136 Poster abstracts ACTA PEDIATR SUPPL 423 ( I 997)

Turner syndrome. Precocious puberty. Renal transplantation

Non-disjunction of sex chromosomes in sperm from the father of monozygotic twins with Turner syndrome C Noguts', 0 Martinez-Pasarell', E Vicens-Calvet2, C Templado', J Egozcue' and A Carrascosa* Departament de Biologia Cellular i Fisiologia ', Universitat Audnoma de Barcelona, and Servei d'endrocrinologia2. Area pediatrica, Hospital Materno-Infantil Val1 d'Hebron, Barcelona, Spain

Aims: Turner syndrome results from errors that occur during cell division. Two monozygotic twin sisters with Turner syndrome (45,X monosomy) were studied to ascertain whether meiotic non-disjunction of the paternal germ cells could be an aetiological factor in Turner syndrome. Patients and methods: The parental origin of the single X chromosome was determined by polymerase chain reaction (PCR) amplification of three microsatellites of X chromosome (DYS II and DMD 49 from Xp, and AR from Xq). Possible Yp mosaicism was ruled out by PCR amplification of the SRY gene. Results: PCR revealed that the girls inherited their single X chromosomes from their mother (45,Xm0). No hidden mosaicism was detected for the X chromosome or for Yp. To determine whether errors in the meiotic disjunction of

the sex chromosomes were increased in the paternal germ cells, 12 587 sperm nuclei from the father of the twins were compared with 21 288 sperm nuclei from two normal donors, using three-colour fluorescence in siru hybridization. Disomy rates in the father of the twins and control donors were similar for XX (0.06% vs 0.06%, respectively) and YY (0.09% vs 0.08%, respectively). However, the father of the twins had a higher rate of XY disomy than the control donors (0.22% vs 0.11%; p < 0.05). Conclusions: These findings reflect an increased tendency of meiotic non-disjunction of the sex chromosomes in the father of the twins with Turner syndrome. This could lead to an increased risk of abnormalities in the number of sex chromosomes in further offspring.

Treatment of patients with Turner syndrome with high doses of growth hormone: relationship between height gain and bone age advancement TE Romer, A Wisniewski and BA Romer The Children 's Memorial Health Institute, Warsaw, Poland

Aims: It is well established that growth hormone (GH) therapy in patients with Turner syndrome accelerates growth and improves final height. Height improvement due to early treatment with GH has a positive impact on the psychological development and school perform- ance of children with Turner syndrome. Final height, however, can be impaired by increased acceleration of skeletal maturity, measured as bone age (BA) progres- sion. The aim of this study was to estimate the effect of high GH doses on the BA of patients with Turner syndrome and the relationship between BA advancement and height gain. Patients and methods: Fifty patients with Turner syndrome (age, 3.12-10.0 years) were randomized into two groups. Group 1 (n = 25) was treated with the standard GH dose of 20 IU/m*/week, and group 2 (n = 25) was treated with a high GH dose of 40 IU/m2/week. In both groups, GH was administered

daily for 3 years. BA was evaluated before commence- ment of treatment and yearly thereafter. The evaluations were carried out by the same observer (BAR) using the Greulich-Pyle method. Results: During the 3 years of GH therapy, the mean (f SD) gain in BA in group 1 was 3.99 k 0.8 years and in group 2 was 4.25 f 1.0 years. The difference was not statistically significant. For group 1, the mean height gain, expressed as an SDS specific for Turner syndrome, for 1 year of BA advancement was 0.33 f 0.3. The mean height gain for group 2 was 0.53 f 0.13. Conclusions: Height velocity is to a large extent related to the GH dose. The mean height gain SDS for 1 year of BA advancement was significantly greater in patients receiving high doses of GH. These findings indicate that better results could be achieved in children with Turner syndrome, in terms of height and growth potential, if higher doses of GH were used.

ACTA PEDIATR SUPPL 423 (1997) Poster abstmcts 137

Bone status in adults with Turner syndrome F Westermann, E Mokov, K Scheidhauer, F Haverkamp, D Michalk and E Schonau University Children 5 Hospital, Koln, Germany

Aims: This study set out to investigate the bone status in adults with Turner syndrome. Patients and methods: Peripheral quantitative compu- terized tomography (pQCT) of the appendicular skeleton was used to study bone mineral density in ten adults with Turner syndrome (age, 18-31 years). Peak cortical bone density (CBD) values were calculated using a new software system (Concpeel, Stratec Electronics, Horzheim, Germany), which is based on concentric peeling of the measured bone area. Bone strength was estimated on the basis of geometric data for the polar moment of resistance in combination with CBD. Total bone density (TBD), spongiosa bone density (SBD) and CBD were measured by pQCT (Bone Scanner XCT 900, Stratec Electronics) at the radius. Bone strength was derived from the section modulus and the volumetric density of the corticalis area at the proximal radius. Wilcoxon’s test was used for the analysis of group differences.

