Final height after treatment of early puberty in short adopted girls with gonadotrophin releasing hormone agonist with or without growth hormone.

OBJECTIVE: To compare final height data after treatment with gonadotrophin releasing hormone agonist (GnRHa) alone or in combination with growth hormone (GH) in short adopted girls with early puberty. DESIGN: A randomized controlled trial. PATIENTS AND METHODS: Twenty-six girls with onset of puberty before 10 years of age were treated for 3 years with either GnRHa alone (group A, n = 12) or with GnRHa and GH (group B, n = 14). Mean age at start of treatment was 9.6 years in both groups, bone age was 10.7 (SD 1.1) years in group A and 11.6 (0.8) years in group B. RESULTS: Initial height prediction with average Bayley & Pinneau tables was 149.8 (5.6) and 146.8 (4.8) cm, respectively. Bone age at discontinuation of treatment was 12.3 (0.9) and 13.0 (0.6) years in group A and B, respectively. Height gain defined as the difference between initial height prediction and attained final height, was significantly different between group A and B (5.2 (3.7) and 8.2 (3.4) cm, P < 0.05) using average tables for height prediction. With accelerated tables for prediction the numbers were -1.0 (3.6) and 3.3 (3.5) cm, respectively. At final height, there was no significant difference in height: group A: 155.0 (5.6) cm and group B: 155.0 (5.5) cm. CONCLUSIONS: After 3 years of GnRHa treatment in adopted girls with early puberty, FH is significantly higher than initial height prediction. The addition of GH resulted in a limited further increase in height gain. In the interpretation of the results methodological issues concerning height prediction have to be taken into account.

[Measuring the length of newborn infants]. / Lengtemeting bij de pasgeborene.

Since 1985, measurement of the length of neonates has been practically abandoned in the Netherlands because it was thought that stretching the legs and knees briefly in order to measure the length immediately after birth could be harmful for the development of the hip joint. However, this fear seems unjustified. Measuring the length of the neonate provides useful information regarding the general condition and has predictive value for the final adult height. If an infant is disproportionately small in comparison with its weight or small for its gestational age with insufficient catch-up growth, this may be an indication of underlying pathology. As a rule, the length of all neonates should be measured immediately after birth and length measurement should be re-introduced as part of standard care. Length measurement can be done with sufficient accuracy after proper instruction. For babies born after incomplete breech presentation, length measurement should be postponed for about a week.

[Turner's syndrome in mother and daughter]. / Syndroom van Turner bij moeder en dochter.

A girl with Turner's syndrome due to a 45,X mosaicism and a ring chromosome was born to a 29-year-old mother with a non-mosaic 45,X in her blood lymphocytes. Cytogenetic investigation revealed that the ring chromosome of the daughter included almost the entire X chromosome with the exception of the uppermost part of the short arm. In the literature, girls with Turner's syndrome are said to have functional ovarian tissue and pregnancies in women with Turner's syndrome after oocyte donation and intracytoplasmatic sperm injection (ICSI) are no longer exceptional. However, since ovarian failure occurs relatively early during adolescence, cryopreservation of ovarian tissue should be considered as soon as the girl or her parents are able to make the necessary decisions. On the other hand, beside risks for congenital anomalies in the newborn, the risks of pregnancies in Turner's syndrome should not be neglected, notably premature delivery due to disproportion between the pelvis and the foetus and aortic dissection in the pregnant woman.

Evaluation of the usefulness of a quantitative ultrasound device in screening of bone mineral density in children.

