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Biomedical subjects

G Van Vliet

Publications and source records attributed to G Van Vliet.

At least 19 recordsLinked to original sources
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↗
PubMed1998

Decreased growth hormone response to glucagon in infants after an apnea of infancy.

We studied glucagon-induced growth hormone secretion in 9 patients with apnea of infancy and in 55 siblings of children who had died of sudden infant death syndrome, who were included as a comparison group. We observed a 33% decrease in growth hormone secretion in patients with apnea of infancy. However, linear growth remained normal. This finding could be related to either repeated episodes of hypoxia or to abnormal maturation of the autonomous nervous system.

Apnea↗
PubMed1998

Severe congenital hypopituitarism with low prolactin levels and age-dependent anterior pituitary hypoplasia: a clue to a PIT-1 mutation.

A 20-month-old boy presented with severe congenital growth hormone, thyrotropin, and prolactin deficiencies resulting from a de novo mutation of the PIT-1 gene. This form of congenital hypopituitarism should be suspected if pituitary anatomy is normal, especially if prolactin levels are low and, in boys, if the external genitalia are normal. Pituitary atrophy appears to be an age-dependent phenomenon in this condition.

DNA-Binding Proteins↗
PubMed1998

Androgens and fetal growth.

Boys are heavier than girls at term birth. Children with a 46,XY karyotype and androgen insensitivity syndrome (clinically complete form and/or proven mutations in the androgen receptor gene) were found to have a birth weight comparable to that of girls. These findings support the hypothesis that the difference in birth weight between boys and girls is generated by androgen action.

Androgen-Insensitivity Syndrome↗
PubMed1998

Apparent congenital athyreosis contrasting with normal plasma thyroglobulin levels and associated with inactivating mutations in the thyrotropin receptor gene: are athyreosis and ectopic thyroid distinct entities?

Loss-of-function mutations in the TSH receptor gene (TSH-R), usually leading to asymptomatic hyperthyrotropinemia, have been reported since 1995 in a total of eight pedigrees, with a pattern of transmission suggesting autosomal recessive inheritance. Although normal TSH secretion and action are not necessary for normal migration of the thyroid analage, they are essential for normal thyroid growth and function. In keeping with this concept, we report a severely hypothyroid boy with a normally located but very hypoplastic and hypofunctional thyroid caused by TSH-R loss-of-function mutations. The propositus' maternal great aunt also had apparent athyreosis. The propositus had undetectable uptake on 99mpertechnetate scintigraphy but normal plasma thyroglobulin at 15 days of age. He was found to be a compound heterozygote for TSH-R mutations, with the maternal allele carrying a splicing mutation (G to C transversion at position +3 of the donor site of intron 6) and the other allele a deletion of two nucleotides (2 bases of codon 655 in exon 10). The great aunt's TSH-R was normal. We also report the sex ratio of hypothyroid newborns referred to our center since 1989 with apparent athyreosis (5 girls, 7 boys) and with ectopic thyroid tissue (41 girls, 15 boys). We conclude that different genetic and nongenetic mechanisms for athyreosis and ectopic thyroid are likely, and that these two distinct entities are themselves heterogeneous. Our results further show that inactivating mutations in TSH-R may account for some cases of apparent congenital athyreosis and should be suspected, especially if plasma thyroglobulin levels are normal.

Amino Acid Sequence↗
PubMed1997

A novel mechanism for isolated central hypothyroidism: inactivating mutations in the thyrotropin-releasing hormone receptor gene.

Isolated central hypothyroidism, characterized by insufficient TSH secretion resulting in low levels of thyroid hormones, is a rare disorder. We report a boy in whom isolated central hypothyroidism was diagnosed at 9 yr of age. Complete absence of TSH and PRL responses to TRH led us to speculate that he had an inactivating mutation of the TRH receptor gene. The patients' genomic DNA was isolated, and the entire coding region of the TRH receptor was amplified by the PCR and sequenced directly. Confirmation of the mutations and haplotyping of the family was performed using restriction enzymes. The biological activity of the wild-type and mutated TRH receptors was verified by evaluating the binding of labeled TRH and stimulation by TRH of total inositol phosphate accumulation in transfected HEK-293 and COS-1 cells. The patient was found to be a compound heterozygote, having inherited a different mutated allele from each of the parents; both mutations were in the 5'-part of the gene. Mutated receptors were unable to bind TRH and to activate total inositol phosphate accumulation. Our report is the first description of naturally occurring inactivating mutations of a G protein-coupled receptor linked to the phospholipase C second messenger pathway. The prevalence and phenotypic spectrum of TRH receptor mutations in isolated central hypothyroidism remain to be established.

