Safety and efficacy of oxandrolone in growth hormone-treated girls with Turner syndrome: evidence from recent studies and recommendations for use.

There has been no consensus regarding the efficacy and safety of oxandrolone (Ox) in addition to growth hormone (GH) in girls with Turner syndrome (TS), the optimal age of starting this treatment, or the optimal dose. This collaborative venture between Dutch, UK and US centers is intended to give a summary of the data from three recently published randomized, placebo-controlled, double-blind studies on the effects of Ox. The published papers from these studies were reviewed within the group of authors to reach consensus about the recommendations. The addition of Ox to GH treatment leads to an increase in adult height, on average 2.3­4.6 cm. If Ox dosages<0.06 mg/kg/day are used, side effects are modest. The most relevant safety concerns are virilization(including clitoromegaly and voice deepening) and a transient delay of breast development. We advise monitoring signs of virilization breast development and possibly blood lipids during Ox treatment, in addition to regular follow-up assessments for TS. In girls with TS who are severely short for age, in whom very short adult stature is anticipated,or in whom the growth rate is modest despite good compliance with GH, adjunctive treatment with Ox at a dosage of 0.03­0.05 mg/kg/day starting from the age of 8­10 years onward scan be considered.

Cholesteatoma has a high prevalence in Turner syndrome, highlighting the need for earlier diagnosis and the potential benefits of otoscopy training for paediatricians.

AIM: Girls with Turner syndrome are prone to cholesteatoma, a serious suppurative middle ear disease. We aimed to confirm its high prevalence in Turner syndrome, identify risk factors and suggest possible strategies for earlier detection. METHODS: We reviewed 179 girls with Turner syndrome between 1989 and 2012 to identify cases of cholesteatoma. RESULTS: Seven girls (3.9%) had cholesteatoma (index girls) and each was compared with three age-matched girls without cholesteatoma (comparison girls). All the index girls had either the 45,X or 45,X/46X,i(Xq) karyotypes. Nine ears were initially affected, with three recurrences in two girls. Median age at first cholesteatoma presentation was 11.9 years (range: 7.5-15.2), with otorrhoea for three (range: one to seven) months in all 12 affected ears. Index girls had a significantly higher proportion of previous recurrent acute (p = 0.007) and chronic otitis media (p = 0.008), chronic perforation (p = 0.038) aural polyps (p < 0.0001) and tympanic membrane retraction (p = 0.0001) than comparison girls. CONCLUSION: Cholesteatoma has a high prevalence in Turner syndrome. Risk factors include 45,X and 46,XiXq karyotypes; a history of chronic otitis media, tympanic membrane retraction and persistent otorrhoea; and older age. Earlier recognition of ear disease is needed and otoscopy training for paediatricians caring for Turner syndrome patients may be beneficial.

Exaggerated adrenarche in a cohort of Scottish children: clinical features and biochemistry.

OBJECTIVE: To investigate the reported association between exaggerated adrenarche (EA) and reduced foetal growth and to identify possible risk factors for future morbidity in Scottish children with clinical features of EA. DESIGN: Three-year prospective study. MEASUREMENTS: Auxology, blood pressure (BP), biochemical analysis of blood and urine, pelvic ultrasound in girls. RESULTS: Fifty-two patients were recruited of whom one girl had nonclassical congenital adrenal hyperplasia (17-OHP 17 nmol/l) and one had insufficient blood for analysis. The final cohort comprised 42 girls of mean (SD) age 7.7 (0.99) and eight boys of 8.8 (0.67) years. Mean (SD) birth weight was 3.27 (0.49) and 3.10 (0.76) kg in girls and boys respectively. Height/weight SDS were 1.13/1.69 in girls and 1.69/1.88 in boys. Mean systolic/diastolic BP was 107.8/60.4 (50th-75th centile) in girls and 115.5/63.9 (75th-91st centile) in boys. Uterine and ovarian development was prepubertal. Median serum dehydroepiandrosterone sulphate (DHEAS) was 2.1 and 4.1 mumol/l, androstenedione 3.1 and 3.8 nmol/l in girls and boys respectively, with DHEAS within the reference range/undetectable in 18/2 and androstenedione in 12/6 patients. Fasting insulin was 9.0 and 15.0 mU/l in girls and boys respectively, with concomitant low normal SHBG. Anti-Mullerian hormone (AMH) was 15.7 pmol/l in 27 girls, compared with 5.0 pmol/l in normal girls aged 5-8 years. CONCLUSIONS: Our Scottish EA cohort showed female predominance, no evidence of reduced foetal growth, a tendency to overweight with commensurate mild hyperinsulinaemia and modest elevation of serum androgens in some patients. We have found raised AMH levels in the girls, indicating advanced ovarian follicular development.

