Jane McNeilly

A Prospective Longitudinal Study of Growth and Pubertal Progress in Adolescents with Inflammatory Bowel Disease

Background: Puberty and growth may be affected in inflammatory bowel disease (IBD) but the extent is unclear. Methods: We performed a prospective study over 12 months in 63 adolescents (Crohns disease, CD, n = 45; ulcerative colitis/IBD unclassified, UC, n = 18) with a median age of 13.4 years (range 10-16.6). Assessment included anthropometry, biochemical markers of growth and puberty and an assessment of quality of life by IMPACT-III. Results: Compared to the normal population, boys with CD were shorter, with a median height SDS (HtSDS) of -0.13 (-2.52 to 1.58; p < 0.05). In addition, the study cohort had a lower median IGF-1 SDS of -0.29 (-4.53 to 2.96; p = 0.008) and a higher median IGFBP3 SDS of 0.45 (-3.15 to 2.55; p = 0.002). Over the study period, the median Ht velocity (HV) was 5 cm/year (0.2-8.7) and the change in HtSDS was 0.06 (-0.48 to 0.57). The median difference between the chronological and bone age was 0.3 years (-2.5 to 3.0) and pubertal examination was not delayed. In the whole group, the erythrocyte sedimentation rate (ESR) showed an inverse association with HV (r = -0.29; p = 0.025) and IGF-1:IGFBP3 (r = -0.34; p = 0.016). The score in the body image domain, IMPACT-III, was inversely associated with HtSDS (r = -0.31; p = 0.03). Conclusion: Despite no evidence of pubertal delay, adolescents with IBD display growth retardation which may be associated with raised ESR, adverse quality of life measures and an abnormality of IGF-1 bioavailability.

A Case of Functional Growth Hormone Deficiency and Early Growth Retardation in a Child With IFT172 Mutations

CONTEXT Ciliopathies are a group of rare conditions that present through a wide range of manifestations. Given the relative common occurrence of defects of the GH/IGF-I axis in children with short stature and growth retardation, the association between ciliopathies and these defects needs further attention. CASE Our patient is a boy who was born at term and noted to have early growth retardation and weight gain within the first 18 months of life. Biochemical tests demonstrated low IGF-I but a normal peak GH on stimulation and an adequate increase in IGF-I on administration of recombinant human growth hormone (rhGH). A magnetic resonance imaging scan revealed pituitary hypoplasia and an ectopic posterior pituitary. His growth responded well to rhGH therapy. Subsequently he also developed a retinopathy of his rods and cones, metaphyseal dysplasia, and hypertension with renal failure requiring renal replacement therapy. Whole-exome sequencing demonstrated compound heterozygous mutations of IFT172, thus consistent with a ciliopathy. CONCLUSIONS This is the first reported case of a child with a mutation in IFT172 who presented with growth retardation in early childhood and was initially managed as a case of functional GH deficiency that responded to rhGH therapy. This case highlights the importance of ciliary function in pituitary development and the link between early onset growth failure and ciliopathies.

Prevalence of endocrine and genetic abnormalities in boys evaluated systematically for a disorder of sex development

Abstract STUDY QUESTION What is the likelihood of identifying genetic or endocrine abnormalities in a group of boys with 46, XY who present to a specialist clinic with a suspected disorder of sex development (DSD)? SUMMARY ANSWER An endocrine abnormality of the gonadal axis may be present in a quarter of cases and copy number variants (CNVs) or single gene variants may be present in about half of the cases. WHAT IS KNOWN ALREADY Evaluation of 46, XY DSD requires a combination of endocrine and genetic tests but the prevalence of these abnormalities in a sufficiently large group of boys presenting to one specialist multidisciplinary service is unclear. STUDY, DESIGN, SIZE, DURATION This study was a retrospective review of investigations performed on 122 boys. PARTICIPANTS/MATERIALS, SETTING, METHODS All boys who attended the Glasgow DSD clinic, between 2010 and 2015 were included in the study. The median external masculinization score (EMS) of this group was 9 (range 1–11). Details of phenotype, endocrine and genetic investigations were obtained from case records. MAIN RESULTS AND THE ROLE OF CHANCE An endocrine abnormality of gonadal function was present in 28 (23%) with a median EMS of 8.3 (1–10.5) whilst the median EMS of boys with normal endocrine investigations was 9 (1.5–11) (P = 0.03). Endocrine abnormalities included a disorder of gonadal development in 19 (16%), LH deficiency in 5 (4%) and a disorder of androgen synthesis in 4 (3%) boys. Of 43 cases who had array-comparative genomic hybridization (array-CGH), CNVs were reported in 13 (30%) with a median EMS of 8.5 (1.5–11). Candidate gene analysis using a limited seven-gene panel in 64 boys identified variants in 9 (14%) with a median EMS of 8 (1–9). Of the 21 boys with a genetic abnormality, 11 (52%) had normal endocrine investigations. LIMITATIONS, REASONS FOR CAUTION A selection bias for performing array-CGH in cases with multiple congenital malformations may have led to a high yield of CNVs. It is also possible that the yield of single gene variants may have been higher than reported if the investigators had used a more extended gene panel. WIDER IMPLICATIONS OF THE FINDINGS The lack of a clear association between the extent of under-masculinization and presence of endocrine and genetic abnormalities suggests a role for parallel endocrine and genetic investigations in cases of suspected XY DSD. STUDY FUNDING/COMPETING INTEREST(S) RN was supported by the James Paterson Bursary and the Glasgow Childrens Hospital Charity Summer Scholarship. SFA, RM and EST are supported by a Scottish Executive Health Department grant 74250/1 for the Scottish Genomes Partnership. EST is also supported by MRC/EPSRC Molecular Pathology Node and Wellcome Trust ISSF funding. There are no conflicts of interest. TRIAL REGISTRATION NUMBER None.