Cell Line↗
PubMed1997

Diversity and prevalence of somatic mutations in the thyrotropin receptor and Gs alpha genes as a cause of toxic thyroid adenomas.

A total of 33 different autonomous hot nodules from 31 patients, originating mainly from Belgium, were investigated for the presence of somatic mutations in the TSH receptor and Gs alpha genes. This constitutes an extension of our previous study, including the first 11 nodules of the series. The complete coding sequence of the TSH receptor gene and the segments of Gs alpha known to harbor mutations impairing guanosinetriphosphotase activity were studied by direct sequencing of genomic DNA extracted from the nodules. DNA from the juxtanodular tissue or peripheral white blood cells was analyzed in all patients to confirm that the mutations identified were somatic. Twenty-seven mutations (82%) were found in the TSH receptor gene, affecting a total of 12 different residues or locations. All these mutations but 2 (see below) have been identified previously as activating mutations. Only 2 mutations were found in Gs alpha (6%). In 4 nodules, no mutation was detected. Five residues (Ser281, Ile486, Ile568, Phe631, and Asp633) were found mutated in 3 or 4 different nodules, making them hot spots for activating mutations. Phe631 and Asp633 belong to a cluster of 5 consecutive residues (629-633) in the N-terminal half of transmembrane segment VI; which harbor together 44% of the mutations identified in this cohort. Two novel mutations were identified: a point mutation causing substitution of Phe for Leu at position 629 (L629F); and a deletion of 12 bases removing residues 658-661 at the C-terminal portion of exoloop 3 (del658-661). When tested by transfection in COS-7 cells, both mutant receptors display increase in constitutive stimulation of basal cAMP accumulation. Although it is still capable of binding TSH, the del658-661 mutant has completely lost the ability to respond to the stimulation by the hormone. Our results demonstrate that, in a cohort of patients from a moderately iodine deficient area, somatic mutations increasing the constitutive activity of the TSH receptor are the major cause of autonomous hot nodules.

Adenoma↗
PubMed1996

Does growth-hormone supplementation affect adult height in Turner's syndrome?

BACKGROUND: By comparison with historical controls, the effect of treatment with growth hormone on adult height in Turner's syndrome was initially reported as uniformly and strongly positive. Because randomised controlled trials are not near completion, we report our experiences in an open study. METHODS: We examined adult height, projected and attained, in 31 patients (17 treated with subcutaneous recombinant human growth hormone, up to 15 mg a week, outside of a controlled trial and 14 untreated contemporaries). FINDINGS: Contingency table analysis of attained versus projected height showed significantly higher values in treated patients although only 4 of 17 had final heights of 5 cm or more over projection. Patients' and treatment variables (height, bone-age delay, oestrogen replacement) that interfere with adult height projection confounded the analysis of adult height data. INTERPRETATION: Girls with Turner's syndrome should be counselled cautiously about the expectation of a strongly positive effect of treatment on adult height. Completion of the randomised controlled trials to adult height is needed to establish the effect of growth-hormone supplementation on adult height in Turner's syndrome and the psychological effect of treatment.

Adult↗
PubMed1996

Effects of 14-day infusions of growth hormone and/or insulin-like growth factor I on the obesity of growing Zucker rats.

