Severity of acute phase reaction in children receiving the first dose of zoledronic acid and the impact of the underlying condition: a cross-sectional study.

INTRODUCTION: Zoledronic acid (ZA), used for treatment of children with osteoporosis, can cause acute phase reaction (APR) following the first infusion. Many institutions have a policy to admit and monitor all children for their first ZA infusion. OBJECTIVE: To determine if the APR with the first ZA dose warrants hospital-level care and evaluate if its severity correlates with the underlying condition. DESIGN: Retrospective cross-sectional analysis. SETTINGS: Two tertiary centres across the UK that run paediatric metabolic bone disease services. PATIENTS: Children who received first ZA infusion as inpatients at these centres. INTERVENTIONS: Nil. MAIN OUTCOME MEASURES: The Paediatric Early Warning Score (PEWS) and length of hospital stay to assess the severity of APR. RESULTS: 107 patients were included. Peak PEWS≤3 was found in 85% of children. 83% required admission for <24 hours. The various patient populations (osteogenesis imperfecta (OI), immobility-induced osteoporosis, idiopathic juvenile osteoporosis, systemic inflammatory disorders and steroid-induced osteoporosis, Duchenne muscular dystrophy (DMD)) did not differ significantly in the mean peak PEWS and the length of hospital stay. However, when compared directly, the group with DMD and that with systemic inflammatory disorders and steroid-induced osteoporosis differed significantly in the mean peak PEWS (p=0.011) and the length of hospital stay (p=0.048), respectively, as compared with the OI group. CONCLUSION: Most patients had a mild APR not requiring overnight hospital admission, after their first ZA dose. However, certain groups seem to suffer more severe APR and may warrant consideration of inpatient monitoring with the first infusion.

Characterisation of parathyroid hormone concentration in extremely preterm or very low birthweight infants in routine clinical screening for metabolic bone disease: A service evaluation cohort study.

AIM: To characterise parathyroid hormone (PTH) concentrations in infants at high risk for metabolic bone disease, in order to assist clinical decisions around the use of PTH for screening. METHODS: Infants born under 28 weeks' postmenstrual age or with birthweight under 1.5 kg in a tertiary neonatal unit in the UK were included. Clinical guidance was to assess PTH concentration in the first 3 weeks after birth. Clinical information was extracted from prospective records. RESULTS: Sixty-four infants had mean birth gestation of 26 weeks and birthweight of 882 g. Median PTH (sent on median day 18 of life) was 9.2 pmol/L (interquartile range 5.3-17 pmol/L). Sixty-seven per cent of infants had a PTH greater than 7 pmol/L. For 22% of the infants, raised PTH was not accompanied by abnormal phosphate or alkaline phosphatase. Eighty-nine per cent of infants tested were insufficient or deficient for 25-hydroxyvitamin D. CONCLUSIONS: Universal screening highlights the high frequency of high PTH in this high-risk population, implying a need for calcium supplementation. A considerable number of infants would not be identified as showing potential signs of metabolic bone disease if the assessment excludes the use of PTH. The high level of 25-hydroxyvitamin D deficiency may be a confounder.

Refractory Rickets.

Nutritional rickets, caused by vitamin D and/or calcium deficiency is by far the most common cause of rickets. In resource-limited settings, it is therefore not uncommon to treat rickets with vitamin D and calcium. If rickets fails to heal and/or if there is a family history of rickets, then refractory rickets should be considered as a differential diagnosis. Chronic low serum phosphate is the pathological hallmark of all forms of rickets as its low concentration in extracellular space leads to the failure of apoptosis of hypertrophic chondrocytes leading to defective mineralisation of the growth plate. Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) control serum phosphate concentration by facilitating the excretion of phosphate in the urine through their action on the proximal renal tubules. An increase in PTH, as seen in nutritional rickets and genetic disorders of vitamin D-dependent rickets (VDDRs), leads to chronic low serum phosphate, causing rickets. Genetic conditions leading to an increase in FGF23 concentration cause chronic low serum phosphate concentration and rickets. Genetic conditions and syndromes associated with proximal renal tubulopathies can also lead to chronic low serum phosphate concentration by excess phosphate leak in urine, causing rickets.In this review, authors discuss an approach to the differential diagnosis and management of refractory rickets.

