Current concepts in osteogenesis imperfecta: bone structure, biomechanics and medical management.

The majority of patients with osteogenesis imperfecta (OI) have mutations in the COL1A1 or COL1A2 gene, which has consequences for the composition of the bone matrix and bone architecture. The mutations result in overmodified collagen molecules, thinner collagen fibres and hypermineralization of bone tissue at a bone matrix level. Trabecular bone in OI is characterized by a lower trabecular number and connectivity as well as a lower trabecular thickness and volumetric bone mass. Cortical bone shows a decreased cortical thickness with less mechanical anisotropy and an increased pore percentage as a result of increased osteocyte lacunae and vascular porosity. Most OI patients have mutations at different locations in the COL1 gene. Disease severity in OI is probably partly determined by the nature of the primary collagen defect and its location with respect to the C-terminus of the collagen protein. The overall bone biomechanics result in a relatively weak and brittle structure. Since this is a result of all of the above-mentioned factors as well as their interactions, there is considerable variation between patients, and accurate prediction on bone strength in the individual patient with OI is difficult. Current treatment of OI focuses on adequate vitamin-D levels and interventions in the bone turnover cycle with bisphosphonates. Bisphosphonates increase bone mineral density, but the evidence on improvement of clinical status remains limited. Effects of newer drugs such as antibodies against RANKL and sclerostin are currently under investigation. This paper was written under the guidance of the Study Group Genetics and Metabolic Diseases of the European Paediatric Orthopaedic Society.

Elemental formula associated hypophosphataemic rickets.

OBJECTIVES: Hypophosphataemic rickets (HR) is usually secondary to renal phosphate wasting but may occur secondary to reduced intake or absorption of phosphate. We describe a series of cases of HR associated with the use of Neocate®, an amino-acid based formula (AAF). METHODS: A retrospective review of cases with HR associated with AAF use presenting to centres across the United Kingdom. RESULTS: 10 cases were identified, over a 9 month period, all associated with Neocate® use. The age at presentation was 5 months to 3 years. The majority (8/10) were born prematurely. Gastro oesophageal reflux disease (6/10) was the most frequent indication for AAF use. Radiologically apparent rickets was observed after a median of 8 months (range 3-15 months) of exclusive Neocate® feed. The majority (7/10) were diagnosed on the basis of incidental findings on radiographs: rickets (6/10) or fracture with osteopenia (5/10). All patients had typical biochemical features of HR with low serum phosphate, high alkaline phosphatase, normal serum calcium and 25 hydroxyvitamin D. However, in all cases the tubular reabsorption of phosphate (TRP) was ≥96%. Phosphate supplementation resulted in normalisation of serum phosphate within 1-16 weeks, and levels remained normal only after Neocate® cessation. In patients with sufficient follow up duration (4/10), normalisation of phosphate and radiological healing of rickets was noted after 6 months (range: 6-8 months) following discontinuation of Neocate®. CONCLUSION: The presence of a normal TRP and resolution of hypophosphataemia and rickets following discontinuation of Neocate® indicates this is a reversible cause likely mediated by poor phosphate absorption. Close biochemical surveillance is recommended for children on Neocate®, especially in those with gastrointestinal co-morbidities, with consideration of a change in feed or phosphate supplementation in affected children.

Immune Response of Healthy Adults to the Ingested Probiotic Lactobacillus casei Shirota.

Daily ingestion of a probiotic drink containing Lactobacillus casei Shirota (LcS; 1.3 × 1010 live cells) by healthy adults for (1) 4-week LcS, (2) 6-week discontinuation of LcS and (3) a final 4 weeks of LcS was investigated. There was a significant increase in expression of the T cell activation marker CD3+ CD69+ in ex vivo unstimulated blood cells at weeks 10 and 14, and there was a significant increase in the NK cell marker CD3+ CD16/56+ in ex vivo unstimulated blood cells at weeks 4, 10 and 14. Expression of the NK cell activation marker CD16/56+ CD69+ in ex vivo unstimulated blood cells was 62% higher at week 10 and 74% higher at week 14. Intracellular staining of IL-4 in ex vivo unstimulated and PMA-/ionomycin-stimulated CD3+ ß7+ integrin blood cells was significantly lower at weeks 10 and 14. Intracellular staining of IL-12 in ex vivo unstimulated and LPS-stimulated CD14+ blood cells was significantly lower at weeks 4, 10 and 14. Intracellular staining of TNF-α in LPS-stimulated CD14+ blood cells was significantly lower at weeks 4, 10 and 14. Mucosal salivary IFN-γ, IgA1 and IgA2 concentrations were significantly higher at week 14, but LcS did not affect systemic circulating influenza A-specific IgA or IgG and tetanus-specific IgG antibody levels. In addition to the decrease in CD3+ ß7+ integrin cell IL-4 and a reduced CD14+ cell pro-inflammatory cytokine profile, at week 14 increased expression of activation markers on circulating T cells and NK cells and higher mucosal salivary IgA1 and IgA2 concentration indicated a secondary boosting effect of LcS.

