Malcolm Donaldson

Growth and endocrine function after bone marrow transplantation

Since the introduction of bone marrow transplantation (BMT) as a treatment for various haematological, neoplastic, immunological and metabolic disorders, many children and adults are now surviving for long periods. Marrow transplant preparative regimens are designed to suppress the immune system and to eradicate the underlying haematological disorder or malignancy. Commonly used regimens have included high dose cyclophosphamide (CY) given alone or in combination with total body irradiation (TBI) or total lymphoid irradiation (TLI); more recently, the combination of high dose busulphan with cyclophosphamide has been used. In the survivors there is a high risk of thyroid, pituitary and gonadal dysfunction; in children, growth is often adversely affected. The relative risk of these adverse events is infiuenced by the underlying pathological condition, previous treatment for that condition, the use of TBI and the irradiation schedule, and the nature and quantity of the cytotoxic drugs used in the BMT preparative regimen.

A decade of growth hormone treatment in girls with Turner syndrome in the UK

Fifteen per cent of children treated with growth hormone (GH) are receiving treatment for Turner syndrome, but few results are available on final height in the UK. In this study, data were obtained from the UK KIGS database for 485 girls with Turner syndrome who were treated from 1986, allowing an audit of practice and outcome over 10 years. Over the decade, the mean age of starting growth hormone treatment fell from 10.4 to 8.5 years and the starting dose increased from 0.55 to 0.95 IU/kg/week. The frequency of injections increased from three to six or seven/week. Some girls received suboptimal doses, which also differed depending on whether they were based on weight or surface area. To assess what height gain might be expected at final height, all 52 girls who were prepubertal at the start of treatment, which continued for four years or more, and who had reached final height or had a growth velocity < 2 cm/year were selected. Their mean gain in final height was 5.2 cm and the GH dose was 0.78 IU/kg/week over 5.8 years. Final height gain correlated significantly with duration of treatment, total dose received, and first year response, which itself related to starting dose. This audit shows a changing pattern of treatment over the past decade, which in many instances has been inadequate. When treatment starts before puberty and continues through to final height, with a dose of 30 IU/m2/week in six or seven injections, a mean increase in final height of 5 cm or more would be expected.

Gigantism due to growth hormone excess in a boy with optic glioma.

True gigantism is rare in early childhood and is usually due to excess GH secretion from a pituitary adenoma. We report a case in which the endocrine abnormality is secondary to an optic glioma. Careful endocrine evaluation has shown that GH peak amplitude was not increased but rather there was failure of GH levels to suppress to baseline and a lack of pulsatility. There is no evidence of a direct secretory role for the tumour and we postulate that the tumour is affecting GH secretion through an effect on somatostatin tone. Specific tumour therapy is not indicated for this patient in the absence of mass effect or visual disturbance. The GH excess is being treated with somatostatin analogue (Octreotide) and as he has developed precocious puberty he is also receiving long acting GnRH analogue (Zoladex). This boy appears likely to have neurofibromatosis type 1 (NF1) which raises the question of subtle GH excess in NF1 patients with tall stature.

GONADOTROPHIN RESPONSES TO GnRH IN PRECOCIOUS PUBERTY TREATED WITH GnRH ANALOGUE

The gonadotrophin releasing hormone analogue Buserelin was given by intranasal spray to 13 children with precocious puberty. The LH responses to GnRH reverted to prepubertal levels in the boys on 200–400 μg daily of the analogue while doses of 400–1200 μg daily were needed to suppress the girls. The significance of this apparent sex difference is uncertain.

