Final height after combined growth hormone and GnRH analogue treatment in adopted girls with early puberty.

BACKGROUND: Girls adopted from developing countries often have early or precocious puberty, requiring treatment with gonadotrophin-releasing hormone (GnRH) analogues. During such treatment, decreased growth velocity is frequent. AIM: To study whether the addition of growth hormone (GH) to GnRH analogue treatment improves final height in girls with early or precocious puberty. METHODS: Forty-six girls with early or precocious puberty (age < or =9.5 y) adopted from developing countries were randomized for treatment for 2-4 y with GnRH analogue, or with a combination of GH and GnRH analogue. RESULTS: During treatment, the mean growth velocity in the GH/GnRH analogue group was significantly higher compared to the control group. Combined GH/GnRH analogue treatment resulted in a higher final height: 158.9 cm compared to 155.8 cm in the GnRH analogue-treated group. Three out of 24 girls (13%) in the combined group and nine of the 22 girls (41%) treated with GnRH analogue alone attained a final height below -2 standard deviation scores (SDS). CONCLUSION: The difference between the two groups is statistically significant, and possibly of clinical importance. A future challenge is to identify a subgroup with clinically significant advantage of GH addition to GnRH analogue treatment. Being very short on arrival in Sweden and being short and young at start of treatment are possible indicators.

Effect of growth hormone (GH) during puberty in GH-deficient children: preliminary results from an ongoing randomized trial with different dose regimens.

This paper reports results from an ongoing, randomized, multicentre national trial. The aim is to elucidate whether a dose of growth hormone (GH) of 0.2 IU/kg (0.07 mg/kg), given either as once-daily or twice-daily injections during puberty, is more effective than a once-daily dose of 0.1 IU/kg/day (0.03 mg/kg/day) in improving final height in children with GH deficiency (GHD). The twice-daily regimen comes closer to the spontaneous GH secretion pattern in puberty. Ninety-two children with GHD who had been receiving GH therapy for at least 1 year, and with spontaneous puberty or who were prepubertal and due to be started on replacement therapy to induce puberty, were randomly assigned to receive GH as follows: group A, 0.1 IU/kg/day (0.03 mg/kg/day), administered once daily; group B, 0.2 IU/kg/day (0.07 mg/kg/day), administered once daily; and group C, 0.2 IU/kg/day (0.07 mg/kg/day), divided into two equal injections given at 12-hour intervals. Pubertal height gain was 0.7, 0.7 and 1.3 SDS for groups A, B and C, respectively. The gain in height during puberty was thus most marked in group C. Mean final height, when corrected for parental height, was between 0 and 1 SDS in all treatment groups. All but seven children reached a final height within +/- 2 SD of the general population. There was a wide range of final heights in all three treatment groups. This variation in response suggests the need to individualize treatment in order to achieve an appropriate final height for most individuals.

Recurrent Pseudomonas bronchopneumonia and other symptoms as in cystic fibrosis in a child with type I pseudohypoaldosteronism.

We report a child with multiple target organ pseudohypoaldosteronism type 1 with frequent recurrent pulmonary infections caused by Pseudomonas aeruginosa and Pasteurella multocida and high levels of chloride in sweat, urine and nasal secretion. Repetitive faecal chymotrypsin samples have all shown pathological values in spite of no other sign of exocrine pancreas dysfunction. The similarities with cystic fibrosis and the importance of the salt content in bronchial fluid are discussed.

Growth hormone treatment of short children born small-for-gestational-age: the Nordic Multicentre Trial.

The aims of this study were to evaluate the efficacy and safety of different doses of growth hormone (GH) treatment in prepubertal short children born small-for-gestational-age (SGA). Forty-eight children born SGA from Sweden, Finland, Denmark and Norway were randomly allocated to three groups: a control group of 12 children received no treatment for 2 y, one group was treated with GH at 0.1 IU/kg/d (n=16), and one group was treated with GH at 0.2 IU/kg/d (n=20). In total 42 children completed 2 y of follow-up, and 24 children from the treated groups completed 3 y of treatment. Their mean (SD) age at the start of the study was 4.69 (1.61) y and their mean (SD) height was -3.16 (0.70) standard deviation scores (SDS). The children remained prepubertal during the course of the study. No catch-up growth was observed in the untreated group, but a clear dose-dependent growth response was found in the treated children. After the third year of treatment, the group receiving the higher dose of GH, achieved their target height. The major determinants of the growth response were the dose of GH used, the age at the start of treatment (the younger the child, the better the growth response) and the family-corrected individual height deficit (the higher the deficit, the better the growth response). Concentration of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 increased during treatment. An increase in insulin levels was found without negative effects on fasting glucose levels or glycosylated haemoglobin levels. GH treatment was well tolerated. In conclusion, short prepubertal children born SGA show a dose-dependent growth response to GH therapy, and their target height SDS can be achieved within 3 y of treatment given GH at 0.2 IU/kg/d. However, the long-term benefit of different regimens of GH treatment in children born SGA remains to be established.

