John Welbourn Gregory

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.

A pilot study of motivational interviewing in adolescents with diabetes

Aims: To obtain preliminary data on the impact of motivational interviewing, a counselling approach to behaviour change, on glycaemic control, wellbeing, and self-care of adolescents with diabetes. Methods: Twenty two patients aged 14–18 years participated in motivational interviewing sessions during a six month intervention. The effects of the intervention on HbA1c and a range of psychological factors were assessed. Results: Mean HbA1c decreased from 10.8% to 9.7% during the study and remained significantly lower after the end of the study. Fear of hypoglycaemia was reduced and diabetes was perceived as easier to live with. There were no other significant changes in the psychological measures. By contrast no reduction in HbA1c values was observed in a comparison group who did not receive the motivational interviewing intervention. Conclusion: The findings of this pilot study indicate that motivational interviewing may be a useful intervention in helping adolescents improve their glycaemic control. A larger, longer term randomised controlled study is indicated to clarify the mechanisms and extent of these benefits.

Daily energy expenditure and physical activity in survivors of childhood malignancy.

Changes in body composition, in particular the onset of obesity, may result from reductions in total daily energy expenditure (TDEE) as a consequence of relative physical inactivity. Children previously treated for acute lymphoblastic leukemia (ALL) become obese, yet the mechanism remains undefined. TDEE and physical activity levels [PAL = TDEE/basal metabolic rate(BMR)] were measured in 34 long-term survivors of ALL and compared with results from 21 survivors of other malignancies and 32 healthy sibling control subjects using the flex-heart rate technique. Body composition was measured by dual energy x-ray absorptiometry. The median TDEE was reduced in the ALL group(150 kJ·kg d-1) compared with other malignancies and controls(207 and 185 kJ·kg d-1, respectively, p < 0.01). This reduction was accounted for mainly by a relative decrease in the PAL of the ALL group (1.24) compared with both other malignancies and controls (1.58 and 1.47, respectively, p < 0.01). TDEE and PAL were correlated with percentage body fat (r = -0.39, p < 0.001 and r = -0.24, p < 0.05, respectively). Obesity in survivors of ALL may, in part, be explained by a reduction in TDEE as a consequence of reduced PAL. The cause of such reduction is uncertain.

SOX2 Plays a Critical Role in the Pituitary, Forebrain, and Eye during Human Embryonic Development

CONTEXT Heterozygous, de novo mutations in the transcription factor SOX2 are associated with bilateral anophthalmia or severe microphthalmia and hypopituitarism. Variable additional abnormalities include defects of the corpus callosum and hippocampus. OBJECTIVE We have ascertained a further three patients with severe eye defects and pituitary abnormalities who were screened for mutations in SOX2. To provide further evidence of a direct role for SOX2 in hypothalamo-pituitary development, we have studied the expression of the gene in human embryonic tissues. RESULTS All three patients harbored heterozygous SOX2 mutations: a deletion encompassing the entire gene, an intragenic deletion (c.70_89del), and a novel nonsense mutation (p.Q61X) within the DNA binding domain that results in impaired transactivation. We also show that human SOX2 can inhibit beta-catenin-driven reporter gene expression in vitro, whereas mutant SOX2 proteins are unable to repress efficiently this activity. Furthermore, we show that SOX2 is expressed throughout the human brain, including the developing hypothalamus, as well as Rathkes pouch, the developing anterior pituitary, and the eye. CONCLUSIONS Patients with SOX2 mutations often manifest the unusual phenotype of hypogonadotropic hypogonadism, with sparing of other pituitary hormones despite anterior pituitary hypoplasia. SOX2 expression patterns in human embryonic development support a direct involvement of the protein during development of tissues affected in these individuals. Given the critical role of Wnt-signaling in the development of most of these tissues, our data suggest that a failure to repress the Wnt-beta-catenin pathway could be one of the underlying pathogenic mechanisms associated with loss-of-function mutations in SOX2.

Measured and predicted bone mineral content in healthy boys and girls aged 6-18 years: adjustment for body size and puberty

Dual‐energy X‐ray absorptiometry (DEXA) is a rapid and precise technique for the assessment of bone mineralization in children. Interpretation of the results in growing children is complex as results are influenced by age, body size (height and weight) and puberty. Conventionally, bone mineral data derived from DEXA have been presented as an areal density [BMD; bone mineral content (BMC, g)/projected bone area (BA, cm2)], yet this fails to account for changes in BMC that result from changes in age, body size or pubertal development. Measurement of BMC and BA of the whole body, lumbar spine and left hip were made in 58 healthy boys and girls using DEXA. The relationship between BMC and BA was curvilinear, with the best fit being that of a power model (BMD = BMC/BAλ, where λ is the exponent to which BA is raised in order to remove its influence on BMC). The value of λ changed when measures of body size and puberty were taken into account (e.g. for lumbar spine from 1.66 to 1.49). Predictive formulae for BMC were produced using regression analysis and based on the variables of age, body size and pubertal development. This provides a method for interpreting the measured BMC which is independent of such variables and a constant reference range for children aged 6–18 y.