Islet autoantibody status in a multi-ethnic UK clinic cohort of children presenting with diabetes.

OBJECTIVE: We prospectively determined islet autoantibody status in children presenting with diabetes to a single UK region in relation to ethnicity. DESIGN: 316 (68.0% non-white) children presenting with diabetes between 2006 and 2013 were tested centrally for islet cell autoantibodies (ICA) and glutamic acid decarboxylase autoantibodies (GAD-65) at diagnosis, and if negative for both, tested for insulin autoantibodies (IAA). The assay used to measure GAD-65 autoantibodies changed from an in-house to a standardised ELISA method during the study. RESULTS: Even with use of the standardised ELISA method, 25.8% of children assigned a diagnosis of type 1 diabetes still tested negative for all three autoantibodies. 30% of children assigned a diagnosis of type 2 diabetes were autoantibody positive, and these had the highest glycated haemoglobin (HbA1c) levels at 12 months follow-up compared with other groups (p value for analysis of variance <0.001), although the sample size was small. Autoantibody positivity was similar between non-white and white children regardless of assay used (60.0% (n=129) vs 56.4% (n=57), χ(2)=0.9, p=0.35), as was mean GAD-65 autoantibody levels, but fewer non-white children had two or more autoantibodies detectable (13% (n=28) vs 27.7% (n=28), χ(2)=12.1, p=0.001). CONCLUSIONS: Islet autoantibody positivity was associated with a more severe phenotype, as demonstrated by poorer glycaemic control, regardless of assigned diabetes subtype. Positivity did not differ by ethnic group.

Surgical treatment of children with hyperparathyroidism: single centre experience.

BACKGROUND: Hyperparathyroidism (HPT) in children is rare and surgical management is supported only by limited evidence. METHODS: Retrospective case series of all children under the age of 16 years who underwent parathyroidectomy (PTx) between 1978 and 2012. RESULTS: We identified 29 children who had surgery for HPT. Six were neonates with neonatal severe hyperparathyroidism (NSHPT) and 23 older children (age range 7-16 years) with sporadic (16) or familial (7) HPT and 93% were symptomatic. Accuracy of ultrasound and MIbi in localising solitary parathyroid adenomas was 96%, but less helpful in hyperplasia and neonates. Children with NSHPT underwent 5 curative total and 1 subtotal PTx (no reoperations). Children with familial HPT underwent 3 total and 4 subtotal PTx. One child with subtotal PTx required a reoperation. Children with sporadic HPT underwent subtotal PTx prior to 1980 (2), exploration and removal of enlarged glands 1980-2002 (5) and minimally invasive PTx since 2002 (9) and all cured by the first operation. CONCLUSIONS: Our study documents that HPT in children is predominantly symptomatic on presentation and genetically determined in 46% of cases. Imaging is accurate in localising parathyroid adenomas, but not hyperplasias. Total PTx for familial HPT was curative and minimally invasive PTx is the operation of choice for older children with sporadic HPT.

Changes in insulin sensitivity in response to different modalities of exercise: a review of the evidence.

Type 2 diabetes is an increasingly prevalent condition with complications including blindness and kidney failure. Evidence suggests that type 2 diabetes is associated with a sedentary lifestyle, with physical activity demonstrated to increase glucose uptake and improve glycaemic control. Proposed mechanisms for these effects include the maintenance and improvement of insulin sensitivity via increased glucose transporter type four production. The optimal mode, frequency, intensity and duration of exercise for the improvement of insulin sensitivity are however yet to be identified. We review the evidence from 34 published studies addressing the effects on glycaemic control and insulin sensitivity of aerobic exercise, resistance training and both combined. Effect sizes and confidence intervals are reported for each intervention and meta-analysis presented. The quality of the evidence is tentatively graded, and recommendations for best practice proposed.

Stimulating whole saliva affects the response of antimicrobial proteins to exercise.