Neurodevelopmental Abnormalities in Patients with Familial Hypocalciuric Hypercalcemia Type 3.

OBJECTIVES: To evaluate the prevalence and degree of any neurodevelopmental abnormalities in children with familial hypocalciuric hypercalcemia type 3 (FHH3). STUDY DESIGN: A formal neurodevelopmental assessment was performed in children diagnosed with FHH3. The Vineland Adaptive Behavior Scales, which is a standardized parent report assessment tool for adaptive behavior, was used to assess communication, social skills, and motor function and to generate a composite score. RESULTS: Six patients were diagnosed with hypercalcemia between 0.1 and 8 years of age. All had neurodevelopmental abnormalities in childhood consisting of either global developmental delay, motor delay, expressive speech disturbances, learning difficulties, hyperactivity, or autism spectrum disorder. Four out of the 6 probands had a composite Vineland Adaptive Behavior Scales SDS of < -2.0, indicating adaptive malfunctioning. Significant deficits were observed in the domains of communication (mean SDS: -2.0, P < .01), social skills (mean SDS: -1.3, P < .05), and motor skills (mean SDS: 2.6, P < .05). Individuals were equally affected across domains, with no clear genotype-phenotype correlation. All family members affected with FHH3 also described evidence of neurodevelopmental dysfunction, including mild-to-moderate learning difficulties, dyslexia, and hyperactivity. CONCLUSION: Neurodevelopmental abnormalities appear to be a highly penetrant and common feature of FHH3, and early detection is warranted to provide appropriate educational support. This case series also supports consideration of serum calcium measurement as part of the diagnostic work-up in any child presenting with unexplained neurodevelopmental abnormalities.

The skeletal muscle phenotype of children with Neurofibromatosis Type 1 - A clinical perspective.

Neurofibromatosis type 1 (NF1) can affect multiple systems in the body. An under recognised phenotype is one of muscle weakness. Clinical studies using dynamometry and jumping mechanography have demonstrated that children with NF1 are more likely to have reduced muscle force and power. Many children with NF1 are unable to undertake physical activities to the same level as their peers, and report leg pains on physical activity and aching hands on writing. Children and adolescents with NF1 reporting symptoms of muscle weakness should have a focused assessment to exclude alternative causes of muscle weakness. Assessments of muscle strength and fine motor skills by physiotherapists and occupational therapists can provide objective evidence of muscle function and deficits, allowing supporting systems in education and at home to be implemented. In the absence of an evidence base for management of NF1-related muscle weakness, we recommend muscle-strengthening exercises and generic strategies for pain and fatigue management. Currently, trials are underway involving whole-body vibration therapy and carnitine supplementation as potential future management options.

Normal Mid-Gestation Fetal Ultrasonography Cannot Reliably Exclude Severe Perinatal Hypophosphatasia.

INTRODUCTION: Hypophosphatasia is a systemic bone disease characterized by inhibition of bone mineralization due to mutations in the ALPL gene that results in a deficiency of tissue nonspecific alkaline phosphatase. The perinatal form is the most severe. In the past, this form was lethal, although human recombinant enzyme replacement therapy has now been developed and licensed, which improves survival. Perinatal hypophosphatasia is usually suggested on antenatal ultrasonography with undermineralization of the long bones, skull, and thoracic cavity. In the UK, antenatal ultrasonography for fetal anomalies is conducted at mid-gestation (i.e., 18-21 weeks gestational age), and if normal, no further routine scans are performed. Usually, this would identify abnormalities in bone mineralization suggestive of perinatal hypophosphatasia. CASES: We describe 2 cases of perinatal hypophosphatasia where mid-gestation ultrasonography was normal. In the first case, where a previous pregnancy had been terminated for perinatal hypophosphatasia, third trimester ultrasonography revealed skeletal features of hypophosphatasia. In the second case, the diagnosis of perinatal hypophosphatasia was made only immediately after birth. CONCLUSION: We conclude that serial antenatal ultrasonography or antenatal genetic testing should be considered in all pregnancies with a positive family history of hypophosphatasia, as mid-gestation ultrasonography cannot reliably exclude perinatal hypophosphatasia. This is especially important given that effective enzyme replacement therapy is now available.

