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Vision in very early infancy is probably subserved by subcortical pathways, with many cortical processes only fully emerging by 3 months of age. The improvement of vision in delayed visual maturation (DVM) occurs around this time, and this has given rise to the suggestion that the condition may have a subcortical basis that resolves with the appearance of cortical function. To explore further the role of cortical and subcortical visual systems in DVM we studied the visual development in identical twins, one of whom had type 1b DVM. Two non-invasive methods of investigating visual pathway function were employed: the acuity card procedure (a behavioural response) and luminance and grating pupillometry. While the former reflects both subcortical and cortical function and can be detected at birth, pupil responses to gratings reflect cortical activity alone and normally become measurable at 1 month of age. Development of both behavioural and pupillary responses was delayed in DVM, indicating that although the underlying defect is primarily subcortical, secondarily it delays the emergence of cortically mediated responses. The observed rapidity of improvement--over a very few days and within a narrow age range--suggests a discrete rather than a widespread structural abnormality, the improvement of which is closely linked to postmenstrual age.

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OBJECTIVE: Mutations of the GNAS1 gene, which is located on chromosome 20q13.11 and encodes the alpha-subunit of the stimulatory GTP-binding protein, have been identified in patients with pseudohypoparathyroidism type Ia (PHPIa) and pseudopseudohypoparathyroidism (PPHP). We have undertaken studies to determine the prevalence of GNAS1 mutations and to explore methods for their more rapid detection. METHODS: Thirteen unrelated families (8 with PHPIa and PPHP patients, and 5 with PPHP patients only) were investigated for GNAS1 mutations in the 1050 base-pair (bp) region spanning exons 2-13 by single-stranded conformational polymorphism (SSCP) and DNA sequence analysis. RESULTS: GNAS1 mutations were detected in 4 of the 8 families with PHPIa patients. These consisted of: two novel de novo missense mutations (Pro115Ser and Glu259Val) in two families and an identical 4 bp deletion of codons 189 and 190 resulting in a frame-shift in two unrelated families. These results expand the spectrum of GNAS1 mutations associated with this disorder and confirm the presence of a mutational hot-spot involving codons 189 and 190. SSCP analysis was found to be a specific and sensitive method that detected all 4 mutations. GNAS1 mutations were not detected in any of the PPHP only families. CONCLUSIONS: The pseudohypoparathyroid disorders appear to represent a heterogeneous group with GNAS1 mutations forming the molecular aetiology in approximately 50% of pseudohypoparathyroidism type Ia families. Such mutations can be reliably identified by single-stranded conformational polymorphism and this will help to supplement the clinical evaluation of some patients and their families, particularly as the disease may not be fully penetrant.

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UNLABELLED: In children with hypothalamic causes for GH deficiency there are theoretical reasons why a GHRH analogue might be better than conventional GH therapy in promoting growth. OBJECTIVE: We have aimed to determine the efficacy and safety of growth hormone-releasing hormone (GHRH) (1-29)-NH2 given as a twice daily subcutaneous injection in the treatment of growth failure in children with radiation-induced GH deficiency. DESIGN: A multicentre study comparing growth before and after 1 year of treatment with GHRH (1-29)-NH2, 15 micrograms/kg twice daily, by subcutaneous injection in children with radiation-induced GH deficiency. On completion of the study year all children were treated with GH (0.5 U/kg/week) and growth parameters were documented over the next year. PATIENTS: Nine children (six boys) with radiation-induced GH deficiency following cranial (n = 4) or craniospinal (n = 5) irradiation for a brain tumour distant from the hypothalamic-pituitary axis (n = 8) or prophylaxis against central nervous system leukaemia (n = 1) were studied. All were prepubertal when the study commenced, which was at least 2 years from radiotherapy. MEASUREMENTS: Anthropometry and pubertal staging were carried out at 3-monthly intervals and bone age estimations at 6-monthly intervals (TW2 method). Pretreatment standing height velocities were compared with values during the year of GHRH treatment and then after the first year of GH therapy. In those that had received craniospinal irradiation, a change in leg-length Standard deviation score (SDS) was noted before and after GHRH therapy. Changes in skin-fold thickness and bone age during the GHRH study year were documented. Adverse events and 3-monthly measurements of clinical chemistry, haematology, lipid profile and thyroid function were recorded. RESULTS: There was a significant increase in height velocity from 3.3 (SD 1.1) cm/year before treatment, to 6.0 (SDS 1.5) cm/year after 1 year of GHRH treatment (P = 0.004). GHRH maintained or improved the leg length SDS in children who had received craniospinal irradiation. Bone age increased by a mean of 1.1 years/chronological year during treatment with GHRH. Subsequent height velocity during 1 year of GH therapy was 7.5 (SD 1.5)cm/year. No adverse changes in biochemical or hormonal analyses were noted or adverse events that could be attributed to GHRH therapy. One child went into puberty during the GHRH study year and three were pubertal during the first year of GH therapy. CONCLUSION: In cranially irradiated children, GHRH was effective in increasing growth velocity but this was less than that seen in response to GH therapy, although it matched that in children with isolated idiopathic GH deficiency treated with the same dose and schedule of GHRH administration.

