Likelihood of persistent GH deficiency into late adolescence: relationship to the presence of an ectopic or normally sited posterior pituitary gland.

OBJECTIVES: The presence of an ectopic posterior pituitary gland (EPP) in childhood is associated with isolated GH deficiency (IGHD) and multiple pituitary hormone deficiency. GHD in late adolescence has been defined as a peak GH level <5 microg/l. The aim of this study was to identify the likelihood of persistent GHD in late adolescence in patients with an EPP compared with those with a normally sited posterior pituitary (NPP). METHODS: In 18 patients with an EPP and 15 patients with an NPP, clinical, biochemical and radiographic data were collected. RESULTS: In the EPP vs. the NPP group, the change in peak GH levels at the end of growth was less (+0.4[95% confidence interval (CI) - 0.8 to 2.7] vs. +4.1[95%CI + 0.4 to +10.5] microg/l, P-value for ancova = 0.03, after adjustment for age and sex). Using a peak GH level of <5 microg/l as a cut-off for GHD, 66% of EPP subjects compared with 40% of NPP subjects had GHD (P = 0.3). Hundred per cent of EPP subjects had a peak GH level on retesting <10 microg/l, compared with 40% of NPP subjects (P < 0.001). CONCLUSION: It is important to document GH status at the end of growth, even if there is a structural abnormality of the hypothalamic-pituitary axis. The presence of an EPP compared to an NPP increases the likelihood of persistent GHD by 26%. As all EPP patients had a peak GH level of <10 microg/l, the cut-off for persistent GHD in late adolescence may need to be revised.

Skewed X inactivation is associated with phenotype in a female with adrenal hypoplasia congenita.

Adrenal hypoplasia congenita (AHC) can occur due to deletions or mutations in the DAX 1 (NR0B1) gene on the X chromosome (OMIM 300200). This form of AHC is therefore predominantly seen in boys. Deletion of the DAX 1 gene can also be part of a larger contiguous deletion including the centromeric dystrophin and glycerol kinase (GK) genes. We report a girl with a de novo deletion at Xp21.2 on the maternal chromosome, including DAX1, the GK gene and 3' end of the dystrophin gene, who presented with salt losing adrenal insufficiency and moderate developmental delay, but relatively mild features of muscular dystrophy. Investigation using the androgen receptor as a marker gene identified skewed inactivation of the X chromosome. In the patient's leucocytes, the paternal X chromosome was completely inactive, but in muscle 20% of the active chromosomes were of paternal origin. Thus skewed X inactivation (deletion on the active maternal X chromosome with an inactive paternal X chromosome) is associated with AHC in a female. Variability in X inactivation between tissues may account for the pronounced salt loss and adrenal insufficiency but mild muscular dystrophy.

Associations with multiple pituitary hormone deficiency in patients with an ectopic posterior pituitary gland.

INTRODUCTION: The presence of an ectopic posterior pituitary gland (EPP) on magnetic resonance imaging (MRI) is associated with hypopituitarism with one or more hormone deficiencies. We aimed to identify risk factors for having multiple pituitary hormone deficiency (MPHD) compared to isolated growth hormone deficiency (IGHD) in patients with an EPP. METHODS: In 67 patients (45 male) with an EPP on MRI, the site (hypothalamic vs. stalk) and surface area (SA) [ x (maximum diameter/2) x (maximum height/2), mm(2)] of the EPP were recorded and compared in patients with IGHD and MPHD in relation to clinical characteristics. RESULTS: In MPHD (n = 32) compared to IGHD (n = 35) patients: age of presentation was younger (1.4 [0.1-10.7]vs. 4.0 [0.1-11.3] years, P = 0.005), major incidents during pregnancy were increased (47%vs. 20%, P = 0.02) as were admissions to a neonatal intensive care unit (NICU) (60%vs. 26%, P = 0.04), whilst EPP SA was lower (12.3 [2.4-34.6]vs. 25.7 [6.9-48.2] mm(2), P < 0.001). In patients with a hypothalamic (n = 56) compared to a stalk sited EPP (n = 11): prevalence of MPHD was greater (55%vs. 9%,P = 0.05) and EPP surface area was smaller (17.3 [2.4-48.2]vs. 25.3 [11.8-38.5] mm(2), P < 0.001). In regression analysis, after adjusting for age, presence of MPHD was associated with: major incidents during pregnancy (RR 6.8 [95%CI 1.2-37.7]), hypothalamic EPP site (RR 10.9 [1.0-123.9]) and small EPP SA (RR 2.5 [1.0-5.0] for tertiles of SA). CONCLUSION: In patients with an EPP, adverse antenatal events, size (small) and position (hypothalamic) of the posterior pituitary gland on MRI were associated with MPHD. These findings suggest that adverse factors during pregnancy may be important for the development of an EPP.

