Association of lipoprotein(a) with puberty in IDDM.

OBJECTIVE: To determine serum lipoprotein(a) in a large sample of IDDM and control children and to examine a possible association with puberty. RESEARCH DESIGN AND METHODS: Serum lipoprotein(a), apoB-100, and apoA-I were measured under identical conditions in 170 Caucasian children with IDDM aged 12.3 +/- 3.59 yr and 233 Caucasian control children aged 13.6 +/- 1.12 yr. Patients with persistent microalbuminuria were excluded. Lipoprotein(a), apoB-100, and apoA-I were measured by nephelometry using a specific monoclonal antibody. Pubertal assessment was performed using Tanner staging and testicular volume measurement. RESULTS: Lipoprotein(a) was higher in the IDDM than control group (geometric mean 237 mg/L, 25-75th percentile 134-465 vs. 172 [99-316] mg/L, P = 0.0008). When analyzed according to pubertal stage, only pubertal and postpubertal patients had higher levels than control subjects (265 [148-560] vs. 174 [101-320] mg/L, P = 0.0001), with prepubertal patients showing no difference. Pubertal and postpubertal patients showed both higher lipoprotein(a) (P = 0.01) levels and higher albumin excretion rates (P = 0.02) than prepubertal patients, correcting for the other variable. Lipoprotein(a) was not related to HbA1c, albumin excretion rate, duration, age, sex, mean arterial pressure, or a family history of premature coronary artery disease in the IDDM group. Lipoprotein(a) was not higher in patients with overnight albumin excretion rate above the 95th percentile but below the microalbuminuric range. ApoB-100 did not differ between IDDM and control children. ApoA-I was significantly lower in the IDDM group (1.04 [0.94-1.17] vs. 1.21 [1.10-1.31] g/L; P < 0.0001). CONCLUSIONS: Pubertal and postpubertal IDDM patients have higher serum lipoprotein(a) than Caucasian control subjects. Our findings suggest a rise in lipoprotein(a) may occur during puberty in IDDM. Longitudinal studies are required to clarify the relationship between lipoprotein(a), albumin excretion rate, and puberty.

Accelerated growth in short children with chronic renal failure treated with both strict dietary therapy and recombinant growth hormone.

In a 12-month study, nine boys, aged 4.8-15.6 years, with bone ages 4.6-13 years, with moderate to severe chronic renal failure and resultant growth failure were treated with daily recombinant human growth hormone (rhGH), in conjunction with a strict low-protein/low-phosphate diet supplemented with keto and amino forms of the essential amino acids, histidine and additional energy. Improved growth had previously been observed with this dietary management over that obtained with conventional treatment for chronic renal failure. Each child had been on this diet for at least 2 years before rhGH was commenced. Mean height velocity increased from 4.6 +/- 1.3 to 9.0 +/- 1.3 cm/year (P < 0.001) in the pre-pubertal group, and in the pubertal group from 5.4 +/- 1.4 to 10.4 +/- 1.8 cm/year (P < 0.01). The mean height velocity standard deviation scores (SDSs) increased from -1.2 +/- 0.6 to +2.3 +/- 0.9 (P < 0.001) in the pre-pubertal group and from -0.4 +/- 0.6 to +1.9 +/- 1.1 (P < 0.01) in the pubertal group. Mean height SDS for chronological age increased from -2.2 +/- 0.7 to -1.5 +/- 0.5 (P < 0.01) in the pre-pubertal group and from -1.9 +/- 0.7 to -1.3 +/- 0.9 in the pubertal group (P < 0.02). There was no significant deterioration in renal function or renal bone disease, and bone age did not advance more than chronological age over the 12-month period.

Limb deformity and metaphyseal abnormalities in thalassaemia major.