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OBJECTIVE: Although recently developed specific and sensitive assays of bioactive dimeric inhibin A and B have given new insights into the pituitary-gonadal axis in adult men and during the adult female menstrual cycle, there have been no reports on circulating inhibin A and B during normal human puberty. The aim of this study was to assess the relationship of dimeric inhibin A and B to pubertal stage, FSH and testosterone or oestradiol in late prepuberty and in early puberty. STUDY DESIGN AND SUBJECTS: Serial samples were collected during a prospective longitudinal trial of GH treatment in short normal children. Seven boys were studied from late prepuberty to genital stage 3, and six pre-menarche girls from late prepuberty to breast stage 4. MEASUREMENTS: Dimeric inhibin A (girls only) and inhibin B (boys and girls) were measured by highly specific and sensitive two-site ELISAs, FSH by IRMA, testosterone and oestradiol by RIA. RESULTS: In boys, inhibin B increased progressively from pubertal stages 1 to 3 (ANOVA P < 0.0001) and correlated strongly with mean testicular volume (r = 0.72, P = 0.0005). Prepubertal boys showed a positive correlation between inhibin B and FSH (r = 0.65, P = 0.056), whereas pubertal boys gave a strong negative correlation (r = 0.75, P = 0.012). In both prepubertal and pubertal boys positive correlations were observed between inhibin B (y) and testosterone (x) (r = 0.81, P = 0.008 and r = 0.62, P = 0.054 respectively), but the slope of the regression line between the two was much steeper before than after the onset of clinical puberty. In girls, both inhibin A and B increased through pubertal stages 1-4 (ANOVA P = 0.01 and P = 0.047 respectively). Both showed strong positive correlations with oestradiol (r = 0.80 and 0.79, P = 0.001) and with FSH (r = 0.83, P = 0.0004 and r = 0.80, P = 0.001). Inhibin A and B were also strongly correlated with each other (r = 0.92, P = 0.0001). CONCLUSIONS: In boys, testicular production of inhibin B increases as puberty progresses. Our results show for the first time that the initiation of puberty is accompanied by a dramatic switch from a positive to a negative relation between inhibin B and FSH as inhibin B begins to exert the expected negative feedback on FSH. The results in girls suggest that, prior to menarche, the ovarian follicles produce inhibin A and B in strict proportion, and in progressively greater amounts as puberty proceeds. Measurement of dimeric inhibin A and B may provide a sensitive new tool for determining gonadal maturity in late prepuberty and early puberty.

