Aortic dissection in children and adolescents with Turner syndrome: risk factors and management recommendations.

There is a general lack of awareness of the risk of aortic dissection in Turner syndrome (TS) from both patients with TS and their physicians. Patients often ignore symptoms for up to 24 h before seeking medical advice, significantly increasing their risk of death. A clinical profile of those at risk of dissection is emerging and includes the presence of congenital heart defects, aortic dilatation and hypertension. MRI has revolutionised the visualisation of cardiovascular anatomy in TS but remains underutilised, especially in children and adolescents, and there is currently little guidance on blood pressure (BP) assessment or hypertension management. Children and adolescents with TS at risk of dissection could be easily identified by timely imaging and BP assessment. This would allow medical management or surgical intervention to be put in place to reduce the risk of this major, and often fatal, complication. Since guidance is lacking, we have reviewed the literature on the risk factors for dissection in TS during childhood and adolescence, and make recommendations on the assessment and management of these patients.

Physiological sex steroid replacement in premature ovarian failure: randomized crossover trial of effect on uterine volume, endometrial thickness and blood flow, compared with a standard regimen.

BACKGROUND: Premature ovarian failure (POF) is currently managed by non-physiological sex steroid regimens which are inadequate at optimizing uterine characteristics. Previous short-term studies have demonstrated some benefits of a sex steroid replacement (SSR) regimen devised to replicate the physiological cycle. This study aimed to directly compare the effects of longer-term administration of physiological SSR (pSSR) and standard SSR (sSSR) regimens on the uterine volume, blood flow and endometrial thickness (ET) in women with POF. METHODS: In a controlled crossover trial, 34 women with POF were randomized to receive 12 months of 4-week cycles of transdermal estradiol and vaginal progesterone (pSSR) followed by 12 months of 4-week cycles of oral ethinylestradiol and norethisterone (sSSR), or vice versa. Each treatment period was preceded by a 2-month washout period. At 0, 3, 6 and 12 months of each treatment period, transvaginal ultrasound examined the uterine volume and ET, as primary end-points, and uterine artery resistance (UARI) and pulsatility indices (UAPI), as secondary end-points. Serum estradiol, progesterone and gonadotrophins were also measured. RESULTS: Of the 29 women eligible for the uterine analysis, 17 completed the entire study protocol, but 25 women contributed data to statistical analysis of treatment effect. There was a greater estimated mean ET with the use of pSSR (4.8 mm) compared to that with standard therapy (3.0 mm), with an estimated difference of 1.8 mm [95% confidence interval (CI), 0.7 to 2.8, P=0.002]. The estimated mean uterine volume was also greater during physiological treatment (24.8 cm(3)) than during standard treatment (20.6 cm(3)), but the estimated difference of 4.2 cm(3) (95% CI -0.4 to 8.7) was not statitsically significant, P=0.070. The small differences between the two treatments in the mean UARI and mean UAPI were not statistically significant. The estimated treatment differences were fairly constant across the treatment periods, suggesting that prolonged treatment does not increase response. CONCLUSIONS: pSSR has a greater beneficial effect upon ET in women with POF in comparison with standard therapy. A similar trend was seen for uterine volume. Further studies are required to optimize treatment and to assess pregnancy rate and outcome. Trial Registration www.ClinicalTrials.gov, NCR00732693.

Undetectable salivary testosterone in young women with premature ovarian failure.

BACKGROUND: The extent of androgen deficiency in young women with premature ovarian failure (POF) is unclear. AIM: Cross-sectional study of androgen status in young women with POF. PATIENTS: Twenty women with POF: six had Turner syndrome (group A); eight had iatrogenic POF either secondary to bilateral oophorectomy or treatment of malignancy (group B); and six had idiopathic POF (group C). The median age was 30.5 years (range 19-39); in groups B and C the median duration of ovarian failure was 10.0 years (range 1-35). METHODS: After a 2-month wash-out period without sex steroid replacement (SSR), serum testosterone (T), androstenedione (A4), dehydroepiandrosterone (DHEAS), SHBG, salivary testosterone (SalT) and the free androgen index [FAI = (serum T/SHBG) x 100] were measured. RESULTS: Median serum A4 was 4.6 nmol/l (10th, 90th centiles, 3.6, 5.1) and DHEAS was 3.2 micromol/l (10th, 90th centiles, 2.3, 9.3). Although median serum T was relatively low at 1.4 nmol/l (10th, 90th centiles, 1.1, 1.7), median SHBG was also low at 34 nmol/l (10th, 90th centiles 22.2, 67.5) and the median calculated FAI was within the normal range at 3.7 (10th, 90th centiles, 2.3, 7.0). However, SalT was undetectable in almost all subjects in the three groups of POF. CONCLUSIONS: Serum T and SHBG are relatively low in young women with POF and their FAI is therefore within the normal range. However, SalT, which measures free testosterone, is consistently low to undetectable in these young women with POF. The reliability of the FAI as a marker of androgen deficiency remains questionable.

