Hypogonadism in the Prader-Willi syndrome from birth to adulthood: a 28-year experience in a single centre.

BACKGROUND: Hypogonadism is a key feature of Prader-Willi syndrome (PWS) but clear strategies for hormone replacement are lacking. OBJECTIVE: To evaluate gonadal status and outcome in patients attending a Scottish PWS clinic from 1991-2019. METHODS: In 93 (35F:56M) patients, median follow-up 11.2 years, gonadal and pubertal status were assessed clinically. Pelvic ultrasound findings and basal/stimulated gonadotrophins were compared with age-matched controls. RESULTS: Females: Of 22 patients aged >11, 9 had reached B4-5, while 5 were still at B2-3, and 6 remained prepubertal. Eight patients experienced menarche aged 9.8-21.4 years, none with a normal cycle. Uterine length and ovarian volumes were normal but uterine configuration remained immature, with low follicular counts. Gonadotrophins were unremarkable, serum estradiol 129 (70 - 520) pmol/L. Only 5 patients received oestrogen replacement. Males: Fifty-four (96%) patients were cryptorchid (9 unilateral). Weekly hCG injections resulted in unilateral/bilateral descent in 2/1 of 25 patients. Of 37 boys aged >11, 14 (9 with failed/untreated bilateral cryptorchidism) failed to progress beyond G1, 15 arrested at G2-3 (testes 3-10 ml), and 8 reached G4-5. Gonadotrophins were unremarkable except in boys at G2-5 in whom FSH was elevated: 12.3/27.3 vs 3.25/6.26 U/L in controls (p<0.001). In males aged >13, testosterone was 3.1 (0.5-8.4) nmol/L. Androgen therapy, given from 13.5-29.2 years, was stopped in 4/24 patients owing to behavioural problems. CONCLUSION: Despite invariable hypogonadism, few females and only half the males with PWS in this study received hormone replacement. Double-blind placebo-controlled crossover trials of sex steroids are required to address unproven behavioural concerns.

Neonatal Features of the Prader-Willi Syndrome; The Case for Making the Diagnosis During the First Week of Life

Objective: Early diagnosis is of proven benefit in Prader-Willi syndrome (PWS). We therefore examined key perinatal features to aid early recognition. Methods: Data were collected from case records of subjects attending a multi-disciplinary clinic and from a retrospective birth questionnaire. Results: Ninety patients (54 male-36 female) were seen between 1991-2015, most with paternal deletion (n=56) or maternal isodisomy (n=26). Features included cryptorchidism in 94% males, preterm birth (26%), birthweight <2500 g (24%), polyhydramnios (23%), breech presentation (23%) and need for nasogastric feeding (83%). Reduced fetal movements (FM) were reported in 82.5% patients compared with 4% healthy siblings. Of 35 children born since 1999, 23 were diagnosed clinically within 28 days while diagnosis in 12 was >28 days: 1-12 months in seven; and 3.75-10.5 years in five. Typical PWS features in these 12 infants included hypotonia (100%), feeding difficulties (75%), cryptorchidism (83% males) and reduced FM (66%). Causes other than PWS including neuromuscular disease were considered in nine patients. Conclusion: Neonatal hypotonia, reduced FM, feeding difficulties and cryptorchidism should immediately suggest PWS, yet late diagnosis continues in some cases. Awareness of the typical features of PWS in newborn units is required to allow prompt detection even in the presence of confounding factors such as prematurity.

Short Stature Screening by Accurate Length Measurement in Infants with a Birth Weight <9th Centile.

BACKGROUND/AIMS: Intrauterine growth restriction is an indication for growth hormone treatment. Birth length (BL) is needed to evaluate the influence of birth size on childhood short stature. However, BL is commonly measured only approximately, if at all. A single-centre study was undertaken to determine the value of measuring accurate and targeted BL and parental height (PH) for neonates with a birth weight (BW) ≤9th centile, identifying short [BL ≤-2 standard deviation scores (SDS)] and light newborns (BW ≤-2 SDS), and remeasuring short neonates at 2 years in order to detect those not showing catch-up growth. METHODS: Information was collected on all live births (n = 3,798) in a single maternity unit during a 1-year period. RESULTS: BW was ≤9th centile in 481 neonates (12.7%) of whom 47 were light but not short, 46 were short, and 60 were both light and short. Of 107 eligible infants, 57 (53%) attended the 2-year follow-up; failure of catch-up growth was identified in 6 infants (11%) of whom only 1 was already known to medical services. PH was measured in both parents of 52/153 (34%) light and/or short infants. CONCLUSION: Targeted and accurate BL measurement in newborns with a BW ≤9th centile is a promising alternative to the current practices. The feasibility of PH measurement after birth still requires further evaluation. © 2015 S. Karger AG, Basel.

