[From gene to disease; adrenocortical insufficiency, achalasia and disrupted tear secretion: Allgrove syndrome].
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Adrenal Insufficiency↗
Biomedical subjects
T Vulsma
Publications and source records attributed to T Vulsma.
Lower neonatal screening thyroxine concentrations in down syndrome newborns.
There is an unexplained higher incidence of congenital hypothyroidism (CH) detected by T(4)-based neonatal screening programs and a very high prevalence of (mild) plasma TSH elevation in young children with Down syndrome (DS). To determine whether newborns with DS have decreased blood T(4) concentrations at the time of the neonatal screening, we conducted an observational study in a large and representative cohort of Dutch children with DS born in 1996 and 1997. CH screening results (T(4), TSH, and T(4)-binding globulin concentrations) were analyzed in comparison with clinical information obtained by interviewing the parents and data from the general newborn population and a large control group. The mean T(4) concentration of the studied children with DS (n = 284) was significantly decreased. The individual T(4) concentrations were normally (Gaussian) distributed but shifted to lower concentrations. This could not be explained by prematurity, nonthyroidal illness, or iodine exposure. Mean TSH and T(4)-binding globulin concentrations were significantly increased and normal, respectively. The decreased T(4) concentration, left-shifted normal distribution, and mildly elevated TSH concentrations point to a mild hypothyroid state in newborns with DS and support the existence of a DS-specific thyroid (regulation) disorder. The question remains whether this contributes to the brain maldevelopment.
Cohort Studies↗
Longitudinal analysis of growth and puberty in 21-hydroxylase deficiency patients.
AIMS: To evaluate growth from diagnosis until final height (FH) in 21-hydroxylase deficiency patients. METHODS: A retrospective longitudinal study was performed. Only patients treated with hydrocortisone and fludrocortisone (in case of salt wasting) were evaluated. This resulted in a sample of 34 (21 male, 13 female) salt wasting patients (SW) and 26 (13 male, 13 female) non-salt wasting patients (NSW). Auxological data were compared to recent Dutch reference values. RESULTS: In the first three months of life, the mean length SDS decreased to -1.50, probably because of the high average glucocorticoid dose (40 mg/m2/day). FH corrected for target height (FH(corr)TH) was -1.25 and -1.27 SDS in females and males, respectively. Patients treated with salt supplements during the first year, had a better FH(corr)TH (-0.83 SDS). In NSW patients, FH(corr)TH was -0.96 and -1.51 SDS in females and males, respectively. In SW and NSW, age at onset of puberty was within normal limits, but bone age was advanced. Mean pubertal height gain was reduced in males. Body mass index was only increased in NSW females. CONCLUSION: In SW, loss of final height potential might be a result of glucocorticoid excess in the first three months and sodium depletion during infancy. In NSW, loss of FH potential was caused by the delay in diagnosis. In SW and NSW, the advanced bone age at onset of puberty (undertreatment in prebertal years) resulted in loss of height gain during puberty. The effect of intensive sodium chloride support in early infancy should be examined prospectively. Neonatal screening is required if the height prognosis in NSW patients is to be improved.
Adrenal Hyperplasia, Congenital↗
[From gene to disease; POU1F1- and PROP1-mutations in pituitary hormone deficiency].
Multiple pituitary hormone deficiency can be caused by mutations in at least three pituitary transcription factors: POU1F1 (formerly called PIT1), PROP1 or HESX1. The role of the various pituitary transcription factors in pituitary ontogeny has been elucidated in part for the mouse. In humans, mutations in POU1F1 result in a total deficiency of growth hormone and prolactin, and a variable deficiency of TSH. Cases of mutations in PROP1 exhibit the same deficiencies, with additional deficiencies of gonadotrophins and a variable deficiency of ACTH. In the Netherlands, cases of multiple pituitary hormone deficiency are not only detected on the basis of the classical signs and symptoms of pituitary deficiency, but also by means of screening on congenital hypothyroidism with an incidence of approximately 1:20,000.
Animals↗
Adult height and age at menarche in childhood cancer survivors.