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OBJECTIVE: A number of long-term research studies are in progress to evaluate the effects of treatment with GH on growth and final height in children with short stature but no demonstrable abnormality of GH secretion. Such treatment is invasive, expensive and carries some risk to the child. An early indication of growth response would allow restriction of treatment to those children most likely to benefit, but anthropometric measurements are relatively subjective, insensitive and imprecise. The aim of this study was to evaluate bone alkaline phosphatase, procollagen Type I C-terminal propeptide, procollagen Type III N-terminal propeptide and the cross-linked carboxy-terminal telopeptide of Type I collagen as early biochemical predictors of height velocity response to growth-promoting treatments in short normal children. DESIGN: A prospective intervention study, partially placebo controlled on a double blind basis. PATIENTS: Fifty healthy children with familial short stature or constitutional delay in growth and puberty (8 girls, 42 boys, ages 5.5-16.5 years and all either prepubertal (45) or in very early puberty (5 boys) at the start of treatment) were treated with placebo (6), GH alone (32), GH plus oxandrolone (8) or GH plus testosterone (4). MEASUREMENTS: Bone alkaline phosphatase and the collagen markers were measured at the start of treatment and 3 months later. Height velocity was calculated at the start of treatment and again after one year. RESULTS: Pre-treatment biochemical marker concentrations did not predict height velocity response after one year. Increments in all markers after 3 months were significantly correlated with height velocity increments after one year of treatment, the highest correlations being observed for bone alkaline phosphatase (r = 0.67, P < 0.0001) and procollagen Type III N-terminal propeptide (r = 0.57, P < 0.0001). Highly significant correlations (P < 0.0001) were also observed between bone alkaline phosphatase and procollagen Type I C-terminal propeptide (r = 0.55) and between procollagen Type III N-terminal propeptide and the cross-linked carboxy-terminal telopeptide of Type I collagen (r = 0.62). Multiple linear regression with stepwise selection of variables identified bone alkaline phosphatase and procollagen Type III N-terminal propeptide as the only two independent variables that contributed significantly to the prediction of height velocity response after one year (analysis of variance, P < 0.0001). Together they predicted 59% of the variability in height velocity response after a year. CONCLUSIONS: The best early predictors of height velocity response were bone alkaline phosphatase (a protein found in hypertrophic chondrocytes in the epiphyseal growth plate, in calcifying matrix vesicles and in mature osteoblasts) and procollagen Type III N-terminal propeptide, a marker of interstitial fibril biosynthesis in soft tissues. Using these markers, GH treatment could be targeted to those children most likely to benefit in the medium term.

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BACKGROUND AND OBJECTIVE: To assess how the Delfia time-resolved immunofluorometric assay can most conveniently and economically be used to differentiate normal prepuberty from complete idiopathic hypogonadotrophic hypogonadism (IHH, Kallmann's syndrome). SUBJECTS: 42 prepubertal boys aged 8.06-14.1 years and 11 adult male patients with IHH. DESIGN AND MEASUREMENTS: Blood samples were withdrawn at 20-min intervals for 8 h from 23.00 to 07.00. Samples from the 6 h commencing 1 h after sleep onset were analysed for LH by Delfia. RESULTS: Mean LH over this 6-hour period discriminated between IHH and normal prepuberty after the age of 12.5 years (no IHH subject > 0.31 U/l, no prepubertal subject < 0.33 U/l). The maximum hourly mean LH value for each subject gave a greater degree of mutual exclusivity (no IHH subject > 0.45 U/l, no prepubertal subject < 0.50 U/l). CONCLUSION: Kallmann's syndrome patients can be distinguished from prepubertal boys aged 12.5 years or over by blood sampling every 20 min for 6 h, commencing 1 h after sleep onset. The pooling of these samples into six 1-hour samples and subsequent Delfia assay will yield six 1-hour mean LH concentrations for each subject. The highest of these six concentrations will give a value with mutual exclusivity between the two groups.

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Three studies to evaluate procollagen type I C-terminal propeptide, type I collagen cross-linked telopeptide and bone alkaline phosphatase (BALP) in the assessment of bone turnover and growth in children are presented. (1) In 50 short normal children treated with placebo or growth hormone, delta BALP after 3 months of treatment was highly correlated with height velocity response after 1 year (r = 0.67, p < 0.0001). (2) In 12 children with acute lymphoblastic leukaemia, marked changes in collagen peptides, BALP, and lower leg length velocity were seen during the first 6 months of chemotherapy. Suppression occurred during induction and the two intensification phases, with catch-up during the intervening phase (paired t-tests, p < 0.001). (3) Fourteen babies (birthweight < 1,500 g) treated with high-dose dexamethasone for bronchopulmonary dysplasia were compared with 25 non-steroid-treated babies < 1,500 g. Both collagen peptides decreased rapidly and dramatically (mean decreases 41-68%) after dexamethasone was started, accompanied by weight loss and lower leg shrinkage and followed by recovery during steroid weaning.

