Increased height in diabetes mellitus corresponds to the predicted and the adult height.

This study was conducted to analyse the effect of childhood-onset diabetes mellitus on adult height. The height at time of diagnosis of 35 children with insulin-dependent diabetes mellitus (IDDM) was compared with growth reference data. Predictions of the adult height were made at the time of diagnosis using the target height and the Tanner-Whitehouse II method. The adult height was compared with both the predicted values and the height of healthy adults. The height at time of diagnosis of the prepubertal children was increased compared with growth reference data, in contrast to pubertal children who had normal heights. Only the prepubertal boys were taller at time of diagnosis. The adult height of the prepubertal patients was taller than growth reference data. The mean adult height in all patients did not differ significantly from the predicted heights. In conclusion, the increased height at the start of IDDM in prepubertal children persists until adulthood.

Pubertal growth in IDDM is determined by HbA1c levels, sex, and bone age.

OBJECTIVE: In cross-sectional studies of subjects with IDDM, the relationship between suboptimal pubertal growth, glycemic control, and abnormal insulin-like growth factor I (IGF-I) levels has proved difficult to define. The objective of this study was to examine these relationships in a longitudinal prospective study. RESEARCH DESIGN AND METHODS: A total of 46 children (23 boys) were measured every 3 months, and their bone age was assessed annually. Blood samples were obtained for HbA1c, IGF-I, and C-peptide. Growth data were compared with national standards, and IGF-I data were compared with a parallel longitudinal study of normal schoolchildren. Data were analyzed as SD scores (mean +/- SD). RESULTS: The onset of puberty was not delayed, although in the girls, bone age was advanced (bone age, 11.48 +/- 1.01 years vs. chronological age, 10.93 +/- 0.86 years [mean +/- SD]; P = 0.04). The timing of peak height velocity (PHV) was normal in both sexes, but the magnitude was reduced in girls (PHV SDS = -0.56 +/- 0.90, P < 0.02), and reductions in height SDS between diagnosis and final height were observed (P = 0.014). At PHV, IGF-I levels were reduced in both sexes, and there were no sex differences in HbA1c levels and insulin doses. IGF-I SDS correlated with insulin dose (r = 0.47, P = 0.004) but not with PHV SDS, whereas HbA1c correlated negatively with PHV SDS in both sexes (r = -0.35, P = 0.03). In a stepwise multiple regression analysis, the major determinants of PHV SDS were HbA1c (P = 0.04), sex (P = 0.0007), and bone age (P = 0.01). CONCLUSIONS: We conclude that the magnitude of the pubertal growth spurt is related to HbA1c levels in both sexes, but it is reduced only in girls. This sexual dimorphism cannot be explained by differences in IGF-I levels and may relate to the bone age advance at the onset of puberty in the girls.

The daily cortisol production reinvestigated in healthy men. The serum and urinary cortisol production rates are not significantly different.

We have measured the urinary cortisol production rate (uCPR) simultaneously with the serum cortisol production rate (sCPR) in four healthy men within a period of 3 days. uCPR, determined by isotope dilution of 11-oxoetiocholanolone was compared with sCPR, which was measured in three different ways (a, b, c). Blood was sampled at 10-min intervals for 24 h, and deconvolution analysis was applied to the cortisol concentrations. The daily serum cortisol production per liter, multiplied by the distribution volume yielded sCPR. The measurement methods are characterized as follows: a) the secretion and elimination terms were free; b) like method a, but with the input of the rate constants alpha and beta into the elimination function; c) the average 24-h cortisol concentration was multiplied by the metabolic clearance rate. uCPR was 25.4 +/- 4.7 [range: 21.3-31.4] micromol/(m2 x day), sCPR (method a) was 28.8 +/- 4.5 [range: 23.5-34.3] micromol/(m2 x day), sCPR (method b) was 27.9 +/- 8.1 [range: 18.5-37.7] micromol/(m2 x day), and sCPR (method c) was 29.3 +/- 4.8 [range: 22.7-33.2] micromol/(m2 x day). uCPR did not significantly differ from each of the 3 sCPR values (P > 0.30; > 0.46; and > 0.06, respectively). The patterns of the cortisol secretory rates in the present and previous studies do not necessarily represent the physiological process of the secretory bursts. We conclude that the estimated CPR, being 25-30 micromol/(m2 x day) [9-11 mg/(m2 x day)], can serve as a guideline for glucocorticoid replacement dose and that the urinary route to measure CPR is preferred because of its relative ease.

