OBJECTIVE: Evaluation of school attainments in children with congenital hypothyroidism (CH) detected by neonatal screening and treated early in life. PATIENTS AND METHODS: Text comprehension, mathematics, reading, writing and verbal and spatial memory, as indices of school learning, were evaluated in nineteen 5- to 10-year-old children with CH attending nursery or elementary school. l-Thyroxine substitution (starting dose 8-10 microg/kg body weight per day) was initiated at a mean age of 30+/-10 days of life. The control group included 298 unaffected children matched with the CH children for age and school grade. Thirty per cent of controls were classmates of CH children. Intelligence quotients (IQ), language performances and motor development were evaluated in CH children at age 5 years, and were related to their school attainments. School performances of CH children were also compared with their neonatal serum thyroxine (T4) concentration, and with the social-cultural level of the family. RESULTS: Four out of 19 (21%) children with CH, 3 in the nursery and 1 in the elementary school, displayed a generalized learning disorder. Symbol copy, geometric copy, phrase repetition, dictation writing and spontaneous writing were particularly defective in nursery school CH children, while orthographic error recognition was defective in elementary school CH children. School learning disorders in CH children were significantly correlated with a borderline-low IQ, poor language performances and a low social-cultural level of the family, but not with motor skills or neonatal T4 concentration. CONCLUSION: School attainments of early treated CH children were within the normal range in most affected cases. However, about 20% of CH children, most of them attending nursery school, showed a generalized learning disorder. Low IQ scores and poor language performances at age 5 years were associated with defective learning, mainly in CH children living in a poor social-cultural environment. In this subset of CH children, prompt initiation of speech and psychomotor rehabilitation therapy is recommended in order to prevent subsequent school learning disorders.
S Bargagna, D Dinetti, A Pinchera, M Marcheschi, L Montanelli, S Presciuttini, and L Chiovato
Susan M. Scott, Carmela Guardian, Cathy Rogers, Pam Angelus, and Sher Werner
We have previously demonstrated that changes in urinary epidermal growth factor/creatinine ratios relate to gestational age and gender. It is unclear what controls this developmental pattern although chronic renal disease and thyroid aberrations have significant effects on epidermal growth factor and creatinine excretion in childhood and in adults. Therefore, we chose to explore the effects of these disease states on epidermal growth factor excretion during the perinatal time period. We collected urine samples from 8 infants with congenital renal disease and 45 infants with low T4 and normal TSH values who 'failed' the newborn screen. In addition, 2 infants with hypothyroidism and 2 infants with neonatal Grave's disease had urine samples examined. Values were compared with the epidermal growth factor and creatinine excretion from 190 infants. We demonstrated that epidermal growth factor excretion increased earlier in gestation than does creatinine excretion. In infants with renal disease or hypothyroidism, epidermal growth factor excretion was decreased while hyperthyroidism enhanced excretion. Epidermal growth factor excretion increased with relief of an obstruction but still remained low and creatinine excretion was unchanged. We confirm that in preterm infants as in childhood there are similar effects of thyroid and renal diseases on epidermal growth factor excretion.
Paul van Trotsenburg, Thomas Vulsma, André M. Bloot, Reindert D. Van der Gaag, Jan Willem Lens, Hemmo A. Drexhage, and JanJ. de Vijlder
Antibodies against the so called 'second colloid antigen' (CA2 antibodies) occurred in 51% of the mothers of hypothyroid children detected by screening for neonatal congenital hypothyroidism in Quebec (N = 49) and in The Netherlands (N = 26). In The Netherlands where corresponding neonatal serum was available, 31% (8 of 26) of the infants with congenital hypothyroidism were positive for antibodies against the second colloid antigen. When during follow-up, 3 to 5 years after diagnosis, the mothers and their children were investigated, 46% (7 of 15) of the mothers were positive for antibodies against the second colloid antigen, whereas 29% (4 of 14) of the hypothyroid children were also positive. Various control groups did not show more than a 12% positivity. This presence of thyroid-reactive antibodies in a proportion of the hypothyroid children 3 to 5 years after diagnosis is not compatible with a mere transplacental passage; it indicates that the antibodies must be produced by the mothers and by the children themselves. We conclude that a thyroid autoimmune response occurs in a considerable part of infants with congenital hypothyroidism and their mothers and that this immune response seems to persist in both of them for years.