Competitive replacement of invasive congeners may relax impact on native species: interactions among zebra, quagga, and native unionid mussels.

Determining when and where the ecological impacts of invasive species will be most detrimental and whether the effects of multiple invaders will be superadditive, or subadditive, is critical for developing global management priorities to protect native species in advance of future invasions. Over the past century, the decline of freshwater bivalves of the family Unionidae has been greatly accelerated by the invasion of Dreissena. The purpose of this study was to evaluate the current infestation rates of unionids by zebra (Dreissena polymorpha) and quagga (D. rostriformis bugensis) mussels in the lower Great Lakes region 25 years after they nearly extirpated native unionids. In 2011-2012, we collected infestation data for over 4000 unionids from 26 species at 198 nearshore sites in lakes Erie, Ontario, and St. Clair, the Detroit River, and inland Michigan lakes and compared those results to studies from the early 1990 s. We found that the frequency of unionid infestation by Dreissena recently declined, and the number of dreissenids attached to unionids in the lower Great Lakes has fallen almost ten-fold since the early 1990s. We also found that the rate of infestation depends on the dominant Dreissena species in the lake: zebra mussels infested unionids much more often and in greater numbers. Consequently, the proportion of infested unionids, as well as the number and weight of attached dreissenids were lower in waterbodies dominated by quagga mussels. This is the first large-scale systematic study that revealed how minor differences between two taxonomically and functionally related invaders may have large consequences for native communities they invade.

Effect of oxandrolone and timing of oral ethinylestradiol initiation on pubertal progression, height velocity and bone maturation in the UK Turner study.

BACKGROUND: A UK study showed final height in Turner syndrome (TS) girls receiving growth hormone is affected by age at pubertal induction and oxandrolone (Ox). Using data from that study, we analysed the effect of timing of oral ethinylestradiol (EE2) and Ox on height velocity (HV), bone maturation and pubertal progression, and compared growth response in EE2-treated versus spontaneous puberty. METHODS: Analysis of HV, bone age and pubertal stage in 92 TS girls (7-13 years) randomised to Ox (0.05 mg/kg/day; max: 2.5 mg/day) or placebo from 9 years, and EE2 (year 1: 2 µg/day; year 2: 4 µg/day; year 3: 6/8/10 µg/day×4 months) or placebo at 12 years with EE2 at 14 years. Girls enrolled at >12.25 years received EE2 at 14 years ('late group'). RESULTS: Fifty-six girls were randomised to EE2 at 12 years (n=28, 11 Ox) or 14 years (n=28, 13 Ox); there were 19 girls in the late group (9 Ox) and 17 girls with spontaneous puberty (10 Ox). Girls receiving EE2 at 12 versus 14 years had faster bone maturation, but neither group showed acceleration. Ox increased HV without altering bone maturation or pubertal progression. Girls with spontaneous puberty had greater pubertal growth (mean PHV 8.5 cm/year; p<0.001) and height gain (p<0.001) than EE2-treated girls despite similar mean enrolment height SD and dysmorphology scores. CONCLUSION: Pubertal induction with EE2 does not replicate the acceleration observed in unaffected girls or TS girls with spontaneous puberty.

Effect of oxandrolone and timing of pubertal induction on final height in Turner's syndrome: randomised, double blind, placebo controlled trial.