Results: SBD and TBD values in patients with Turner syndrome were significantly lower than those in controls ( p < 0.01). CBD values did not differ significantly between controls and patients, whereas peak CBD (n = 7) was significantly lower in patients than in controls (p c 0.05). Also, the calculated bone strength was significantly diminished ( p c 0.01) in patients with Turner syndrome (Table 1). Previous results, demon- strating a decreased TBD and SBD in patients with Turner syndrome are thus confirmed. Conclusions: Our findings, in combination with pre- viously reported data on bone metabolism, indicate diminished osteoblastic activity in patients with Turner syndrome. These data, together with the reduced cortical thickness of bone in patients with Turner syndrome, suggest a general disturbance in the apposition of bone in Turner syndrome.

Table 1. Bone status in adults with Turner syndrome. Values are means f SD.

TBD SBD CBD Peak CBDt Bone strength n (mg/cm3) (mg/cm3) (mg/cm3) (mg/cm3) (mm’)

Turner syndrome 10 245.9 f 37.6** 109.3 f 34.7** 1033.2 f 70.8 1096.2 f 82.2* 177.3 f 49.8** Controls 35 309.9 f 54.0 153.3 f 34.5 1063.5 f 47.2 1217.9 f44 .5 274.3 f 65.0

* p < 0.05, **p < 0.01 compared with controls; ‘only measured in seven patients with Turner syndrome.

Glucose tolerance and serum insulin levels in patients with Turner syndrome after long-term growth hormone treatment A Wisniewski and TE Romer The Children’s Memorial Health Institute, Warsaw, Poland

Aims: The aim of this study was to estimate glucose tolerance and the insulin response to a glucose load in patients with Turner syndrome who had been treated with growth hormone (GH) for 3 years. Patients and methods: The patients were divided into two groups. Group 1 (n = 25) received GH at a dose of 20 IU/m2/week, and group 2 (n = 25) received a dose of 40 IU/m2/week. Oral glucose tolerance tests, with estimations of blood glucose and serum insulin levels, were performed before and after GH treatment in each patient. Areas under the glucose curve (AGC) were calculated for each patient on both occasions. Results: Mean (f SD) AGC values before GH treatment were 236 f 153 and 230 f 128 pU/ml/hour for groups 1 and 2, respectively. After GH treatment, however, mean AGC

values were sigtllficantly lower for both groups: 125 f 89 and 109 f 72 pU/ml/hour for groups 1 and 2, respectively. The decrease in AGC values was more pronounced in group 2 (group 1, p < 0.01; group 2, p c 0.001). Mean fasting levels of insulin were sigrdk.ntly higher after GH treatment in both groups: 14 f 7 versus 24 f 24 pU/ml in group 1, and 11 f 6 versus 19 f 12 p U / d in group 2. There were also higher insulin values on the 30-, 60- and 90-minute time-points on the curves. Conclusions: Lower AGC values after GH treatment could be the result of higher serum insulin levels, as a response to exogenous GH. This suggests a dual effect of GH: stimulation of endogenous insulin secretion and decreased sensitivity to insulin, with the net effect of a decreased glucose level in an oral glucose tolerance test.

138 Poster abstracts ACTA PEDIATR SUPPL 423 (1997)

Treatment with growth hormone and oxandrolone improves final height in girls with Turner syndrome KO Nilsson, for the Swedish Paediatric Group for Growth Hormone Treatment Department of Paediatrics, University Hospital, Malmo, Sweden

Aims: Results from the first Swedish multicentre study on growth-promoting therapy in patients with Turner syndrome, started in 1986, have recently been published (1). Here, we report on two further studies started in 1987 and 1988, which included 57 girls with Turner syndrome. Patients and methods: The girls’ chronological age at the start of treatment was 9-16 years, with a mean of 11.6 years. They were divided into two groups. Group 1 (n = 22; mean age, 11.4 f 2.0 years) was treated with growth hormone (GH) (Genotropin@; Pharmacia & Upjohn, Stockholm, Sweden) and ethinyloestradiol (EE). After 3 years of therapy, oxandrolone was added to the treatment. Group 2 (n = 35; mean age, 11.8 f 2.1 years) was treated with GH, and oxandrolone was added to the treatment after 1-2 years. Initiation of oestrogen substitution in group 2 was allowed after 2-3 years, depending on the girls’ age at the start of the study. The doses for both groups were: GH, 0.1 IU/kg/day; oxandrolone, 0.05 m a d d a y ; EE, 100 ngjkdday. Results: Mean (f SD) final heights were 152.3 f 5.9 cm