Y. Rakover, O. Sadeh, E. Sobel, A. Shneyour, and Z. Kraiem
Transient neonatal hypothyroidism has been observed in three successive offspring of a mother with autoimmune thyroiditis. Thyroxine replacement therapy was initiated in a 23-year-old woman with overt clinical and laboratory findings of non-goitrous primary hypothyroidism. While on such treatment, she gave birth to three infants manifesting hypothyroidism immediately after birth. The neonates were treated with thyroxine replacement therapy which was discontinued in the three siblings at ages 2½ years, 3½ years, and 13 months. Continuous observation following cessation of therapy revealed clinical and biochemical euthyroidism in the children. Thyroid scanning during the neonatal period in the first child failed to identify functional thyroid tissue, suggesting thyroid agenesis, whereas thyroid scan performed on subsequent follow-up revealed a normal gland. Sequential serum measurements of autoantibodies directed towards the thyrotropin receptor were made in the mother and third child by a cAMP bioassay. High titres (five-six fold above normal) of blocking antibodies (tested by measuring the inhibition of TSH-stimulated cAMP production of cultured human thyroid cells by serum immunoglobulin preparations) were present in the mother and newborn 10 days after birth. The levels remained persistently high in the mother, whereas they declined and were undetectable in the child at four months. Thyroid-stimulating immunoglobulin was absent in both mother and child. The data are compatible with transient neonatal hypothyroidism caused by transplacental transfer of antibodies which block thyroid response to TSH. The half-life of the maternally-derived blocking antibody in the infant was estimated as 1-2 months. This is the first report on sequential serum measurements and estimate of half-life of the blocking antibodies performed by a cAMP bioassay (using thyroid cells of human origin). Unlike the radioreceptor assay employed so far in such cases, this assay can distinguish between stimulating and blocking TSH receptor antibodies.
Peter M. Messer, Berthold P. Hauffa, Thomas Olbricht, Georg Benker, Peter Kotulla, and Dankwart Reinwein
With regard to their thyroid function, somatic and intellectual development, we compared 17 children of 13 hyperthyroid mothers (group I) receiving antithyroid drug treatment during their pregnancies with 25 children of 15 mothers who were euthyroid without any antithyroid treatment during their pregnancy (group II). Mean duration of maternal treatment was 3.5 months in group I, using carbimazole or thiamazole (N=12) and propylthiouracil (N=1). Age at examination in group I was 7.2±6.2 years, in group II 8.7±7.1 years (mean±sd). Both groups showed no significant differences in the results of the clinical examination and in the degree of their mental and psychomotoric development at the time of study. We found the mean birth weight of the infants in group I significantly lower than in group II(3165±339 vs 3666±670 g, p<0.03). The individual birth weights, however, were normal for gestational age. The body weight difference between groups disappeared during the further somatic development of the children. The serum concentration of free thyroxine in group I was significantly higher than in group II (17.2 ± 2.4 vs 14.9±1.9 pmol/l, p<0.003), but fell in both groups within the normal range. The evaluation of the psychomotoric and intellectual capacity of the children at different developmental stages showed no abnormalities detectable by our tests. Thus, in the children of the two groups we found no adverse effects of a maternal antithyroid drug treatment during pregnancy or of inactive maternal Graves' disease alone, neither on thyroid gland size and function nor on the physical or intellectual development, after the neonatal period.
Michel Polak, Jo Blair, Primoz Kotnik, Effie Pournara, Birgitte Tønnes Pedersen, and Tilman R Rohrer
To investigate the effect of age at growth hormone (GH) treatment start on near adult height (NAH) in children with isolated GH deficiency (GHD).
NordiNet® International Outcome Study (IOS) (Nbib960128), a non-interventional, multicentre study, evaluates the long-term effectiveness and safety of Norditropin® (somatropin) (Novo Nordisk A/S) in the real-life clinical setting.