The aim of this study was to assess the long-term effects of cancer treatments on adult height and age at menarche in survivors of various types of childhood cancer. 285 childhood cancer survivors (161 men and 124 women), at least 18 years old and having been off treatment for at least 5 years, were examined. The effects of cranial (CrRT) and craniospinal irradiation (CrSpRT), other treatments and age at diagnosis on adult height and age at menarche were investigated. Patients who did not receive CrRT or CrSpRT, reached normal adult heights. However, a significant reduction in adult height was observed in men and women treated with CrRT or CrSpRT, especially if the treatment was given at the age of 8 years or younger. In girls, CrRT resulted in a significantly earlier menarche, compared with the Dutch population. Chemotherapy, radiation dose and age at menarche did not affect adult height. The relative risk (RR) of attaining an adult height below the 3rd percentile (20% 49/244) of the study population) was 6 times increased (RR=6.4; 95% confidence interval (CI) 1.46-28.52) after CrSpRT, 4 times (RR=4.2; 95% CI 1.81-9.63) after Crth and 5 times (RR=51; 95% CI 2.23-11.59) when irradiation was administered at the age of 8 years or younger. CrRT and CrSpRT and age at treatment are the main determinants of short stature in male and female childhood cancer survivors.
Adult↗
Behavioural correlates of early-treated congenital hypothyroidism.
UNLABELLED: Parents' and teachers' ratings were used to evaluate the behavioural characteristics of children with early-treated congenital hypothyroidism (CH). Comparisons were made between 63 children with early-treated CH and 34 healthy controls at the ages of 7.5 and 9.5 y. Additional comparisons were made between the two largest CH subgroups (thyroid agenesis, thyroid dysgenesis) and controls. The most marked differences were found on the introversion cluster and the motor clumsiness scale within it. Children with CH, particularly those with thyroid agenesis, showed introversion and motor clumsiness rather than social negativity and inattention. It is suggested that this behavioural profile may well have its origins in the often-reported inefficient motor behaviour of these children. Results are discussed in the light of recent findings suggesting an association between thyroid hormone problems and attention deficit hyperactivity disorder. CONCLUSION: Early-treated CH is associated with introversion rather than with social negativity.
Age Factors↗
Serum thyroglobulin and urinary iodine concentration are the most appropriate indicators of iodine status and thyroid function under conditions of increasing iodine supply in schoolchildren in Benin.
Iodine deficiency control programs have greatly reduced iodine deficiency disorders worldwide. For monitoring changes in iodine status, different indicators may be used. The aim of this study was to evaluate the suitability of indicators of iodine status and thyroid function, thyroglobulin (Tg), thyroid-stimulating hormone (TSH) and free thyroxine (FT4) in serum, thyroid volume and urinary iodine concentration, in iodine-deficient schoolchildren under conditions of increasing iodine supply. The study was established as a double-blind, placebo-controlled oral administration of a single dose of iodized oil to schoolchildren (7-10 y old), living in an iodine-deficient area of Benin, with an observation period of 10 mo. However, 3-4 mo after supplementation, iodized salt became available in the area. The study population therefore comprised an iodized oil-supplemented group and a nonsupplemented group, both of which had variable, uncontrolled intakes of iodized salt during the last 6 mo of the study. Initial mean serum concentrations of TSH and FT4 were within the normal range, whereas serum Tg concentration, urinary iodine concentration and thyroid volume were indicative of moderate-to-severe iodine deficiency. At the end of the study, all indicators had improved significantly, except thyroid volume, which had decreased only in the supplemented group. The supplemented group also still had significantly lower serum Tg and higher urinary iodine concentrations than the nonsupplemented group. Serum Tg and urinary iodine concentrations are the indicators most influenced by a changing iodine supply. Current normal reference ranges of serum concentrations of TSH and FT4 are too wide for detecting iodine deficiency in this age group.
Anthropometry↗
Maternal isodisomy for chromosome 2p causing severe congenital hypothyroidism.
Severe congenital hypothyroidism (CH) due to a total iodide organification defect (TIOD) is usually due to mutations in the thyroid peroxidase (TPO) gene located at chromosome 2p25. A homozygous deletion [DeltaT2512 (codon 808)] in exon 14 was identified in a patient with classical TIOD. The transmission pattern of the TPO gene in this family was anomalous; the mother was heterozygous for the deletion; and the mutation was absent in the father. Polymorphic short tandem repeat (STR) markers confirmed paternity and demonstrated on chromosome 2 that the propositus was homozygous for most markers on chromosome 2p and that these were identical to one of the maternal 2p homologs. A normal karyotype was found in the propositus, his parents and sister. We conclude that the homozygosity in the patient is due to partial maternal isodisomy of the short arm of chromosome 2, carrying a defective TPO gene. The patient, born small for gestational age, develops and grows well and appears healthy (while being treated with thyroxine) and has a normal phenotype except for a unilateral preauricular skin tag. This shows that partial maternal isodisomy for chromosome 2p (2pter - 2p12) is compatible with a minimal influence on normal development.