Efficacy of Zoladex LA (goserelin) in the treatment of girls with central precocious or early puberty

OBJECTIVE To assess the efficacy of a longer acting preparation of the gonadotrophin releasing hormone (GnRH) analogue goserelin (Zoladex LA, 10.8 mg) in 12 girls with central precocious or early puberty. METHODS Two girls started treatment de novo; the remainder had been on suppressive treatment for a median duration of 1.5 (range, 0.2–5.6) years. Assessment comprising auxology, pubertal staging, and pelvic ultrasound examination was carried out at weeks 0, 4, 8, 10, and 12 (first cycle) and weeks 8, 10, and 12 (second cycle) to evaluate the required injection frequency. Thereafter, assessment was performed on the day of injection. Zoladex LA was given every 12 weeks unless pubertal progression occurred. RESULTS Satisfactory control was achieved in eight patients using this regimen, and three patients required more frequent injections. One girl was removed from the study because of clinical progression and extreme mood swings. No serious adverse effects occurred. Mean height velocity during the study period was 4.5 cm/year (range, 3.1–6.6) compared with 6.5 cm/year (range, 3.8–9.6) before treatment in nine patients for whom data were available. CONCLUSIONS Zoladex LA was effective in controlling precocious puberty in girls when given at intervals of 9–12 weeks and it is recommended that an initial assessment is made eight weeks after beginning treatment.

Biosynthetic human growth hormone treatment in the UK: an audit of current practice. Kabi Pharmacia International Growth Study.

Biosynthetic human growth hormone was licensed for use in the UK in 1985, shortly after the withdrawal of human pituitary derived growth hormone because of the risk of Creutzfelt-Jakob disease.1 The primary indication remains the treatment of short stature due to growth hormone deficiency; the short stature of Turners syndrome was a later approved indication. The release of biosynthetic growth hormone was paralleled by the cessation of the Health Service Human Growth Hormone Committee that had succeeded the Medical Research Council in supervising the selection of children for treatment. These bodies supported by a national network of growth centres had maintained a structured information base with the capacity for regular clinical audit.24 This mechanism became impractical with the dispersal of prescribing recommendations to many additional clinics. The premature demise of this mechanism has meant that, in relation to a costly health resource, we are unaware of the number of children treated with growth hormone, whether there are selection differences between major centres, whether children are treated early enough and with appropriate doses and frequency of injections, and whether they respond adequately. The Kabi Pharmacia International Growth Study (KIGS), an international postmarketing safety and efficacy study, provides growth hormone prescribing centres with the opportunity to review their own practice by comparison with national and international standards. The current KIGS database holds anonymised data on over 10 000 children of whom more than 1300 have been enrolled in the UK since 1988. Thus 30-40% of all children receiving growth hormone in the UK are entered into KIGS. In this paper the KIGS database has been used to compare practice in the UK with that in other European countries, to compare clinics within the UK, and to identify criteria that could be used in audit.

A novel mutation in the PAX8 promoter region causes permanent congenital hypothyroidism in a patient with Down’s Syndrome

Thyroid dysfunction is common in newborn infants with Down’s syndrome (DS) but defects in organogenesis have not been described. A female infant was diagnosed to have trisomy 21, atrio-ventricular septal defect and patent ductus. Newborn screening showed capillary TSH 43.8 mU/L(day 5), venous TSH >150 mU/l and free T4 15.1 pmol/L (day 12). Thyroid ultrasound showed a small gland with heterogenous echotexture and cystic changes. Scintigraphy showed normal uptake into an eutopic gland. The infant was treated with thyroxine and underwent cardiac repair at 69 days. Sequencing analysis of candidate genes involved in thyroid development revealed a new heterozygous mutation close to the transcription initiation site of the PAX8 gene. Electromobility shift assay (EMSA) studies exhibited that the sequence at this position is not involved in specific protein binding. However, the mutant PAX8 promoter showed a significantly reduced transcriptional activation of a luciferase reporter gene in vitro tested in HEK, PCCL3 as well as in HeLa cells indicating that the mutation is very likely to lead to a reduced PAX8 gene expression. Further study in infants with DS and TSH elevation are indicated to investigate whether or not there is a true association between DS and PAX8 mutations.