This study investigated the salivary secretion rates of antimicrobial proteins in response to prolonged, exhaustive exercise in both stimulated (STIM) and unstimulated (UNSTIM) saliva flow sample methods. Twenty-four trained men cycled for 2.5 h at 60% V̇O2max and then to exhaustion at 75% V̇O2max. Timed collections of whole saliva were made before exercise, mid-exercise, at the end of the moderate exercise bout and post-exhaustive exercise. After each UNSTIM collection, a STIM sample was collected following chewing flavored gum for 1 min. Saliva was analysed for lysozyme, α-amylase and salivary immunoglobulin A (s-IgA), and secretion rates were calculated. Saliva flow was 156% higher in STIM compared with UNSTIM (P < 0.001) and decreased with exercise in STIM only (P < 0.001). Exercise increased lysozyme and α-amylase levels and secretion rates were 144% higher and 152% higher in STIM compared with UNSTIM for lysozyme and α-amylase, respectively (all P < 0.001). S-IgA concentration (P < 0.05) and secretion rate (P < 0.001) increased with exercise but were both lower in STIM compared with UNSTIM (P < 0.001). In conclusion, a STIM saliva flow collection during exercise by chewing flavored gum increased the quantity of saliva and the secretion of lysozyme and α-amylase, but had a limited impact on the secretion of s-IgA.

The effect of insulin intensification in children and young persons with Type 1 diabetes differs in relation to ethnic group; a prospective observational study.

AIMS: We prospectively evaluated the effect of insulin intensification on glycaemic control and lipid levels in children and young persons with Type 1 diabetes in relation to ethnicity. METHODS: In the first 2 years of a 3-year observation period, as part of routine clinical care, 231 children and young persons (40% white, 28% South Asian, 32% black) from a single clinic were offered intensive insulin therapy. After 2 years, 222 were on intensive therapy and their data were compared between ethnic groups at the end of year 3. RESULTS: We observed ethnic differences in HbA(1c) levels during the study [study beginning and end: white children and young persons 77 and 70 mmol/mol (9.2 and 8.6%) vs. South Asian 72 and 68 mmol/mol (8.7 and 8.4%) vs. black 83 and 79 mmol/mol (9.7 and 9.4%), P-value for ANCOVA = 0.007]. By study end, South Asians had the lowest HDL cholesterol (2.0 vs. 1.4 vs. 1.6 mmol/l, P-value = 0.03) and highest triglyceride levels (0.9 vs. 1.8 vs. 1.0 mmol/l, P-value = 0.001). In linear mixed modelling, after adjustment for socio-economic deprivation and other covariates: (1) black ethnicity was associated with poorer glycaemic control (P < 0.001) and (2) South Asian ethnicity was associated with higher triglyceride levels (P < 0.001), independent of HbA(1c). CONCLUSIONS: The effect of insulin intensification on glycaemic control and lipid profile in children and young persons with Type 1 diabetes differs in relation to ethnic group.

Effect of vitamin supplementation on lung injury and running performance in a hot, humid, and ozone-polluted environment.

In this study, the effect of vitamin C and E supplementation on lung injury and performance of runners were analyzed. Using a randomized, double-blinded, crossover design, nine runners participated in two experimental trials: a 2-week Vitamin trial (vitamin C = 500 mg/day + vitamin E = 100 IU/day) and a 2-week Placebo trial. At the end of each supplementation period the runners performed an 8-km time-trial run in a hot (31°C), humid (70% rh), and ozone-polluted (0.10 ppm O(3)) environmental chamber. Nasal lavage and blood samples were collected pre-, post-, and 6-h post-exercise to assess antioxidant status and CC16 as lung injury marker. Higher plasma (pre- and post-exercise) and nasal lavage (post-exercise) antioxidant concentration were found for the Vitamin trial. Nevertheless, this did not result in performance differences (Vitamin trial: 31:05 min; Placebo trial: 31:54 min; P = 0.075) even though significant positive correlations were found between antioxidant concentration and improvement in time to complete the run. CC16 was higher post-exercise in the Placebo trial (P < 0.01) in both plasma and nasal lavage. These findings suggest that antioxidant supplementation might help to decrease the lung injury response of runners when exercising in adverse conditions, but has little effect on performance.

Use of intravenous etomidate to control acute psychosis induced by the hypercortisolaemia in severe paediatric Cushing's disease.