Metabolic bone disease of prematurity-National survey of current neonatal and paediatric endocrine approaches.

AIM: This study aimed to identify current trends in the management of metabolic bone disease of prematurity (MBDP) in the United Kingdom. METHODS: A nationwide electronic survey was disseminated to all neonatal networks across the United Kingdom, as well as to paediatric endocrinologists for comparison. Weighted averages were used to compare relative importance placed on screening and diagnostic investigations (1 = not important, 5 = essential). RESULTS: Sixty-nine individuals responded from 53 neonatal units. Greatest emphasis was placed on levels of serum phosphate and alkaline phosphatase for screening (weighted average 4.5 and 4.6, respectively), diagnosis (weighted average 4.1 and 4.5, respectively) and monitoring (93% and 97% of neonatal responders, respectively) of MBDP by neonatologists. Although similar results were obtained for endocrinologists, significantly greater emphasis was placed on plasma parathyroid hormone (PTH) level for screening, diagnosis and monitoring (p < 0.001 for each). Phosphate supplementation was reported almost universally by neonatal responders (99%), but was significantly less for endocrine responders (62%) for the treatment of MBDP (p < 0.001). CONCLUSION: There is an under-utilisation of plasma PTH as a screening, diagnostic and monitoring investigation to guide appropriate supplementation for MBDP by neonatologists.

Current status in therapeutic interventions of neonatal bone mineral metabolic disorders.

Neonatal care has significantly improved in the past decade with improved survival of preterm and sick neonates. Similarly, the field of bone and mineral disorders is continuing to accelerate with better understanding of pathophysiology and genetic basis of diseases, as well as availability of newer diagnostic and therapeutic modalities. In this extensive and rapidly expanding field, metabolic bone disease specialists are frequently called upon to translate progress into better care for neonates with bone and mineral disorders. Accordingly, this chapter provides a review of clinical manifestations and evidence-based investigation and management (where available) of common, rare and ultra-rare disorders of bone and mineral metabolism manifesting in the neonatal period. Besides medical treatment we emphasise the crucial role of the multidisciplinary team, which include physical therapists, occupational therapists and dieticians, in the care of neonates with bone disorders such as osteogenesis imperfecta and achondroplasia.

Central venous catheter-associated thrombosis in children with congenital hyperinsulinism

Summary: Congenital hyperinsulinism (CHI) is an important cause of severe hypoglycaemia in infancy. To correct hypoglycaemia, high concentrations of dextrose are often required through a central venous catheter (CVC) with consequent risk of thrombosis. We describe a series of six cases of CHI due to varying aetiologies from our centre requiring CVC for the management of hypoglycaemia, who developed thrombosis in association with CVC. We subsequently analysed the incidence and risk factors for CVC-associated thrombosis, as well as the outcomes of enoxaparin prophylaxis. The six cases occurred over a 3-year period; we identified an additional 27 patients with CHI who required CVC insertion during this period (n = 33 total), and a separate cohort of patients with CHI and CVC who received enoxaparin prophylaxis (n = 7). The incidence of CVC-associated thrombosis was 18% (6/33) over the 3 years, a rate of 4.2 thromboses/1000 CVC days. There was no difference in the frequency of genetic mutations or focal CHI in those that developed thromboses. However, compound heterozygous/homozygous potassium ATP channel mutations correlated with thrombosis (R2 = 0.40, P = 0.001). No difference was observed in CVC duration, high concentration dextrose or glucagon infused through the CVC. In patients receiving enoxaparin prophylaxis, none developed thrombosis or bleeding complications. The characteristics of these patients did not differ significantly from those with thrombosis not on prophylaxis. We therefore conclude that CVC-associated thrombosis can occur in a significant proportion (18%) of patients with CHI, particularly in severe CHI, for which anticoagulant prophylaxis may be indicated. Learning Points: CVC insertion is one of the most significant risk factors for thrombosis in the paediatric population. Risk factors for CVC-associated thrombosis include increased duration of CVC placement, malpositioning and infusion of blood products. To our knowledge, this is the first study to evaluate CVC-associated thrombosis in patients with congenital hyperinsulinism (CHI). The incidence of CVC-associated thrombosis development is significant (18%) in CHI patients and higher compared to other neonates with CVC. CHI severity may be a risk factor for thrombosis development. Although effective prophylaxis for CVC-associated thrombosis in infancy is yet to be established, our preliminary experience suggests the safety and efficacy of enoxoaparin prophylaxis in this population and requires on-going evaluation.