Efficacy of a monthly compared to 3-monthly depot GnRH analogue (goserelin) in the treatment of children with central precocious puberty.

AIMS: To compare the efficacy of goserelin 10.8 mg (Zoladex LA-ZLA) administered 9-12 weekly with 3.6 mg (Zoladex-Z) given monthly in suppressing pubertal development, and effect on body mass index (BMI). METHODS: Children with central precocious puberty (CPP) treated with Z (n = 34) or ZLA (n = 28) were studied retrospectively. Pubertal scores and BMI SDS during 24 months' treatment were compared. RESULTS: To attain adequate pubertal suppression, more patients on ZLA than Z required increase in injection frequency (p = 0.02) and this was so for 7/8 patients with a structural aetiology for CPP on ZLA and 2/8 on Z. A greater proportion of patients on ZLA had BMI >+2 SDS before (p = 0.05), and at 18 and 24 months (p = 0.02 and 0.04). BMI SDS transiently increased during the first 6 months on ZLA (p = 0.04). CONCLUSION: Both Z and ZLA were effective in suppressing puberty. To achieve adequate suppression, increased injection frequency was more likely with ZLA than Z, and particularly in patients with structural defects. Children with CPP had an elevated BMI at the onset of therapy and ZLA had a transient positive influence on BMI.

Diabetes mellitus following paediatric renal transplantation: a single centre experience.

BACKGROUND/AIMS: Post-transplant diabetes mellitus (PTDM) has a variably reported incidence of 4-41% among adults and children. We describe our recent experience of four children with PTDM in a paediatric renal transplantation centre. METHODS: We undertook a retrospective analysis of the glycaemic status of all paediatric patients undergoing renal transplantation at our centre in the 2-year study period. The clinical features and investigations of those who developed PTDM were further reviewed. RESULTS: Five episodes of PTDM occurred in 4/32 children. There was a variable onset and a wide range of symptoms. Investigations revealed a combination of insulinopenia with peripheral insulin resistance. Insulin therapy was required for variable durations with resolution of PTDM in four episodes. PTDM did not adversely affect the renal graft function. CONCLUSION: PTDM requires increased awareness among paediatric nephrologists and endocrinologists for early recognition and prompt effective intervention.

Diagnostic accuracy of fracture detection in suspected non-accidental injury: the effect of edge enhancement and digital display on observer performance.

AIM: To compare the effect of varying degrees of edge enhancement and method of digital image display on fracture detection in suspected non-accidental injury (NAI). MATERIALS AND METHODS: Fifty radiographs from post-mortem skeletal surveys in 13 children with suspected NAI were selected. Images were obtained using a Fuji 5000R computed radiography system. Hard copies were printed with edge enhancement factors 0, 0.5 and 1.2. Images (edge enhancement 0.5) were also displayed on a 1K(2) monitor. Six observers independently evaluated all 200 images for the presence of abnormality. Observers also scored each image for visualization of soft tissues, visualization of trabecular markings and overall image quality. The paired Student's t-test and location receiver operating curve (ROC) analysis were used to compare quality scores and diagnostic accuracy of each display method. Individual and pooled true-positive rates (sensitivity) were determined. For the purposes of ROC analysis, histology was taken as the gold standard. RESULTS: There was no difference in duration of hard and soft-copy reading sessions (p=0.76). After image manipulation soft-copy radiographs scored significantly better for image quality than hard copy (p<0.0001). Pooled observer sensitivity (at a specificity of 90%) was below 50% for all display methods. Diagnostic accuracy varied significantly between observers. Diagnostic accuracy of individual observers was not affected by display method. CONCLUSION: In suspected NAI, diagnostic accuracy of fracture detection is generally low. Diagnostic accuracy appears to be affected more by observer-related factors than by the method of digital image display.

Optimal exposure parameters for digital radiography of the infant skull: a pilot study.