Improved final height in girls with Turner's syndrome treated with growth hormone and oxandrolone.

The spontaneous growth process in Turner's syndrome is characterized by a progressive decline in height velocity during childhood and no pubertal growth spurt. Therefore, therapy aimed at improving height during childhood as well as increasing final height is desirable for most girls with Turner's syndrome. Forty-five girls with Turner's syndrome, 9-16 yr of age (mean age, 12.2 yr), were allocated to three study groups. Group 1 (n = 13) was initially treated with oxandrolone alone; after 1 yr of treatment, GH without (group 1a; n = 6) or with (group 1b; n = 7) ethinyl estradiol was added. Group 2 (n = 17) was treated with GH plus oxandrolone. Group 3 (n = 15) was treated with GH, oxandrolone, and ethinyl estradiol. The dosage were: GH, 0.1 IU/kg.day; oxandrolone, 0.05 mg/kg.day; and ethinyl estradiol, 100 ng/kg.day. A height of 150 cm or more was achieved in 61%, 75%, and 60% of the girls in groups 1, 2, and 3, respectively. The most impressive increase in height was seen in group 2. In this group the mean final height was 154.2 cm (SD = 6.6), which is equivalent to a mean net gain of 8.5 cm (SD = 4.6) over the projected final height. In group 3, in which ethinyl estradiol was included from the start of therapy, the initially good height velocity decelerated after 1-2 yr of treatment. Their mean final height was 151.1 (SD = 4.6) cm, equivalent to a mean net gain of 3.0 cm (SD = 3.8). A similar growth-decelerating effect of ethinyl estradiol was seen in group 1b. We conclude that in girls with Turner's syndrome who are older than 9 yr of age, treatment with GH in combination with oxandrolone results in significant growth acceleration, imitating that in normal puberty, leading to a more favorable height during childhood. This mode of treatment also results in a significantly increased final height, permitting a great number of the girls to attain a final height of more than 150 cm. However, early addition of estrogen decelerates the height velocity and reduces the gain in height.

[Radical or conservative surgery in craniopharyngioma? Importance of individualized treatment!]. / Radikal eller konservativ kirurgi vid kraniofaryngiom? Individualiserad behandling viktig!

In a retrospective study of 36 children aged 3-16 years, undergoing 'radical' surgery for craniopharyngioma, postoperative radiography showed tumour excision to have been complete in 25 cases and partial in 11 cases. The recurrence rate was 40% among those treated with surgery alone (N = 27), whereas there were no recurrences among those given adjunctive radiotherapy (RT) (N = 9). Although surgery in the hypothalamic region carries a high risk of severe lasting sequelae, long-term follow-up (mean duration 15 years) showed no difference in this respect between the RT and non-RT subgroups. Until large, preferably international, prospective studies may resolve the lack of consensus regarding the optimal treatment of craniopharyngioma, the authors advocate a more individualised approach, the choice between different treatment modalities and combinations being based on tumour size, location and structure.

Sleep and wakefulness after treatment for craniopharyngioma in childhood; influence on the quality and maturation of sleep.

Craniopharyngiomas are situated in immediate vicinity of sleep regulating structures in the basal forebrain area, and the tumor and its treatment might influence the regulation of sleep and wakefulness. In 10 patients treated for craniopharyngioma nighttime sleep quality and daytime vigilance were examined with polygraphic sleep records and multiple sleep latency tests (MSLT). Two girls and 8 boys, 7.1-22.9 years of age, were studied after a follow-up time of 1.5-16.1 years postoperatively. The results were compared to those of 18 normal children. The regulation of the ultradian sleep rhythm was normal but the ability to maintain nighttime sleep was severely disturbed. The patients had an increased number of awakenings and spent long time awake during two recorded nights. Two patients had excessive daytime somnolence during this examination, one after severe sleep disturbance, the other without any known cause. The pattern of sleep and vigilance did not change in puberty in the expected fashion. The disturbances may well have an impact on the psychosocial situation of the patients.