Base Sequence↗
Plasma thyrotropin bioactivity in Down's syndrome children with subclinical hypothyroidism.
OBJECTIVE: Subclinical hypothyroidism occurs in a number of children with Down's syndrome (DS). The reason for the mildly elevated plasma thyrotropin (TSH) concentrations is not known. The present study investigated whether decreased TSH bioactivity plays a role in this phenomenon. DESIGN: A retrospective study of plasma specimens from DS children with mildly elevated plasma TSH concentrations and thyroid hormone levels within the reference range, using a TSH receptor-adenylate cyclase mediated bioassay. METHODS: Strain JP26 Chinese hamster ovary (CHO) cells, stable transfected with the human TSH receptor, were incubated with unfractionated plasma (1/10 diluted in hypotonic incubation medium) of 10 DS children with subclinical hypothyroidism and nine euthyroid children with insulin-dependent diabetes mellitus as controls. cAMP released in the incubation medium was measured by RIA. Mock-transfected CHO cells were used to correct for non-specific CHO response. WHO Second International Reference Preparation of human TSH was dissolved and diluted in pooled normal human plasma and simultaneously bioassayed to match patient and control results. RESULTS: Plasma TSH levels were slightly increased in DS (mean +/- S.D., 6.5+/-1.3 mU/l, reference range 0.4-4.0 mU/l). Plasma TSH levels for controls (1.3+/-0.4 mU/l) were within the reference range. Plasma thyroid hormone levels in patients and controls were normal, plasma TSH binding inhibitory immunoglobulin and thyroid peroxidase antibodies were negative. cAMP levels (corrected for non-specific CHO response) in DS patients (18.4+/-3.9 pmol/well) and in controls (14.3+/-1.3 pmol/well) did not significantly differ from cAMP levels generated by patient-TSH equivalent TSH standards (16.3+/-0.9 pmol/well). CONCLUSIONS: The present results demonstrate normal TSH bioactivity in plasma of DS children, indicating that subclinical hypothyroidism in these patients is of primary (thyroidal) origin.
Adolescent↗
Impact of exposure to maternal PCBs and dioxins on the neonate's thyroid hormone status.
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Environmental Pollutants↗
Two decades of screening for congenital hypothyroidism in The Netherlands: TPO gene mutations in total iodide organification defects (an update).
Presented is a cohort study to assess the nature and frequency of thyroid peroxidase (TPO) mutations in 45 patients (35 families) with congenital hypothyroidism due to a total iodide organification defect; incidence is 1:66,000 in The Netherlands. The presentation is consistently similar with a severe form of congenital hypothyroidism and also characterized by a complete and immediate release of accumulated radioiodide from the thyroid after sodium perchlorate administration. Sixteen different mutations were found, including eight novel mutations; the majority occurs in exons 8, 9, or 10. The GGCC insertion in exon 8 at nucleotide 1277, leading to an early termination signal in exon 9, is the most frequently occurring mutation. These mutations were detected in 29 families in both TPO alleles (13 homozygous and 16 compound heterozygous). In one family, partial maternal isodisomy of 2p was detected, in four families only one mutated TPO allele could be detected, and in one family no inactivating TPO mutation could be found. Because all patients clearly had the clinicopathologic features of a total iodide organification defect, we conclude that in these five families the mutations in the (other) alleles could be either located in the intronic sequences or in the promoter region. Mutations in the TPO gene result in total iodide organification defects.
Child↗
Neurologic development of the newborn and young child in relation to maternal thyroid function.