Incidental radiological diagnosis of rickets.

Rickets fortunately remains rare in the United Kingdom, although its actual incidence is currently undetermined.1 Many still consider it to be a disease of poverty prevalent during the Victorian era. However, a number of recent articles have highlighted concern among British health professionals about the number of cases still being diagnosed in this country. These cases have nearly all involved non-Caucasian children who are considered to be at high risk due to skin colour, prolonged breast feeding, and low maternal vitamin D levels. Their presentations are variable ranging from failure to thrive, bone deformities, seizures, and even stridor. The diagnosis is usually made in babies and toddlers.We present a series of patients attending our accident and emergency (A&E) department, over a five month period, where the diagnosis of rickets was primarily a radiological diagnosis.

Spontaneous conception in a young woman who had ovarian cortical tissue cryopreserved before chemotherapy and radiotherapy for a Ewing's sarcoma of the pelvis: case report.

We report the case of a 14 year old girl who presented with a non-metastatic Ewing's sarcoma involving her superior pubic ramus. She received 14 courses of alkylating agent-based chemotherapy and direct radiation to her hemi-pelvis (55 Gy) and is alive and disease-free 8 years later. Multiple biopsies of ovarian cortical tissue were cryopreserved, with her written consent, before treatment began. Ovarian failure was confirmed on completion of treatment with cessation of menses and persistently elevated serum gonadotrophin and low estradiol levels on repeated measurement over 2 years. HRT was initiated. Irregular vaginal bleeding occurred due to radiation vaginitis. Reimplantation of ovarian cortical tissue was considered at 19 years as fertility was desired, but the decision deferred. A spontaneous conception occurred 1 year later and a healthy boy (birthweight 2.9 kg, 3rd-10th centile) was delivered at term by elective Caesarean section. This is the first case of a spontaneous conception occurring in a young woman with documented ovarian failure in whom ovarian cortical tissue had been cryopreserved. Clinicians should be aware of the possibility of spontaneous conception despite confirmed ovarian failure in young women successfully treated for cancer.

Cortisol responses to the insulin hypoglycaemia test in children.

AIM: To determine the timing of the peak cortisol response to the insulin hypoglycaemia (IH) test in children and to establish paediatric reference data. METHODS: We retrospectively reviewed all IH tests in a tertiary paediatric endocrine referral centre over a 6-year period. Inclusion criteria were age <16 years and adequate hypoglycaemia (glucose < or =2.0 mmol/l). Patients with an impaired hypothalamic-pituitary-adrenal axis or receiving glucocorticoid medication were excluded. Fifty-four subjects (35 males) met the criteria. Blood samples were collected at -30, 0, 20, 30, 60, 90, 120, and 150 min in relation to insulin bolus injection (0.15 U/kg) at 0 min. Glucose, cortisol, and growth hormone (GH) were measured in all samples. RESULTS: Peak cortisol and GH responses occurred by 90 min in all subjects. Peak cortisol was inversely correlated with age (rs -0.65, p<0.0001). The median (5th centile) peak cortisol value was 689 nmol/l (547 nmol/l) in children younger than 10 years as compared with 555 nmol/l (468 nmol/l) in those older than 10 years (p<0.0001). Peak cortisol was not related to peak GH (rs -0.20, p=0.15). CONCLUSIONS: Blood sampling in the IH test may be curtailed 90 min after injection. The peak cortisol response to IH is age related.

Depletion of ovarian reserve in young women after treatment for cancer in childhood: detection by anti-Müllerian hormone, inhibin B and ovarian ultrasound.

BACKGROUND: Treatment of cancer during childhood may result in loss of primordial follicles from the ovary. METHODS: Ten cancer survivors and 11 controls with regular menstrual cycles, in addition to 10 cancer survivors and 10 controls taking the combined oral contraceptive pill (COCP) were recruited. Subjects were investigated on days 3-5 of a menstrual cycle, or week 3 of COCP administration before and 24 h after administration of 225 IU FSH. RESULTS: Serum FSH levels were elevated in cancer survivors with regular menstrual cycles (7.5 +/- 1.4 versus 4.2 +/- 0.3 IU/l; P = 0.02), while anti-Müllerian hormone (AMH) levels were lower (13.0 +/- 3.0 versus 21.0 +/- 3.4 pmol/l; P < 0.05). Other hormone levels were unchanged. Ovarian volume was smaller in cancer survivors than controls (3.0 +/- 0.5 versus 5.0 +/- 0.8 ml; P < 0.05), but antral follicle count (AFC) was similar. During COCP administration, inhibin B remained undetectable in six cancer survivors after FSH administration, whereas all controls showed a rise in inhibin B levels. The AFC was lower in cancer survivors than in controls (4.2 +/- 0.8 versus 7.2 +/- 0.8; P = 0.02). Ovarian volume was low in both groups, but did not differ between them. CONCLUSIONS: The study results demonstrate both hormonal and biophysical evidence of partial loss of the ovarian reserve in young cancer survivors. This was detected both in women with normal menstrual cycles and during COCP administration.