The response of fat tissue to GH or insulin-like growth factor I (IGF-I) differs between humans with hypopituitarism and those with exogenous obesity; the effects of combined GH and IGF-I administration have not been compared in these two situations. In GH-deficient dwarf rats (who have a primary GH deficiency), the excessive fat deposition induced by a high fat diet is completely reversed by combined infusion of GH and IGF-I. Whether the same phenomenon would be observed in genetically obese Zucker rats (in whom, as in obese humans, the decrease in GH secretion is secondary to the obese state) remained to be determined. Growing (6-week-old) female obese Zucker rats received a continuous sc infusion of vehicle, recombinant human GH, recombinant human IGF-I, or GH plus IGF-I for 14 days (3 mg/kg x day for both GH and IGF-I). Combined GH and IGF-I stimulated body weight gain and in naso-anal length to the same extent as IGF-I alone, whereas GH alone was less potent. Because all treatments stimulated weight linear growth proportionately, the progression of obesity was similar in treated and control animals. However, GH plus IGF-I (but not either agent alone) induced a 25% decrease in the relative weight of inguinal fat. GH and IGF-I exerted distinct effects on the relative weights of liver, kidney, and spleen and on the circulating levels of IGF-I and IGF-binding protein-3. Circulating glucose and insulin levels did not change in any group. In summary, GH plus IGF-I infusions decrease the relative weight of inguinal fat in Zucker rats as in obese GH-deficient dwarf rats; however, this effect is of more modest magnitude despite the use of a 2- to 3-fold higher dose and is limited to the inguinal site. Thus, GH plus IGF-I infusions did not influence the obesity index in Zucker rats. Inasmuch as Zucker rats are a better model of childhood-onset obesity than dwarf rats fed a high fat diet, the present results do not appear promising for extrapolation to clinical studies in children. The mechanisms by which the primary vs. secondary nature of the decreased GH secretion influences the effect of GH plus IGF-I on obesity remain to be determined.

Analysis of Variance↗
PubMed1996

Outcome of severe congenital hypothyroidism: closing the developmental gap with early high dose levothyroxine treatment.

We have previously reported that despite neonatal screening, children with severe congenital hypothyroidism treated at 5 weeks of age with 6 micrograms/kg.day levothyroxine have clinically significant intellectual impairment, whereas those with the moderate form of the disease are indistinguishable from controls. The developmental outcome of children with severe congenital hypothyroidism treated earlier with higher initial doses of levothyroxine remained to be determined. In the present study, 45 infants with permanent congenital hypothyroidism detected by neonatal screening are described. For the group, the median age at starting treatment was 14 days, and the median initial dose of levothyroxine was 11.6 micrograms/kg.day. Based on the area of their knee epiphyses at diagnosis, the patients were divided into 2 subgroups: severe (< 0.05 cm2; n = 10) and moderate (> or = 0.05 cm2; n = 35). The psychomotor development of 8 patients in each subgroup, matched for the socioeducational level of their families, was assessed at 18 months. Mean plasma free T4 levels were supraphysiological during the first few months of life, but mean plasma T3 levels remained within the normal range, and there were no signs or symptoms of hyperthyroidism. The mean plasma TSH concentration was less than 4.5 mIU/L 4 weeks after starting treatment. Bone maturation remained delayed at 12 months in the severe cases and was not unduly advanced in the moderate cases. The mean (+/- SD) developmental quotients at 18 months were similar in severe and moderate cases (107 +/- 10 and 110 +/- 5, respectively). We conclude that with earlier treatment and a higher initial dose of levothyroxine, the early developmental outcome of infants with severe congenital hypothyroidism is now indistinguishable from that of infants with the moderate form of the disease who were used as controls.

Child Development↗
PubMed1996

Somatostatin pretreatment enhances growth hormone (GH) responsiveness to GH-releasing hormone: a potential new diagnostic approach to GH deficiency.

