Pregnancy Vitamin D Supplementation and Childhood Bone Mass at Age 4 Years: Findings From the Maternal Vitamin D Osteoporosis Study (MAVIDOS) Randomized Controlled Trial.

In the Maternal Vitamin D Osteoporosis Study (MAVIDOS) randomized trial, vitamin D supplementation in pregnancy did not lead to greater neonatal bone mass across the trial as a whole, but, in a prespecified secondary analysis by season of birth, led to greater neonatal bone mass among winter-born babies. Demonstrating persistence of this effect into childhood would increase confidence in a long-term benefit of this intervention. We investigated whether antenatal vitamin D supplementation increases offspring bone mineralization in early childhood in a prespecified, single-center follow-up of a double-blinded, multicenter, randomized controlled clinical trial based in the UK (MAVIDOS). A total of 1123 women in early pregnancy with a baseline 25-hydroxyvitamin D level 25-100 nmol/L from three research centers (2008-2014) were randomized to 1000 IU/d cholecalciferol or matched placebo from 14 weeks of gestation to delivery. Offspring born at the Southampton, UK research center were assessed at age 4 years (2013-2018). Anthropometry and dual-energy X-ray absorptiometry (DXA) were performed (yielding whole body less head [WBLH] bone mineral content [BMC], areal bone mineral density [aBMD], bone area [BA], and body composition). Of 723 children, 564 (78.0%) children attended the 4-year visit, 452 of whom had a useable DXA. Maternal vitamin D supplementation led to greater WBLH aBMD in the children compared with placebo (mean [95% confidence interval {CI}]: supplemented group: 0.477 (95% CI, 0.472-0.481) g/cm2; placebo group: 0.470 (95% CI, 0.466-0.475) g/cm2, p = 0.048). Associations were consistent for BMC and lean mass, and in age- and sex-adjusted models. Effects were observed across the whole cohort irrespective of season of birth. Maternal-child interactions were observed, with a greater effect size among children with low milk intake and low levels of physical activity. Child weight, height, and body mass index (BMI) were similar by maternal randomization group. These findings suggest a sustained beneficial effect of maternal vitamin D supplementation in pregnancy on offspring aBMD at age 4 years, but will require replication in other trials. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Comparison of prevalence and characteristics of fractures in term and preterm infants in the first 3 years of life.

BACKGROUND: Preterm infants may be more vulnerable to fractures due to various factors, including metabolic bone disease, but an increased risk of fractures up to the age of 2 is unproven. OBJECTIVE: To compare fracture patterns in premature and full-term children in the first 3 years of life. MATERIALS AND METHODS: A retrospective study was conducted. We excluded any child who returned with the same injury, with known metabolic bone disease, with any disease or condition known to reduce bone density, who received any medication known to affect Vitamin D metabolism within 3 months of enrollment or who had fractures post-surgery/resuscitation. Variables such as the number of fractures sustained each year, age of presentation to the Emergency Department and mechanism of injury were compared between the preterm and term groups using statistical analysis (χ2 and Fisher exact test for categorical variables and Student's t-test for continuous variables). Simple linear regression was performed on the total number of fractures sustained by age 3. RESULTS: Forty-four children with fractures were included. Of these, none were born extremely preterm, 24 (55%) were preterm, and 20 (45%) were born at term. Mean gestational ages of the preterm and term groups were 32 weeks 3 days and 39 weeks 6 days, respectively. There were no extremely low birth weight or very low birth weight children. There was no significant difference in the number of fractures sustained yearly, the age of presentation to the Emergency Department or the site of fracture between preterm and term groups. Linear regression showed that the total number of fractures sustained by age 3 years was unrelated to prematurity status, gender or birth weight category. CONCLUSION: No significant difference in fracture number or pattern was identified.

Maternal pregnancy vitamin D supplementation increases offspring bone formation in response to mechanical loading: Findings from a MAVIDOS Trial sub-study.