Effect of high versus low initial doses of L-thyroxine for congenital hypothyroidism on thyroid function and somatic growth.

BACKGROUND AND AIMS: The optimal dose of thyroxine (T4) in congenital hypothyroidism (CH) during infancy is controversial. Higher doses lead to improvement in cognitive scores, but have been linked to later behavioural difficulties. We have examined the effects of initial T4 dosage on somatic growth--a putative surrogate marker of overtreatment. METHODS: 314 CH children (214 girls, 100 boys) were analysed according to initial daily dose of T4: Group 1 (25 mug, n = 152), Group 2 (30-40 mug, n = 63) and Group 3 (50 mug, n = 99). Thyroid function and weight, length and occipito-frontal head circumference (OFC) standard deviation score (SDS) were compared at 3, 6, 12, 18, 24 and 36 months of age. Linear growth SDS was compared between the three groups using a regression adjustment model at 12 and 18 months of age using birth weight and 3-month data as baselines. Thyroid function was also compared at diagnosis (T 0), and 7-21 days after the start of treatment (T1). RESULTS: At T1 median thyroid stimulating hormone (TSH) for Groups 1, 2 and 3 was 58, 29 and 4.1 mU/l, respectively (p<0.001), Group 3 values remaining significantly lower at 3 and 6 months. Median free T4 (fT4) was within or just above the reference range in all groups at T1, but 7.4% of Group 1 had values <9 pmol/l compared with 5.1% and 0% for Groups 2 and 3, respectively. At 3 months weight, length and OFC SDS values were -0.39, -0.35, 0.09; -0.30, -0.47, 0.32; and -0.03, -0.13, 0.18 for Groups 1, 2 and 3, respectively, indicating relatively large OFC in all infants. A regression adjustment model showed no significant difference in growth rate from baseline and 12 or 18 months of age, between the three groups. CONCLUSION: An initial T4 dose of 50 mug daily, normalises thyroid function several months earlier than lower-dose regimes, with no evidence of sustained somatic overgrowth between 3 months and 3 years.

Fatal and near-fatal encephalopathy with hyponatraemia in two siblings with fluticasone-induced adrenal suppression.

AIM: To document previously unreported acute effects of adrenal insufficiency. METHODS: We describe two siblings who presented acutely with hyponatraemia and cerebral oedema following prolonged treatment with high dose inhaled fluticasone. RESULTS: A girl aged 5.5 years presented with vomiting, headache, visual impairment and seizures. She was hyponatraemic but not hypoglycaemic. Her conscious level continued to deteriorate and she died, post mortem examination showing small adrenal glands and cerebral oedema. Four weeks later her 7-year-old brother presented with similar symptoms. Assessment showed hyponatraemia with cerebral oedema. His illness responded to intensive care. A diagnosis of adrenal insufficiency was made retrospectively in both cases. The siblings had been receiving Fluticasone propionate (FP) in doses of up to 2000 microg/day for several years. CONCLUSION: We believe that the hyponatraemia and cerebral oedema was related to cortisol deficiency, leading to impaired excretion of water. We emphasize the need for careful cerebral monitoring in acute adrenal insufficiency presenting with impaired consciousness.