OBJECTIVE: To examine the effect of oxandrolone and the timing of pubertal induction on final height in girls with Turner's syndrome receiving a standard dose of growth hormone. DESIGN: Randomised, double blind, placebo controlled trial. Setting 36 paediatric endocrinology departments in UK hospitals. PARTICIPANTS: Girls with Turner's syndrome aged 7-13 years at recruitment, receiving recombinant growth hormone therapy (10 mg/m(2)/week). INTERVENTIONS: Participants were randomised to oxandrolone (0.05 mg/kg/day, maximum 2.5 mg/day) or placebo from 9 years of age. Those with evidence of ovarian failure at 12 years were further randomised to oral ethinylestradiol (year 1, 2 µg daily; year 2, 4 µg daily; year 3, 4 months each of 6, 8, and 10 µg daily) or placebo; participants who received placebo and those recruited after the age of 12.25 years started ethinylestradiol at age 14. MAIN OUTCOME MEASURE: Final height. Results 106 participants were recruited, of whom 14 withdrew and 82/92 reached final height. Both oxandrolone and late pubertal induction increased final height: by 4.6 (95% confidence interval 1.9 to 7.2) cm (P = 0.001, n = 82) for oxandrolone and 3.8 (0.0 to 7.5) cm (P = 0.05, n = 48) for late pubertal induction with ethinylestradiol. In the 48 children who were randomised twice, the effects on final height (compared with placebo and early induction of puberty) of oxandrolone alone, late induction alone, and oxandrolone plus late induction were similar, averaging 7.1 (3.4 to 10.8) cm (P < 0.001). No cases of virilisation were reported. CONCLUSION: Oxandrolone had a positive effect on final height in girls with Turner's syndrome treated with growth hormone, as did late pubertal induction with ethinylestradiol at age 14 years. However, these effects were not additive, so using both had no advantage. Oxandrolone could, therefore, be offered as an alternative to late pubertal induction for increasing final height in Turner's syndrome. Trial registration Current Controlled Trials ISRCTN50343149.

Ethinyl estradiol treatment for growth limitation in girls with Marfan's syndrome--experience from a single center.

OBJECTIVES: Tall stature, a major characteristic of Marfan's syndrome, may be of concern to the family, particularly if the patient is a girl. Experience with treatment options-sex steroid or somatostatin analogue-for height reduction in girls is limited. We have evaluated our experience of estrogen treatment in girls with Marfan's syndrome attending the pediatric endocrine clinic in Glasgow between 1989 and 2005. DESIGN AND METHODS: Retrospective case note analysis combined with ascertainment of final/near final height, comparing outcome in treated and untreated girls. Cardiovascular health was assessed by examining aortic root diameter and blood pressure. RESULTS: The study cohort comprised four treated and five untreated girls, of whom three were sisters. Treatment was started in the four girls at chronological age 10.0 (2.1) years, mean (SD) height 155.0 (9.8) cm, and Tanner breast stage B1 in three and B2 in one. Ethinyl estradiol was administered in stepwise incremental regimens, starting at 10 microg/day and reaching 100 microg/day after 10 weeks in two girls and starting at 2 microg/day and reaching a maximum of 30-50 microg/day over a 2- to 3-year period in two girls. Mean +/- SD (range) final/near final height of the four treated girls was 174.3 (2.6) (170.6-176.6) cm compared with 183.0 (6.9) (171.5-190.3) cm in the five untreated girls. No deaths occurred in the treated group while one untreated girl died from presumed arrhythmia aged 18 years. Aortic root diameter increased with age, by mean (SD) 5.0 (2.1) and 5.8 (4.5) mm in treated and untreated groups, respectively, but with no between-group differences after treatment. CONCLUSIONS: The estrogen doses used in this study are lower than in previous reports. The results, although unsuitable for statistical analysis due to small numbers, are encouraging with no adverse events being recorded. Future research should be multicenter in design.

Hashimoto's thyroiditis in Down's syndrome: clinical presentation and evolution.

