Pharmacokinetics and pharmacodynamics of orally administered clonidine: a model-based approach.

BACKGROUND/AIMS: The oral clonidine test is a diagnostic procedure performed in children with suspected growth hormone (GH) deficiency. It is associated with untoward effects, including bradycardia, hypotension and sedation. Serum clonidine levels have not previously been assessed during this test. METHODS: In 40 children referred for an oral clonidine test, blood samples were drawn for clonidine and GH. Vital statistics and sedation scores were recorded until 210 min post-dose. We explored the relationship between clonidine concentrations and effects such as GH peak and blood pressure. RESULTS: Of 40 participants, 5 children were GH deficient. Peak clonidine concentrations of 0.846 ± 0.288 ng/ml were reached after 1 h. Serum levels declined slowly, with concentrations of 0.701 ± 0.189 ng/ml 210 min post-dose. A large interindividual variation of serum levels was observed. During the procedure, systolic blood pressure dropped by 12.8%, diastolic blood pressure by 19.7% and heart rate by 8.4%. Moderate sedation levels were observed. Concentration-effect modeling showed that the amount of GH available for secretion as determined by previous bursts was an important factor influencing GH response. CONCLUSION: Clonidine concentrations during the test were higher than necessary according to model-based predictions. A lower clonidine dose may be sufficient and may produce fewer side effects.

Extending the phenotype of recurrent rearrangements of 16p11.2: deletions in mentally retarded patients without autism and in normal individuals.

Array CGH (comparative genomic hybridization) screening of large patient cohorts with mental retardation and/or multiple congenital anomalies (MR/MCA) has led to the identification of a number of new microdeletion and microduplication syndromes. Recently, a recurrent copy number variant (CNV) at chromosome 16p11.2 was reported to occur in up to 1% of autistic patients in three large autism studies. In the screening of 4284 patients with MR/MCA with various array platforms, we detected 22 individuals (14 index patients and 8 family members) with deletions in 16p11.2, which are genomically identical to those identified in the autism studies. Though some patients shared a facial resemblance and a tendency to overweight, there was no evidence for a recognizable phenotype. Autism was not the presenting feature in our series. The assembled evidence indicates that recurrent 16p11.2 deletions are associated with variable clinical outcome, most likely arising from haploinsufficiency of one or more genes. The phenotypical spectrum ranges from MR and/or MCA, autism, learning and speech problems, to a normal phenotype.

[The incidence and initial symptoms of diabetes mellitus type 1 in 0-14-year-olds in the Netherlands, 1996-1999]. / De incidentie en de eerste symptomen van diabetes mellitus type 1 bij 0-14-jarigen in Nederland, 1996-1999.

OBJECTIVE: To determine the incidence and characteristics of type-1 diabetes mellitus (DM) in children aged 0-14 years during the period 1996-1999 and to compare this with previous measurements of the incidence. DESIGN: Descriptive. METHOD: Data were collected via reports from all practicing paediatricians to the Dutch Paediatric Surveillance Unit and a questionnaire among members of the Dutch Diabetes Association. The incidence was calculated by the capture-recapture method, and the characteristics and symptoms of the children were determined from the questionnaires. RESULTS: The incidence of DM type 1 among 0-14-year-olds increased to 18.6/100,000/year (95% CI: 17.7-19.4) compared to 11.1/100,000/year (10.5-11.7) in 1978-1980. The increase was highest in the youngest age group, 0-4 years. DM type 1 was diagnosed at an average age of 7.6 years (7.4-7.9) and in 1988-1990 at 9.2 years (9.0-9.5). The boy-girl ratio also increased. Children with a mother from Surinam, Turkey or The Netherlands Antilles had lower risk of DM type 1 while a higher risk was calculated for children from Moroccan and Somali mothers. In comparison with 1993-1994, there were less frequent lethargy or dehydration; lower average serum-glucose values, a better blood pH and less frequent ketonuria at the time of diagnosis. Treatment on an outpatient basis had increased. However, over the time span 1993-1999, Moroccan children (n = 108) showed dehydration, ketonuria and low blood-pH values more frequently than children of Dutch parents (n = 1825) and their hospital admission lasted longer. CONCLUSION: The incidence of DM type 1 had increased and the disease manifested itself at a younger age. The clinical condition at time of diagnosis, however, was better. The incidence and clinical characteristics differed between children of different ethnic origin.