Regular bone survey radiographs have allowed identification of limb deformity and metaphyseal changes in several patients with thalassaemia major treated at the Adelaide Children's Hospital. Following the progression of limb deformity in five of these patients who were receiving human growth hormone therapy, the records of 25 thalassaemia patients were reviewed. Six patients had evidence of limb deformity, four of whom also had metaphyseal changes. Three additional patients had metaphyseal changes alone. Patients with either type of skeletal change shared similar characteristics, including younger age, earlier commencement of desferrioxamine therapy, better compliance and, in general, lower levels of ferritin. Females predominated in both groups. The frequency of sensorineural hearing loss was similar in affected and nonaffected groups and biochemical parameters, especially plasma calcium, phosphate, alkaline phosphatase, and zinc, which were normal in all patients. The cause of these skeletal changes is not clear; however, several potential factors need to be considered. Among these are focal marrow expansion in the metaphyseal region due to incomplete suppression of erythropoiesis and possible effects of desferrioxamine, including direct interference with bone growth, altered response of bone to inflammation or infection, and altered bone metabolism related to chelation of trace metals. While we can only speculate on aetiological factors, it is clear that human growth hormone therapy has resulted in exaggeration of deformity due to an increased rate of bone growth or decreased rate of mineralization of physeal cartilage. We believe that bone survey radiographs are useful in early identification of skeletal changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Prenatal diagnosis and successful intrauterine treatment of a female fetus with 21-hydroxylase deficiency.

OBJECTIVE: To present the first reported Australian case of prenatal treatment of a female fetus with congenital adrenal hyperplasia resulting from 21-hydroxylase deficiency. CLINICAL FEATURES: A couple whose son had congenital adrenal hyperplasia resulting from 21-hydroxylase deficiency sought prenatal diagnosis and treatment in their next pregnancy. INTERVENTION: Maternal treatment with dexamethasone was commenced at seven weeks' gestation to suppress androgen production by the fetal adrenal glands and prevent virilisation of an affected female fetus. At ten weeks' gestation chorionic villus sampling demonstrated a female fetus, who was shown subsequently to be affected by means of a linkage method in which probes to HLA genes DQA and DRB were used as markers for the 21-hydroxylase genes. Increased 17-hydroxyprogesterone and androstenedione immunoactivity in amniotic fluid obtained at 14.5 weeks confirmed the fetus to be affected and demonstrated incomplete suppression of fetal adrenal androgen production. Dexamethasone was continued to term and maintained suppression of the fetal and maternal adrenal glands. OUTCOME: The infant was born with normal female genitalia. Growth retardation was present but the relationship between this and the dexamethasone treatment remains uncertain. The mother had excessive weight gain during pregnancy. CONCLUSION: Dexamethasone treatment commenced in the first weeks of pregnancy can prevent or reduce virilisation of female fetuses with congenital adrenal hyperplasia resulting from 21-hydroxylase deficiency.

Management and outcome of children with congenital hypothyroidism detected on neonatal screening in South Australia.

Thirty-eight congenitally hypothyroid children who were detected in a neonatal screening programme have been treated for a mean period of 3.8 years (range, 0.5-8.5 years) by the maintenance of the free thyroxine index in the upper normal range as the main determinant of the dose of thyroxine. Only excessive elevation of, or serial rises in, thyroid stimulating hormone (TSH) level influenced the dose of thyroxine. This treatment strategy, which aims to avoid the potentially adverse effects of thyroxine overdosage, has often resulted in delayed return of TSH levels to normal, especially in athyrotic children (mean TSH +/- SD at one year of age in athyrotic children, 72 +/- 90 mU/L; in children with ectopic thyroid glands, 24 +/- 16 mU/L; normal range, 0-7 mU/L). The mean thyroxine dose of about 100 micrograms/m2 did not change significantly with age, and is lower than the doses that are sometimes quoted in the literature; athyrotic children require significantly more thyroxine (P less than 0.05) than those with ectopic thyroid glands. Symptoms and signs of congenital hypothyroidism, although subtle, were significantly more common (P less than 0.05 for symptoms and P less than 0.001 for signs) in athyrotic children compared with those with ectopic glands. No physical or developmental abnormality related to congenital hypothyroidism has been demonstrated on follow-up; mean height and weight percentiles approximate the 50th percentile at ages one to six years and mean developmental scores +/- SD at about two years of age by the Griffiths Mental Development Scale and at 4.5-6.5 years by the Wechsler Preschool and Primary Scale are 102.4 +/- 10.4 and 111.2 +/- 12.2, respectively. Long-term follow-up studies are necessary to exclude more subtle developmental and neurological abnormalities.