Frequency and aetiology of hypercalcaemia

Background Hypercalcaemia is rare in children and may present with characteristic signs/symptoms or coincidentally following investigations for a variety of non-specific conditions. The aetiologies of childhood hypercalcaemia are diverse. Untreated sustained hypercalcaemia has serious clinical consequences. However there is limited data regarding the true frequency and aetiologies of childhood hypercalcaemia. Aim To determine the frequency of severe childhood hypercalcaemia in routine clinical practice. Methods The laboratory database was searched for all children (0–17 years) with severe hypercalcaemia defined as non-adjusted ≥2.90 mmol/L from 2007–2012. Hypercalcaemia was categorised as either transient (1 day) or sustained (≥2 consecutive days). Retrospective analysis of all cases of sustained severe hypercalcaemia was performed to identify the underlying aetiology. Results Over the 5 year period, 206 children were identified as severely hypercalcaemic ≥2.90 mmol/L (0.3% all 61 380 calcium requests). Of these 131 (63.3%) children were classified as having sustained hypercalcaemia. The frequency of severe hypercalcaemia was highest in neonates (42% of sustained cases) and was inversely related to age. Sepsis was the most common aetiology (24%), particularly in neonates where it accounted for 41% of all causes of neonatal hypercalcaemia. Endocrine aetiologies included congenital adrenal hyperplasia (2 cases), fat necrosis (1), Addisons disease (2). A genetic cause was identified in 3 children (2 familial hypocalciuria hypercalcaemia, 1 Williams syndrome). Conclusions Sustained hypercalcaemia affects 1 in 500 children in a general hospital setting. The frequency was highest in neonates and underlying aetiology differed markedly with age. All children with sustained hypercalcaemia require thorough investigation to determine the underlying aetiology to ensure appropriate management.

The measurement of urinary gonadotropins for assessment and management of pubertal disorder

OBJECTIVE: Measurement of urinary LH (uLH) and FSH (uFSH) may facilitate non-invasive pubertal assessment but there is a need for further validation by studying children and adolescents with disorders of puberty. DESIGN: 65 cases (Male: 25) with a median age of 12 years (2.9–18.1) supplied at least one non-timed urine sample for uLH and uFSH measurement by immunoassay and corrected for creatinine excretion. 25 cases were receiving GnRH-agonist (GnRH-a) at the time of sample collection. In 41 cases, urine samples were collected prior to a LHRH test and in 12 cases matched serum samples for basal LH (sLH) and FSH (sFSH) were also available. RESULTS: There was a significant correlation between sLH and uLH:uCr (r=0.82; p-value <0.001) and sFSH and uFSH:uCr (r=0.93; p-value <0.001). Based on receiver operator characteristics analysis, a uLH:uCr value of 0.05 IU/mmol as a cut-off would detect a LH peak >5U I/L with a sensitivity of 86% and a specificity of 72% with a positive predictive value of 93%. In pubertal boys (6) and girls (22) with a sLH peak >5UI/L, median uLH:uCr was 0.27 IU/mmol (0.27–0.28) and 0.17 IU/mmol (0.09–0.43), respectively. The median uFSH:uCr was 0.51 IU/mmol (0.41–0.60) for boys and 1.1 IU/mmol (0.21–2.44) for girls. In the 25 cases on GnRH-a, the median uLH:uCr for boys and girls was 0.02 IU/mmol (0.01–0.02) and 0.02 IU/mmol (0.004–0.07), respectively, and the median uFSH:uCr was 0.07 IU/mmol (0.05–0.09) and 0.27 IU/mmol (0.09–0.54), respectively. CONCLUSION: Urinary gonadotrophins reflect serum gonadotrophin concentration and may represent a reliable non-invasive method of assessing pubertal progress.