Clinical usefulness of bone age determination in the management of tall stature.

Measurements of skeletal maturation are used in the study and management of growth and growth disorders because of the correlation between the degree of skeletal maturation and the potential for further growth. In a study of 147 tall girls, final height was overpredicted by 0.7 +/- 2.5 cm (mean +/- SD) when based on the Bayley-Pinneau method. The radius-ulna-short bones (Tanner-Whitehouse 2) mark II method of assessment produced an underprediction of final height by 0.8 +/- 2.9 cm and 1.0 +/- 2.8 cm when the rating was performed by a skilled human or by a computer-aided system, respectively. These errors in prediction were considered acceptable, although when predictions were made on five girls below 11 years of age, they were less accurate.

Assessment of bone ages by the Tanner-Whitehouse method using a computer-aided system.

A computer-aided system to estimate bone age based on Fourier analysis was assessed by reference to the original radiographs used to produce the Tanner-Whitehouse 2 (TW2) standards for the radius, ulna and short finger bones. The computer-aided system involved matching a template of each bone to the scanned image of the radiograph. The computer then generated a stage of bone maturity, individual and total bone scores and a value for bone age. The bone ages assessed by the computer-aided system were no different from the original TW2 reference values, indicating the applicability of the system. The system was used to assess the bone ages of tall Dutch girls, and the results obtained were compared with more traditional assessments made by an experienced rater. For the radiographs from the tall girls, there was good agreement for individual bones between this method and the traditional assessment by the rater, but less agreement for the total 13-bone score and bone age.

A persisting secular trend for body measurements in Dutch children. The Oosterwolde II Study.

To investigate whether the secular trend for growth in Dutch children still exists, the Oosterwolde I study of 1980 was repeated in 1989. A persisting secular trend was visible for height while the z scores of body proportions show no change during the past 10 years, which suggests that there is no change in the timing of puberty.

Synthesis and identification of twelve A-ring reduced 6 alpha- and 6 beta-hydroxylated compounds derived from 11-deoxycortisol, corticosterone and 11-dehydrocorticosterone.

The synthesis and identification of 12 A-ring reduced 6 alpha-(and 6 beta-)hydroxylated compounds derived from 11-deoxycortisol (S), corticosterone (B) and 11-dehydrocorticosterone (A) are reported here. These steroids were prepared in two steps from the corresponding 6 6 alpha-(and 6 beta-)hydroxy-4-pregnene-3-ones. Selective reduction of the 4,5 double bond yielded 12 6 alpha-(and 6 beta)hydroxy-5 alpha-(and 5 beta)pregnane-3,20-diones. Enzymatic reduction of these compounds with NADH and 3 alpha-hydroxysteroid dehydrogenase yielded the corresponding tetrahydro steroids. The steroids were characterized by high performance liquid chromatography (HPLC), gas chromatography mass spectrometry (GC and GC/MS) and in part by 1H-NMR. 6 beta OH-THS and 6 beta OH-5 alpha THS were identified by 1H-NMR. The structures of the two precursors, i.e. 6 beta OH-5 beta DHS and 6 beta OH-5 alpha DHS were confirmed by 1H-NMR using two-dimensional spectra. 6 alpha OH-THS was identified by comparing its HPLC, GC and MS data with those of the steroid obtained by enzymatic oxidation of the standard reference steroid 6 alpha OH-20 beta HHS to the corresponding 20-ketosteroid. The other steroids, e.g. 6 alpha OH-THB and 6 alpha OH-5 alpha THB were identified by using the proved sequence of elution of each of the epimer pairs on the normal phase HPLC column (5 alpha < 5 beta), and by the reversed order of elution of the same epimer pair as the methoxime-trimethylsilyl ethers on the GC column (5 alpha > 5 beta) and by the mass spectra, with the exception of 6 beta OH-THA.