and 155.8 f 5.3 cm for groups 1 and 2, respectively. The mean differences between final height and projected height (using the North European Turner syndrome reference values) at the start of treatment (i.e. height gain) were 7.1 f 6.6 cm and 8.1 f 5.8 cm for groups 1 and 2, respectively. As many as 55% of the girls in group 1 and 66% in group 2 achieved a gain in final height of 5 cm or more. A final height of 150 cm or more was achieved in 75% of the patients in group 1 and in 93% of the patients in group 2. Conclusions: The results from the 1986 study on girls with Turner syndrome, who were older than 9 years of age, have been confirmed by two more multicentre studies. These results demonstrate the beneficial effect on growth of treatment with GH in combination with oxandrolone in girls with Turner syndrome.

1. Nilsson KO, Albertsson-Wikland K, Alm J, Aronson S, Gustafsson J, Hagenh L, et al. Improved final height in girls with Turner’s syndrome treated with growth hormone and oxandrolone. J Clin Endocrinol Metab 1996;s 1 :635-40

The effect and mechanism of traditional Chinese medicine on skeletal development in children with precocious puberty D -P Cai Paediatnc Hospital, Shanghai Medical University, Shanghai, China

Aims: The aim of this study was to observe the effect of traditional Chinese medicine (TCM) on skeletal development in children with precocious puberty and to elucidate the mechanism of action of TCM. Patients and methods: In this study, 82 girls with idiopathic precocious puberty were treated by TCM. The formula consisted of Radix rehmanniae, Carapax et Plastrum testudinis, Cortex phellodendri, Rhizoma anemarrhenae, etc. All medicines were extracted and concentrated (1 ml mixture contained approximately 2.5 g crude extract). The dosage was 60 ml/day. Linear growth rate and bone age (BA) were measured, and bone mineral content (BMC) and serum bone ~gla-protein (BGP) were determined. Final heights were predicted before therapy and after clinical remission.

Results: All values are expressed as means f SD. After an average of 1 year of therapy, the growth rate of the girls decelerated, with the change in BA per change in chrono- logical age decreasing from 1.35 f 0.18 to 0.65 f 0.15 (p < 0.001). BMC decreased from 0.585 f 0.098 to 0.519 f 0.07 g/cm2 (p < 0.001), serum BGP decreased from 17.24 f 3.48 to 10.55 f 3.57 pg/l (p < 0,001) and predicted final height increased from 153.3 f 3.5 to 158.5 f 4.2 cm (p < 0.001). C nclusions: Therapy with TCM could decelerate

thereby preventing premature epiphyseal fusion and increasing final height. One possible mechanism of TCM on ameliorating skeletal development in girls could be to inhibit excessive functional activity of osteoblasts.

s i! eletal growth and delay skeletal maturity in girls,

ACTA PEDIATR SUPPL 423 (1997) Poster abstracts 139

Long-term growth after renal transplantation in children treated with cyclosporine K Ito and H Kawaguchi Department of Puediutric Nephrology and Surgev, Women’s Medical College, Tokyo, Japan

Aims: Growth failure has been one of the most serious problems of children with chronic renal failure. Renal transplantation is regarded as the best way to improve growth and final height in these children. In this study we evaluated the growth performance of 37 children who had received renal transplants before the age of 15 years, followed by a minimum of 5 years of cyclosporine immunosuppression. Patients and Results: The patients were divided into four groups according to their sexual maturity and graft function. In prepubertal children with good graft function, the mean height SDS for chronological age (HSDS,,) improved significantly (from -2.91 f 1.23 to -1.60 f 1.38; p = 0.019). In pubertal children with good graft function, the improvement in HSDS, was less (from -1.67 +: 0.59 to -1.30 f 0.78; not significant). In children with a poorly functioning graft, HSDS,,

decreased markedly in both prepubertal (-0.89 f 1.06) and pubertal (-1.41 0.93) patients. Eighteen children reached their final height. However, only one child, who stopped taking corticosteroids, reached an average adult height. At final height, mean HSDS,, was -2.28 f 1.97 for boys and -3.05 f 1.45 for girls. Three out of four children in whom corticosteroid treatment was discontinued showed marked catch-up growth. Conclusions: Prepubertal children with a good graft function have a reasonable growth rate. However, growth rate is lower in postpubertal children, and children with a poorly functioning graft show poor growth, even if they receive transplantation before the appearance of puberty. In order to achieve a good final height, a strategy involving prepubertal transplantation, cessation of corticosteroids and the use of growth hormone should be adopted where possible.