Biomedical subjects
Publications and source records attributed to D B Grant.
Analysis of growth in nine girls after successful surgical removal of a virilising adrenocortical adenoma showed that five girls continued to grow rapidly for up to 18 months after operation and subsequently had normal growth velocities. The other four girls grew at normal rates after surgery. Only one girl showed progressive advance in bone age after operation and she subsequently had precocious puberty.
AIMS: To examine the relation between plasma total thyroxine and free thyroxine in children with congenital hypothyroidism. METHODS: Regression analysis was performed on 114 cases on the paired total thyroxine and free thyroxine measurements taken from the same blood sample. Conversion equations were derived using structural relation models. RESULTS: A linear relation was found between log total thyroxine and log free thyroxine values. The regression slopes for values taken before treatment and values taken while patients were receiving replacement treatment were significantly different. CONCLUSIONS: The data suggest that there is a close association between total and free thyroxine in congenital hypothyroidism, but that the relation is changed by thyroid replacement treatment.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
The cognitive functioning, motor skills and behaviour of 5-year-old children with early-treated congenital hypothyroidism was assessed. The study group was 57 children with congenital hypothyroidism (CH) diagnosed by neonatal screening in N.E. and N.W. Thames regions between 1978 and 1981 along with 51 non-affected controls matched for age, sex, social class and language background. Small differences in I.Q. and behaviour between the patients and the controls were not statistically significant. However, children with CH showed significant deficits in motor skills (M 79.9 SE 3.7) compared to the controls (M 99.8 SE 4.0) (P = 0.0003). Deficits were particularly marked for balance. In addition, children with more severe hypothyroidism at diagnosis (Plasma thyroxine less than 20 nmol/l) did significantly less well in respect to I.Q. and motor skills than those with less severe hypothyroidism (plasma thyroxine greater than 60 nmol/l). These findings provide further evidence for the importance of the severity of hypothyroidism in determining the outcome for intelligence and motor skills in children with early-treated congenital hypothyroidism. Deficits in motor skills, particularly in relation to balance, suggest that early impairment of the vestibular system may occur despite early treatment.
Eleven teenage boys with bilateral anorchia and 12 with gonadotrophin deficiency were treated by injections of testosterone ester (enanthate) at an initial dose of 100 mg every six to eight weeks, rising to 250 mg every four weeks after three to four years. In the anorchic boys average adult height was 177.1 cm, compared with a mean mid-parental height of 174.4 cm, and mean predicted adult heights of 177.0 cm (Tanner-Whitehouse method) and 178.0 cm (Bayley-Pinneau method). In the patients with gonadotrophin deficiency, mean adult height was 176.9 cm, compared with a mean mid-parental height of 176.1 cm, and mean predicted adults heights of 174.0 cm (Tanner-Whitehouse method) and 177.3 cm (Bayley-Pinneau method). We conclude that this testosterone regimen allows achievement of full growth potential in such patients.
The risk of recurrence of nesidioblastosis is unclear. Thirty patients from 28 families were studied; the marriages were consanguineous in five families. The ratio of subsequent affected to unaffected siblings was similar to that of an autosomal recessive condition and the sex ratio was close to 1.
Explore the source record for details and available documents.
The long term growth of 20 girls and nine boys with juvenile primary hypothyroidism was studied until they reached final height. At diagnosis the girls had a mean age of 8.8 years (range 3.0-13.0); mean bone age was 5.4 years. The mean age of the boys at diagnosis was 9.5 years (range 3.7-14.2); mean bone age was 6.3 years. The patients were treated with thyroxine 100 micrograms/m2/day and serum thyroxine concentrations were maintained in the normal range. During treatment the rate of skeletal maturation exceeded the change in chronological age. Initial mean height SD score for bone age before treatment in the girls was +0.59 and after 11 years of treatment fell to -0.55 Mean height SD score for bone age in the boys decreased from +1.6 to -0.87 during treatment. In the girls the onset of puberty was 1.2 years later than the normal population but the duration of puberty was reduced. Mean age (SD) of menarche was 13.8 (1.7) years. The pattern of growth in girls with treated hypothyroidism was abnormal as growth continued after menarche, at a time when normal girls have almost stopped growing. During the second year after menarche our patients still had a mean growth velocity of 4.1 cm/year. Our data suggest that juvenile primary hypothyroidism results in a permanent height deficit. In addition, there is a loss of the normal harmony between growth and sexual maturation in girls, despite adequate treatment, in that growth continues for much longer after menarche than in normal girls.