BACKGROUND: Osteoporosis is a major public health problem, and its prevention is of great importance. It is known that bone mass later in life is determined by the peak bone mass acquired during adolescence and the subsequent rate of bone loss. Therefore we should give special attention to children that are 'at risk' of low bone mass, and we must seek simple yet reliable methods to measure their bone mineral density (BMD) regularly. AIM: We investigated the value of a quantitative ultrasound device (QUS), the Sahara clinical bone sonometer (Hologic), in screening of low bone mass in children. In contrast to dual energy X-ray absorptiometry (DEXA), the most commonly used technique for measurement of BMD today, the QUS method is free of ionizing radiation, easy to handle and inexpensive. SUBJECTS AND METHODS: Intra- and inter-observer variability of the QUS method was assessed using replicate measurements by two observers in 15 randomly chosen children. QUS parameters were measured in 226 healthy schoolchildren (121 boys, 105 girls) as well as in 41 children at risk for low bone mass (15 boys, 26 girls) between 7 and 18 years old. For comparison we also determined BMD by DEXA in those children at risk. RESULTS: Reproducibility of the QUS device was moderate, as well as the correlation between QUS and DEXA (r = 0.14-0.50). The QUS device was not able to recognize children with low bone mass as determined by DEXA. Although it is well known that BMD increases with age and pubertal stage, we could not find significant differences in QUS parameters between age and pubertal stage groups. CONCLUSION: We conclude that there is enough evidence that the Sahara clinical bone sonometer is not useful in screening of low bone mass in children.

[Bladder control in 1-4 year old children in the the Eindhoven and Kempen region (The Netherlands) in 1996 and 1966]. / Zindelijkheid voor urine bij 1-4-jarige kinderen in de regio Eindhoven en de Kempen, in 1996 en in 1966.

OBJECTIVE: To determine the age at which children gain bladder control and to compare this with the data from 30 years ago. DESIGN: Questionnaires. METHOD: On the basis of the findings of a 1966 study into toilet training in the Eindhoven and de Kempen region, the Netherlands, a questionnaire was drawn up and distributed via 30 child-health clinics in this region to parents of children aged 12-59 months, during the period 1 March-30 June 1996. The results were compared with those of the earlier study. RESULTS: Data from 1176 children could be evaluated (response rate: 65%). In 1996, the median age for bladder control in boys during the day was 32.6 months and 40.5 months for night-time control. In 1996 boys achieved daytime bladder control 6.7 months earlier and night-time control 7.2 months earlier. In 1996, the median age for girls was 29.7 months for daytime control and 35.4 months for night-time bladder control: in 1966 girls achieved daytime and night-time bladder control 8.2 and 4.8 months earlier, respectively. Factors associated with earlier bladder control were: early age at which parents started toilet training, presence of other children in the family, early age at which the child attended a day-care centre, early age at which the child was able to walk. Other factors such as the presence of a complete family set, parental level of education and professional situation did not show a correlation with the age at which the child achieved bladder control. The type of diaper used was an additional factor for bladder control at all ages but was only statistically significant for 3-year-olds, both during the day and during the night. CONCLUSION: Children in the Eindhoven region achieved daytime and night-time bladder control at a significantly later age than 30 years ago. Various factors such as toilet-training age, day-care attendance, family size and type of diaper played a role in this phenomenon.

Influence of knowledge, training and experience of observers on the reliability of anthropometric measurements in children.

OBJECTIVE: To elucidate the impact of the observer's level of technical knowledge, training and experience with measuring height and triceps skinfold thickness on the reliability of these measurements in children. Despite of instructions and encouraging careful measurements, these factors may significantly affect measurements and lead to interpretation difficulties, especially of short term growth data. SUBJECTS AND METHODS: A cross-sectional study was designed in which 18 children, aged 2-7 years, were measured in duplo by 12 observers with different backgrounds and levels of experience, protocol knowledge and protocol training. The main outcome measures, precision and accuracy, were expressed as technical error of measurement (TEM) and average bias (AB) in comparison with an expert anthropometrist. RESULTS: As expected, the best educated and most experienced observers scored the best precision and accuracy. By ranking analysis and multiple regressions we learned that precision and accuracy in measuring height and triceps skinfold thickness are mainly predicted by allround knowledge of the measurement protocol (p< 0.05) and the years of experience (p< 0.05). A practical training course of only a few hours does not seem to improve reliability significantly. CONCLUSION: To get a more reliable insight in growth of a child it is important to be aware of the influence on measurement outcome values of protocol knowledge and years of experience. Growth studies should use detailed anthropometric standardization protocols and train people to acquire better insight into these protocols.

GH treatment and its effect on bone mineral density, bone maturation and growth in short children born small for gestational age: 3-year results of a randomized, controlled GH trial.