Synthesis and characterization of the 6 alpha- and 6 beta-hydroxylated derivatives of corticosterone, 11-dehydrocorticosterone, and 11-deoxycortisol.

This report describes the synthesis of 6 alpha, 17,21- and 6 beta, 17,21-trihydroxypregn-4-ene-3,20-dione, 6 alpha, 7,21- and 6 beta, 11 beta, 21-trihydroxypregn-4-ene-3,20-dione, and--for the first time--that of 6 alpha, 21- and 6 beta, 21-dihydroxypregn-4-ene-3,11,20-trione. The former four compounds were prepared by 6-hydroxylation of 17,21-trihydroxypregn-4-ene-3,20-dione and 11 beta, 21-dihydroxypregn-4-ene-3,20-dione, respectively. This was achieved by autoxidation or by oxidation with 3-chloroperbenzoic acid, of the 3-methoxy-pregna-3,5-dienes of the latter two steroids. The yield of the 6 beta-hydroxylated steroids, but not of their corresponding 6 alpha-epimers, was higher using autoxidation than the peracid. The two 6-hydroxylated pregnenetriones were prepared from 6 alpha, 21-diacetoxy-11 beta-hydroxypregn-4-ene-3,20-dione and 6 beta, 21-diacetoxy-11 beta-hydroxypregn-4-ene-3,20-dione, respectively, by oxidation with pyridinium chlorochromate. The above-mentioned six steroids were identified and characterized by nuclear magnetic resonance, infrared, ultraviolet, high performance liquid chromatography, gas chromatography, and mass spectrometry.

New identified 15 beta-hydroxylated 21-deoxy-pregnanes in congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

The identification of 3 new 15 beta-hydroxylated 21-deoxy-pregnanes in the urinary steroid profile of a 4-month-old girl with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is reported here. These steroids were identified by gas chromatography and gas chromatography-mass spectrometry as 3 alpha,15 beta,17-trihydroxy-5 alpha-pregnan-20-one (5 alpha II), 3 alpha,15 beta,17,20 alpha-tetrahydroxy-5 alpha-pregnane, and 3 alpha,15 beta,17,20 alpha-tetrahydroxy-5 beta-pregnane (20 alpha DH-II). Two other compounds in the urine, 3 beta,15 beta,17- trihydroxy-5 alpha-pregnan-20-one and 3 beta,15 beta,17-trihydroxy-5 beta-pregnan-20-one were also characterized. The identification of the former 3 steroids was obtained by comparing their methylene unit values and mass spectral data with the corresponding data of the standard steroids synthesized from 15 beta,17-dihydroxy-4-pregnene-3,20-dione. Seven other synthesized and identified 15 beta-hydroxylated steroids were 3 alpha,15 beta,17-trihydroxy-5 beta-pregnan- 20-one (II), 3 alpha,15 beta,17,20 beta-tetrahydroxy-5 beta-pregnane, 15 beta,17-dihydroxy-5 alpha-pregnane-3,20-dione, 15 beta,17-dihydroxy-5 beta-pregnane-3,20-dione, 3 alpha,15 beta-dihydroxy-5 alpha-androstan-17-one (15 beta OH-An), 3 alpha,15 beta-dihydroxy-5 beta-androstan-17-one (15 beta OH-Et) and 3 alpha,15 beta,17,20 beta- tetrahydroxy-5 alpha-pregnane. Of these the latter two have not been reported previously. This study supports the findings that 15 beta-hydroxylated steroids are common in the neonate and could play an important role in the diagnosis of CAH due to 21OHD, where II and the newly identified steroids from this investigation viz., 5 alpha II and 20 alpha DH-II appear the most important 15 beta-hydroxysteroid markers for this disease.

Effect of growth hormone treatment on craniofacial growth in Turner's syndrome.