Cerebrospinal fluid total protein cannot reliably distinguish true subarachnoid haemorrhage from other causes of raised cerebrospinal fluid net bilirubin and net oxyhaemoglobin absorbances

Background In cerebrospinal fluid (CSF) spectrophotometry, if the net bilirubin absorbance (NBA) and net oxyhaemoglobin absorbance (NOA) are both raised with a visible oxyhaemoglobin peak, the revised national guidelines for analysis of CSF bilirubin advise interpreting the results as ‘Consistent with subarachnoid haemorrhage (SAH)’ regardless of the CSF total protein concentration of the specimen. We wanted to study the range of CSF total protein concentrations found in confirmed SAH to establish if the CSF total protein value can give further guidance on the likelihood of SAH. Methods Consecutive cases from five different hospital sites were included if the CSF NBA was greater than 0.007 AU and the NOA was greater than 0.02 AU with a visible oxyhaemoglobin peak. For the cases identified, the laboratory information management system and patient records were interrogated to identify the total protein concentration of the CSF specimen and whether SAH had ultimately been confirmed or excluded by other methods and supporting evidence. Results Results from 132 patients were included. The CSF total protein range in confirmed SAH was 0.23–3.08 g/L with a median concentration of 0.7 g/L (n = 51). In the SAH excluded group, the CSF total protein range was 0.43–29 g/L with a median concentration of 1.9 g/L (n = 81). Conclusions Although confirmed SAH was not associated with the very highest concentrations of CSF total protein, a definite CSF protein cut-off concentration above which SAH could reliably be excluded cannot be recommended.

A retrospective analysis of longitudinal changes in bone mineral content in cystic fibrosis

Abstract Background: We aimed to describe the longitudinal changes in bone mineral content and influencing factors, in children with cystic fibrosis (CF). Methods: One hundred children (50 females) had dual X-ray absorptiometry (DXA) performed. Of these, 48 and 24 children had two to three scans, respectively over 10 years of follow-up. DXA data were expressed as lumbar spine bone mineral content standard deviation score (LSBMCSDS) adjusted for age, gender, ethnicity and bone area. Markers of disease, anthropometry and bone biochemistry were collected retrospectively. Results: Baseline LSBMCSDS was >0.5 SDS in 13% children, between −0.5; 0.5 SDS, in 50% and ≤−0.5 in the remainder. Seventy-eight percent of the children who had baseline LSBMCSDS >−0.5, and 35% of the children with poor baseline (LSBMCSDS<−0.5), showed decreasing values in subsequent assessments. However, mean LS BMC SDS did not show a significant decline in subsequent assessments (−0.51; −0.64; −0.56; p=0.178). Lower forced expiratory volume in 1 s percent (FEV1%) low body mass index standard deviation scores (BMI SDS) and vitamin D were associated with reduction in BMC. Conclusions: Bone mineral content as assessed by DXA is sub-optimal and decreases with time in most children with CF and this study has highlighted parameters that can be addressed to improve bone health.

Use of Cortisol and Adrenal Weight at Pediatric Postmortem

ABSTRACT We studied the relationship between adrenal weight and postmortem cortisol level in cases of infant death, and examined use of these measurements in adrenal insufficiency. We analyzed procurator-fiscal postmortem reports in the West of Scotland over a three year period. Combined adrenal weight was expressed as percentage of total body weight (%TBW). Of 106 cases, median (5th, 95th) %TBW was 0.056 (0.025, 0.23) and median plasma cortisol was 8.4 ug/dl (1.0, 47.1). There was no correlation between %TBW and plasma cortisol (r = 0.09, p = 0.4). The lowest and highest plasma cortisol quartile had medians of 1.9 ug/dl (1.0, 3.4) and 34.3 ug/dl (17.3, 71.5), respectively. Infection was present in 6 cases (23.1%) in the lowest quartile and in 16 cases (61.5%) in the highest quartile (p = 0.01). Our results highlight the difficulty in interpretation of cortisol at postmortem and suggest that adrenal weight measurement alone may be insufficient for diagnosis of adrenal insufficiency.

Urinary gonadotrophins: role in assessment and management of disorders of puberty

AND MANAGEMENT OF DISORDERS OF PUBERTY Laura Lucaccioni1,2, Jane McNeilly3, Avril Mason1, Claudio Giacomozzi1,4, M Guftar Shaikh1, Lorenzo Iughetti2, S Faisal Ahmed1 1 Developmental Endocrinology Research Group, Royal Hospital for Sick Children, University of Glasgow, G3 8SJ, UK 2 Paediatric Unit, Department of Medical and Surgical Sciences of the Mother, Children and Adults, University of Modena and Reggio Emilia, Modena, Italy 3 Dept. Biochemistry, Royal Hospital for Sick Children, Glasgow G3 8SJ,UK 4 U.O.C. Broncopneumologia, Department of Paediatric Medicine, Bambino Gesù Childrens Hospital, Rome, Italy