A prospective observational study was performed in pregnant women with known thyroid disease. We studied the effect of maternal thyroid function in the first half of pregnancy on the neurologic development of the infant in the first 2 y of life. Clinical and thyroid function data were collected from 20 pregnant women with known thyroid disease and their newborn children. Infants were divided into three groups according to their maternal thyroid function within the first half of pregnancy: Group A (n = 7): maternal subclinical hypothyroidism, Group B (n = 6): maternal euthyroidism, and Group C (n = 7): maternal hyperthyroidism or subclinical hyperthyroidism. Neurophysiologic, i.e. motor nerve conduction velocity and somatosensory evoked potentials and neurologic and developmental (Bayley scales) assessments were done. One infant, born to a mother with Graves' disease, developed transient hyperthyroidism. At the age of 6 and 12 mo, the mean mental developmental index (MDI) score was 16 points lower for infants in Group A than for those in Group B (p = 0.03 and 0.02, respectively). At the age of 24 mo, the mean MDI score was 6 points lower, which was not statistically significant. Neurophysiologic and neurologic assessments and the mean Psychomotor Developmental scores did not differ among the three groups. In conclusion, maternal subclinical hypothyroidism in the first half of pregnancy was associated with a lower mean MDI score in their infants during the first year of life.
Developmental Disabilities↗
Should all pregnant women be screened for hypothyroidism?
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Developmental Disabilities↗
Acquired protein S deficiency caused by estrogen treatment of tall stature.
OBJECTIVE: To evaluate the potential thrombogenic changes in the coagulation and fibrinolytic system related to treatment with ethinyl estradiol (200 and 300 microg). SUBJECTS AND METHODS: Twenty-five healthy girls with expected final height exceeding 185 cm, as calculated by the method of Bayley and Pinneau, were treated with 200 microg or 300 microg of ethinyl estradiol. Coagulation and fibrinolytic parameters were determined before and during estrogen treatment and 2 and 4 weeks after estrogen withdrawal. RESULTS: No difference in the effects on hemostasis was found between the 2 treatment groups. All 25 patients developed protein S deficiency during estrogen treatment, which in most girls lasted for 4 weeks after cessation of estrogen administration. During therapy, protein C activity increased, whereas antithrombin did not change. Plasminogen and plasmin-alpha(2) antiplasmin complexes significantly increased. Protein S deficiency was accompanied by significantly increased prothrombin fragment 1+2 and fibrinopeptide A. In contrast, thrombin-antithrombin complexes did not change. CONCLUSION: High-dose estrogen treatment to reduce the final height in tall girls is associated with a reversible acquired protein S deficiency with indications of a pre-thrombotic state. Risk of venous thrombo-embolism may be enhanced, especially when additional risk factors for thrombosis are present.
Blood Coagulation↗
Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy.
BACKGROUND: Maternal thyroid function during early pregnancy is an important determinant of early fetal brain development because the fetal thyroid is unable to produce any T4 before 12-14 weeks' gestation. Overt maternal hypothyroidism as seen in severe iodine-deficient areas is associated with severely impaired neurological development of the offspring. At present, it is not known whether low free T4 (fT4) levels during pregnancy in healthy women from iodine sufficient areas may affect fetal neurodevelopment. METHODS: Neurodevelopment was assessed at 10 months of age in a cohort of 220 healthy children, born after uncomplicated pregnancies and deliveries, using the Bayley Scales of Infant Development. Maternal TSH, fT4 and TPO antibody status were assessed at 12 and 32 weeks' gestation. Maternal gestational fT4 concentration was defined as an independent parameter for child development. RESULTS: Children of women with fT4 levels below the 5th (< 9.8 pmol/l, n = 11) and 10th (< 10.4 pmol/l, n = 22) percentiles at 12 weeks' gestation had significantly lower scores on the Bayley Psychomotor Developmental Index (PDI) scale at 10 months of age, compared to children of mothers with higher fT4 values (t test, mean difference: 14.1, 95% confidence interval (CI): 5.9-22 and 7.4, 95% CI: 1.1-13.9, respectively). At 32 weeks' gestation, no significant differences were found. In the group of women with the lowest 10th percentile fT4 concentrations at 12 weeks' gestation, a positive correlation was found between the mothers' fT4 concentration and children's PDI scores (linear regression, R: 0.46, P = 0.03). After correction for confounding variables, a fT4 concentration below the 10th percentile at 12 weeks' gestation was a significant risk factor for impaired psychomotor development (RR): 5.8, 95% CI: 1.3-12.6). CONCLUSIONS: Low maternal plasma fT4 concentrations during early pregnancy may be an important risk factor for impaired infant development.