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.

Does the risk of childhood diabetes mellitus require revision of the guideline values for nitrate in drinking water?

In recent years, several studies have addressed a possible relationship between nitrate exposure and childhood type 1 insulin-dependent diabetes mellitus. The present ecologic study describes a possible relation between the incidence of type 1 diabetes and nitrate levels in drinking water in The Netherlands, and evaluates whether the World Health Organization and the European Commission standard for nitrate in drinking water (50 mg/L) is adequate to prevent risk of this disease. During 1993-1995 in The Netherlands, 1,104 cases of type 1 diabetes were diagnosed in children 0-14 years of age. We were able to use 1,064 of these cases in a total of 2,829,020 children in this analysis. We classified mean nitrate levels in drinking water in 3,932 postal code areas in The Netherlands in 1991-1995 into two exposure categories. One category was based on equal numbers of children exposed to different nitrate levels (0.25-2.08, 2.10-6.42, and 6.44-41.19 mg/L nitrate); the other was based on cut-off values of 10 and 25 mg/L nitrate. We determined standardized incidence ratios (SIRs) for type 1 diabetes in subgroups of the 2,829,020 children with respect to both nitrate exposure categories, sex, and age and as compared in univariate analysis using the chi-square test for trend. We compared the incidence rate ratios (IRRs) by multivariate analysis in a Poisson regression model. We found an effect of increasing age of the children on incidence of type 1 diabetes, but we did not find an effect of sex or of nitrate concentration in drinking water using the two exposure categories. For nitrate levels > 25 mg/L, an increased SIR and an increased IRR of 1.46 were observed; however, this increase was not statistically significant, probably because of the small number of cases (15 of 1,064). We concluded that there is no convincing evidence that nitrate in drinking water at current exposure levels is a risk factor for childhood type 1 diabetes mellitus in The Netherlands, although a threshold value > 25 mg/L for the occurrence of this disease can not be excluded.

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.

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.

Confirmation of high incidence of type 1 (insulin-dependent) diabetes mellitus in Moroccan children in The Netherlands.

The incidence of Type 1 (insulin-dependent) diabetes mellitus among Moroccan children aged (0-19 years) in The Netherlands was determined. Point of reference was the data derived from the second nationwide incidence study on Type 1 diabetes among children under 20 years of age. In that study the incidence among Dutch children was 13.2 100000(-1) year(-1). To scrutinize the data and to obtain more information a questionnaire was sent in 1993 to all specialists who had reported that they had diagnosed a patient with Type 1 diabetes during the years 1988-1990 whose parents originated from Morocco, Turkey or other foreign countries. The questionnaire requested information on origin and migration of child and parents. The response to the questionnaire was 86% for the Moroccan children, 75% for the Turkish children and 100% for the children from other countries. In only one case a wrong country had been recorded. None of the patients had been in The Netherlands for less than 6 months before the diagnosis. The incidence for Moroccan children was 20.0 (95% CI 14.6-26.9) and for Turkish children 4.5 (95% CI 2.2-8.0) 100,000(-1) year(-1). It is concluded that the incidence of Type 1 diabetes in Moroccan children (0-19 years) is 1.5 times higher than in Dutch children and 4.5 times higher than in Turkish children.

Yearly stepwise increments of the growth hormone dose results in a better growth response after four years in girls with Turner syndrome. Dutch Working Group on Growth Hormone.

