Justin H. Davies

Bone mass acquisition in healthy children

Although 80% of the variance in bone mass is determined genetically, there are many other factors which influence the accumulation of bone in early life and affect future risks of osteoporosis. This review considers the genetic, fetal, and environmental influences on bone mass acquisition in healthy children, and highlights important areas where paediatricians may have a role by counselling children and their families to adopt a healthy lifestyle which promotes bone health.

Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6.

Spontaneous pathologic arterial calcifications in childhood can occur in generalized arterial calcification of infancy (GACI) or in pseudoxanthoma elasticum (PXE). GACI is associated with biallelic mutations in ENPP1 in the majority of cases, whereas mutations in ABCC6 are known to cause PXE. However, the genetic basis in subsets of both disease phenotypes remains elusive. We hypothesized that GACI and PXE are in a closely related spectrum of disease. We used a standardized questionnaire to retrospectively evaluate the phenotype of 92 probands with a clinical history of GACI. We obtained the ENPP1 genotype by conventional sequencing. In those patients with less than two disease-causing ENPP1 mutations, we sequenced ABCC6. We observed that three GACI patients who carried biallelic ENPP1 mutations developed typical signs of PXE between 5 and 8 years of age; these signs included angioid streaks and pseudoxanthomatous skin lesions. In 28 patients, no disease-causing ENPP1 mutation was found. In 14 of these patients, we detected pathogenic ABCC6 mutations (biallelic mutations in eight patients, monoallelic mutations in six patients). Thus, ABCC6 mutations account for a significant subset of GACI patients, and ENPP1 mutations can also be associated with PXE lesions in school-aged children. Based on the considerable overlap of genotype and phenotype of GACI and PXE, both entities appear to reflect two ends of a clinical spectrum of ectopic calcification and other organ pathologies, rather than two distinct disorders. ABCC6 and ENPP1 mutations might lead to alterations of the same physiological pathways in tissues beyond the artery.

Maternal plasma polyunsaturated fatty acid status in late pregnancy is associated with offspring body composition in childhood

CONTEXT Maternal diet during pregnancy has been linked to offspring adiposity, but it is unclear whether maternal polyunsaturated fatty acid (PUFA) status during pregnancy affects offspring body composition. OBJECTIVE We investigated the associations between maternal plasma n-3 and n-6 PUFA status at 34 wk gestation and offspring body composition. DESIGN AND SETTING A prospective United Kingdom population-based mother-offspring cohort, the Southampton Womens Survey (SWS), was studied. PARTICIPANTS A total of 12,583 nonpregnant women were recruited into the SWS, among whom 1987 delivered a baby before December 31, 2003; 293 mother-child pairs had complete measurements of maternal plasma PUFA concentrations in late pregnancy and offspring body composition at both ages 4 and 6 yr. MAIN OUTCOMES MEASURED We measured offspring body composition by dual-energy x-ray absorptiometry, yielding fat mass, lean mass, percentage fat mass, and percentage lean mass. Results are presented as β-coefficients for standardized variables, therefore reflecting the sd change of the outcome for every 1 sd of the predictor. RESULTS After adjustment for maternal factors and child factors including height and duration of breast-feeding, maternal plasma n-6 PUFA concentration positively predicted offspring fat mass at 4 yr (β = 0.14 SD/SD; P = 0.01) and 6 yr (β = 0.11 SD/SD; P = 0.04), but there was no association with offspring lean mass at either age (β = 0.005 SD/SD, P = 0.89; and β = 0.008 SD/SD, P = 0.81, respectively). Maternal plasma n-3 PUFA concentration was not associated with offspring fat mass at 4 yr (β = 0.057 SD/SD; P = 0.34) or 6 yr (β = 0.069 SD/SD; P = 0.21). Maternal plasma n-3 PUFA status was positively associated with offspring lean mass on univariate analysis (4 yr, β = 0.11, P = 0.06; 6 yr, β = 0.14; P = 0.02); however, this was confounded by a positive association with offspring height. CONCLUSIONS This observational study suggests that maternal n-6 PUFA status during pregnancy might influence offspring adiposity in childhood.

Hypophosphatemia, hyperphosphaturia, and bisphosphonate treatment are associated with survival beyond infancy in generalized arterial calcification of infancy.

Background—Generalized arterial calcification of infancy has been reported to be frequently lethal, and the efficiency of any therapy, including bisphosphonates, is unknown. A phosphate-poor diet markedly increases survival of NPP1 null mice, a model of generalized arterial calcification of infancy. Methods and Results—We performed a multicenter genetic study and retrospective observational analysis of 55 subjects affected by generalized arterial calcification of infancy to identify prognostic factors. Nineteen (34%) patients survived the critical period of infancy. In all 8 surviving patients tested, hypophosphatemia due to reduced renal tubular phosphate reabsorption developed during childhood. Eleven of 17 (65%) patients treated with bisphosphonates survived. Of 26 patients who survived their first day of life and were not treated with bisphosphonates only 8 (31%) patients survived beyond infancy. Forty different homozygous or compound heterozygous mutations, including 16 novel mutations in ENPP1, were found in 41 (75%) of the 55 patients. Twenty-nine (71%) of these 41 patients died in infancy (median, 30 days). Seven of the 14 (50%) patients without ENPP1 mutations died in infancy (median, 9 days). When present on both alleles, the mutation p.P305T was associated with death in infancy in all 5 cases; otherwise, no clear genotype-phenotype correlation was seen. Conclusion—ENPP1 coding region mutations are associated with generalized arterial calcification of infancy in ≈75% of subjects. Except for the p.P305T mutation, which was universally lethal when present on both alleles, the identified ENPP1 mutations per se have no discernable effect on survival. However, survival seems to be associated with hypophosphatemia linked with hyperphosphaturia and also with bisphosphonate treatment.