The Maternal Vitamin D Osteoporosis (MAVIDOS) trial reported higher total body bone mineral content in winter-born infants of mothers receiving vitamin D supplementation [1000 IU/day cholecalciferol] compared with placebo from 14 weeks gestation until delivery. This sub-study aimed to determine whether antenatal vitamin D supplementation altered postnatal bone formation in response to mechanical stimulation. Thirty-one children born to MAVIDOS participants randomised to either placebo (n=19) or cholecalciferol (n=12) were recruited at age 4-5 years. Children received whole body vibration (WBV) for 10 minutes on 5 consecutive days. Fasting blood samples for bone homeostasis, 25 hydroxyvitamin D (25OHD), parathyroid hormone (PTH), and bone turnover markers (Pro-collagen Type 1 N-terminal propeptide, P1NP; Cross-linked C-telopeptide of Type I Collagen, CTX) were collected pre-WBV and on day 8 (D8). Mean changes (D) in P1NP (ng/ml) between baseline and D8 in the vitamin-D intervention and placebo groups were 40.6 and -92.6 respectively and mean changes (Δ) in CTX (ng/ml) were 0.034 (intervention) and -0.084 (placebo) respectively. Between-group DP1NP difference was 133.2ng/ml [95% CI 0.4, 266.0; p=0.049] and ΔCTX 0.05ng/ml (95% CI -0.159, 0.26ng/mL; p=0.62). Antenatal vitamin-D supplementation resulted in increased P1NP in response to WBV, suggesting early life vitamin D supplementation increases the anabolic response of bone to mechanical loading in children.

Phenotypic diversity and correlation with the genotypes of pseudohypoaldosteronism type 1.

Background Type I pseudohypoaldosteronism (PHA1) is a rare condition characterised by profound salt wasting, hyperkalaemia and metabolic acidosis due to renal tubular resistance to aldosterone (PHA1a) or defective sodium epithelial channels (PHA1b or systemic PHA). Our aim was to review the clinical presentation related to the genotype in patients with PHA1. Methods A questionnaire-based cross-sectional survey was undertaken through the British Society of Paediatric Endocrinology and Diabetes (BSPED) examining the clinical presentation and management of patients with genetically confirmed PHA1. We also reviewed previously reported patients where genotypic and phenotypic information were reported. Results Genetic confirmation was made in 12 patients with PHA1; four had PHA1a, including one novel mutation in NR3C2; eight had PHA1b, including three with novel mutations in SCNN1A and one novel mutation in SCNN1B. It was impossible to differentiate between types of PHA1 from early clinical presentation or the biochemical and hormonal profile. Patients presenting with missense mutations of SCNN1A and SCNN1B had a less marked rise in serum aldosterone suggesting preservation in sodium epithelial channel function. Conclusions We advocate early genetic testing in patients with presumed PHA1, given the challenges in differentiating between patients with PHA1a and PHA1b. Clinical course differs between patients with NR3C2 and SCNN1A mutations with a poorer prognosis in those with multisystem PHA. There were no obvious genotype-phenotype correlations between mutations on the same gene in our cohort and others, although a lower serum aldosterone may suggest a missense mutation in SCNN1 in patients with PHA1b.

Effect of vitamin D supplementation on free and total vitamin D: A comparison of Asians and Caucasians.