AIM: To determine optimal exposure parameters when performing digital skull radiographs in infants with suspected non-accidental injury (NAI). METHOD: Anteroposterior and lateral post-mortem skull radiographs of six consecutive infants with suspected NAI were made at six exposure levels for each projection. Entrance surface doses ranged from 75-351 microGy. Exposures were made with a Fuji 5000R computed radiography system onto a standard resolution imaging plate. In three patients exposures were repeated using a high-resolution imaging plate. Hard copy images with an edge-enhancement factor of 0.5 were produced. Six observers assessed and scored the radiographs from 1=poor to 5=excellent for visualization of five criteria. The criteria scored included outer table of skull vault, inner table of skull vault, suture margins, vascular markings and soft tissues of the scalp. Radiographs were then ranked in order of overall image quality. Film density and sensitivity values were recorded. Local research committee approval was obtained. RESULTS: Current parameters give an average entrance surface dose of 253 microGy and 246 microGy for anteroposterior and lateral radiographs, respectively. The study demonstrated no perceived improvement in image quality above an entrance surface dose of 200 microGy (80% of current dose) or by the use of a high-resolution imaging plate. CONCLUSION: The potential exists to reduce radiation exposure in infants. A study has commenced to determine the effects of dose reduction on diagnostic accuracy in suspected NAI.

Increased first-trimester fetal nuchal translucency thickness in association with chondroectodermal dysplasia (Ellis-Van Creveld syndrome).

Increased nuchal translucency thickness (NT) is an established sonographic marker of fetal chromosomal abnormality. Several structural fetal defects and genetic syndromes including a range of skeletal dysplasias have been reported in association with increased NT. We report the first case of fetal Ellis-Van Creveld syndrome presenting as raised fetal NT at 13 weeks' gestation. Ultrasonography at 18 weeks' gestation demonstrated a narrow thorax, marked shortening of the long bones with bowed femora and hexadactyly of hands and feet. Pregnancy was terminated at 23 weeks' gestation. The postmortem radiological examination revealed short and bowed long bones with rounded metaphyses, postaxial polydactyly of hands and feet, short ribs and narrow thorax. The acetabular roofs were horizontal with medial and lateral spurs. This case adds a further type of severe skeletal dysplasia to the list of genetic syndromes which may present as increased fetal NT in the late first trimester.

Female preponderance in congenital adrenal hyperplasia due to CYP21 deficiency in England: implications for neonatal screening.

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase (CYP21) deficiency causes symptoms ranging from life-threatening neonatal adrenal crises to minimal virilization in adulthood. The relationship between CYP21 genotype and phenotypic markers in a non-screened population of 73 CAH children (44 female, 29 male; 54 white, 19 Asian) treated at the Royal Manchester Children's Hospital was investigated and ethnic and sex differences assessed. The patients were categorized according to the mutation on the mildest allele. The age at the time of diagnosis differed significantly between the groups (p = 0.02): all 25 Null and 25 of 26 of the I2 splice patients were diagnosed during the neonatal period, whereas 7 of 11 I172N patients were diagnosed late. Degree of female genital virilization, 17-hydroxyprogesterone level at diagnosis, and fludrocortisone requirement during the 1st year of treatment correlated with the genotype, although Asian Null patients required more fludrocortisone than their white counterparts (p = 0.055). There was an equal sex ratio in both the I2 splice (12 female/14 male) and I172N (5 female/6 male) groups. However, in the Null group, the ratio was 4.0 (20 female/5 male; p = 0.003), suggesting that some Null male infants perish before being clinically detected to have CYP21 deficiency. Our findings strongly support the need for implementation of a neonatal screening programme for CAH in the UK which may reduce the male infant mortality.

Forearm blood glucose testing in diabetes mellitus.

AIMS: To compare the accuracy and acceptability of capillary blood glucose testing from the forearm with finger prick testing in diabetic children. METHODS: Blood glucose measurements from samples taken from the forearm and the finger were compared in an outpatient setting from 52 children and adolescents with diabetes mellitus aged 6-17 years. Opinions on forearm sampling were collected by questionnaire. RESULTS: Blood glucose results obtained from forearm sampling correlated well with results from the finger measured by the Yellow Springs Instrument analyser. Error grid analysis showed that 100% of measurements were clinically acceptable; 61% of children reported that forearm testing was painless and 19% that it was less painful than finger prick testing. CONCLUSION: Forearm testing is an acceptable alternative to finger prick testing for blood glucose measurement in children and adolescents.