Dual-Energy X-ray Aborptiometry Assessment in Children and Adolescents with Diseases that May Affect the Skeleton: The 2007 ISCD Pediatric Official Positions

The Task Force focusing on the use of dual energy X-ray absorptiometry (DXA) in children and adolescents with diseases that may affect the skeleton reviewed over 300 articles to establish the basis for the Official Positions. A significant number of studies used DXA-based outcome measures to assess the effects of specific interventions and charted the natural history of incremental changes in bone size and mass in specific disease states in children. However, the utility of DXA in clinical practice has not been evaluated systematically, in large part due to the lack of a workable definition for childhood osteoporosis. Thus, in combination with the Official Positions addressing the diagnosis of osteoporosis in children, and the reporting of DXA results in children, this document presents clear guidelines from which clinicians and researchers alike can work. This report delineates a set of disorders in which it is appropriate to use DXA as part of the comprehensive assessment of skeletal health in children and adolescents, and provides guidance concerning the initiation of assessment and the frequency of monitoring. Importantly, this document also highlights significant gaps in our knowledge, emphasizing areas for future research.

Methylation analysis of 79 patients with growth restriction reveals novel patterns of methylation change at imprinted loci

This study was an investigation of 79 patients referred to the Wessex Regional Genetics Laboratory with suspected Russell–Silver Syndrome or unexplained short stature/intra uterine growth restriction, warranting genetic investigation. Methylation status was analysed at target sequences within eleven imprinted loci (PLAGL1, IGF2R, PEG10, MEST1, GRB10, KCNQ1OT1, H19, IGF2P0, DLK1, PEG3, NESPAS). Thirty seven percent (37%) (29 of 79) of samples were shown to have a methylation abnormality. The commonest finding was a loss of methylation at H19 (23 of 29), as previously reported in Russell–Silver Syndrome. In addition, four of these patients had methylation anomalies at other loci, of whom two showed hypomethylation of multiple imprinted loci, and two showed a complete gain of methylation at IGF2R. This latter finding was also present in five other patients who did not have demonstrable changes at H19. In total, 7 of 79 patients showed a gain of methylation at IGF2R and this was significantly different from a normal control population of 267 individuals (P=0.002). This study in patients with growth restriction shows the importance of widening the epigenetic investigation to include multiple imprinted loci and highlights potential involvement of the IGF2R locus.

Temple syndrome: improving the recognition of an underdiagnosed chromosome 14 imprinting disorder: an analysis of 51 published cases

Chromosome 14 harbours an imprinted locus at 14q32. Maternal uniparental disomy of chromosome 14, paternal deletions and loss of methylation at the intergenic differentially methylated region (IG-DMR) result in a human phenotype of low birth weight, hypotonia, early puberty and markedly short adult stature. The analysis of the world literature of 51 cases identifies the key features that will enhance diagnosis and potentially improve treatment. We found a median birth weight SD score (SDS) of −1.88 and median adult final height of −2.04 SDS. Hypotonia and motor delay were reported in 93% and 83% of cases, respectively. Early puberty was reported in 86% of cases with the mean age of menarche at 10 years and 2 months of age. Small hands and feet were reported frequently (87% and 96%, respectively). Premature birth was common (30%) and feeding difficulties frequently reported (n = 22). There was evidence of mildly reduced intellectual ability (measured IQ 75–95). Obesity was reported in 49% of cases, and three patients developed type 2 diabetes mellitus. Two patients were reported to have recurrent hypoglycaemia, and one of these patients was subsequently demonstrated to be growth hormone deficient and started replacement therapy. We propose the use of the name ‘Temple syndrome’ for this condition and suggest that improved diagnosis and long-term monitoring, especially of growth and cardiovascular risk factors, is required.

Final adult height and body mass index after cure of paediatric Cushing's disease

Objective  Linear growth data after cure of paediatric Cushings disease (CD) have been reported infrequently. We evaluated final adult height (FH) and body mass index (BMI) in a cohort of paediatric patients treated successfully for CD.

Skeletal morbidity in childhood acute lymphoblastic leukaemia

Skeletal morbidity is increasingly being recognized inthese individuals and may occur at diagnosis, during and followingtreatment. This is an important problem, which may result infractures, pain, loss of mobility and deformity, with resultant adverseconsequences on quality of life. The recognition of these complica-tions is essential to enable the institution of rational strategies formonitoring and optimizing bone health.This review will consider the many influences that adversely affectbone health in children treated for ALL and will focus on thecommonest abnormality, osteopenia (Fig. 1). Osteopenia is charac-terized by a low bone mineral density (BMD). A low BMD duringchildhood may lead to a failure to achieve peak bone mass, whichis thought to be a major determinant for the subsequent risk ofosteoporotic fractures in later life.

Osteopenia, excess adiposity and hyperleptinaemia during 2 years of treatment for childhood acute lymphoblastic leukaemia without cranial irradiation

objective  Osteopenia and excess adiposity occur following treatment of childhood acute lymphoblastic leukaemia (ALL) and the use of cranial irradiation is thought to be a significant contributory factor. Hyperleptinaemia has also been demonstrated following cessation of treatment for childhood ALL. Therefore a prospective study was undertaken to evaluate serial changes in percentage bone mineral content (BMC), adiposity and serum leptin concentrations during 2 years of treatment of children with ALL with chemotherapy but without cranial irradiation.