Combined ultrasound and isotope scanning is more informative in the diagnosis of congenital hypothyroidism than single scanning.

BACKGROUND: Thyroid imaging is helpful in confirming the diagnosis of congenital hypothyroidism and in establishing the aetiology. Although isotope scanning is the standard method of imaging, ultrasound assessment may be complementary. AIM: To determine the strengths and weaknesses of thyroid ultrasound and isotope scanning in neonates with thyroid stimulating hormone (TSH) elevation. METHODS: Babies from the West of Scotland with raised capillary TSH (>15 mU/l) on neonatal screening between January 1999 and 2004 were recruited. Thyroid dimensions were measured using ultrasonography, and volumes were calculated. Isotope scanning was carried out with a pinhole collimator after an intravenous injection of 99m-technetium pertechnetate. RESULTS: 40 infants (29 female) underwent scanning at a median of 17 days (range 12 days to 15 months). The final diagnosis was athyreosis (n = 11), ectopia (n = 12), hypoplasia (n = 8; 3 cases of hemi-agenesis), dyshormonogenesis (n = 5), transient hypothyroidism (n = 2), transient hyperthyrotropinaemia (n = 1) and uncertain status with gland in situ (n = 1). 6 infants had discordant scans with no isotope uptake but visualisation of thyroid tissue on ultrasound. This was attributed to TSH suppression from thyroxine (n = 3); maternal blocking antibodies (n = 1); cystic degeneration of the thyroid (n = 1); and possible TSH receptor defect (n = 1). CONCLUSIONS: Isotope scanning was superior to ultrasound in the detection of ectopic tissue. However, ultrasound detected tissue that was not visualised on isotope scanning, and showed abnormalities of thyroid volume and morphology. We would therefore advocate dual scanning in newborns with TSH elevation as each modality provides different information.

Optimising management in Turner syndrome: from infancy to adult transfer.

Turner syndrome can be defined as loss or abnormality of the second X chromosome in at least one cell line in a phenotypic female. The condition occurs in approximately 1 in every 2000 live female births,(1) so that in the UK the prevalence for any year of life is in the region of 200 girls. The condition is much more common in utero, it being estimated that 1-2% of all conceptuses are affected, of whom only 1% will survive to term.

Improvement in screening performance and diagnosis of congenital hypothyroidism in Scotland 1979-2003.

AIM: To assess the Scottish newborn screening programme for congenital hypothyroidism from 1994 to 2003 (period 2) for performance and compare with an initial audit covering 1979 to 1993 (period 1). DESIGN: Performance data-age at blood spot sampling, notification by screening laboratory, start of treatment, and the prevalence of late testing, notification or treatment-were compared, together with the incidence of congenital hypothyroidism. RESULTS: Comparing data for period 2 with period 1, the mean annual incidence of true congenital hypothyroidism was 1:3655 live births v 1:4363. Median age for Guthrie sampling (all referrals) was 6 v 7 days (p<0.0001). Late sampling (>10 days) had fallen from 10.7% to 7%. For infants requiring repeat sampling before notification, the median (range) interval between initial and final repeat samples was 11 (1 to 52) compared with 14 (3 to 73) days. Median age at notification for true congenital hypothyroidism was 10 v 12 days (p <0.0001). Late notification (>15 days) was justifiable (mild TSH elevation) in 10 of 13 patients in period 2. Median age at start of treatment for true congenital hypothyroidism had improved to 11 days from 13.5 days. For true congenital hypothyroidism, late treatment (>16 days) occurred in 7% of patients compared with 19% (p<0.0001). CONCLUSIONS: There has been an improvement in performance measures for the congenital hypothyroidism screening programme in Scotland. However, late sampling, occurring primarily in inpatients and which is never justified, remains a problem, while the interval between initial and recall sampling is a further source of delay.