A cephalometric study was performed in 19 patients with Turner's syndrome, aged 8.7-16.5 years. A lateral roentgen-encephalogram was taken before and after two years of treatment with biosynthetic growth hormone in a dose of 24 IU/m2/week. During two years of growth hormone treatment, the mandibular length increased mainly due to vertical growth. The initially posteriorly rotated mandible showed an anterior rotation, although the normal position was not reached. The other linear measurements and angles did not change during treatment. No indications were found for an increase in the disproportionate growth or for excessive chin growth as a sign of acromegaly during growth hormone treatment. In conclusion, growth hormone treatment in patients with Turner's syndrome resulted in an increase in mandibular length, mainly due to vertical growth of the ramus and in the anterior rotation of the mandible.

Results of long-term therapy with growth hormone in two dose regimens in Turner syndrome. Dutch Growth Hormone Working Group.

Girls with Turner syndrome were divided according to age (group A 6-12 years, and group B 12-19 years) and human growth hormone (GH) dose regimen (A1 and B1, three injections/week; A2 and B2, six injections/week). All groups responded to GH, 24 IU/m2/week, with an increase in height velocity, though in the older girls, the response was comparatively poor. Therefore, the dose regimens in groups B1 and B2 were increased to 36 IU/m2/week given as six injections in both groups. This change resulted in an increase in height velocity only in group B1. During the first 2 years only, the height velocity was greater in group A2 than group A1. The conclusion is that a regimen of six injections/week is more effective than one of three injections/week in terms of initial height gain and change in predicted adult height. In girls with Turner syndrome aged over 16 years, GH therapy has no significant effect.

Kinetics and metabolism of 11-deoxycortisol in a patient with congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency.

The kinetic features of 11-deoxycortisol (S) were studied in a 11 beta-hydroxylase deficient boy. After i.v. administration of 35 kBq [3H]S (11 pmol) together with 44 nmol [13C]cortisol all his urine was collected during the next 3 days. A recently reported kinetic model, by which the fate of radioactive cortisol (F) in the body can be described by analysis of only the urinary radioactivity, has been used to calculate the rate constants of S metabolism. The overall half-life of S in the circulation was 4.7 min, which is very close to a reported half-live of the rapid phase: 4.1 min determined from the plasma radioactivity. The time of maximal accumulation of S in the first metabolic pool--26 min is about one quarter of that found for F--109 +/- 20 min (n = 8). The half-live of the S metabolites in the body was 7.0 h, equal to that of F: 6.1 +/- 0.9 h (n = 8). Obviously S is taken up into the metabolic organs 4 times faster than F, but it is not metabolized faster. The production rates of S and F were 127 and 2.1 mumol/(m2*d), respectively, pointing to a severely deficient synthesis of F. However, from the urinary excretion of 3 alpha,21-dihydroxy-5 beta-pregnan-20-one in relation to 3 alpha,11 beta,21-trihydroxy-5 beta-pregnan-20-one it cannot be concluded that the synthesis of corticosterone was strongly impaired.

Shape of the craniofacial complex in children with Turner syndrome.

The shape of the craniofacial complex was established in 69 children with Turner syndrome aged between 3.5 and 16.6 years. The children had not been treated with growth hormone (GH) or anabolic steroids. On a standardized lateral roentgenencephalogram 13 linear and 7 angular variables were measured. Data of all variables were available from normal Dutch children for comparison. The main abnormalities were located in the cranial base and in the mandible and consisted of a short posterior cranial base, all increased cranial base angle and a short, retrognathic and posteriorly rotated mandible. The maxilla was smaller than normal and also slightly posteriorly rotated. The abnormalities were already present in young children with Turner syndrome. Indications were found that in Turner syndrome interstitially as well as appositionally growing cartilage is affected. The changes in the maxilla can be explained in various ways. They may be due to defective growth of the nasal cartilage or to a disorder in the intramembranous ossification of the maxilla or they may be adaptive to the changes in the cranial base and the mandible. From this study it can be concluded that patients with Turner syndrome exhibit several craniofacial abnormalities, probably due to a cartilage disorder.

Molecular heterogeneity of the fourth component of complement (C4) and its genes in vitiligo.