AIM: It was the aim of this study to describe the presentation and clinical course of Hashimoto's thyroiditis (HT) in children with Down's syndrome (DS) in 2 Scottish health regions. PATIENTS AND METHODS: We retrospectively analysed clinical, biochemical and thyroid antibody status in 38 patients with DS with HT diagnosed from 1989 to 2004. RESULTS: The sex distribution was similar (20 males, 18 females), with a median age of 12.3 years (range 2.1-17.7). Of the 38 patients reviewed, 29 were identified by screening. A goitre was present in 6/38 patients. Thyroid antibodies were positive in 36/38 patients, negative in 1/38, and data were unavailable for 1/38. At presentation, 37/38 patients were hypothyroid: 21/37 with compensated hypothyroidism (6 treated initially) and 16/37 with decompensated hypothyroidism (all treated). Of the 15/21 compensated patients who were untreated initially, only 3 remitted while 12 showed disease progression prompting treatment. In the decompensated group, 1/16 patient pursued a fluctuating course between hypo- and hyperthyroidism. The final patient, who was hyperthyroid at presentation, also showed marked fluctuation in thyroid function over a 5-year period. CONCLUSION: The natural history of HT in DS is unusual, with no female predominance and infrequent goitre in our cohort. While almost all patients required treatment eventually, clinicians should be aware that the disease may pursue a fluctuating course between hypo- and hyperthyroidism.

A novel missense mutation in DAX-1 with an unusual presentation of X-linked adrenal hypoplasia congenita.

A male presented at age 2.2 years with a 6-week history of intermittent vomiting and hyperpigmentation. Investigations showed salt wasting with hyperkalaemia, a grossly impaired cortisol response to ACTH stimulation, elevated renin and ACTH. Family history revealed that two maternal uncles had died soon after birth. A third uncle failed to thrive during infancy but improved with a course of cortisone, then being untreated until further investigation revealed adrenal insufficiency. A fourth uncle died aged 10 days, with urinary salt loss and hypoplastic adrenal glands at postmortem. Molecular studies on the proband, his mother, maternal grandmother, and surviving uncle showed a novel C to G substitution at nucleotide position 794 (missense mutation T265R) in the DAX1 (NR0B1) gene. The proband has responded well to steroid replacement but has proved sensitive to 9alpha-fludrocortisone treatment, developing hypertension on a dose of 133 microg/m(2)/day. At 8.8 years he was noted to have testicular volumes of 4 ml, despite no other evidence of secondary sexual development and prepubertal gonadotrophin levels. Novel features of this family include a novel DAX1 mutation, marked variability in age of presentation, hypertension on 'standard' doses of 9alpha-fludrocortisone and mild testicular enlargement.

Deterioration of visual acuity associated with growth hormone therapy in a child with extreme short stature and high hypermetropia.

BACKGROUND: Growth hormone (GH) has long been implicated in the pathogenesis of diabetic retinopathy, although its precise role remains ill-defined. In 1998, an association between exogenous human GH and retinal pathology in non-diabetic subjects was described. CASE REPORT: A female child with extreme short stature of unknown aetiology (height -7.38 SD at 11.3 years) and severe hypermetropia developed retinopathy with visual deterioration during two separate empiric trials of GH therapy. On the first occasion, a relatively high dose of GH (10.5 mg/m2/week) administered from age 4.4 to age 4.7 years was associated with the development of central serous retinopathy, resulting in marked reduction in visual acuity. On cessation of GH, the macular oedema resolved, and visual acuity improved. At age 5.6 years, GH therapy was re-introduced at a lower dose (3.9 mg/m2/week) and her vision monitored closely. Bilateral retinal oedema recurred after 3 months, and GH therapy was stopped. Once again, the macular oedema regressed, and visual acuity improved following withdrawal of GH. These ophthalmic changes contra-indicated further GH therapy. CONCLUSION: We suggest that GH may be a risk factor in the development of retinopathy in certain non-diabetic patients, especially in the presence of a severe refractive error.

Maternal age in patients with septo-optic dysplasia.

AIM: To determine whether patients with septooptic dysplasia (SOD) are of normal birth weight and gestation but are born to mothers who are significantly younger than average. METHODS: Retrospective study of 30 patients with SOD attending the Royal Hospital for Sick Children, Glasgow. Birth data for the Scottish population were used for comparison. RESULTS: Mean birth weight was 3.42 (range 2.66-4.18) kg. One patient was born preterm while the rest were born at term. Data for the Scottish population were available from 1979 onwards and 26 patients born after this year were selected for analysis. Median maternal age in this group was 21 (range 16-41) years, significantly lower than the median maternal age for Scotland of 27.12 (range 25.8-28.6) years (95% CI 4.8-8.0 years). CONCLUSION: Patients with SOD are of normal birth weight and gestation but are born to mothers who are significantly younger than average.