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We studied the temporal and quantitative relation between bone alkaline phosphatase (ALP) and height velocity in 62 short normal children as part of a prospective randomized study to compare placebo, growth hormone, oxandralone, and testosterone, singly and in combination, in promoting short-term growth acceleration and increased final height. The pretreatment cross-sectional correlation between bone ALP and height velocity was poor (P > or = 0.25), but was much higher (P = 0.0001) 3 months after treatment started. In each treatment group, there was a parallel relation between bone ALP and height velocity through time. Individual children showed a variety of growth responses over 12-42 months, but in almost all cases bone ALP paralleled height velocity. Within individual children, bone ALP was strongly correlated with 6-month height velocity (r > 0.9 in 30% of the children, r > 0.7 in 70%). We conclude that bone ALP is a useful short-term marker of growth in short normal children treated with growth hormone.

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An adult woman with pseudopseudohypoparathyroidism had a child with normal calcium and parathyroid hormone concentrations and cyclic AMP response to injected parathyroid hormone in infancy. By 2.5 years he had features of pseudohypoparathyroidism with raised parathyroid hormone and 'flat' cyclic AMP response. This is the first documented case of a change in parathyroid hormone responsiveness. The abnormal cyclic AMP response to parathyroid hormone in pseudohypoparathyroidism can evolve during childhood.

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A child is described who has skeletal malformations, gelastic epilepsy, precocious puberty and a hypothalamic hamartoma. The skeletal abnormalities were detected at birth, she developed gelastic epilepsy at the age of 3 years 5 months and precocious puberty at 3 years 8 months. A hypothalamic hamartoma was found on MRI. The precocious puberty has been successfully medically managed, though her seizures are difficult to control. The combination of all four features has not been described previously.

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In the management of constitutional delayed growth and/or puberty, there is a need for simple tests which can assess the overall developmental maturity of the hypothalamic-pituitary-testicular axis in clinically prepubertal patients. This would enable the physician to predict the likelihood or otherwise of an individual entering puberty spontaneously within subsequent months. Based on our previous physiological data on the sequential pattern of peripubertal pituitary-testicular activation by hypothalamic GnRH, we hypothesized that the nocturnal secretion of testosterone, in response to sleep-entrained LH secretion, may provide a basis for an in vivo bioassay of neuroendocrine sexual maturity. Overnight testosterone secretion by the testis in clinically prepubertal boys was assessed with respect to their subsequent clinical progress, the target being the attainment of testicular volumes of greater than or equal to 4 mL (a clinical landmark when puberty has assuredly begun and virilization will soon follow). Forty-five prepubertal (Tanner stage G1PH1 testicular volume < or = 2 mL) boys aged 10.0-15.3 yr (mean +/- SEM 11.8 +/- 0.2) with short stature had paired plasma T concentration measured at 2000 h and 0800 h the following morning. After the initial assessment, all patients were reviewed clinically at 3-month intervals for a minimum of 21 months (mean 26.0 +/- 1.1, range 21-50 months). During this period, 38 (84.4%) patients received treatment in the form of sc human GH 2-4 IU daily or oxandrolone 2.5 mg daily by mouth to improve short-term growth although this did not have any significant effect on the subsequent timing of pubertal onset. The patients were divided according to whether 1) there was a demonstrable increase in plasma T between 2000 and 0800 h and 2) morning plasma T concentration was less than or greater than or equal to 0.7 nmol/L at their initial assessment. In those with a significant overnight T increment, 58% and 89% achieved testicular volume of greater than or equal to 4 mL after 12 and 21 months, respectively. In contrast, only 12% and 56% of patients who had not shown a T increase went into puberty by these times. In patients who had morning plasma testosterone concentrations greater than or equal to 0.7 nmol/L, 77% entered puberty within 12 months and 100% within 15 months. However, in those with a morning testosterone of less than 0.7 nmol/L, only 12.5% and 25% entered puberty within 12 and 15 months, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

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A five-year-old girl presented with profound growth failure, lethargy, vomiting and acidosis. A diagnosis of Munchausen syndrome by proxy was made after the demonstration of egg albumin, diphenhydramine and phenothiazine metabolites in her urine. Growth improved dramatically, but a subsequent child in the family died of sudden infant death syndrome.