In view of evidence suggesting vitiligo is an autoimmune disease, we investigated whether vitiligo is associated with inherited deficiencies of the fourth (C4) and second (C2) component of complement and with certain human leukocyte antigens (HLA). Analysis of functional activities of C4 and C2 in sera of patients with vitiligo (n = 42) showed that 17% of them had a heterozygous C4 deficiency and 5% had a heterozygous C2 deficiency. In the normal control group (n = 30), 3% had a heterozygous C4 deficiency and none had a C2 deficiency. C4 typing by Western blot analysis showed the frequency of the C4A*Q0 allele in the vitiligo patient group to be close to normal. However, the frequency of one C4B*Q0 allele was three times higher, and that of two C4B*Q0 alleles five times higher in the vitiligo patient group than the reported frequencies in normal control groups. Southern blot analysis of Taq1 digests of DNA using C4 and 21-hydroxylase probes showed that two patients with two C4B*Q0 alleles had a deletion of a 21-OHA-C4B segment. In the other patients, having one or two C4B*Q0 alleles, these null alleles probably occurred due to a loss of C4 gene expression. HLA analysis did not show any allelic association of C4A*Q0 or C4B*Q0 with any HLA antigen in vitiligo, but confirmed the previous findings of a negative association with HLA-DR3 and a positive association with HLA-DR4. These results suggest that abnormalities of the C4B gene and the above-mentioned associations with HLA antigens may be some of the risk factors in vitiligo.

Does growth hormone treatment of patients with Turner's syndrome cause an abnormal body shape?

The effect of human growth hormone on the body shape of 51 patients with Turner's syndrome (aged 6-19 years) was evaluated. Biosynthetic growth hormone was given in a dose of 24 IU/m2 body surface/week for two years. Karyotype analysis on peripheral blood was performed. Patients older than 12 years also received 0.1 microgram ethinyl oestradiol/kg body weight/day orally. Body shape was characterized by studying pairs of measurements expressed as SD scores (z scores). As reference data, our own locally obtained data from normal children were used. After two years of growth hormone therapy, height, sitting height, bi-acromial and bi-iliac diameter increased from -3.7, -2.9, -1.7 and -1.2 to -1.3, -2.5, -0.6 and +0.5 z scores, respectively. The shape of the patients, expressed as height/bi-iliac diameter and also as sitting height/bi-iliac diameter became more abnormal. As no difference could be noted between the prepubertal and pubertal groups or between the XO and mosaic groups, it is suggested that growth hormone treatment causes a relatively wide pelvis in patients with Turner's syndrome.

[The treatment of leg length discrepancy using Phemister's method of epiphysiodesis]. / Behandeling van beenlengteverschillen met behulp van de epifysiodes volgens Phemister.

A retrospective study is reported of the results of epiphysiodesis in 67 children. In 47 patients (70%) the final inequality was less than or equal to 1.0 cm. In 9 patients the final inequality was greater than or equal to 1.6 cm. The average leg length inequality could be reduced from 3.2 cm preoperatively to 1.2 cm at maturity. Technical errors were minimal. Failures (9 patients) resulted mainly from problems in timing epiphysiodesis.

Growth hormone therapy in Turner's syndrome. Impact of injection frequency and initial bone age.