Growth hormone-induced changes in myofibrillar protein breakdown in hypopituitary children.

1. Creatinine and N tau-methylhistidine excretion rates have been measured in 13 hypopituitary children to calculate the body muscle contents and rates of myofibrillar protein breakdown. Analyses have been made during periods of growth hormone withdrawal and subsequent administration. 2. The creatinine excretion rate was lower in the hypopituitary children, indicating a lower muscle content per kg body weight. This difference persisted even in children who had received growth hormone for several years. 3. Excretion of N tau-methylhistidine was reduced by the administration of growth hormone. 4. The fractional breakdown rate of myofibrillar protein, as calculated from the N tau-methylhistidine to creatinine molar excretion ratio, averaged 1.76%/day in the four youngest children during growth hormone withdrawal. This was significantly higher than for control children of a similar age (P less than 0.02) and was reduced to the normal rate of 1.47%/day by growth hormone administration. 5. In older children the fractional rate of myofibrillar protein degradation remained in the normal range irrespective of growth hormone treatment. 6. These results are discussed in the context of the anabolic effects of growth hormone on muscle being partly explained by its action to decrease rates of protein breakdown.

Indices of serum androgens in normal puberty: correlations of two indices with chronological age, bone age and pubertal development in boys and girls.

Two indices of free serum androgenic activity, the normalized androgen ration (NAR) and the free androgen index (FAI) were determined in 218 normal children aged 8-17.9 years. Before the onset of puberty and between chronological age 8 and 11.9 years, NAR and FAI were similar in both sexes, the NAR being less than 0.8 and FAI less than 0.1. In boys mean NAR value increased from 0.87 to 1.39 between 12.5 and 17.5 years, and mean FAI from 0.14 to 1.85 between 12.5 and 17.5 years. In girls mean NAR increased from 0.79 to 0.85 between 12.5 and 15.5 years, and mean FAI from 0.11 to 0.23, between 12.5 and 15.5 years. Both indices did not change significantly between 15.5 and 17.5 years in girls. A rapid increase in NAR and FAI occurred in boys from a mean testicular volume of 4.1 to greater than 20 ml and from genital stage G2+ to 5+. In girls a gradual increase in NAR and FAI occurred from breast stage B2+ to 5+ . Although the androgen indices increased in both sexes between pubic hair stages PH2+ and 6+, the values in girls were always less than in boys at corresponding stages suggesting an increased androgen sensitivity of the female pubic hair follicle during adolescence. The peak rise in NAR and FAI in boys between 13 and 15 years correlated closely with the timing of the pubertal growth spurt in this sex. A similar rise was not seen in girls at the time of their peak growth velocity between 11 and 13 years and suggested that androgens play only a minor or complementary part in the female growth spurt.

Gonadotrophin response to LH-RH in boys with delayed growth and adolescence.

Plasma luteinising hormone (LH) and follicle-stimulating hormone (FSH) concentrations were measured before and after intravenous luteinising hormone-releasing hormone (LH-RH) in 33 boys with growth delay. Eighteen were prepubertal and 15 pubertal. Basal LH and FSH levels were low in both groups with mean increments after LH-RH of 3.2 +/- 0.8 U/l (mean +/- SEM) and 2.6 +/- 0.4 U/l respectively in the prepubertal and 7.4 +/- 0.7 U/l and 2.0 +/- 0.3 U/l in the pubertal boys. The LH increment showed a positive correlation with increasing bone age (r = 0.71, P less than 0.001); FSH did not. The LH-RH response thus appeared normal in relation to the stage of maturity.

Premature craniosynostosis-a complication of thyroid replacement therapy.

Three hypothyroid children with premature craniosynostosis are presented, who have been treated intensively with 1-thyroxine from early infancy. It is postulated that the craniosynostosis is the result of iatrogenic hyperthyroidism during a critical period of skull growth. Various regimens of treatment for hypothyroidism are discussed with recommendations for avoiding this potentially hazardous complication of therapy.