BACKGROUND: Psychosis secondary to paediatric Cushing's disease (CD) is extremely rare and presents a significant management challenge. METHOD: We report a 14.7-year-old CD patient with acute psychosis and self-inflicted injuries following failed transsphenoidal pituitary surgery. Her mental state rapidly deteriorated precluding medical therapy. RESULTS: Emergency intravenous low-dose etomidate infusion (3-3.5 mg/h) with dose titration according to the serum cortisol combined with a hydrocortisone infusion, in an intensive care setting, was effective in controlling the hypercortisolaemia. Her mental state improved with normalisation of her cortisol levels enabling oral administration of ketoconazole and bilateral adrenalectomy to be performed. CONCLUSION: This case illustrates the safe and effective use of a low-dose etomidate infusion in an unusual case of paediatric CD.

Severe insulin resistance secondary to insulin antibodies: successful treatment with the immunosuppressant MMF.

We have evaluated the use of the immunosuppressant mycophenolate mofetil (MMF) in the treatment of severe insulin resistance caused by neutralising anti-insulin antibodies in type 1 diabetes mellitus (T1DM). A 12-yr-old boy with a 5-month history of T1DM developed severe immunological insulin resistance secondary to human insulin antibodies. Various different treatment modalities, including lispro insulin, intravenous insulin, prednisolone and immunoabsorption, were tried, all without a sustained response to treatment. Although the introduction of the immunosuppressant MMF only resulted in a small reduction in haemoglobin A1c (from 10.9 to 9.8%), it did result in a significant reduction in insulin requirements from 6000 to 250 U/d (75 to 3.1 U/kg/d), disappearance of the severe nocturnal hypoglycaemia associated with high titres of insulin antibodies and a reduction in the level of these antibodies from 34.6 to 2.7 mg/dL. MMF may be considered as a means of immunosuppression in patients with markedly raised insulin antibodies whose diabetes cannot be controlled with insulin alone.

Hypocalcaemia and vitamin D deficiency: an important, but preventable, cause of life-threatening infant heart failure.

BACKGROUND: In recent large paediatric cardiomyopathy population studies from North America and Australia, vitamin D deficiency was not identified as a cause of infant heart failure. However, rickets is resurgent in developed countries. OBJECTIVE: To review the prevalence of this cardiomyopathy in paediatric cardiology units of southeast England and determine the prognosis. METHODS AND RESULTS: A retrospective review from 2000 to 2006 in southeast England. Sixteen infants (6 Indian subcontinent, 10 black ethnicity) were identified: median (range) age at presentation was 5.3 months (3 weeks-8 months). All had been breast fed. Ten presented at the end of the British winter (February-May). Median shortening fraction was 10% (range 5-18%) and median left ventricular end diastolic dimension z score was 4.1 (range 3.1-7.0). Six had a cardiac arrest; three infants died. Eight were ventilated, two required mechanical circulatory support and 12 required intravenous inotropic support. Two were referred for cardiac transplantation. Median (range) of biochemical values on admission was: total calcium 1.5 (1.07-1.74) mmol/l; alkaline phosphatase 646 (340-1057) IU/l; 25-hydroxyvitamin D 18.5 (0-46) nmol/l (normal range >35) and parathyroid hormone 34.3 (8.9-102) pmol/l (normal range <6.1). The clinical markers and echocardiographic indices of all survivors have improved. The mean time from diagnosis to achieve normal fractional shortening was 12.4 months. CONCLUSIONS: Vitamin D deficiency and consequent hypocalcaemia are seen in association with severe and life-threatening infant heart failure. That no infant or mother was receiving the recommended vitamin supplementation highlights the need for adequate provision of vitamin D to ethnic minority populations.

Factors influencing skeletal maturation at diagnosis of paediatric Cushing's disease.

BACKGROUND/AIMS: Growth retardation is a recognised complication of paediatric Cushing's disease (CD), but there are few published data on skeletal maturation at diagnosis. We assessed factors contributing to skeletal maturation in patients with paediatric CD. PATIENTS/METHODS: 17 patients, 12 males, 5 females (median age 12.1 years, range 5.8-17.4) were studied. The bone age (BA) of each child was determined by a single observer using the TW3 RUS method. BA delay, i.e. the difference between chronological age (CA) and BA, was compared with clinical and biochemical variables. RESULTS: BA delay was present in 15/17 patients (mean delay 2.0 years, range -0.5 to 4.1 years) and correlated negatively with height SDS (r = -0.70, p < 0.01) and positively with duration of symptoms (r = 0.48, p = 0.05) and CA (r = 0.48, p = 0.05). No relationships were found with midnight cortisol, ACTH, DHEA-S or cortisol suppression during the low-dose dexamethasone suppression test. CONCLUSIONS: BA in most children with CD was delayed and related to length of symptoms and height SDS at diagnosis. Early diagnosis will reduce delay in skeletal maturation and thus contribute to optimal catch-up growth.