Lidocaine for treatment of severe seizures in newborn infants. II. Blood concentrations of lidocaine and metabolites during intravenous infusion.

The blood concentrations of lidocaine and its main active metabolites, methylethylglycinexylidide (MEGX) and glycinexylidide (GX), were measured in 24 newborn infants during anticonvulsive treatment with an iv infusion of lidocaine. After a bolus dose of 1.5-2.2 mg/kg and continuous infusion of lidocaine (4.7-6.3 mg/kg/h) there was accumulation of the drug and MEGX within 24 h. After termination of the iv infusion, both lidocaine and the metabolites were eliminated within 24-48 h. The anticonvulsive effectiveness--estimated by clinical observation and continuous amplitude integrated EEG monitoring (cerebral function monitor)--was immediate in 15 infants (nine term and six preterm). There was no correlation between blood concentrations of lidocaine and metabolites, and anticonvulsive effect (i.e. good, intermediate or no response). No differences in blood concentrations were found between full-term and preterm babies, or between infants with or without birth asphyxia. In combination with a fast withdrawal of the drug, few adverse reactions were seen with the dosages used, even though blood concentrations were high. Routine measurements of lidocaine concentrations during anticonvulsive treatment in neonates seem to be of little clinical value. For evaluation of the anticonvulsive effect and for early detection of seizure activity during lidocaine withdrawal, continuous EEG monitoring is preferable.

Suppressed spontaneous secretion of growth hormone in girls after treatment for acute lymphoblastic leukaemia.

The spontaneous secretion of growth hormone during a 24 hour period and the response of growth hormone to growth hormone releasing hormone was studied in 13 girls who had received treatment for acute lymphoblastic leukemia that included cranial irradiation with 20-24 Gy in 12-14 fractions. At the time of investigation the girls were at varying stages of puberty and had normal concentrations of thyroid hormones. The mean interval between the end of treatment and investigation was 4.6 years. The mean age at onset of the disease was 3.2 years and at investigation 10.7 years. The average attained height equalled -0.3 SD at onset, and -1.0 SD at the time of investigation. Secretion of growth hormone was substantially reduced compared with controls and did not increase during puberty. A prompt rise in growth hormone secretion was seen after injection of growth hormone releasing hormone, but the mean maximum growth hormone concentration was, however, only 25 mU/l. There was no correlation between the 24 hour secretion and growth hormone response to growth hormone releasing hormone, or the time since irradiation. These results confirm earlier work that suggested that girls who had received treatment for acute lymphoblastic leukaemia, that included cranial irradiation, have a comparative growth hormone insufficiency characterised by normal prepubertal growth and slow growth during puberty because of an inability to respond to the increased demands for growth hormone at that time.

Recombinant somatropin in treatment of growth hormone deficient children in Sweden and Finland.

A total of 23 previously untreated and 28 previously treated GH deficient children were included for at least 12 months in a trial of recombinant somatropin, 0.1 IU/kg/day given by subcutaneous injection. All the children increased their height velocity over the pretreatment values, to nearly 11 cm/year, corresponding to a significant increase in height of 1 SD score for chronological age. The increase in height SD score for bone age was also statistically significant. No adverse effects were recorded, though one child experienced local itching and redness at the injection site which did not recur after a short cessation of therapy. One child developed detectable antibodies to recombinant somatropin, but the binding capacity was low and no clinical symptoms or growth attenuation occurred. Recombinant somatropin was shown to be safe and effective during the first year of therapy in children with GH deficiency.

Blunted pubertal growth after leukemia: a new pattern of growth hormone insufficiency.

Growth, age at menarche and spontaneous GH secretion were studied in girls after treatment for acute lymphoblastic leukemia (ALL). These girls had normal prepubertal growth but subnormal pubertal growth. Mean final height was 1 SD less than expected before puberty. The average age at menarche was significantly lower than the normal mean for Swedish girls. The mean 24-hour GH secretion was severely blunted and there was no increase during puberty. We suggest that girls treated for ALL, including CNS irradiation, have a relative GH insufficiency which becomes clinically obvious only when the girls cannot respond to the increased demands for GH in puberty.

Lidocaine for treatment of severe seizures in newborn infants. I. Clinical effects and cerebral electrical activity monitoring.

