the thyroid follicular cells leading to athyreosis; and (3) growth of a thyroid with the normal bilobed shape and in the normal cervical position (orthotopic hypoplasia). Mouse knock-outs have demonstrated that thyroid transcription factor-1 (TTF-1) and PAX8 are required for the survival and proliferation of thyroid follicular cell precursors, TTF-2 for their downward migration and the thyrotropin receptor (TSHR) for post-natal thyroid growth. In humans, thyroid dysgenesis is generally a sporadic malformation but an affected relative is found in 2% of cases, a figure 15-fold higher than by chance alone. Pedigree analysis is most compatible with dominant inheritance with variable penetrance. However, mutations in TTF-1, TTF-2, PAX8 and TSHR are found in <10% of patients with congenital hypothyroidism and these predominantly have orthotopic thyroid hypoplasia, often associated with other malformations. This low yield and the discordance of >90% of monozygotic twin pairs suggests that isolated thyroid ectopy or athyreosis most often results from early somatic mutations, epigenetic modifications or stochastic developmental events.

Animals↗
PubMed2003

IGF-I transcript levels in whole-liver tissue, in freshly isolated hepatocytes, and in cultured hepatocytes from lean and obese Zucker rats.

BACKGROUND: The mechanisms underlying the maintenance of normal to high rates of linear growth and plasma insulin-like growth factor I (IGF-I) levels in spite of a low growth hormone secretion in obese children remain unknown. Among the animal models of early-onset obesity, obese Zucker (FA/FA) rats (which are homozygous for an inactivating missense mutation in the leptin receptor) are particularly appropriate, because their linear growth shows this growth hormone independence. METHODS: To study the regulation of IGF-I synthesis in this model, we have established primary cultures of hepatocytes derived from 12-week-old Zucker male obese and lean rats. The rat IGF-I gene contains six exons, and alternative splicing generates different mRNAs, one of which (called IGF-1B) has been shown to be decreased by fasting. We report steady state mRNA levels for IGF-I (all transcripts) and for IGF-IB in hepatocytes after 3 days in culture, in freshly isolated hepatocytes, and in whole-liver tissue. RT-PCRs using primers specific for IGF-I or IGF-IB were performed with two different internal competitors for quantification. RESULTS: In primary cultures of hepatocytes, the IGF-IB mRNA was increased by >50-fold (p = 0.01) in cells derived from obese animals as compared with cells from lean animals. However, these transcript levels were not significantly different when measured in freshly isolated hepatocytes or in whole-liver tissue. CONCLUSIONS: Increased IGF-IB transcription could be an intrinsic characteristic of cultured hepatocytes harbouring leptin receptors that bear the FA mutation. However, the modulation of this characteristic by cell-cell interactions and by in vivo hormone and metabolic status remains to be studied.

Animals↗
PubMed2001

Nine novel mutations in NR0B1 (DAX1) causing adrenal hypoplasia congenita.

X-linked adrenal hypoplasia congenita (AHC) is caused by mutations in the NR0B1 gene. This gene encodes an orphan member of the nuclear receptor superfamily, DAX1. Ongoing efforts in our laboratory have identified nine novel NR0B1 mutations in X-linked AHC patients (Y81X, 343delG, 457delT, 629delG, L295P, 926-927delTG, 1130delA, 1141-1155del15, and E428X). Two additional families segregate previously identified NR0B1 mutations (501delA and R425T). Sequence analysis of the mitochondrial D-loop indicates that the 501delA family is unrelated through matrilineal descent to our previously analyzed 501delA family.

Adrenal Insufficiency↗
PubMed2001

Molecular characterization of a pediatric pheochromocytoma with suspected bilateral disease.

An 11-year-old boy with hypertension was suspected of having bilateral adrenal pheochromocytomas and hyperplasia. Molecular analysis of specific tumor suppressor genes and oncogenes excluded the familial syndromes, von Hippel-Lindau (VHL) disease and multiple endocrine neoplasia (MEN) type 2A. Further evaluation identified a unilateral adrenal pheochromocytoma with a VHL heterozygous somatic mutation (G695A) and loss of the maternal allele at 11p15.5-11p14 exclusively in the tumor tissue. Both reverse-transcriptase polymerase chain reaction and immunohistochemistry confirmed increased expression of IGF2 within the tumoral tissue, relative to a normal control adrenal gland. These results ruled out familial syndromes and suggested that the VHL mutation and the loss of maternal allele on chromosome 11 could have contributed to tumor development.

Adrenal Gland Neoplasms↗
PubMed2000

Congenital central isolated hypothyroidism caused by a homozygous mutation in the TSH-beta subunit gene.