OBJECTIVES: It is well established that UK Asians typically have lower vitamin D levels than Caucasians. It is also known that vitamin D binding protein (DBP) is lower in some races than Caucasians. To investigate how ethnicity, skin colour and genetic variation affect the response to vitamin D (15000 IU) administered to young Asian and Caucasian men. DESIGN: Prospective, single-centre clinical trial. PARTICIPANTS: Sixty young men (18-25 year) of Asian (n = 30) and Caucasian (n = 30) origin. MEASUREMENTS: We measured serum calcium, phosphate, magnesium, alkaline phosphatase, albumin, parathyroid hormone; total 25 hydroxyvitamin D (25OHD); calculated and directly measured free 25OHD; DBP at baseline and 4 weeks; DBP genotype, skin colour (Fitzpatrick scale), dietary vitamin D and calcium intake at baseline; and urine calcium:creatinine ratio at baseline, 1 and 4 weeks. RESULTS: At baseline, Asians had lower serum total 25OHD (26.4 [13.7] vs 34.1 [12.3] nmol/L P = 0.0272) and DBP (6.7 [3.4] vs 9.6 [4.4] nmol/L; P = 0.0065) but similar free 25OHD (16.7 [10.4] vs 17.8 [7.5] pmol/L P = 0.6530). After dosing, total 25OHD rose similarly in each group (≈56 nmol/L), but measured free 25OHD rose more in Asians (18.1 [9.4] vs 12.2 [13.3] pmol/L P = 0.0464). Lower DBP at baseline, possibly reflecting genotype differences, was associated with a greater change in measured free 25OHD in Caucasians, but not in Asians. CONCLUSIONS: Asian compared with Caucasian males had a larger increment in measured free 25OHD following 150 000 units vitamin D3, possibly reflecting differences in DBP affinity for 25OHD. Ethnicity should be considered when devising guidelines for the treatment of vitamin D deficiency.

Feasibility of quantitative ultrasonography for the detection of metabolic bone disease in preterm infants - systematic review.

Metabolic bone disease of prematurity is characterised by disordered bone mineralisation and is therefore an increased fracture risk. Preterm infants are especially at risk due to incomplete in utero bone accretion during the last trimester. Currently, diagnosing metabolic bone disease mainly relies on biochemistry and radiographs. Dual-energy x-ray absorptiometry and quantitative ultrasound (US) are used less frequently. However, biochemical measurements correlate poorly with bone mineralisation and although scoring systems exist for metabolic bone disease, radiographs are subjective and do not detect early features of osteopenia. Dual energy x-ray absorptiometry is the reference standard for determining bone density in older children and adults. However, challenges with this method include movement artefact, difficulty scanning small and sick infants and a lack of normative data for young children. Quantitative US has a relatively low cost, is radiation-free and portable, and may hence be suitable for assessing bone status in preterm infants. This review aims to provide an overview of the use of quantitative US in detecting metabolic bone disease in preterm infants.

Dilemma of diagnosing sulphonylurea overdose in children: deliberations and considerations before reaching a diagnosis.

A 15-year-old non-diabetic Caucasian girl presented with sudden onset of seizures, unrecordable blood glucose readings and acute renal failure. She denied any medication ingestion and no other precipitating factors were encountered for this acute presentation. She was treated with intravenous glucose infusion and hydrocortisone injection. Investigations showed a non-ketotic hypoglycaemia with high C-peptide and insulin levels. It took several days and multiple investigations to establish the exact cause of her persistent hypoglycaemia before it was concluded to be secondary to gliclazide overdose in a suicide attempt by the young girl. She made a complete recovery in a week with no apparent lasting neurological or renal impairment.

The neuroendocrine sequelae of paediatric craniopharyngioma: a 40-year meta-data analysis of 185 cases from three UK centres.

OBJECTIVES: The management of paediatric craniopharyngiomas was traditionally complete resection (CR), with better reported tumour control compared to that by partial resection (PR) or limited surgery (LS). The subsequent shift towards hypothalamic sparing, conservative surgery with adjuvant radiotherapy (RT) to any residual tumour aimed at reducing neuroendocrine morbidity, has not been systematically studied. Hence, we reviewed the sequelae of differing management strategies in paediatric craniopharyngioma across three UK tertiary centres over four decades. METHODS: Meta-data was retrospectively reviewed over two periods before (1973-2000 (Group A: n = 100)) and after (1998-2011 (Group B: n = 85)) the introduction of the conservative strategy at each centre. RESULTS: Patients had CR (A: 34% and B: 19%), PR (A: 48% and B: 46%) or LS (A: 16% and B: 34%), with trends reflecting the change in surgical approach over time. Overall recurrence rates between the two periods did not change (A: 38% vs B: 32%). More patients received RT in B than A, but recurrence rates were similar: for A, 28% patients received RT with 9 recurrences (32%); for B, 62% received RT with 14 recurrences (26%). However, rates of diabetes insipidus (P = 0.04), gonadotrophin deficiency (P < 0.001) and panhypopituitarism (P = 0.001) were lower in B than those in A. In contrast, post-operative obesity (BMI SDS >+2.0) (P = 0.4) and hypothalamic (P = 0.1) and visual (P = 0.3) morbidity rates were unchanged. CONCLUSION: The shift towards more conservative surgery has reduced the prevalence of hormone deficiencies, including diabetes insipidus, which can be life threatening. However, it has not been associated with reduced hypothalamic and visual morbidities, which remain a significant challenge. More effective targeted therapies are necessary to improve outcomes.