The anticonvulsive effect of lidocaine was evaluated in 46 newborn infants with severe, recurrent seizures. Before the lidocaine all infants were being given phenobarbital, and 22 infants were also treated with diazepam. Different dosages of lidocaine were tested. A loading dose of 2 mg/kg followed by i.v. infusion of 6 mg/kg/hour was the most effective dosage and had an immediate anticonvulsive effect in 18 of 25 infants; within 30 min the same effect was attained in another five of the infants, with an overall seizure control in 92% of the sample population. During the lidocaine treatment cerebral electrical activity was followed continuously with a cerebral function monitor (CFM), which also enabled evaluation of the treatment. No serious side effects on blood-pressure, heart-rate or cerebral electrical activity were registered. For newborn infants with severe recurrent seizures not responding to other drugs, lidocaine is an effective additional mode of treatment.

Disturbed pubertal growth in girls treated for acute lymphoblastic leukemia.

Pubertal growth was studied in 10 girls previously treated for acute lymphoblastic leukemia. The average age at menarche was 12.2 years, which is significantly lower (p less than 0.01) than the expected 13.1 years. Compared with normal girls, these girls showed a subnormal (p less than 0.05) peak height velocity during the second year before menarche. The remaining growth before menarche as well as the total postmenarchal growth was close to the normal average. The average final standing height was 1 SD less than what would be expected from their height 1 year after the cessation of therapy. A relative growth hormone deficiency in combination with early onset of puberty could account for this loss in final height.

Rickets in very low birthweight infants. Influence of supplementation with vitamin D, phosphorus and calcium.

The influence of extra phosphorus (P) and calcium (Ca) on the incidence of rickets was studied in 40 infants with a birthweight below 1.5 kg. All were fed breastmilk and all received vitamin D 1200 IU/day. Half of the infants were supplemented with P 20 mg/kg/day and Ca 30 mg/kg/day. Rickets, diagnosed with X-ray at 5 to 7 weeks of age, developed in 12 infants, 11 of whom weighed below 1.0 kg. In infants below 1.0 kg rickets was significantly more common in the group not receiving extra P and Ca. After diagnosis all were substituted and radiographic healing occurred in all. Serum Ca concentrations were normal in both groups whereas serum P was significantly lower in non-supplemented patients. Serum alkaline phosphatases (ALP) were normal in all patients at the time of diagnosis demonstrating the risk of using ALP as a diagnostic test for rickets in very low birthweight.

Oral desmopressin in central diabetes insipidus.

Seven paediatric patients with central diabetes insipidus were studied in an open dose ranging study in hospital followed by a six month study on an outpatient basis to assess the efficacy and safety of peroral administration of DDAVP (desmopressin) tablets. In the dose ranging study a dose dependent antidiuretic response was observed. The response to 12.5-50 mcg was, however, less effective in correcting baseline polyuria than were doses of 100 mcg and above. Patients were discharged from hospital on a preliminary dosage regimen ranging from 100 to 400 mcg three times daily. After an initial adjustment in dosage in three patients at one week follow up, all patients were stabilised on treatment with tablets and reported an adequate water turnover at six months. As with the intranasal route of administration dosage requirements varied from patient to patient, and a dose range rather than standard doses were required. A significant correlation, however, was found for the relation between previous intranasal and present oral daily dosage. No adverse reactions were reported. No clinically significant changes were noted in blood chemistry and urinalysis. All patients expressed a preference for the oral over existing intranasal treatment. Treatment with tablets offers a beneficial alternative to the intranasal route, particularly in patients with chronic rhinitis or impaired vision.

Daily subcutaneous administration of human growth hormone in growth hormone deficient children.

Sixteen children (10 boys, 6 girls) on treatment for some years with i.m. injections twice or thrice weekly of human growth hormone (hGH; Crescormon Kabi Vitrum), participated in a prospective study. The weekly amount of hGH (8, 12, or 16 IU) was kept the same in each child, but divided into daily (7) s.c. injections at bedtime. The growth rate increased in all children during the first year on s.c. daily hGH (5.3 to 7.4 cm/year; 1.95 to 4.27 SDS). This increased growth rate did not persist during the second year on daily s.c. hGH, but an increased growth rate did not persist during the second year on daily s.c. hGH, but an increased predicted final height was found. The plasma profile of hGH was followed: i.m. injected hGH gave mostly a high (200 mU/l) plasma level of some hours (wide intra- and interpatient variation), and s.c. injected hGH a lower max level of longer duration (wide inter patient variation). The daily s.c. regimen of hGH was extremely well accepted by the children and their parents and no GH-antibodies or other adverse effects were found. We recommend daily s.c. injection of hGH as an alternative in the treatment of GH-deficient children.