Is inhibin B a potential marker of gonadotoxicity in prepubertal children treated for cancer?

BACKGROUND AND OBJECTIVE: Chemotherapy treatment of childhood cancer may impair gonadal function, which may be manifested only in adulthood as permanent sterility. Detection of gonadal dysfunction in prepubertal children has been hampered by the absence of a sensitive marker. Inhibin B is secreted by small antral follicles and Sertoli cells in females and males, respectively, and may be a marker of gonadal function in prepubertal children. The aim of this pilot study was to evaluate inhibin B in relation to sensitive measurements of gonadotrophins as markers of the early gonadotoxic effects of chemotherapy in prepubertal children treated for cancer. STUDY DESIGN AND SUBJECTS: Twenty-five prepubertal children (9 females), median age 4.5 years (range 1.2-12.8 years) with cancer (16 solid tumours, nine acute lymphoblastic leukaemia, ALL) were studied longitudinally. Blood samples were collected before and during chemotherapy (solid tumours) or immediately following induction and first intensification (ALL). Post-treatment (1-6 months) samples were collected in 12 of the patients (5 females). MEASUREMENTS: Dimeric inhibin B was measured by double antibody enzyme-linked immunosorbent assay (ELISA). FSH and LH were measured by sensitive time-resolved immunofluorescence. RESULTS: Girls: Pretreatment inhibin B was slightly high in one girl but normal for age and sex in all others: median 16.1 (range 9.4-186.2) ng/l, median SD score +0.2 (-1.3 to +2.6). Inhibin B decreased to undetectable levels (< 8 ng/l) in 8/9 girls during treatment (P = 0.03), with no accompanying rise in FSH or LH. Post-treatment recovery of inhibin B was variable: median 16.1 (range < 8.0-44.2) ng/l, median SD score +0.1 (range < -2.4 to +1.8). Sustained undetectable inhibin B levels were observed in 2/5 girls with correspondingly elevated FSH concentrations (11.8 and 10.9 U/l). Boys: Inhibin B was normal for age and sex in all boys before treatment with no significant change during or after treatment (medians 93 ng/l, 85 ng/l and 94 ng/l, SD scores -0.3, -0.6 and -0.2, respectively). Inhibin B decreased to undetectable levels in one boy post-treatment with no accompanying increase in FSH or LH. CONCLUSIONS: In prepubertal girls with cancer, chemotherapy is associated with suppression of inhibin B, usually transient, which may indicate arrest of follicle development. Sustained suppression of inhibin B following treatment may be indicative of permanent ovarian damage. In prepubertal boys, chemotherapy had little immediate effect on Sertoli cell production of inhibin B, although one boy showed a delayed effect. Inhibin B, together with sensitive measurements of FSH, may be a potential marker of the gonadotoxic effects of chemotherapy in prepubertal children with cancer.

Hypothalamic-pituitary-ovarian dysfunction after prepubertal chemotherapy and cranial irradiation for acute leukaemia.

BACKGROUND: We assessed adult hypothalamic-pituitary-ovarian function following treatment with chemotherapy and cranial irradiation for childhood acute lymphoblastic leukaemia. METHODS: The patients (n = 12) had median age at diagnosis of 4.7 years, and at assessment of 20.8 years. They collected a daily urine sample over two to five consecutive menstrual cycles (total of 41 cycles) for analysis of LH and steroid excretion. Blood sampling and ovarian ultrasound examination was performed in the early follicular phase. Sixteen healthy women with regular menstrual cycles were recruited as controls. RESULTS: Urinary LH excretion was significantly lower in patients throughout the cycle, particularly during the LH surge (P < 0.0001). The length of the luteal phase was significantly shorter in patients than in normal controls (12.2 +/- 0.3 versus 13.6 +/- 0.4 days, P = 0.01) with a high prevalence of short (< or =11 days) luteal phases (15/39 cycles). Luteal phase pregnanediol excretion was slightly but not significantly lower. Follicular and luteal phase excretion of oestrone was lower in patients than in controls (P = 0.01). Early follicular phase plasma oestradiol was also lower in the patient group (P = 0.032) although LH, FSH, inhibin A and B concentrations were similar. CONCLUSIONS: These data indicate that treatment for childhood leukaemia results in subtle ovulatory disorder in some patients, probably related to cranial irradiation. Follow-up of these women is required to detect any effect on reproductive potential.