To optimize the growth promoting effect of growth hormone (GH), 65 previously untreated girls with Turner syndrome (TS), chronological age (CA) 2-11 yr, were randomized into 3 dosage regimen groups: A, B, and C, with a daily recombinant-human GH dose during 4 study years of 4-4-4-4, 4-6-6-6, and 4-6-8-8 IU/m2 b.s. The first GH dosage increase in groups B and C resulted in a significantly higher mean height velocity (HV) compared with constant dose group A. During the third year, when the dose was raised again only in group C, mean HV was significantly higher in groups B and C than in group A, and in group C compared with group B. In year 4 only group C mean HV remained significantly higher than group A. The pattern of change in HSDSCA (Dutch-Swedish-Danish Turner references) was identical; however, in year 4 mean delta HSDSCA in group B also remained significantly higher than group A. After 4 yr GH treatment, the following was determined. 1) The mean delta HSDSCA was significantly higher for groups B and C compared with group A, but not significantly different between groups B and C. 2) Although significantly higher compared with estimated values for untreated Dutch girls with TS, bone maturation of the GH treated girls was not significantly different between groups. 3) It was positively related with the degree of bone age (BA) retardation at start of study and negatively with baseline CA. 4) Both the modified Index of Potential Height (mIPHRUS) and a recently developed Turner-specific final height (FH) prediction method (PTSRUS), based on regression coefficients for H, CA, and bone age, showed significant increases in mean FH prediction, without significant differences between groups. PTSRUS values were markedly higher than the mIPHRUS values. Dose dependency could be shown for the area under the curve (AUC) for GH, but delta HSDSCA was not linearly related with AUC. Baseline GH binding protein (BP) levels were in 84% of the cases within the normal age range; the decrease in mean levels after 6 months GH was not significant. Mean insulin-like growth factor I (IGF-I) and IGFBP-3 plasma levels increased significantly, without significant differences between groups. delta HSDSCA during GH was dependent on IGF-I plasma levels at baseline and during the study period, beta-0.002 and beta-0.0004. Thus, a stepwise GH-dosing approach reduced the "waning" effect of the growth response after 4 yr treatment without undue bone maturation. FH prediction was not significantly different between treatment groups. Irrespective of the GH dose used, initiation of GH treatment at a younger age was beneficial after 4 yr GH when expressed as actual cm gained or as gain in FH prediction, but was not statistically significant when expressed as delta HSDSCA over the study period.

Screening for coeliac disease in Dutch children with associated diseases.

Our objective was to assess the frequency of coeliac disease in children with associated disorders in the province of "Zuid-Holland". The Netherlands. We therefore screened 115 children with Down's syndrome, 62 children with juvenile rheumatoid arthritis (JRA) and 46 children with diabetes mellitus for CD using the IgA-class of antigliadin, antiendomysium and antireticulin antibodies in serum, and a functional sugar absorption test. The antiendomysium antibody test was the screening test that performed the best. Every patient who has at least one positive test underwent a jejunal biopsy for the diagnosis of CD. No association could be demonstrated between CD and diabetes mellitus. The frequency of CD in Down's syndrome was 7.0%, which is much higher than that found from screening the general population. CD was found in one child with JRA (1.5%), who also had Down's syndrome. We recommend screening for CD in all persons with Down's syndrome using at least the antiendomysium antibody test.

Trends in hospital admissions among children aged 0-19 years with type I diabetes in The Netherlands.

OBJECTIVE: To determine the number and duration of hospital admissions due to diabetes in children aged 0-19 years between 1980-1991. RESEARCH DESIGN AND METHODS: Secondary analysis of data collected by the SIG Health Care Information was based on the 9th revision of the International Classification of Diseases. The subjects were all children in The Netherlands, aged 0-19 years. The main outcome measures were number and duration of hospital admissions due to type I diabetes (ICD 9 code 250.0-250.9). RESULTS: The hospital admission rate due to diabetes decreased > 30%. This decrease was statistically significant in all age subgroups. The total number of days in hospital due to diabetes decreased dramatically: from 24,961 in 1980 to 11,305 in 1991. The average duration of hospital stay length due to diabetes decreased as well from 14.5 days in 1980 to 11.9 days in 1991. CONCLUSIONS: The hospital admission rate and the length of hospital stay for diabetes in children aged 0-19 years have decreased, in spite of an increasing incidence. The hospital admission rate may decrease still further if more children with newly diagnosed diabetes can be adequately managed by team management at home in the initial phase.