We report a Belgian girl born in 1983 with isolated thyrotropin (TSH) deficiency. Hypothyroidism without goiter was diagnosed at the age of 2 months, with extremely low total thyroxine (T4) at 0.3 microg/dL (4 nmol/L; N[normal]: 5.6-11.4 microg/dL). Basal TSH, only moderately elevated at 14.8 mU/L (N: 0-5.3; competitive radioimmunoassay, RIA), increased to 18.2 mU/L after thyrotropin-releasing hormone (TRH) stimulation, whereas prolactin increased normally. At age 15 years, after withdrawal of levothyroxine (LT4) therapy for 6 weeks, TRH stimulation slightly increased serum TSH using two immunometric assays, from less than 0.03 to 0.07 and from 0.2 to 0.3 (a monoclonal and polyclonal antibody), and from 1.9 to 4.1 mU/L using a polyclonal TSH antibody and iodinated recombinant TSH. Sequencing of the TSH-beta subunit gene revealed a homozygous single nucleotide deletion in codon 105 producing a frame shift that results in a truncated TSH-beta with nonhomologous 9 carboxyterminal amino acids and a loss of the 5 terminal residues. This mutation was previously reported in one Brazilian and two German families. The abnormal, and presumably biologically inactive, TSH can be detected in serum using appropriate antibodies. Its relatively small amount in serum is due to either reduced secretion or rapid degradation. The occurrence of the same mutation in three families of different ethnic origin suggests that this mutation may be prevalent in the population. Common ancestry or de novo mutations in a hot spot cannot be excluded. Finally, we must be aware that neonatal screening of congenital hypothyroidism based on blood spot TSH measurement will not detect this rare but severe genetic defect.

Adolescent↗
PubMed2000

A novel A10E homozygous mutation in the HSD3B2 gene causing severe salt-wasting 3beta-hydroxysteroid dehydrogenase deficiency in 46,XX and 46,XY French-Canadians: evaluation of gonadal function after puberty.

Severe 3beta-hydroxysteroid dehydrogenase (3betaHSD) deficiency is a rare form of congenital adrenal hyperplasia resulting from mutations in the HSD3B2 gene that impair steroidogenesis in both the adrenals and gonads and cause salt-wasting in both sexes and incomplete masculinization of the external genitalia in genetic males. About two thirds of the reported patients are 46,XY. We describe two French-Canadian patients from two families without a known relationship who presented with severe salt-wasting 3betaHSD deficiency in infancy. Although the diagnosis was considered clinically, plasma steroid profiles were confusing. We have thus directly sequenced DNA fragments generated by PCR amplification of the four exons, exon-intron boundaries, and the 5'-flanking regions of the HSD3B2 gene. Sequencing of exon II revealed the presence of a C to A transversion in both alleles of these two cases, thus converting codon 10 (GCA), which codes for Ala, into GAA, encoding Glu. This Ala is highly conserved in the vertebrate 3betaHSD gene family and is located in the putative NAD-binding domain of the enzyme. The mutant type II 3betaHSD enzyme carrying an A10E substitution exhibited no detectable activity in intact transfected Ad293 cells. Both homozygous patients share the same haplotype, spanning approximately 3.3 centimorgans surrounding the HSD3B2 locus, which is consistent with a founder effect for this missense mutation. The 46,XY patient presented with ambiguous genitalia at birth and underwent normal masculinization at puberty, but was azoospermic at 18.5 yr of age. The 46,XX patient presented progressive breast development, menarche, and evidence of progesterone secretion. The only previously reported cases with pubertal follow-up revealed paternity in one male and hypogonadism in one female. These findings demonstrate the complex relationships between the genotype and the gonadal phenotype in severe 3betaHSD deficiency and the difficulty in predicting fertility.

3-Hydroxysteroid Dehydrogenases↗
PubMed2000

A new insight into the molecular basis of 3beta-hydroxysteroid dehydrogenase deficiency.

Classical 3beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase (3beta-HSD) deficiency is a rare form of congenital adrenal hyperplasia that impairs steroidogenesis in both the adrenals and gonads resulting from mutations in the HSD3B2 gene, causing varying degrees of salt-loss in both sexes and incomplete masculinization of the external genitalia in genetic males. To date a total of 34 mutations (including 5 frameshift, 4 nonsense, 1 in-frame deletion, 1 splicing and 23 missense mutations) have been identified in the HSD3B2 gene. Results from functional charaterization studies of the mutant proteins agrees with the prediction that no functional type II 3beta-HSD isoenzyme is expressed in the adrenals and gonads of the patients with the severe salt-losing form, whereas the nonsalt-losing form causes an incomplete loss in enzymatic activity, thereby leaving sufficient enzymatic activity to prevent salt loss. Recent studies have highlighted the fact that various mutations appear to have a drastic effect upon the stability of the protein, therefore providing molecular evidence of a new mechanism involved in classical 3beta-HSD deficiency. Finally, the functional characterization of the missense mutations known to be involved in this autosomal recessive disorder provides valuable information concerning the structure-function relationships of the 3beta-HSD enzyme superfamily.