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To study the ontogeny of spontaneous pulsatile LH and FSH secretion before the onset of puberty, plasma LH and FSH were measured by an ultrasensitive time-resolved immunoflurometric assay in 16 boys and 6 girls, aged 6.5 +/- 0.2 yr (+/- SEM; range, 4.4-8.0) with short stature. Eight male patients with idiopathic hypogonadotropic hypogonadism (Kallmann's syndrome), aged 24.1 +/- 3.4 yr, were also investigated. Blood samples were withdrawn at 10- to 20-min intervals for 12 h from 2000-0800 h. Pituitary responsiveness was assessed by a standard iv LHRH challenge test. LH and/or FSH pulses were detectable in all but two prepubertal subjects. In boys, low amplitude LH (0.16 +/- 0.06 U/L) and FSH (0.19 +/- 0.03 U/L) pulses were detectable at mean frequencies of 2.19 +/- 0.37 and 2.13 +/- 0.46 pulses/12 h, respectively. In girls, low amplitude LH (0.29 +/- 0.18 U/L) pulses, but higher (P less than 0.05 compared to boys) amplitude FSH (1.62 +/- 1.05 U/L) pulses were observed at frequencies of 1.71 +/- 0.56 and 1.67 +/- 0.53 pulses/12 h, respectively. Mean FSH in prepubertal girls (1.95 +/- 0.88 U/L) was significantly (P less than 0.05) higher than that in boys (0.46 +/- 0.07 U/L), but mean LH was not different at 0.17 +/- 0.07 and 0.10 +/- 0.03 U/L, respectively. Patients with Kallmann's syndrome had mean LH and FSH levels indistinguishable from those of prepubertal boys. Nocturnal augmentation of pulsatile LH or FSH secretion was observed in 74% of children (71% in girls and 75% in boys), but in none of the eight patients with Kallmann's syndrome. A close temporal association was observed between sleep onset and the appearance of nocturnal pulsatile gonadotropin secretion. The FSH response to exogenous LHRH in prepubertal girls was significantly greater than that in patients with Kallmann's syndrome and prepubertal boys, but LH responses were not different. Our results show that pulsatile LH and FSH secretion occurs in the majority of boys and girls in midchildhood, with a robust association with nocturnal sleep onset. Between the ages of 4-8 yr, these low amplitude and low frequency pulses are unable to activate gonadal function. The regulation of FSH secretion in prepubertal girls appears to be different from that in prepubertal boys.(ABSTRACT TRUNCATED AT 400 WORDS)

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A mother with pseudopseudohypoparathyroidism and her short son showed poor spontaneous growth hormone secretion, and provocation tests suggested a deficiency of growth hormone releasing factor. This is the first report of growth hormone releasing factor deficiency in pseudopseudohypoparathyroidism. The boy has responded well to growth hormone treatment over a period of three years.

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Highly purified bovine parathyroid hormone (PTH) was given by intravenous bolus injection to patients being investigated for disorders of mineral metabolism, and to adult volunteer controls. Plasma cyclic AMP measured basally and at 10 min gave reliable discrimination between the normal response and cases of pseudohypoparathyroidism. Infants under 3 months of age tended to have higher basal levels of cAMP and a flatter pattern of response to the dose of PTH used. This simplified test procedure in children offers considerable advantages over previous tests of PTH responsiveness which involve urine collections and multiple blood sampling. It is suitable for selective screening of individuals suspected of pseudohypoparathyroidism on the basis of their family history or physical abnormalities.

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An infant with antenatal diagnosis of intracranial bleeding from the choroid plexus is reported; diagnosis was by ultrasound. Postnatally the site, extent of the bleed and hydrocephalus were verified by ultrasound, and Doppler flow studies showed that cerebral blood-flow was compromised. A ventriculostomy was performed and intracranial pressure was monitored and relieved; removal of cerebrospinal fluid pending insertion of a ventriculo-peritoneal shunt was monitored by daily ultrasound. Thus the management of every stage of this infant's treatment depended on ultrasound.

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Smoking causes changes in the appearance of adults and has profound effects on the fetus, but little is known about its effects on the appearance of newborn infants. Two colour photographs (face and whole body) of 15 newborn infants (seven born to mothers who had smoked during pregnancy and eight born to mothers who had not) were shown to 100 medical and nursing staff, who in a double blind trial were asked to identify which babies had been born to smokers. The mean number correctly identified was 9.1, which was significant compared with the number expected by random selection (7.5). No specific features were identified that distinguished the two groups of infants; selection was intuitive. Nevertheless, the fact that differences can be detected in some way may be useful for antismoking health education.

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