The clinicopathologic and radiologic features of 12 children with complete and incomplete forms of Drash syndrome are reported. Their common denominator was a nephropathy. Four had the full triad, consisting of nephropathy, Wilms tumor, and genital abnormalities; five had nephropathy and genital abnormalities, and three had nephropathy and Wilms tumor. Of the 11 children who had proteinuria, eight had the nephrotic syndrome. Of the 10 whose condition progressed to end-stage renal failure, seven were less than 3 years of age. The histologic features of Wilms tumor were favorable in all seven children, and the tumor was bilateral in three. Of the nine patients who had genital abnormalities, eight had 46,XY karyotype and either ambiguous genitalia (six patients) or normal female phenotype (two). One other patient had a normal 46,XX female karyotype and phenotype but had both müllerian and wolffian structures and a streak ovary. Nine patients had a distinct pelvicaliceal abnormality not previously reported as a feature of this syndrome. Other congenital abnormalities were aniridia, mental retardation, deafness, nystagmus, and cleft palate. This syndrome must be considered in any infant with unexplained nephropathy, particularly in young phenotypic female infants and in those children with ambiguous genitalia or Wilms tumor with an early presentation.
Seventy-seven female patients (36 adults and 41 children aged under 16 years) with congenital adrenal hyperplasia (CAH) were assessed using pelvic ultrasound, as well as with standard endocrine tests and HLA typing. Forty-six close female relatives were also tested for ovarian morphology using ultrasound after assessment of their heterozygous state using HLA typing. The association of CAH with ultrasonically detected polycystic ovaries (PCO) was confirmed in 30/36 (83%) adult patients, 4/10 (40%) postpubertal girls and 1/31 (3%) pre and peripubertal girls: in all, 35/46 (76%) postmenarcheal patients. Six out of nine (67%) pre-menopausal mothers of patients with PCO, and 8/10 (80%) sisters of patients with PCO also had PCO. The proportions of both CAH patients and heterozygote subjects with PCO were significantly greater than that found in a normal population (P less than 0.0001). The finding, however, of two homozygous non-CAH-affected adult sisters with PCO and, conversely, of 10 heterozygous adult relatives and of 12 postmenarcheal CAH patients with normal ovaries, indicates that the ovarian morphological change may be independent of the adrenal lesion.
Children diagnosed as congenitally hypothyroid and treated from a very early age were followed up at 1 and 3 years. At 1 year they seemed to be developing normally, unless they were undertreated or had an additional disorder. There were no significant correlations between biochemical or social factors and psychological outcome at 1 year. At 3 years, however, those children whose T4 and/or T3 had been very low initially had significantly lower IQ scores than both other hypothyroid children and matched controls. Children with only moderately low initial T4 and/or T3, however, were doing just as well as their matched controls. Initial levels of TSH, the number of symptoms at first clinical interview and the age at the start of treatment were not good indicators of ability at 3 years. Undertreatment was rare but did appear to affect ability. Psychological outcome at 3 years was also correlated with social class (for both cases and controls). Multiple regression analyses indicated that both low initial T4 (less than 20 nmol/l) and social class contributed significantly to outcome.
Fifty-four neonates with congenital hypothyroidism identified by the North East and North West Thames Regional hypothyroid screening programme between January 1985 and December 1987 were investigated with radioisotope (Tc99m) and ultrasound scans of the thyroid before treatment with 1-thyroxine was commenced. Compared with the radioisotope scans, ultrasound identified normally sited thyroid tissue in only 7 out of 10 cases, and ectopic thyroid tissue in only 5 out of 26 cases. Three out of 18 cases with no isotope uptake in the neck appeared to have normally sited tissue on ultrasound scan. We conclude that in our hands ultrasound of the neck is of only limited value in the assessment of young infants with congenital hypothyroidism.