BACKGROUND: To investigate in a group of short children born small for gestational age (SGA), the effects of 3 years of GH treatment vs. no treatment on bone age (BA), height and bone mineral density (BMD). Also, to evaluate the influence of the severity of growth retardation at start and the GH dose on the gain in height. PATIENTS AND METHODS: The study design was an open-labelled, controlled multicentre GH study for 3 years. Non-GH-deficient (GHD) children (n = 87) were randomized to either a GH group (n = 61) or an untreated control group (n = 26). In addition, 12 SGA children had GHD (GHD group) and were treated in parallel. Both the GH and the GHD group were treated with a GH dose of 33 microg/kg/day. BMD was evaluated using dual energy X-ray absorptiometry (DEXA). In addition, data of our first GH trial in which short SGA children were treated with a GH dose of 66 microg/kg/day (n = 24) were used for comparison of height gain. RESULTS: In contrast to the control group, the GH group showed a significant increase in height (P < 0.001), as did the parallel GHD group. Bone maturation [delta bone age (BA)/delta calendar age (CA)] increased significantly during the first 2 years of GH treatment but slowed-down thereafter. The 3-year deltaBA/deltaCA ratio correlated significantly with the gain in height (r = 0.6, P < 0.001). At start, mean BMD SDS and mean BMAD SDS were significantly lower than zero. During GH treatment both increased impressively (P < 0.001). The gain in height of children with severe short stature at start (< or = -3.00 SDS), did not differ between those receiving either a GH dose of 33 or 66 microg/kg/day. CONCLUSION: Three years of GH treatment in short children born SGA results in a normalization of height during childhood. Also, bone maturation increased proportionately to the height gain. At start, mean values of BMD and BMAD were significantly reduced but normalized during GH treatment. We did not find an indication to treat very short SGA children (H SDS < or = -3.00) with a higher GH dose. We rather suggest to start GH treatment at an early age in order to achieve a normal height before puberty starts.

High dose growth hormone treatment induces acceleration of skeletal maturation and an earlier onset of puberty in children with idiopathic short stature.

BACKGROUND: Long term growth hormone (GH) treatment in children with idiopathic short stature (ISS) results in a relatively small mean gain in final height of 3-9 cm, which may not justify the cost of treatment. As it is unknown whether GH treatment during puberty adds to final height gain, we sought to improve the cost-benefit ratio, employing a study design with high dose GH treatment restricted to the prepubertal period. AIMS: To assess the effect of short term, high dose GH treatment before puberty on growth, bone maturation, and pubertal onset. METHODS: Five year results of a randomised controlled study are reported. Twenty six boys and nine girls were randomly assigned to a GH treatment group (n = 17) or a control group (n = 18). Inclusion criteria were: no signs of puberty, height less than -2 SDS, age 4-8 years for girls or 4-10 years for boys, GH concentration >10 micro g/l after provocation, and normal body proportions. To assess GH responsiveness, children assigned to the GH treatment group received GH treatment for two periods of three months (1.5 IU/m2/day and 3.0 IU/m2/day), separated by three month washout periods, during the first year of study. High dose GH treatment (6.0 IU/m2/day) was then started and continued for at least two full years. When puberty occurred, GH treatment was discontinued at the end of a complete year's treatment (for example, three or four years of GH treatment). RESULTS: In response to at least two years on high dose GH treatment, mean (SD) height SDS for chronological age increased significantly in GH treated children from -2.6 (0.5) to -1.3 (0.5) after two years and -1.4 (0.5) SDS after five years of study. No changes in height SDS were observed in controls. A rapid rate of bone maturation of 3.6 years/2 years in treated children compared to 2 years/2 years in controls was observed in response to two years high dose GH treatment. Height SDS for bone age was not significantly different between groups during the study period. GH treated children entered into puberty at a significantly earlier age compared to controls. CONCLUSIONS: High dose GH treatment before puberty accelerates bone age and induces an earlier onset of puberty. This may limit the potential therapeutic benefit of this regimen in ISS.

Psychological assessments before and after treatment of early puberty in adopted children.

