Treatment of congenital hypothyroidism.
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Age Factors↗
Biomedical subjects
G Van Vliet
Publications and source records attributed to G Van Vliet.
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↗
Hyperfunctioning malignant thyroid nodule in an 11-year-old girl: pathologic and molecular studies.
We identified a papillary carcinoma in an 11-year-old girl with a hyperfunctioning thyroid nodule. A met453thr mutation in TSHR was found in the nodule but not in normal thyroid tissue or in leukocytes. This case documents that this activating mutation is associated with neoplasia.
Carcinoma, Papillary↗
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↗
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↗
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↗
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↗
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↗
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↗
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↗
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↗
Growth hormone supplementation in Turner's syndrome.
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Body Height↗
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↗
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↗
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↗
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↗
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↗