Increasing incidence of type I diabetes in The Netherlands. The second nationwide study among children under 20 years of age.

OBJECTIVE: A nationwide retrospective study was conducted to assess the incidence of type I diabetes in The Netherlands among children < 20 years of age in 1988-1990. The first study with a similar design covered 1978-1980. RESEARCH DESIGN AND METHODS: The capture-recapture census method was chosen for analysis of the data. A questionnaire was sent to all Dutch pediatricians and internists, and for the ascertainment, a similar questionnaire was sent out separately to members of the Dutch Diabetes Association, which is the national patient association. RESULTS: The average achieved ascertainment rate was 81%. The ascertainment-adjusted annual incidence was 13.2/100,000 for 0- to 19-year-old children, indicating an increase of 23% compared with the 1978-1980 survey; for 0- to 14-year-olds, the increase amounted to 17%. CONCLUSIONS: This study suggests a sustained increase of type I diabetes in The Netherlands because the cumulative incidence studied previously in the 1960-1970 birth cohorts of male army conscripts 18 years of age was also found to rise. In contrast to Northern European countries, an increase in incidence for the age category 0-4 years could not be found.

[Ambulatory treatment and monitoring of children with insulin-dependent diabetes mellitus (IDDM)]. / De ambulante behandeling en begeleiding van het kind met insuline afhankelijke diabetes mellitus (IDDM).

In recent years diabetes research has made substantial progress. Insight in epidemiology, aetiology, patho-physiology of diabetes and pharmacokinetics of insulin is increased. Furthermore the development of self-monitoring has changed the management of diabetes. In this paper the consequences of this progress for modern ambulatory treatment of diabetes in childhood are discussed.

The effect of large doses of ethinylestradiol on apolipoprotein levels in excessively tall prepubertal girls.

Seventeen constitutionally tall prepubertal girls, aged 10 to 14 years, were treated with large doses of ethinyl estradiol (EE) to reduce their final height. The serum concentration of cholesterol, triglyceride, and apolipoproteins before and after four to 17 months of treatment were compared with the same variables in a reference group, initially matched for bone age and height. In the patients, cholesterol rose by 24% (1.1 +/- 0.8 mmol/L), triglyceride by 105% (0.97 +/- 0.70 mmol/L), LDL apo B by 48% (27 +/- 19 mg/dL), apo A-I by 45% (62 +/- 17 mg/dL), and apo A-II by 21% (12 +/- 11 mg/dL). In the reference group, none of these variables changed significantly. The ratio of LDL apo B/apo A-I remained constant in both groups.

Progression of endocrinological and neurological dysfunction in adrenoleukodystrophy. Endocrinological evidence of an affection of the adrenal cortex independent of the cerebral disorder.

In a boy suffering from adrenoleukodystrophy (ALD) the function of the adrenal cortex and pituitary gland was followed prospectively. At the onset of the disease an autonomic hyperfunction of the adrenal cortex was shown. Subsequently the secretion of cortisol dropped to low levels despite high plasma levels of ACTH. The results suggest a primary disorder of the adrenal cortex in ALD, which up till now could only be postulated on anatomical evidence. With the use of computerized tomography and electroencephalography abnormalities characteristic for ALD were shown. The progression of the disease was followed using these noninvasive methods of examination.

Reduction of adult height in tall girls.

Assessment of the results of treatment of tall girls with estrogens by comparing actual mature height with predicted mature height is unreliable, unless the accuracy of prediction has been tested in untreated tall girls. We report such an investigation in 14 tall girls who were treated with estrogens and in 14 untreated tall girls. Of the three prediction methods, those of Bayley and Tanner were reliable in our hands, whereas the method of Roche was less adequate. The mean reduction of height by treatment was about 7 cm using Tanner's method of prediction, 10 cm when Bayley's method was used. The standard deviation of the difference between actual and predicted height as found in untreated girls makes it hazardous to assess the amount of height reduction in the individual treated case with any certainty.