Antibodies↗
Final height in girls with Turner's syndrome treated with once or twice daily growth hormone injections. Dutch Advisory Group on Growth Hormone.
OBJECTIVES: To study final height in girls with Turner's syndrome treated with once or twice daily injections of growth hormone (GH) in combination with low dose ethinyl oestradiol. DESIGN: Until final height was reached, the effect of fractionated subcutaneous injections given twice daily was compared with once daily injections of a total GH dose of 6 IU/m2/day. Twice daily injections were given as one third in the morning and two thirds at bedtime. All girls concurrently received low dose oestradiol (0.05 microgram ethinyl oestradiol/kg/day, increased to 0.10 microgram/kg/day after 2.25 years). PATIENTS: Nineteen girls with Turner's syndrome aged > or = 11 years (mean (SD) 13.6 (1.7) years). MEASUREMENTS: To determine final height gain, we assessed the difference between the attained final height and the final height predictions at the start of treatment. These final height predictions were calculated using the Bayley-Pinneau (BP) prediction method, the modified projected adult height (mPAH), the modified index of potential height (mIPHRUS), and the Turner's specific prediction method (PTSRUS). RESULTS: The gain in final height (mean (SD)) was not significantly different between the once daily and the twice daily regimens (7.6 (2.3) v 5.1 (3.2) cm). All girls exceeded their adult height prediction (range, 1.6-12.3 cm). Thirteen of the 19 girls had a final height gain > 5.0 cm. Mean (SD) attained final height was 155.5 (5.4) cm. A "younger bone age" at baseline and a higher increase in height standard deviation score for chronological age (Dutch-Swedish-Danish references) in the first year of GH treatment predicted a higher final height gain after GH treatment. CONCLUSIONS: Division of the total daily GH dose (6 IU/m2/day) into two thirds in the evening and one third in the morning is not advantageous over the once daily GH regimen with respect to final height gain. Treatment with a GH dose of 6 IU/m2/day in combination with low dose oestrogens can result in a significant increase in adult height in girls with Turner's syndrome, even if they start GH treatment at a relatively late age.
Adolescent↗
Normalization of height in girls with Turner syndrome after long-term growth hormone treatment: results of a randomized dose-response trial.
Short stature and ovarian failure are the main features in Turner syndrome (TS). To optimize GH and estrogen treatment, we studied 68 previously untreated girls with TS, age 2-11 yr, who were randomly assigned to one of three GH dosage groups: group A, 4 IU/m2 day (approximately 0.045 mg/kg x day); group B, first yr 4, thereafter 6 IU/m2 x day (approximately 0.0675 mg/kg/day); group C, first yr 4, second yr 6, thereafter 8 IU/m2 x day (approximately 0.090 mg/kg x day). In the first 4 yr of GH treatment, no estrogens for pubertal induction were given to the girls. Thereafter, girls started with 17beta-estradiol (5 microg/kg bw x day, orally) when they had reached the age of 12 yr. Subjects were followed up until attainment of adult height or until cessation of treatment because of satisfaction with the height achieved. Seven-year data of all girls were evaluated to compare the growth-promoting effects of three GH dosages during childhood. After 7 yr, 85% of the girls had reached a height within the normal range for healthy Dutch girls. The 7-yr increment in height SD-score was significantly higher in groups B and C than in group A. In addition, we evaluated the data of 32 of the 68 girls who had completed the trial after a mean duration of treatment of 7.3 yr (range, 5.0 - 8.75). Mean (SD) height was 158.8 cm (7.1), 161.0 cm (6.8), and 162.3 cm (6.1) in groups A, B, and C, respectively. The mean (SD) difference between predicted adult height before treatment and achieved height was 12.5 cm (2.1), 14.5 cm (4.0), and 16.0 cm (4.1) for groups A, B, and C, respectively, being significantly different between group A and group C. GH treatment was well tolerated in all three GH dosage groups. In conclusion, GH treatment starting in relatively young girls with TS results in normalization of height during childhood, as well as of adult height, in most of the individuals. With this GH and estrogen treatment regimen, most girls with TS can grow and develop much more in conformity with their healthy peers.
Adolescent↗
On the origin of circulating thyroglobulin.
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Biomarkers↗