UNLABELLED: Early puberty is frequently observed in adopted children. This randomized trial treated 30 adopted children with early puberty and short stature with either gonadotropin-releasing hormone agonist (GnRHa) alone or in combination with growth hormone (GH) for 3 y. Before the start of treatment (T1) in the trial and at discontinuation (T2) the children and their parents underwent a psychological evaluation. At the start of treatment the children did not have increased levels of behavioural or emotional problems as assessed by the Child Behaviour Checklist (CBCL). During treatment the CBCL scores did not increase. Self-perception of the children appeared to be normal, and after 3 y a significantly higher score for acceptance by peers was observed. At T1, an overestimation of future height was present in 80% of the children and 17% of the parents. Lower family stress was observed at T1 and T2 compared with reference values. Intelligence quotient levels decreased significantly during treatment. The findings are discussed with reference to the reported levels of behavioural and emotional problems in adopted children and the psychosocial effects of precocious puberty. CONCLUSION: This psychological evaluation did not reveal any consistent abnormalities in adopted children with early puberty. Treatment with GnRHa with or without GH did not increase emotional and behavioural problems in adopted children, nor was their self-perception decreased.

Genotype versus phenotype in families with androgen insensitivity syndrome.

Androgen insensitivity syndrome encompasses a wide range of phenotypes, which are caused by numerous different mutations in the AR gene. Detailed information on the genotype/phenotype relationship in androgen insensitivity syndrome is important for sex assignment, treatment of androgen insensitivity syndrome patients, genetic counseling of their families, and insight into the functional domains of the AR. The commonly accepted concept of dependence on fetal androgens of the development of Wolffian ducts was studied in complete androgen insensitivity syndrome (CAIS) patients. In a nationwide survey in The Netherlands, all cases (n = 49) with the presumptive diagnosis androgen insensitivity syndrome known to pediatric endocrinologists and clinical geneticists were studied. After studying the clinical phenotype, mutation analysis and functional analysis of mutant receptors were performed using genital skin fibroblasts and in vitro expression studies. Here we report the findings in families with multiple affected cases. Fifty-nine percent of androgen insensitivity syndrome patients had other affected relatives. A total of 17 families were studied, seven families with CAIS (18 patients), nine families with partial androgen insensitivity (24 patients), and one family with female prepubertal phenotypes (two patients). No phenotypic variation was observed in families with CAIS. However, phenotypic variation was observed in one-third of families with partial androgen insensitivity resulting in different sex of rearing and differences in requirement of reconstructive surgery. Intrafamilial phenotypic variation was observed for mutations R846H, M771I, and deletion of amino acid N682. Four newly identified mutations were found. Follow-up in families with different AR gene mutations provided information on residual androgen action in vivo and the development of the prepubertal and adult phenotype. Patients with a functional complete defective AR had some pubic hair, Tanner stage P2, and vestigial Wolffian duct derivatives despite absence of AR expression. Vaginal length was functional in most but not all CAIS patients. The minimal incidence of androgen insensitivity syndrome in The Netherlands, based on patients with molecular proof of the diagnosis is 1:99,000. Phenotypic variation was absent in families with CAIS, but distinct phenotypic variation was observed relatively frequent in families with partial androgen insensitivity. Molecular observations suggest that phenotypic variation had different etiologies among these families. Sex assignment of patients with partial androgen insensitivity cannot be based on a specific identified AR gene mutation because distinct phenotypic variation in partial androgen insensitivity families is relatively frequent. In genetic counseling of partial androgen insensitivity families, this frequent occurrence of variable expression resulting in differences in sex of rearing and/or requirement of reconstructive surgery is important information. During puberty or normal dose androgen therapy, no or only minimal virilization may occur even in patients with significant (but still deficient) prenatal virilization. Wolffian duct remnants remain detectable but differentiation does not occur in the absence of a functional AR. In many CAIS patients, surgical elongation of the vagina is not indicated.

A randomized controlled trial of three years growth hormone and gonadotropin-releasing hormone agonist treatment in children with idiopathic short stature and intrauterine growth retardation.