Patients (n = 172) treated to NAH (height at ≥18 years, or height velocity <2 cm/year at ≥16 (boys) or ≥15 (girls) years) were grouped by age (years) at treatment start (early (girls, <8; boys, <9), intermediate (girls, 8–10; boys, 9–11) or late (girls, >10; boys, >11)) and GHD severity (<3 ng/mL or 3 to ≤10 ng/mL). Multiple regression analysis was used to evaluate the effect of age at treatment start (as a categorical and continuous variable) on NAH standard deviation score (SDS).
Age at treatment start had a marked effect on NAH SDS; NAH SDS achieved by patients starting treatment early (n = 40 (boys, 70.0%); least squares mean (standard error) −0.76 (0.14)) exceeded that achieved by those starting later (intermediate, n = 42 (boys, 57.1%); −1.14 (0.15); late, n = 90 (boys, 68.9%); −1.21 (0.10)). Multiple regression analysis showed a significant association between NAH SDS and age at treatment start (P < 0.0242), baseline height SDS (HSDS) (P < 0.0001), target HSDS (P < 0.0001), and GHD severity (P = 0.0012). Most (78.5%) patients achieved a normal NAH irrespective of age at treatment start.
Early initiation of GH treatment in children with isolated GHD improves their chance of achieving their genetic height potential.
Kerstin Hall, Gösta Enberg, Martin Ritzén, Håkan Svan, Linda Fryklund, and Kazue Takano
Serum somatomedin A (SMA) has been determined in healthy children (n = 188) in relation to age using both a radioimmunoassay and a radioreceptor assay. The SMA levels, only 50% of adult values at birth, rise gradually with age and reach adult levels at 10 years of age. There is a significant correlation (r = 0.46, P < 0.001) between SMA determined by the two methods throughout childhood except during puberty. Immunoreactive SMA shows a marked pubertal rise in values with a peak 2 years earlier for girls than boys, which is not observed by the radioreceptor assay technique. In boys with delayed puberty the increase in immunoreactive SMA is seen first when the testes reach a size of 5 ml. Children with growth hormone deficiency (n = 30) had significantly lower levels of SMA than healthy age-matched controls. Immunoreactive SMA gives a better separation of these groups than the values obtained by radioreceptor assay.
A. Parra, S. Villalpando, E. Junco, B. Urquieta, S. Alatorre, and G. García-Bulnes
Serum thyrotrophin (TSH), thyroxine (T4), triiodothyronine (T3), thyroxine-binding globulin (TBG) and reverse T3 (rT3) were measured by radioimmunoassay in 175 girls and 187 boys aged 6.0 to 16.9 years, who were clinically healthy, and had negative serum antithyroglobulin and antimicrosomal antibodies. All the children had normal weight and height and were grouped at 12 months' intervals. In girls, TSH levels ranged between 5.3 ± 0.4 and 6.9 ± 0.5 μU/ml without significant changes with age; serum T4 decreased up to 13.9 years and rose afterwards; serum TBG was constant up to 13.9 years, decreased subsequently and rose after 15.9 years; serum T3 levels were lower after 13.0 years than previously; serum rT3 decreased between 11.0 and 11.9 years and rose thereafter; the calculated serum free T4 (FT4) and free T3 (FT3) concentrations had a significant rise from 14.0 to 15.9 years followed by a sharp decline; T3:T4, rT3:T3 and rT3:T4 ratios were constant up to 11.9 years, then a rise was seen in T3:T4 and a fall in the later ratios, followed by a drop in T3:T4 ratio and a sustained rise in rT3:T3 and rT3:T4 ratios. In boys, TSH levels were constant between 5.2 ± 0.4 and 6.6 ± 0.4 μU/ml; serum T4 decreased with increasing age; serum TBG was constant up to 13.9 years, and had a sustained fall thereafter; serum T3 was constant over the age range studied; serum rT3 levels decreased up to 13.9 years and rose thereafter; FT4 had no changes with increasing age while FT3, although constant up to 13.9 years, had a sustained rise afterwards; T3:T4 ratio did not change with age, while rT3:T3 and rT3:T4 ratios, although constant up to 13.9 years, showed a tendency toward a sustained rise thereafter. These sex-different variations in serum thyroid hormone concentrations might be related to the fact that girls mature at an earlier chronological age than boys and may represent a partial response of the body to the qualitatively and quantitatively different energy needs in girls as compared with boys, consecutive to the differences in body composition first appearing at puberty.