Metabolic bone disease of prematurity: causes, recognition, prevention, treatment and long-term consequences.

Metabolic bone disease of prematurity (MBDP) is characterised by skeletal demineralisation, and in severe cases it can result in fragility fractures of long bones and ribs during routine handling. MBDP arises from prenatal and postnatal factors. Infants who are born preterm are deprived of fetal mineral accumulation, 80% of which occurs in the third trimester. Postnatally, it is difficult to maintain a comparable intake of minerals, and medications, such as corticosteroids and diuretic therapy, lead to bone resorption. With improvements in neonatal care and nutrition, the incidence of MBDP in preterm infants appears to have decreased, although the recent practice of administering phosphate supplements alone will result in secondary hyperparathyroidism and associated bone loss, worsening MBDP. Postnatal immobilisation and loss of placental supply of oestrogen also contribute to skeletal demineralisation. There is no single diagnostic or screening test for MBDP, with pitfalls existing for most radiological and biochemical investigations. By reviewing the pathophysiology of calcium and phosphate homeostasis, one can establish that plasma parathyroid hormone is important in determining the aetiology of MBDP - primarily calcipaenia or phosphopaenia. This will then direct treatment with the appropriate supplements while considering optimal physiological calcium to phosphate ratios.

Focal Congenital Hyperinsulinism as a Cause for Sudden Infant Death.

Congenital hyperinsulinism (CHI) is the commonest cause of persistent and severe hypoglycemia in infancy due to unregulated insulin secretion from pancreatic ß-cells. Prompt early diagnosis is important, as insulin reduces glucose supply to the brain, resulting in significant brain injury and risk of death. Histologically, CHI has focal and diffuse forms; in focal CHI, an inappropriate level of insulin is secreted from localized ß-cell hyperplasia. We report a 4-month-old male infant, who presented with sudden illness and collapse without a recognized cause and died. Postmortem examination revealed pancreatic histopathology compatible with focal CHI. Immunofluoresence staining showed limited expression of p57kip2 ß-cells reinforcing the diagnosis. Mutation testing for genes associated with CHI from DNA from the focal lesion was negative. This case highlights the recognition of focal CHI as a possible cause for sudden infant death. In children dying suddenly and unexpectedly, postmortem pancreatic sections should be carefully examined for focal CHI.

Endogenous neurogenesis in the human brain following cerebral infarction.

Increased endogenous neurogenesis has a significant regenerative role in many experimental models of cerebrovascular diseases, but there have been very few studies in humans. We therefore examined whether there was evidence of altered endogenous neurogenesis in an 84-year-old patient who suffered a cerebrovascular accident 1 week prior to death. Using antibodies that specifically label neural stem/neural progenitor cells, we examined the presence of immunopositive cells around and distant from the infarcted area, and compared this with a control, age-matched individual. Interestingly, a large number of neural stem cells, vascular endothelial growth factor-immunopositive cells and new blood vessels were observed only around the region of infarction, and none in the corresponding brain areas of the healthy control. In addition, an increased number of neural stem cells was observed in the neurogenic region of the lateral ventricle wall. Our results suggest increased endogenous neurogenesis associated with neovascularization and migration of newly-formed cells towards a region of cerebrovascular damage in the adult human brain and highlight possible mechanisms underlying this process.