We assessed the effectiveness and safety of 3 yr combined GH and GnRH agonist (GnRHa) treatment in a randomized controlled study in children with idiopathic short stature (ISS) or intrauterine growth retardation (IUGR). Gonadal suppression, GH reserve, and adrenal development were assessed by hormone measurements in both treated children and controls during the study period. Thirty-six short children, 24 girls (16 ISS/8 IUGR) and 12 boys (8 ISS/4 IUGR), with a height SD score of -2 SD or less in early puberty (girls, B2-3; boys, G2-3), were randomly assigned to treatment (n = 18) with GH (genotropin 4 IU/m(2). day) and GnRHa (triptorelin, 3.75 mg/28 days) or no treatment (n = 18). At the start of the study mean (SD) age was 11.4 (0.56) or 12.2 (1.12) yr whereas bone age was 10.7 (0.87) or 10.9 (0.63) yrs in girls and boys, respectively. During 3 yr of study height SD score for chronological age did not change in both treated children and controls, whereas a decreased rate of bone maturation after treatment was observed [mean (SD) 0.55 (0.21) 'yr'/yr vs. 1.15 (0.37) 'yr'/yr in controls, P < 0.001, girls and boys together]. Height SD score for bone age and predicted adult height increased significantly after 3 yr of treatment; compared with controls the predicted adult height gain was 8.0 cm in girls and 10.4 cm in boys. Furthermore, the ratio between sitting height/height SD score decreased significantly in treated children, whereas body mass index was not influenced by treatment. Puberty was effectively arrested in the treated children, as was confirmed by physical examination and prepubertal testosterone and estradiol levels. GH-dependent hormones including serum insulin-like growth factor I and II, carboxy terminal propeptide of type I collagen, amino terminal propeptide of type III collagen, alkaline phosphatase, and osteocalcin were not different between treated children and controls during the study period. Thus, a GH dose of 4 IU/m(2) seems adequate for stabilization of the GH reserve and growth in these GnRHa-treated children. We conclude that 3 yr treatment with GnRHa was effective in suppressing pubertal development and skeletal maturation, whereas the addition of GH preserved growth velocity during treatment. This resulted in a considerable gain in predicted adult height, without demonstrable side effects. Final height results will provide the definite answer on the effectiveness of this combined treatment.

Gonadotrophin releasing hormone agonist treatment with or without recombinant human GH in adopted children with early puberty.

BACKGROUND: Early onset of puberty is frequently observed in adopted children. During treatment with a gonadotrophin releasing hormone agonist (GnRHa), a decrease in height velocity (HV) precludes height gain. OBJECTIVE AND DESIGN: We studied the effect of the addition of GH to GnRHa treatment in a 3-year prospective randomized trial in 30 adopted children with early puberty. PATIENTS: Mean age (SD) at start of treatment was 9.6 (0.9) years in girls and predicted adult height (PAH) using a segmented bone age (BA) assessment method was 148.0 (5.3) cm. RESULTS: HV decreased gradually in both groups with a higher HV in the group with GH addition (group B). No significant difference between the rates of bone maturation [change in bone age (DeltaBA)/change in chronological age (DeltaCA)] of both treatment groups was observed. After 3 years of treatment, PAH increase was 5.7 (3.8) cm in group A (GnRHa alone) and 10.1 (3.8) cm in group B (P < 0.01). IGF-I levels were higher in group B. HV decreased slowly in both groups during treatment, unlike stabilization of IGF-I levels. CONCLUSION: We conclude that, after 3 years of treatment, the addition of GH to GnRHa results in higher HV and a significant increase in PAH compared to GnRHa alone.

Final height after gonadotrophin releasing hormone agonist treatment for central precocious puberty: the Dutch experience.

Final height (FH) data of 96 children (87 girls) treated with GnRH agonist for central precocious puberty were studied. In girls mean FH exceeded initial height prediction by 7.4 (5.7) cm (p < 0.001); FH was significantly lower than target height, but still in the genetic target range. When treatment started < 6 years of age, height gain was significantly higher than when started > 8 years of age. Bone age (BA) and chronological age (CA) at start of treatment, as well as BA advance at cessation of treatment, were the most important variables influencing height gain in multiple regression analysis. BA advance at start of treatment was most important in simple correlation. In girls, GnRHa treatment seems to restore FH into the target range. A younger age and advanced bone age at start of treatment are associated with more height gain from GnRHa treatment.

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.