STUDY OBJECTIVE: To determine the influence of the injection frequency and the initial bone age on the efficacy of treatment with biosynthetic growth hormone in Turner's syndrome. DESIGN: Randomized study. SETTING: Referral-based pediatric endocrinology departments of seven university medical centers. PATIENTS: Fifty-two patients with Turner's syndrome confirmed with chromosomal analysis. TREATMENT: Somatotropin recombinant DNA (24 IU/m2 of body surface area) subcutaneously administered in three or six injections per week for 2 years. Patients who were older than 12 years at the beginning of the study received low doses of estrogen. RESULTS: The following statistically significant findings supported the use of six injections per week compared with three injections per week: the mean (+/- SD) increment in height during 2 years was 11.3 cm (3.8 cm) with six injections vs 8.6 cm (3.4 cm) with three injections; the increment in height standard deviation score was 0.9 cm (0.5 cm) vs 0.6 cm (0.3 cm); the growth velocity was 6.6 cm/y (2.0 cm/y) vs 5.2 cm/y (1.7 cm/y) in year 1 and 4.7 cm/y (2.0 cm/y) vs 3.4 cm/y (1.7 cm/y) in year 2; and the increment in height standard deviation score for bone age was 0.8 cm (0.5 cm) vs 0.4 cm (0.6 cm). For patients whose initial bone age was more than 13 years, growth velocity increased by 1 to 2 cm in year 1; in year 2 no increment was observed. We did not observe adverse effects. CONCLUSIONS: Biosynthetic growth hormone in a higher-frequency regimen in Turner's syndrome is more efficient in terms of increment in height, growth velocity, and height standard deviation score for bone age than treatment in a lower-frequency regimen. In patients with an initial bone age of more than 13 years, the response was poor. Longer follow-up is necessary to assess the effect on final height.

Kinetics of cortisol metabolism and excretion. A hypothetic model based on the cumulative urinary radioactivity in eight multiple pituitary deficient patients.

A new model is proposed to study the kinetics of [3H]cortisol metabolism by using urinary data only. The model consists of 5 pools, in which changes of the fractions of dose are given by a system of 5 ordinary differential equations. After i.v. administration of [3H]cortisol to 8 multiple pituitary deficient (MPD) patients (group I) the urines from each patient were collected in 9-15 portions during the following 3 days. From the urinary data the rate constants of cortisol metabolism were calculated. A published set of urinary data from patients with a normal cortisol metabolism (group II) was used for comparison. The overall half-life of the label in the circulation was 30 min for both groups; the half-life of the label excretion by both groups was 6 h and the time of maximal activity in the main metabolizing pool was 1.8 h in group I and 1.5 h in group II. The 20% of normal cortisol production rate (CPR) in the 8 MPD patients amounted to 7.2 +/- 1.9 mumol/(m2*d). Therefore, the low CPR but normal rate constants, i.e. a normal metabolic clearance rate of cortisol, in the MPD patients suggest a sensitive adjustment of the cortisol response in the target organs.

Longitudinal anthropometric study in children with acute lymphoblastic leukaemia.

In four groups of patients with acute lymphoblastic leukaemia, anthropometric variables were investigated every 3 months for 2 years. Group 1 (n = 7) was treated with a high-risk protocol, group 2 (n = 13) with a standard-risk protocol including cranial irradiation, group 3 (n = 13) with a standard-risk protocol without cranial irradiation and group 4 (n = 8) was followed after completion of treatment. A height retardation of 0.4-0.6 SD was observed during therapy in groups 1-3. A catch-up of 0.5 SD was found in group 4. The retardation of armspan was significantly larger than the retardation of sitting height when groups 1-3 were taken together. Head circumference was not affected. The anthropometric variables reflecting nutritional status showed a growth above normal during and after treatment. Corticosteroid medication and not cranial irradiation is the most likely explanation for our findings.

Bacterial contamination of growth hormone solution and injection equipment during use by growth hormone deficient children.

The frequency of bacterial contamination of growth hormone solution and injection equipment use by 20 growth hormone deficient children was studied. In a cross-over study the children were randomized to begin using, for their growth hormone injections, either the recently developed growth hormone injection pen or the conventional syringe method. A comparison was then made of these two methods of injection over a 6-week period and the vials, pen-cartridges, syringes and needles were cultured. When the pen was used 5.3% of the 114 vials, 15.5% of the 110 cartridges and 11.2% of the 98 needles were found to be contaminated; when the syringe was used 3.5% of the 113 vials, 7.1% of the 98 syringes and 9.1% of the 99 needles were contaminated. To ensure microbiological safety during the preparation and injection of the growth hormone solution, regular instruction and reassessment of the injection technique for patients on long-term treatment are advocated. This applies even when disposable items are used. As no statistically significant difference was noted between the number of contaminated items used with either the pen or the syringe method, we conclude that the growth hormone pen is suitable for growth hormone administration.