Salvador Villalpando, Ignacia Cisneros, Guadalupe García-Bulnes, Bárbara Urquieta, Lourdes Mondragón, Elisa Junco, and Adalberto Parra
Anti-thyroid antibodies are frequently found in otherwise normal populations (4.5–25.8%); however, there is scanty information about thyroid function status in affected individuals. In this report, the serum concentrations of TSH, T3, T4, rT3 and TBG and the titre of anti-thyroglobulin and anti-microsomal antibodies (haemagglutination technique) were studied in 520 healthy school children (260 boys and 260 girls) aged 6.0–17.9 years. Titres equal or greater than 1:16 of one or both antibodies were detected in 58 boys and in 77 girls (in 33 boys and in 24 girls with, and in 25 boys and 43 girls without, associated abnormalities in the serum concentrations of one or several hormones). The age distribution of thyroid antibodies followed a trimodal pattern with peaks at 7, 11 and 16–17 years in both sexes. The most striking finding was an abnormally elevated T3 concentration in 22 boys and 5 girls with positive antibodies, with no symptoms of thyroid dysfunction and with no clear relationship with simultaneous abnormalities in TSH, T4 or rT3; however, in 5 boys the TBG serum levels were increased. Serum from these patients was incubated with [125I]T3 before free radioactivity was precipitated with dextran-coated charcoal and the aliquots were analyzed by paper electrophoresis. Serum samples with high T3 levels bound significantly more radioactivity than normal or T3-free serum (P < 0.001) and an abnormal peak of radioactivity was present in the gamma globulin fraction, in the former but not in the latter two types of sera. The presence of high serum T3 levels in the absence of clinical symptoms of hyperthyroidism was probably due to sequestration of T3 by the anti-thyroglobulin antibody, which may have cross-reactivity with T3 and T4, as has previously been demonstrated both in animals and humans.
This study was carried out in order to determine whether children with a transitory type of growth hormone deficiency showed an accelerated growth in height velocity on treatment with human growth hormone (HGH).
Following careful diagnostic routine procedures 13 extremely short children were diagnosed as having isolated growth hormone deficiency, and were successfully treated with HGH. A true isolated growth hormone deficiency was present in 5 of the children, whereas 8 showed a normal increase in serum growth hormone on repeated growth hormone stimulation tests after their development of puberty and termination of HGH treatment. Three boys with bone ages of 5.5, 8.0 and 9.5 years showed an undisputable effect following HGH administration. They showed an initial growth at the start of treatment, and a second growth spurt during development of puberty. Two of the boys reached final statures of 14 cm taller than the predicted heights. The other patients, including the children with true isolated growth hormone deficiency showed an initial spurt of growth at the start of the HGH treatment immediately followed by a pubertal growth spurt. The mean acceleration of height velocity for the children with true isolated growth hormone deficiency was from 3.4 cm during the year before treatment to 7.0 cm during the first year on treatment, as compared to 2.8 and 7.4 cm, respectively, for the children with transitory growth hormone deficiency. A girl with severe anorexia nervosa who had a transitory growth hormone deficiency, showed an accelerated high velocity from 1.1 cm to 7.6 cm during the first year following treatment with HGH.
The question whether HGH treatment should be made available to all short children with no known syndrome, and presenting a height less than −3.5 sds, a bone age/chronological age ratio of less than ⅔, and a height velocity less than −2 sds is discussed. The only way to know if a child will respond to HGH treatment is to give it for a trial period of at least six months. At least a physiological stimulus to growth hormone secretion should be decisive in the selection of growth retarded children for HGH treatment. Different mechanisms seem to be responsible for physiological growth hormone secretion to sleep or exercise, and the secretion obtained with pharmacological stimuli.