3-Hydroxysteroid Dehydrogenases↗
PubMed1999

Neonatal hypothyroidism: treatment and outcome.

Systematic neonatal screening for congenital hypothyroidism (CH), which was progressively implemented in industrialized countries over the past 15 to 25 years, has been extremely successful in eradicating severe mental deficiency resulting from CH. However, in the first generation of children diagnosed by screening, the concept that CH has a threshold effect on intelligence was confirmed. In spite of earlier diagnosis through screening, children with severe CH (i.e., those with a marked retardation of bone age and/or a low circulating thyroxine [T4] before treatment) still had clinically significant intellectual sequelae, amounting to a loss of 6 to 19 IQ points. Recent studies suggest that this developmental gap may be closed by treating more rapidly after birth (2 weeks instead of 4-5 weeks in the early years of the screening era) and by using a higher initial dose of levothyroxine (10-15 instead of 5-8 microg/kg per day). This regimen induces transient hyperthyroxinemia, but no clinical signs or symptoms of hyperthyroidism. Longer term follow-up of larger numbers of patients remains necessary to confirm the normalization of intellectual development and the absence of untowards effects of the treatment regimen in children with severe CH.

Congenital Hypothyroidism↗
PubMed1999

A search for the possible molecular mechanisms of thyroid dysgenesis: sex ratios and associated malformations.

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.

Abnormalities, Multiple↗
PubMed1999

Pharmacological manipulation of height: qualitative review of study populations and designs.

OBJECTIVE: Various substances that can have an important effect on height are increasingly available. However, research into pharmacological manipulation of height in children has been criticized. There are concerns about diagnostic criteria; about the medical, ethical, and economic ramifications of modulating growth in children with no endocrinological abnormalities; and about biased results due to weak study designs. The authors reviewed articles published since Jan. 1, 1995, to characterize recent research into this area. METHODS: 70 peer-reviewed articles published in 18 journals in 1995 describing effects of hormonal interventions to affect height were reviewed. Study population, intervention, main purpose (safety, physiology, or therapeutic effect), and methodology were examined. The search was expanded after 1995 to list randomized controlled trials (RCTs) investigating pharmacological manipulation in children and its effect on ultimate height in adults. RESULTS: The inexpensive and brief androgen therapy for pubertal delay has been examined in RCTs, but expensive, long-term treatments to alter final adult height in children have rarely been subjected to RCTs. Some outcome reports pooled subjects with different causes of short stature. Documentation of growth hormone deficiency is problematic. CONCLUSIONS: There is a lack of RCTs in which target populations and growth outcomes are explicitly defined. Further research into overcoming barriers to relevant RCT studies is needed.

Body Height↗
PubMed1999

Outcome of pediatric Graves' disease after treatment with antithyroid medication and radioiodine.

OBJECTIVE: To evaluate the efficacy of antithyroid medication in the initial treatment of pediatric Graves' disease and the frequency of use and outcome of radioiodine as second-line therapy. DESIGN: Retrospective review. SETTING: Tertiary care children's hospital. PATIENTS: Thirty-three patients (29 female, 4 male; mean age 12.7 years) who started treatment for hyperthyroidism between Jan. 1, 1990, and Dec. 31, 1994. INTERVENTIONS: Initial treatment with propylthiouracil or methimazole (with addition of levothyroxine if needed to maintain euthyroidism); subsequent treatment with radioiodine. OUTCOME MEASURES: 1) Clinical and laboratory features at the time of diagnosis; 2) doses and duration of antithyroid drug treatment and response to treatment; 3) need for treatment with levothyroxine to maintain euthyroidism during the trial of antithyroid medication; 4) indications for radioiodine therapy, and the dose and number of treatments with 131iodine (131I); 5) thyroid status at last follow-up visit (at least 2 years after diagnosis). RESULTS: All patients were initially treated with antithyroid drugs, and levothyroxine was added in 16 subjects to maintain euthyroidism. The median duration of drug treatment was 21 months. Ultimately, 24/33 patients (73%) received radioiodine following a trial of antithyroid drugs because of a) side effects of antithyroid medication (in 3 patients); b) inadequate response to medication (in 8 patients); and c) relapse (in 13 patients), which occurred at a median of 6 (range 1 to 16) months following cessation of drug therapy. Five patients required a second dose of radioiodine and 2 patients required 3 doses. Of the 24 patients treated with radioiodine, at last follow-up after the most recent treatment (median 18.5, range 3 to 55 months), 6 patients were euthyroid, 16 required thyroxine replacement, and 2 were-still, or again, hyperthyroid. CONCLUSION: In our population of children and adolescents, treatment of hyperthyroidism with antithyroid drugs frequently resulted in either side effects, inadequate response to medication or subsequent relapse, all of which led to radioiodine therapy. We conclude, therefore, that radioiodine could be considered as one of the first-line options in older children and adolescents with hyperthyroidism.

Adolescent↗