Xanthogranulomatous hypophysitis: a rare and often mistaken pituitary lesion.

UNLABELLED: Xanthogranulomatous hypophysitis (XGH) is a very rare form of pituitary hypophysitis that may present both clinically and radiologically as a neoplastic lesion. It may either be primary with an autoimmune aetiology and can occur in isolation or as a part of autoimmune systemic disease or secondary as a reactive degenerative response to an epithelial lesion (e.g. craniopharyngioma (CP), Rathke's cleft cyst, germinoma and pituitary adenomas) or as a part of a multiorgan systemic involvement such as tuberculosis, sarcoidosis or granulomatosis. It may also present with a variation of symptoms in children and adults. Our case series compares the paediatric and adult presentations of XGH and the differential diagnoses considered in one child and two adult patients, highlighting the wide spectrum of this condition. Endocrine investigations suggested panhypopituitarism in all three patients and imaging revealed a suprasellar mass compressing the optic chiasm suggestive of CP or Rathke's cleft cyst in one patient and non-functioning pituitary macroadenoma in two patients. Magnetic resonance imaging (MRI) demonstrated mixed signal intensities on T1- and T2-weighted sequences. Following endoscopic transsphenoidal surgery, histological analysis revealed necrotic material with a xanthogranulomatous reaction confirming XGH in two patients and a necrobiotic granulomatous chronic inflammatory infiltrate with neutrophils in one patient, which is not typical of current descriptions of this disorder. This case series describes the wide spectrum of XGH disease that is yet to be defined. Mixed signal intensities on T1- and T2-weighted MRI sequences may indicate XGH and diagnosis is confirmed by histology. Histological variation may indicate an underlying systemic process. LEARNING POINTS: XGH is a rare form of pituitary hypophysitis with a wide clinical and histological spectrum and can mimic a neoplastic lesion.XGH primarily presents with growth arrest in children and pubertal arrest in adolescents. In adults, the presentation may vary.A combination of hypopituitarism and mixed signal intensity lesion on MRI is suggestive of XGH and should be considered in the differential diagnosis of sellar lesions.Radical surgery is the treatment of choice and carries an excellent prognosis with no recurrence.

Congenital hyperinsulinism: Role of fluorine-18L-3, 4 hydroxyphenylalanine positron emission tomography scanning.

Congenital hyperinsulinism (CHI) is a rare but complex heterogeneous disorder caused by unregulated secretion of insulin from the ß-cells of the pancreas leading to severe hypoglycaemia and neuroglycopaenia. Swift diagnosis and institution of appropriate management is crucial to prevent or minimise adverse neurodevelopmental outcome in children with CHI. Histologically there are two major subtypes of CHI, diffuse and focal disease and the management approach will significantly differ depending on the type of the lesion. Patients with medically unresponsive diffuse disease require a near total pancreatectomy, which then leads on to the development of iatrogenic diabetes mellitus and pancreatic exocrine insufficiency. However patients with focal disease only require a limited pancreatectomy to remove only the focal lesion thus providing complete cure to the patient. Hence the preoperative differentiation of the histological subtypes of CHI becomes paramount in the management of CHI. Fluorine-18L-3, 4-hydroxyphenylalanine positron emission tomography ((18)F-DOPA-PET) is now the gold standard for pre-operative differentiation of focal from diffuse disease and localisation of the focal lesion. The aim of this review article is to give a clinical overview of CHI, then review the role of dopamine in ß-cell physiology and finally discuss the role of (18)F-DOPA-PET imaging in the management of CHI.