Medical students' attitudes to caring for a young infant--can parenting a doll influence these beliefs?

AIM: To investigate whether attitudes to parenting were altered in final year medical students following a period spent caring for a simulated infant. METHODS: Seventy medical students during their paediatric attachment in the final year completed a questionnaire regarding personal childcare attitudes. Students attached to a teaching hospital were allocated a 24 hour time period to care for "Baby Think It Over" (BTIO), a computerised doll that simulates a 6 week old infant and records care given. The students then completed a second questionnaire assessing the impact of the experience. RESULTS: Forty nine per cent of students thought their advice regarding sick children was less valid than if they had their own children; 96% of students believed their approach to parents caring for young infants could be improved by caring for a 6 week old infant. All the students felt their lifestyle would be affected. Following the BTIO care period, 79% considered the experience straightforward, with 35% expressing a little more empathy and 15% a lot more empathy for parents as a result. Thoughts regarding impact on lifestyle were unaltered. Caring for BTIO, however, was not considered to be a realistic experience and overall not particularly useful. CONCLUSION: Simulated infants are of only limited value in increasing medical student understanding of parental concerns.

Obesity in leukemia survivors: the familial contribution.

A high prevalence of obesity in survivors of acute lymphoblastic leukemia (ALL) has been described, but genetic and social influence in obesity has not been analyzed in this group of patients. The authors studied a population of 33 long-term (25 females, 8 males) in first remission who had reached their final height. All patients received cranial irradiation as part of their central nervous system (CNS)-directed therapy and no patient received growth hormone. The body mass index (BMI: weight/height2) of patients and their biological parents was calculated and submitted to statistical analysis. Obesity was defined as BMI greater than the 85th centile. No excessive obesity was found among the males at final height. Fifty-six percent of the females were obese. In this group of 14 obese female survivors 59% had obese mother, but only 14% had obese fathers. The results indicate a significant maternal predisposition to obesity.

Ovarian and uterine characteristics after total body irradiation in childhood and adolescence: response to sex steroid replacement.

OBJECTIVE: To study the effect of total body irradiation (14.4 Gray) in childhood and adolescence on ovarian and uterine characteristics, and to investigate the response to physiological sex steroid serum concentrations. DESIGN: All long term post-pubertal female survivors of total body irradiation who had been treated in paediatric centres in Scotland were identified. Their ovarian and uterine characteristics were studied. SETTING: Recruitment was from follow up oncology clinics. SAMPLE: Nine women were identified, eight of whom were assessed and five progressed to detailed investigation. A control population of 12 women treated for acute leukaemia, but not treated with total body irradiation, and five healthy women with no history of childhood malignancy were recruited as controls. METHODS: Ovarian function was determined by measurement of serum gonadotrophins and sex steroids. Uterine response to physiological sex steroid replacement was investigated in women with ovarian failure, and to endogenous sex steroid production in women with ovarian function by ultrasound scan. The physiological sex steroid replacement was achieved with transdermal oestradiol patches and self administered vaginal progesterone pessaries. MAIN OUTCOME MEASURES: Determination of ovarian function and uterine response to physiological sex steroid serum concentrations. RESULTS: Six of eight women treated with total body irradiation had ovarian failure; preservation of function was seen in two girls treated pre-pubertally who had biochemical evidence of incipient ovarian failure. Four women with ovarian failure had reduced uterine volume, undetectable blood supply and absent endometrium at baseline assessment; after three months of physiological sex steroid replacement treatment uterine blood supply and endometrial response were not significantly different from controls; uterine volume improved but remained significantly smaller than controls and correlated with age at total body irradiation. CONCLUSIONS: Ovarian failure after total body irradiation is common and risk relates to age at treatment. Physiological sex steroid replacement improved uterine measures and these women may benefit from assisted reproductive technology.

Stage IV malignant intrapericardial germ cell tumor: a case report.

The mediastinum is a common site for germ cell tumors. We describe an unusual case in an 18-month-old girl who presented with respiratory distress and cardiomegaly. An echocardiogram revealed a large pericardial effusion and a mass adjacent to the heart. She underwent detailed investigation and at open exploration was found to have a wholly intrapericardial malignant yolk sac tumor. Staging investigations revealed a bony metastasis. The serum marker alpha-fetoprotein was elevated. She was treated with chemotherapy and is in remission 1 year after completion of treatment. We review the methods of diagnosis and follow-up of children with these tumors.