Growth hormone therapy with three dosage regimens in children with idiopathic short stature. European Study Group Participating Investigators.

OBJECTIVE: In children with idiopathic short stature (ISS) we studied the growth-promoting effect at 4 years of recombinant human growth hormone (rhGH) therapy in three dose regimens and evaluated whether increasing the dosage after the first year could prevent a decline in height velocity (HV). DESIGN: Included were 223 patients who were treated with subcutaneous administrations of rhGH 6 days per week. They were randomized to three groups: 3 IU/m2 body surface/day, 4.5 IU/m2/day, and 3 IU/m2/day during the first year and 4.5 IU/m2/day thereafter, corresponding with dosages of 0.2 and 0.3 mg/kg body weight/week, respectively. Growth was compared with a standard of 229 untreated children with ISS [ISS standard]. RESULTS: During the first year of treatment HV almost doubled and was higher with 4.5 IU/m2 than with 3 IU/m2. In the second year HV no longer differed among the groups, but increasing the dosage slowed the rate of the fall of HV. During 4 years of therapy the height SD score for age increased by a mean (SD) of 2.5 (1.0) [ISS standards], or 1.2 (0.7) (British standards), bone age increased by 4.8 (1.3) years, and predicted adult height SD score increased by 1.5 (0.7). After 4 years the results of the group with 4.5 IU/m2 were slightly better than those of the other groups. When dropouts were included in the analysis (assuming a stable height SD score after discontinuation of rhGH therapy), height gain was still significant. CONCLUSIONS: During 4 years of rhGH therapy, growth and final height prognosis improved, slightly more with 4.5 IU/m2 than with 3 IU/m2 or 3 to 4.5 IU/m2. However, bone age advanced on average 4.8 years during this period; therefore, any effect on final height will probably be modest.

[Acute gastric dilatation and superior mesenteric artery syndrome in the mentally retarded]. / Acute maagdilatatie en A. mesenterica superior-syndroom bij zwakzinnigen.

Three mentally retarded male patients, 24, 30 and 14 years old, died from acute gastric dilatation leading to rupture and perforation. Superior mesenteric artery syndrome (SMA) was the cause of gastric dilatation in two of them. In the third patient the cause was not clear. The three patients had scoliosis and were underweight or thin. Two had spastic quadriplegia of perinatal origin and one had Down's syndrome. One patient with SMA was treated by Nissen fundoplication because of hiatus hernia with vomiting and gastro-oesophageal reflux one week before he died. Another patient had a severe gastric bleeding after decompression of the dilatation. In mentally retarded patients there are often several predisposing factors for SMA (anorexia, severe weight loss in a short time, pronounced lumbar lordosis, scoliosis, correction of scoliosis by operation or plaster cast, prolonged lying position, boulimia). Gastric dilatation may be prevented by ensuring adequate nutritional status.

Congenital hypothyroidism caused by a premature termination signal in exon 10 of the human thyroid peroxidase gene.

The molecular basis of a total iodide organification defect causing severe congenital hypothyroidism has been elucidated. The defect occurred in a family in which two of five siblings were affected. Thyroid tissue from one patient was available for investigation. The total thyroid peroxidase (TPO) messenger ribonucleic acid level was reduced and consisted mainly of the alternatively spliced form of TPO missing exon 10 (TPO-2). No TPO-1 (wild-type) protein was detected by Western blotting. The TPO-2 translation product of a slightly smaller mol wt was present in thyroid tissue of this patient. TPO activity was absent and thyroglobulin was not iodinated, showing that iodination in vivo did not occur. Denaturing gradient gel electrophoresis and subsequent sequencing revealed in both alleles of the patients a C-->T transition of nucleotide 1708 of the TPO gene, involving a CpG dinucleotide. The mutation introduces a premature termination signal in exon 10 of the TPO gene, preventing the synthesis of enzymatic active peroxidase.

Maternal thyroid peroxidase antibodies during pregnancy: a marker of impaired child development?