The adenylate cyclase system of the yeast Saccharomyces cerevisiae contains the CYR1 polypeptide, responsible for catalyzing formation of cyclic AMP (cAMP) from ATP, and two RAS polypeptides, which mediate stimulation of cAMP synthesis of guanine nucleotides. By analogy to the mammalian enzyme, models of yeast adenylate cyclase have depicted the enzyme as a membrane protein. We have concluded that adenylate cyclase is only peripherally bound to the yeast membrane, based on the following criteria: (i) substantial activity was found in cytoplasmic fractions; (ii) activity was released from membranes by the addition of 0.5 M NaCl; (iii) in the presence of 0.5 M NaCl, activity in detergent extracts had hydrodynamic properties identical to those of cytosolic or NaCl-extracted enzyme; (iv) antibodies to yeast adenylate cyclase identified a full-length adenylate cyclase in both membrane and cytosol fractions; and (v) activity from both cytosolic fractions and NaCl extracts could be functionally reconstituted into membranes lacking adenylate cyclase activity. The binding of adenylate cyclase to the membrane may have regulatory significance; the fraction of activity associated with the membrane increased as cultures approached stationary phase. In addition, binding of adenylate cyclase to membranes appeared to be inhibited by cAMP. These results indicate the existence of a protein anchoring adenylate cyclase to the membrane. The identity of this protein remains unknown.
A boy aged 4 with penoscrotal hypospadias and his brother aged 12 with micropenis had typical changes of homozygous 5 alpha-reductase deficiency. After three injections of chorionic gonadotrophin there was a trivial rise in plasma dihydrotestosterone with a normal increase in plasma testosterone. Urine steroid chromatography showed abnormally high 5 beta: 5 alpha ratios and 5 alpha-reductase activity was appreciably reduced in genital skin fibroblasts. The results indicate that 5 alpha-reductase deficiency is not invariably associated with genital ambiguity.
Fifty two children with insulin dependent diabetes mellitus were randomised to receive human isophane or lente insulin preparations in combination with soluble insulin in a double blind trial. Patients were seen every two months, and crossed over after four months of treatment. Control assessed by glycated haemoglobin was significantly lower in children on human isophane insulin, but fasting blood glucose and fructosamine concentrations and the number of episodes of hypoglycaemia were similar on both regimens. In five children on twice daily insulin regimens, insulin profiles throughout a 24 hour period demonstrated greater variability on lente compared with isophane insulin despite identically administered insulin doses. A questionnaire completed at the end of the study showed that two thirds of the children and/or their parents preferred the isophane insulin, and they gave perceived improvement of metabolic control as the major reason for their choice.
Diabetes insipidus is a well-recognized complication of Langerhans-cell histiocytosis (histiocytosis X), but its frequency and natural history are not well defined. Of 52 children with histiocytosis whom we studied, 12 (23 percent) had diabetes insipidus. Only two children had diabetes insipidus at presentation with histiocytosis, but the cumulative risk that it would develop during the first four years after the presentation and diagnosis of histiocytosis was found to be 42 percent. Diabetes insipidus occurred most often among children with multisystem disease and those with proptosis. To determine the natural history of diabetes insipidus in children with histiocytosis, we measured the response of urinary arginine vasopressin to water deprivation every six months in 21 children who did not have diabetes insipidus and who had had histiocytosis for less than four years. Five of the 21 children (24 percent) had subnormal responses during the initial test. One subsequently had spontaneous improvement in the functioning of the posterior pituitary, and diabetes insipidus subsequently developed in two, as it did in one of the children who initially had normal function of the posterior pituitary. Two of the children received irradiation to the pituitary within two to four weeks after diabetes insipidus developed, but they had no improvement in pituitary function. However, diabetes insipidus improved transiently during prednisolone therapy in one of these children and improved permanently after etoposide therapy in another child. We conclude that prospective study with the use of a simple water-deprivation test will allow partial defects of posterior-pituitary function to be detected in patients with histiocytosis and will permit a more appropriate evaluation of the effects of therapeutic intervention.
We describe the clinical, biochemical and ophthalmic findings in four closely related males with X-linked ichthyosis and hypogonadism. Recognition of this association is important for both paediatricians and paediatric dermatologists.