Pseudarthrosis presenting as a late complication of meningococcal septicaemia and disseminated intravascular coagulation.

Late skeletal complications of meningococcal septicaemia and disseminated intravascular coagulation are well recognised in children and are largely centred on the growing epimetaphyseal region of long bones. In this article we describe a case of pseudarthrosis of the mid-ulna presenting 18 months following a devastating episode of meningococcal septicaemia in a 3-year-old boy. Radiographs and MRI demonstrated the ulna abnormality. We briefly review the late skeletal complications of the disease and other causes of pseudarthrosis.

Probable adverse reaction to a pharmaceutical excipient.

Adverse reactions to medication are well recognised although information on the incidence in children is lacking. Adverse reactions have also been attributed to a range of pharmaceutical excipients. This is a report of an adverse reaction to the excipient in clindamycin injection.

Insulin-like growth factor I levels in healthy children.

Measurement of insulin-like growth factor I (IGF-I) levels is used during the assessment of a child for the presence of growth hormone (GH) deficiency and to monitor the efficacy of GH replacement therapy. In either case, robust normative data are required to allow IGF-I values to be expressed as standard deviation scores, enabling comparison between individuals and assessment of change over time. However, IGF-I levels in healthy children are affected by a number of parameters, including age, gender, pubertal status, height, nutrient intake, body composition, intercurrent illness and ethnicity, and the generation of such data requires the collection of samples from significant numbers of healthy children. As external quality assurance schemes for IGF-I and an international standard based on authentic recombinant IGF-I are not widely used, it is imperative for the clinician to understand the performance characteristics and limitations of the IGF-I assay used and to be aware of the source and quality of control data. It must also be recognized that IGF-I measurement is only one component of the diagnostic process and has its limitations, as tissue sensitivity to circulating serum IGF-I levels will differ between individuals.

Ghrelin concentrations in healthy children and adolescents.

OBJECTIVE: In addition to its regulation by GH releasing hormone (GHRH) and somatostatin, release of GH from the pituitary is modulated by a third factor, ghrelin, which is expressed in high concentration in the stomach and is present in the circulation. Ghrelin has also been shown to cause weight gain by increasing food intake and decreasing fat utilization. Ghrelin is a potential candidate hormone to influence nutrient intake and growth. Its role through normal childhood and adolescence has not been fully defined. DESIGN: Cross-sectional study in 121 healthy children (65 male, 56 female) aged 5-18 years, in whom height, weight, body mass index (BMI), pubertal status and measurements of IGF-I, IGFBP-3, IGFBP-1 and leptin were available. METHODS: Serum ghrelin concentrations have been measured in radioimmunoassay (RIA; Phoenix, AZ, USA) that detects active and inactive human ghrelin. Relationships between ghrelin and anthropometric data and growth factors were assessed by correlation and regression analyses. RESULTS: Ghrelin was detected in all samples, with a median concentration of 162 pg/ml, range 60-493 pg/ml. Prepubertal children had higher ghrelin concentrations than those in puberty [218 pg/ml (n = 42) and 157 pg/ml (n = 79), P < 0.001], with significant negative correlations between ghrelin and age (rs = -0.39, P < 0.001) and pubertal stage (rs = -0.42, P < 0.001). The decrease in ghrelin with advancing pubertal stage/age was more marked in boys than girls. In the whole group, ghrelin was negatively correlated to BMI SD (rs = -0.24, P = 0.006) and to weight SD (rs = -0.24, P = 0.008) but not height sds. Ghrelin was also negatively correlated to IGF-I (rs = -0.48, P < 0.001), IGFBP-3 (rs = -0.32, P < 0.001) and leptin (rs = -0.22, P = 0.02) but not IGF-II. It was positively related to IGFBP-1 (rs = +0.46, P < 0.001). In stepwise multiple regression, 30% of the variability in ghrelin through childhood could be accounted for by log IGF-I (24%) and log IGFBP-1 (6%). CONCLUSIONS: The fall in ghrelin over childhood and with puberty does not suggest that it is a direct growth-promoting hormone. However in view of the negative relationship with IGF-I and the positive relationship with IGFBP-1, this fall in ghrelin could facilitate growth acceleration over puberty.