Bone mineralization in children with epidermolysis bullosa.

BACKGROUND: Various factors may have deleterious effects on bone health in patients with epidermolysis bullosa (EB). OBJECTIVES: In a retrospective notes review, to assess bone mineralization in children with EB and to identify the relative contributions of nutrition, activity and disease severity to low bone mass. METHODS: Thirty-nine children with EB [32 recessive dystrophic EB (RDEB), four Dowling-Meara EB simplex (DMEBS) and three junctional EB (JEB)] had lumbar spine bone mass measured using dual X-ray absorptiometry (GE Lunar Prodigy; GE Healthcare, Chalfont St Giles, U.K.). Seventy-six healthy children were also studied. Weight and height were recorded and mobility was rated. RESULTS: Children with RDEB and JEB, but not those with DMEBS, had lower bone mineral density SD scores than controls; differences remained after adjusting for the smaller body size of the patients. Bone mass was best predicted by mobility rating. CONCLUSIONS: Children with RDEB and JEB have low bone mass after adjusting for their smaller size, which may put them at risk for fragility fractures. Low bone mass was best predicted by the level of mobility, raising the hypothesis that improving activity or bone loading may be a potential preventive intervention in these children. However, as low bone mass may be multifactorial in these children, more detailed investigation of potential aetiological factors is required before interventions are planned.

Presentation of vitamin D deficiency.

AIMS: To describe the various ways in which vitamin D deficiency presents in children in selected districts of London and to identify which factors, if any, determine the mode of presentation. METHODS: Retrospective review of patients presenting to Newham General, Royal London, Great Ormond Street, and King's College Hospitals between 1996 and 2001 with either hypocalcaemia or rickets caused by vitamin D deficiency. Children with plasma 25-hydroxyvitamin D levels <25 nmol/l (10 ng/ml) were considered to have vitamin D deficiency. RESULTS: Sixty five children, mostly from Black or Asian ethnic minority groups, were identified, 29 of whom had hypocalcaemic symptoms. Seventeen of these had no radiological evidence of rickets. The remainder (48 children) had radiological evidence of rickets with or without clinical signs. Symptoms and signs reverted to normal in all cases with vitamin D supplementation. All children who presented with symptomatic hypocalcaemia were aged either <3 or >10 years. There was a strong correlation between age at presentation and population growth velocity reference data. CONCLUSIONS: Rickets remains a problem in the UK especially in "at risk" ethnic minority groups. Symptomatic hypocalcaemia is an important, but under-recognised presenting feature. Growth rate is likely to be an important factor in determining the mode of presentation. Unexplained hypocalcaemia should be attributed to vitamin D deficiency in "at risk" ethnic minority groups until proved otherwise.

Low back pain at presentation in a newly diagnosed diabetic.

Insulin dependent diabetes mellitus predisposes to a range of different and unusual infections, including epidural and psoas abscesses. However, they occur mainly in adults with longstanding diabetes. We report the case of a 12 year old boy who presented with diabetic ketoacidosis and low back pain, and was subsequently diagnosed with both a left psoas abscess and an extensive thoracolumbar spinal epidural abscess measuring 20 cm in length. This case report highlights the need to maintain a high index of suspicion for epidural abscesses in children presenting with fever and localised back pain. Early diagnosis with appropriate imaging and aggressive management can prevent development of permanent neurological damage as was the case in our patient.

LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development.

In humans, low peak bone mass is a significant risk factor for osteoporosis. We report that LRP5, encoding the low-density lipoprotein receptor-related protein 5, affects bone mass accrual during growth. Mutations in LRP5 cause the autosomal recessive disorder osteoporosis-pseudoglioma syndrome (OPPG). We find that OPPG carriers have reduced bone mass when compared to age- and gender-matched controls. We demonstrate LRP5 expression by osteoblasts in situ and show that LRP5 can transduce Wnt signaling in vitro via the canonical pathway. We further show that a mutant-secreted form of LRP5 can reduce bone thickness in mouse calvarial explant cultures. These data indicate that Wnt-mediated signaling via LRP5 affects bone accrual during growth and is important for the establishment of peak bone mass.