Craniosynostosis associated with intracranial calcification: a novel recessive syndrome.

We report three siblings who were variably affected by craniosynostosis, calcification of the basal ganglia, and mild facial dysmorphism comprising prominent eyes and a prominent nasal bridge. The children are of normal intelligence and have no limb abnormalities. Their parents are first cousins and are phenotypically normal. We propose that this combination of clinical findings represents a recognizable, autosomal recessive craniosynostosis syndrome.

Final height outcome and value of height prediction in boys with constitutional delay in growth and adolescence treated with intramuscular testosterone 125 mg per month for 3 months.

OBJECTIVES: Constitutional delay in growth and adolescence (CDGA) is common in boys, some of whom request treatment to accelerate growth and attainment of secondary sexual characteristics. The aims of this study were to confirm that a 3-month course of intramuscular testosterone oenanthate does not impair final height in boys with CDGA, and to determine the accuracy of height prediction in this condition. DESIGN AND PATIENTS: Boys with CDGA who had attended the growth clinic, who were now at or close to final height and who had received either testosterone or declined treatment, were identified by retrospective case note analysis. Bone age assessment was carried out by a single observer, using the RUS (TW2) method of Tanner and Whitehouse. MEASUREMENTS: The following auxological data were extracted from the case records: age, bone age, height, pubertal stage, parental heights and predicted final height. All subjects were then measured at age 19 years or greater. The main outcome measures were comparison of final height in treated and untreated boys; final height comparison with mid-parental height and with height prediction [RUS (TW2) method] at initial assessment and at subsequent review. RESULTS: Sixty-four boys met the inclusion criteria, of whom 41 subjects had received testosterone and 23 were untreated. There were no significant differences between the groups (treated mean/SD vs. untreated mean/SD; P-value) in age (14.3/0.7 vs. 14.0/1.1; 0.13), height (144.7/6.2 vs. 144.2/6.2; 0.79), mid-parental heights (170.4/5.5 vs. 171.1/4.5; 0.59), and bone age (12.0/1.2 vs. 12.3/1.3; 0.36). Final heights in both groups (168.9/6.0 vs. 168.2/3.5; 0.65) were closely related to predicted final heights (170.0/5.0 vs. 168.1/4.1; 0.15) and only slightly less than mid-parental heights. Only three subjects had final heights below the initial height prediction range. CONCLUSIONS: Our data support the hypothesis that this treatment regime does not adversely affect the final height achieved in constitutional delay of growth and adolescence and that height prediction, assessed by a single observer, is a useful and accurate tool.

Poor uterine development in Turner syndrome with oral oestrogen therapy.

OBJECTIVE: To evaluate uterine development in Turner syndrome (TS) patients in relation to treatment with oral ethinyl oestradiol (E2 ) for pubertal induction. DESIGN AND PATIENTS: Pelvic ultrasound data for 96 TS patients scanned since 1989 were analysed. Patients were classified into three groups: (1) untreated (n = 48); (2) complete spontaneous puberty (n = 10); and (3) treated with ethinyl oestradiol (n = 38). Uterine development was described in the three groups and compared with the normal data. MEASUREMENTS: Uterine length, fundal-cervical ratio (FCR) and shape were recorded, and presence or absence of ovaries noted. In the treated group, cross-sectional and longitudinal data were combined to compare uterine development with Tanner breast stage. RESULTS: In untreated girls up to age 10 years there was a variable distribution of uterine length and FCR about the mean. Thereafter, the uterus failed to grow and mature normally. Girls with complete spontaneous puberty had morphologically normal ovaries and uteri, but of 7 girls who attained menarche, 3 subsequently developed secondary oligomenorrhoea or amenorrhoea. In the treated group, in general, breast development and uterine length progressed with increasing E2 dose. However, only 50% of girls with complete secondary sexual development had a mature heart-shaped uterine configuration. CONCLUSIONS: Our current E2 treatment regimen for TS girls gives rise to satisfactory pubertal induction and maintenance, but failed to induce a fully mature uterus in half the cohort. In view of the high risk of miscarriage in TS in both spontaneous and assisted pregnancies, the effect of more physiological methods of E2 replacement on uterine development should be investigated.