Endocrine status in patients with optic nerve hypoplasia: relationship to midline central nervous system abnormalities and appearance of the hypothalamic-pituitary axis on magnetic resonance imaging.

We here: 1) describe the phenotypic spectrum, including magnetic resonance imaging (MRI) appearances of the pituitary stalk and anterior and posterior pituitary [H-P (hypothalamic-pituitary) axis], in children with optic nerve hypoplasia (ONH) with or without an abnormal septum pellucidum (SP); and 2) define endocrine dysfunction according to the MRI findings. Medical records of 55 children with ONH who had been assessed by ophthalmology and endocrine services were reviewed. All had MRI of the brain and H-P axis. Forty-nine percent of the ONH patients had an abnormal SP on MRI, and 64% had a H-P axis abnormality. Twenty-seven patients (49%) had endocrine dysfunction, and 23 of these had H-P axis abnormality. The frequency of endocrinopathy was higher in patients with an abnormal SP (56%) than a normal SP (39%). Patients were divided into four groups based on SP and H-P axis appearance: 1) both normal; 2) abnormal SP and normal H-P axis; 3) normal SP and abnormal H-P axis; and 4) both abnormal. The frequency of multiple pituitary hormone deficiency was highest (56%) in group 4, lower (35%) in group 3, and even lower (22%) in group 2. Precocious puberty was most common in group 2. None of the patients in group 1 had endocrine dysfunction. Thus, SP and H-P axis appearances on MRI can be used to predict the likely spectrum of endocrinopathy.

IGF-I and IGF-binding protein-3 measurements on filter paper blood spots in children and adolescents on GH treatment: use in monitoring and as markers of growth performance.

BACKGROUND/AIM: In childhood an appropriate response to GH treatment is achieved by titration of growth response against dose administered, with careful observation for side-effects. In order to evaluate the potential use of IGF monitoring in children treated with GH, a cross-sectional study has been carried in 215 children and adolescents (134 with GH deficiency (GHD), 54 with Turner syndrome (TS) and 27 with non-GHD growth disorders) treated with GH for 0.2-13.7 years. METHODS: IGF-I and IGF-binding protein-3 (IGFBP-3) were measured in ELISAs, using dried capillary blood collected onto filter papers. Results were expressed as the mean S.D. range (SDS). Values of either analyte < -2 or > +2 SDS were considered abnormal. RESULTS: IGF-I and IGFBP-3 SDS were higher in the TS and non-GHD groups (mean +0.01 and +0.1 respectively) than in those with GHD (mean value -0.6). Nineteen per cent of the IGF-I values (13% low, 6% high) and 12% of IGFBP-3 values were abnormal (10% low, 2% high). Abnormalities, either low or high, were most common in the GHD group. There was a weak but significant relationship between change in height SDS over the Year up to the time of sampling in the whole group and IGF-I SDS. Satisfactory growth performance (+0.5>change in height SDS> -0.5) was found in those with high (7.2%), normal (60%) and low (9.3%) IGF-I levels. Overall, it was estimated that 26% of the tests would indicate that an adjustment to GH dose (up in 18% and down in 8%) could be considered. CONCLUSIONS: From this cross-sectional study of IGF monitoring across a broad range of diagnoses and ages, it can be concluded that the majority of children on GH have normal levels of IGF-I and IGFBP-3, but 26% of tests could suggest that a change of GH dose should be considered. Regular monitoring of IGF-I and IGFBP-3 should be considered in any child on GH treatment.

Observational study of skeletal surveys in suspected non-accidental injury.

AIM: To document variability in the standard of skeletal surveys received for a second opinion in suspected non-accidental injury (NAI). MATERIALS AND METHODS: The skeletal surveys of 50 consecutive infants and children under 2 years of age were reviewed. A simple scoring system was developed based on fulfillment of specific parameters. Each radiograph was then assigned a score reflecting its overall clinical quality. RESULTS: There was an average of 10 radiographs per skeletal survey (range 2-13). Of the 50 surveys assessed, there were 37 different combinations. These included five babygrams. No survey complied with the current draft guidelines of the British Society of Paediatric Radiologists (BSPR). CONCLUSIONS: There is significant variability in skeletal surveys referred for a second opinion in suspected NAI. Standardization of projections and improvement in the quality of radiographs obtained for this indication is required. The study highlights the need for the development and dissemination of definitive national guidelines.