Measured versus reported parental height.

BACKGROUND: Parental height data are essential in the assessment of linear growth in children. A number of studies have documented inaccuracy in self-reported adult height. AIMS: To determine whether there is a tendency for men to overestimate and women to underestimate their height. METHODS: Heights of parents of children attending outpatient clinics were measured (MHt) and compared with reported heights (RHt). RESULTS: Two hundred parents (100 males; 100 females), mean (range) age 37.8 (20.8-69.3) years, were measured. Males overestimated height, with mean (SD) RHt-MHt 1.09 (1.96) cm, while females reported height relatively accurately, with RHt-MHt -0.09 (2.37) cm. CONCLUSIONS: The hypothesis that males overestimate height is confirmed. While the hypothesis that women underestimate is not supported, we recommend accurate measurement of both parents, given the considerable degree of individual variation in RHt-MHt for both sexes.

An investigation of executive function abilities in adults with Prader-Willi syndrome.

BACKGROUND: Prader-Willi syndrome (PWS) is a genetic disorder caused by the absence of expression of maternally imprinted genes on the long arm of chromosome 15 (15q 11-13). There are two main genetic sub-types: (1) deletion, caused by the absence of paternally derived genetic material; and (2) uniparental disomy (UPD), where two copies of maternally derived chromosome 15 are present. In addition to generally mild/borderline intellectual disability (ID) and the almost universal feature of hyperphagia, PWS is associated with high rates of behaviour problems including temper tantrums, compulsive behaviour, perseverative speech, skin picking and rigid thinking. The present study seeks to explore whether these behaviours are associated with relative deficits in executive function (EF), which comprises the set of non-automatic processes utilized by an individual when faced with a novel situation. METHODS: Eighteen adult participants with a clinical diagnosis of PWS (12 with deletion sub-type, 6 with UPD) were recruited from a UK Health Service PWS clinic, and compared with 15 participants of similar age and verbal ability on a series of EF tasks and also Digit Span Forwards. An informant completed two ratings of behaviour, the Aberrant Behavior Checklist (ABC) and the Dysexecutive Questionnaire (DEX). RESULTS: The PWS group had significantly higher scores on the ABC but not on the DEX. There were no significant differences between the whole PWS group and the comparison group on any of the EF tasks. The deletion sub-type group was significantly poorer at a non-executive task, Digit Span Forwards. There was an unexpected trend for the deletion sub-type group to show more efficient performance on a visuospatial planning task, the Tower of London (TOL), but this trend did not reach significance. CONCLUSIONS: The lack of relative deficits in EF task performance does not support the hypothesis that EF differences could account for the high levels of behaviour problems found in PWS. Applying the Baddeley and Hitch model of working memory it is suggested that the PWS group have a relatively intact central executive and visuospatial sketchpad but a relative impairment in the phonological loop, perhaps relating to the capacity of the phonological store. This latter finding seems to be particularly salient for those with a deletion. As differences in EF ability were not found, it is suggested that a region of the brain involved in the modulation of emotion but not particularly with EF, the orbitofrontal cortex (OFC), may be implicated in the behaviour problems reported in PWS.

Auxological outcome and time to menarche following long-acting goserelin therapy in girls with central precocious or early puberty.