Despite the availability of numerous testing procedures to evaluate GH secretion in short children, there is still controversy about the most reliable test in the diagnosis of GH deficiency. We have recently demonstrated that in normal short children, priming with the long-acting somatostatin analog. SMS 201-995 (SMS), significantly potentiates their GH response to subsequent GHRH challenge. In the present study, we used the combined SMS + GHRH test in patients with GH deficiency to validate the hypothesis that this test would better discriminate between normal short children and those with truly diminished GH secretion. We studied 24 children classified into three groups according to their GH peak response to up to four conventional tests: 1) children with normal short stature and normal GH response (NSSA: GH peak > or = 10 micrograms/L, n = 6); 2) children with normal short stature with borderline GH response (NSSB: GH peak > or = 7 micrograms/L but < 10 micrograms/L, n = 4); and 3) GH-deficient children (GHD: GH peak < 7 micrograms/L, n = 14). Two study protocols were performed in all subjects: SMS (1 microgram/kg, sc) was randomly administered or omitted (control test) a 0800 h and GHRH (1 microgram/kg, iv) was given 5 h later. Plasma GH levels were measured every 30 min from 0800 h until 2 h after the GHRH injection. Pretreatment with SMS significantly augmented the GH peak response and the GH area under the GH concentration curve over 2 h after GHRH injection in the NSSA group, compared with control tests, but had no effect in the other two groups. While there was wide overlap of individual peak GH values to both the conventional tests and to the GHRH injection in the control test among the three groups of children, pretreatment with SMS resulted in complete discrimination between GHD and normal short children; the mean GH peak response to GHRH after SMS pretreatment was 8- to 9-fold lower in the GHD subjects (5.2 +/- 0.8 micrograms/L) compared with both the NSSA (44.0 +/- 14.3 micrograms/L; P < 0.01) and NSSB (42.9 +/- 5.0 micrograms/L; P < 0.01) groups and, more importantly, there was no overlap in the individual GH responses between GHD and normal short children. These results demonstrate that the combined SMS + GHRH test clearly discriminates normal short children from those with GHD. In view of its testing economy, safety, and accuracy, this combined test could become the test of choice to establish a diagnosis of GH deficiency in the slowly growing child.

Adolescent↗
PubMed1995

The growth hormone (GH)-independent growth of the obese Zucker rat is not due to increased levels of GH receptor messenger RNA in the liver.

Obese Zucker rats maintain normal rates of linear growth and circulating concentrations of insulin-like growth factor-I (IGF-I) and of IGF-binding protein-3 (IGFBP-3) in spite of low GH secretion. The mechanisms underlying this GH-independent growth in obesity are unknown. To assess whether the liver expression of the GH receptor (GHR) messenger RNA (mRNA) is increased and/or if the liver expression of IGFBP-3 mRNA is maintained in the obese, Zucker rats of both genders and phenotypes (four groups, n = 6/group) were studied at 12 weeks of age. By Northern analysis, mRNA levels for GHR and GHBP were not increased in obese rats compared to their sex-matched lean littermates; the expression of these two transcripts was sexually dimorphic and the changes in GHBP mRNA/GHR mRNA ratios associated with obesity were sex-specific. In both genders, IGFBP-1 and IGFBP-3 mRNAs were decreased in the obese. We concluded that the GH-independent growth of obese Zucker rats is not due to increased GHR mRNA or to maintained IGFBP-3 mRNA levels in the liver.

Animals↗
PubMed1995

Thyroid scintigraphy in children and adolescents with Hashimoto disease.

Between 1989 and 1994, 58 children and adolescents with Hashimoto thyroiditis seen at the Sainte-Justine Hospital had thyroid scintigraphy. Their medical records and films were reviewed retrospectively. Eighty-nine percent of the patients had a homogeneous distribution of tracer on thyroid scintigraphy, unlike the heterogeneous distribution classically reported in adults. In children and adolescents, thyroid scintigraphy is not helpful in the diagnosis of typical Hashimoto thyroiditis.

Adolescent↗
PubMed1995

Outcome in three siblings with antibody-mediated transient congenital hypothyroidism.

A woman receiving thyroxine substitution therapy for acquired hypothyroidism caused by autoimmune thyroiditis gave birth to three babies who had transient primary hypothyroidism. All three babies had elevated thyrotropin levels on neonatal screening, but one had normal thyroxine values. Thyrotropin receptor-blocking antibodies were present in maternal serum and in the three neonates. Each baby also had a different congenital malformation. The neurodevelopmental outcome of the children appeared related in part to maternal thyroxine levels, which suggests that transplacental transfer of thyroxine may protect the fetal brain.

Adult↗