Women with antibodies against the enzyme thyroid peroxidase [TPO-Ab; formerly microsomal antibodies (MsAb)] are at particular risk for developing postpartum thyroid dysfunction; the latter is significantly associated with postpartum depression. Although the negative effect of postpartum maternal depression on child development is well documented, the consequences of elevated titers of TPO-Ab during pregnancy and subsequent postpartum thyroid dysfunction on child development are not known. In a prospective study of a cohort of 293 pregnant women, the occurrence of TPO-Ab during gestation, thyroid dysfunction, and depression was investigated. Five years after delivery, child development was assessed in 230 children of the original cohort using the Dutch translation of the McCarthy Scales of Children's Abilities. Children of women with TPO-Ab during late gestation (n = 19, with normal thyroid function) had significantly lower scores (by t test) on the McCarthy Scales of Children's Abilities than antibody-negative women. The difference on the General Cognitive Scale, which reflects IQ scores, was substantial (10.5 points; t = 2.8; P = 0.005). After correction for possibly confounding variables, maternal TPO-Ab during gestation was found to be the most important factor related to the scores on the General Cognitive Scale (odds ratio = 10.5; 95% confidence interval = 3-34; P = 0.003). We conclude that children of pregnant women who had elevated titers of TPO-Ab but normal thyroid function are at risk for impaired development.

Long-term results of growth hormone therapy in children with short stature, subnormal growth rate and normal growth hormone response to secretagogues. Dutch Growth Hormone Working Group.

BACKGROUND AND OBJECTIVE: Growth hormone treatment in children with idiopathic short stature (ISS) leads to growth acceleration in the first years, but the effect on final height is still poorly documented. We therefore studied the long-term effect of GH therapy in children with idiopathic short stature. DESIGN: We have treated 27 prepubertal children with ISS with recombinant human GH (rhGH) in an initial dosage of 2 IU/m2 body surface/day subcutaneously, which was doubled either after the first year if the height velocity increment was less than 2 cm/year, or thereafter if height velocity fell below the P50 for bone age. Growth and bone maturation of the treatment group (ISS group, n = 21) were compared to those of an untreated control group with ISS (ISS controls, n = 27) and of a group of rhGH treated children with isolated GH deficiency (GHD group, n = 7). RESULTS: In 9 patients of the ISS group still on treatment, height standard deviation score (HSDS) for chronological age increased from -3.8 +/- 0.7 to -2.3 +/- 0.9 (mean +/- standard deviation) over 6 years, while in matched ISS controls HSDS for age did not change. HSDS for age in the GHD group increased from -3.9 +/- 0.6 to -1.8 +/- 0.7 after 4 years, significantly more than the ISS group. Bone maturation was accelerated in the ISS and GHD groups. HSDS for bone age and predicted adult height did not change in either group. Final height in 12 children of the ISS group was -2.6 +/- 1.0 SDS. In the untreated controls final height was similar. A low integrated GH concentration over 24 hours, a low GH peak to provocative stimuli, and minimal initial BA delay predicted a favourable outcome. CONCLUSION: rhGH treatment in this group of children with idiopathic short stature did not increase average final height. Part of the heterogeneity of the response can be attributed to the variation in endogenous GH secretion and initial bone age delay.

Treatment with two growth hormone regimens in girls with Turner syndrome: final height results. Dutch Growth Hormone Working Group.

In 1987 a multicentre trial of recombinant human growth hormone (GH) was started in girls with Turner syndrome. Fifty-four patients were randomly assigned to receive GH, 8 IU/m2 3 times/week (group 1), or 4 IU/m2 6 times/week (group 2). In addition, the 35 patients older than 12 years received ethinyloestradiol, 100 ng/kg body weight/day, and after 2 years GH therapy was increased to 6 IU/m2 6 times/week. Recombinant human GH treatment was stopped when the height increment during the previous 6 months of treatment was less than 0.5 cm. Treatment has so far been stopped in 48 patients: treatment was stopped early in 2 patients due to lack of motivation, 1 patient died suddenly and the treatment protocol was completed in 45 patients. The last height measurement obtained, which was considered as (near) final height, was 152.3 +/- 5.3 cm (mean +/- SD) in these patients, which is higher (p < 0.001) than the adult height of 147.0 +/- 6.3 cm reported in 63 untreated adult Dutch patients with Turner syndrome. No differences in outcome were found between the two dose regimens.