OBJECTIVE: Following a successful clinical trial in 1996, the long-acting GnRH analogue goserelin (Zoladex LA 10.8 mg; Astra Zeneca) has been our preferred treatment for central early (CEP) or precocious puberty (CPP). However, some female patients have expressed concern about perceived weight gain during therapy and delay in the onset or resumption of menses on completion of therapy. The primary aim of this study was to investigate these concerns by determining the auxological parameters and timing of menarche or re-menarche in all girls with CEP/CPP who have completed a course of Zoladex LA treatment. The secondary aim was to assess auxological outcome in girls who have attained final height. DESIGN AND PATIENTS: Case records of all girls with idiopathic CEP/CPP or CEP/CPP secondary to CNS pathology treated with Zoladex LA since 1996 were reviewed. A total of 46 girls who have completed therapy were identified, of whom 11 had reached final height. measurements Height, weight and bone age (RUS (TW2) method) were measured before treatment, when Zoladex LA was stopped and at final height. Body mass index (BMI) was calculated as a clinical measure of body fatness. Pubertal status was assessed pre- and post-treatment by Tanner staging and pelvic ultrasonography. Timing of menarche or re-menarche following cessation of treatment was recorded. RESULTS: The mean (range) age of starting GnRH analogue therapy was 8.3 (1.8-10.5) years and the duration of treatment was 2.9 (0.7-8.9) years. Pre-treatment height was above average at 0.72 SD but had declined to 0.28 SD by the end of therapy. The 46 girls were heavier than average before treatment (Wt SDS 1.04) with no change in weight status on completion of therapy. Mean BMI SDS increased significantly from 0.93 to 1.2 during treatment, indicating that the girls became relatively fatter. Using recommended BMI cut-off values for defining overweight and obesity in children of the 85th and 95th centiles, 41% of the cohort were overweight and 28% were obese before treatment, rising to 59% and 39%, respectively, at the end of therapy. The average time interval to onset or resumption of menses after stopping treatment was 1.46 years (median 1.5, range 0.8-2.0 years). None of the following variables was found to be predictive of the time interval to menarche after completion of therapy: duration of treatment; chronological age; bone age; Tanner breast stage or uterine maturation at the end of treatment; the frequency of injections required to suppress puberty; or treatment with alternative GnRH analogue prior to Zoladex LA. Mean final height in 11 girls was 159.7 cm (-0.63 SD), close to the mean parental target height of 160.9 cm (-0.48 SD). Nine of the 11 girls (82%) attained final heights within or above their target range. In keeping with the whole cohort this subset of girls became fatter during treatment, although this difference was not statistically significant. However, they returned to their pretreatment size at final height (mean BMI SDS 1.18, 1.41 and 1.16 before, at the end of treatment and at final height, respectively). CONCLUSIONS: Our cohort of 46 girls treated with long-acting goserelin was already considerably overweight at the start of therapy and became fatter during treatment. However, adiposity appeared to return to pretreatment levels in the 11 girls followed up to final height. Most of the girls who have attained final height are within or above their expected target range. The relatively long time interval to menarche of 1.5 years after stopping treatment is unexplained but may reflect a residual suppressive effect on the hypothalamo-pituitary axis of this long-acting GnRH analogue. Anticipation of the timing of menarche has proved to be of value in planning when to stop therapy in girls in whom treatment is mainly for practical and/or psychological reasons.

Improved final height in Turner's syndrome following growth-promoting treatment at a single centre.

AIMS: To examine the final height (FH) outcome of girls with Turner's syndrome (TS) treated at a single Scottish centre (Glasgow group), to compare it with an earlier national analysis (Scottish group) and to suggest reasons for any change. METHODS: Retrospective growth and treatment data for 29 Glasgow patients were compared with those of 26 Scottish patients. RESULTS: Age at GH start (mean +/- SD) was 10.1 +/- 2.6 vs 12.1 +/- 1.7 y (p < 0.01) in the Glasgow versus Scottish groups, with overall duration of treatment 6.2 +/- 2.4 vs 3.7 +/- 1.1 y (p < 0.001) and years of GH treatment before pubertal induction 2.7 +/- 2.8 vs 0.3 +/- 0.8 y (p < 0.001), respectively. Pubertal induction was at a similar age: 12.7 +/- 1.8 vs 12.8 +/- 1.8 y (ns). FH was 151.1 +/- 4.6 cm in the Glasgow group compared with 142.6 +/- 5.6 cm in the Scottish group (p < 0.001), with FH - projected adult height (PAH) 5.7 +/- 4.6 cm vs 0.6 +/- 3.6 cm (p < 0.001), respectively. Univariate analysis of the Glasgow group's FH - PAH with a number of growth and treatment variables identified no statistically significant relationships. CONCLUSION: This group's improved FH and FH - PAH, relative to an earlier sample, are attributed to the introduction of GH treatment from a younger age and for longer, overall and before pubertal induction. In addition, the authors believe that compliance with treatment has been enhanced by this single centre's dedicated Turner clinic and the efforts of its established "growth team". These data demonstrate that a favourable FH can be achieved using a safe and financially viable dose of GH, while inducing puberty at a "normal" age.

Cleft palate, hypotelorism, and hypospadias: Schilbach-Rott syndrome.

A mother and two sons have cleft palate and facial appearance closely resembling cases described by Schilbach and Rott in 1988. One of the two males has hypospadias and learning disability and, like his mother, is of short stature. The family described by Schilbach and Rott also supports an autosomal dominant inheritance pattern.

Ultrasound of the thyroid gland in the newborn: normative data.

OBJECTIVE: To establish reference ranges for thyroid length, breadth, depth, and volume in healthy term Scottish infants. DESIGN: Prospective observational study of 100 (49 male) neonates. Length, breadth, and depth were measured, and the volume of each lobe was calculated using the formula for a prolate ellipsoid (volume = length x breadth x depth x pi/6). RESULTS: All measurements showed gaussian distribution, with no significant differences between the right and the left lobes. Values (mean (SD) range) were: length (cm), 1.94 (0.24) 0.9-2.5; breadth (cm), 0.88 (0.16) 0.5-1.4; depth (cm), 0.96 (0.17) 0.6-2.0; volume (ml), 0.81 (0.24) 0.3-1.7; combined volume (ml), 1.62 (0.41) 0.7-3.3. Although there was no difference in mean volume between right and left lobes, there was considerable variation (-0.8 to + 0.7 ml) between the two lobes in individual babies. CONCLUSIONS: Both lobes should be measured to give a combined volume. Our findings provide a reference against which thyroid hypoplasia or goitre can be evaluated.

Safety of the insulin tolerance test.

Concerns have been raised about the hazards of the insulin tolerance test (ITT), used to measure growth hormone secretion. In Glasgow, we continue to use this test, adhering to a strict protocol. A review of outcome over a 10 year period (1989-99), during which 550 ITTs were performed, was undertaken. No serious adverse events occurred; in particular, no child fitted or required intravenous glucose. Fewer tests were done during the latter five years, with a higher yield of growth hormone (GH) deficiency, reflecting our increasingly conservative approach to paediatric GH therapy during this period. We conclude that the ITT is safe and reliable in a paediatric setting provided that a strict procedure is followed.

Cushing's syndrome, growth impairment, and occult adrenal suppression associated with intranasal steroids.

We have previously described iatrogenic Cushing's syndrome secondary to intranasal steroids. This report further highlights the potential deleterious effects of intranasal steroids. Nine cases (including the original two cases) are reviewed to show the varied clinical manifestations of adrenal suppression caused by intranasal steroids. Four presented with Cushing's syndrome, three with growth failure, while two asymptomatic patients were discovered in the course of pituitary function testing. Four children had dysmorphic syndromes--Down's, Treacher-Collins, CHARGE association, and campomelic dysplasia--reflecting the vulnerability of such children to ENT problems, together with the difficulty of interpreting steroid induced growth failure in this context. Adrenal suppression was seen not only with betamethasone but also with budesonide, beclomethasone and flunisolide nasal preparations. A careful enquiry as to the use of intranasal steroids should be routine in children presenting with unexplained growth failure or Cushing's syndrome. Particular vigilance/awareness is required in children with dysmorphic syndromes.