Inflammatory bowel disease and predisposition to osteopenia

The prevalence of osteopenia in children with inflammatory bowel disease (IBD) is unknown. The effect of nutritional state, disease activity, and steroid therapy on bone mineral content (BMC) of whole body, lumbar spine, and left femoral neck measured by dual energyx ray absorptiometry in 32 children with IBD was assessed by comparison with 58 healthy local school children. Using the control data, a predicted BMC was calculated taking into account bone area, age, height, weight, and pubertal stage. The measured BMC in children with IBD was expressed as a percentage of this predicted value (% BMC). Mean (SD) % BMC was significantly reduced for the whole body and left femoral neck in the children with IBD (97.0 (4.5)% and 93.1 (12.0)% respectively, p<0.05). Of the children with IBD, 41% had a % BMC less than 1 SD below the mean for the whole body and 47% at the femoral neck. Reduction in % BMC was associated with steroid usage but not with the magnitude of steroid dose, disease activity, or biochemical markers of bone metabolism. In conclusion, osteopenia is relatively common in childhood IBD and may be partly related to the previous use of steroids.

Relative osteopenia after treatment for acute lymphoblastic leukemia.

Osteoporosis in adult life is associated with a significant morbidity and may be predisposed to by osteopenia and failure to reach peak bone mass in childhood. Children treated for acute lymphoblastic leukemia (ALL) may be at risk of osteopenia as a result of previous therapy or as a consequence of the disease process itself. Dual energy x-ray absorptiometry measurements of bone mineral content (BMC) for the whole body and at the lumbar spine and hip were taken in 35 (14 male) long-term survivors of ALL and compared with results in 20 (10 male) survivors of other malignancies and 31 (17 male) healthy sibling controls. The measured BMC was expressed as a percentage of a predicted value derived from the control group and based on the variables that had influence upon it. BMC (%) was reduced at the spine in the ALL group compared with controls [92.4 (8.0)% versus 100.4 (9.7)%, respectively; p < 0.005] and at the hip compared with both other malignancies and controls [89.0 (11.5)% versus 96.1 (11.7)% and 100.4 (9.2)%, respectively; p < 0.0005]. Increasing length of time off therapy was associated with a significant increase in %BMC at both the spine and the hip. For the spine, this association was significantly different between the ALL group and other malignancies, suggesting that any gain in %BMC after therapy was slower in children treated for ALL. Both exercise capacity and levels of physical activity were correlated with %BMC at the hip (r = 0.44, p < 0.001 and r = 0.29, p < 0.01, respectively). Previous exposure to methotrexate, ifosfamide, and bleomycin was associated with a reduction in %BMC at the spine. Exposure to 6-mercaptopurine and cisplatin was associated with a reduction at the hip. In conclusion, children treated for ALL are osteopenic. The mechanism is probably multifactorial but is partially related to previous chemotherapy, limited exercise capacity, and relative physical inactivity.

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.

Relationship between cardiopulmonary response to exercise and adiposity in survivors of childhood malignancy

Many long term sequelae result from previous treatment for malignancy in childhood. However, little information exists on cardiopulmonary response and energy expenditure during exercise and their possible associations with excess body fat. Measurements of body composition and exercise capacity both at low intensity and maximal aerobic capacity were made on 56 long term survivors of childhood malignancy (35 survivors of acute lymphoblastic leukaemia (ALL) and 21 survivors of other malignancies) and 32 siblings acting as controls. Female survivors of ALL had significantly greater mean (SD) body fat than survivors of other malignancies and siblings (32.5 (6.4)%v 24.3 (4.4)% and 26.3 (8.5)% respectively, p<0.005). Energy expenditure at low intensity exercise was reduced in survivors of ALL, and negatively correlated with body fat after controlling for weight (partial r range −0.21 to −0.47, p<0.05). Stroke volume, measured indirectly, was reduced and heart rate raised in ALL survivors at submaximal exercise levels. Peak oxygen consumption was significantly reduced in girls and boys treated for ALL compared with siblings (30.5 v 41.3 ml/kg/min for girls, p<0.05 and 39.9 v 47.6 ml/kg/min for boys, p<0.05 respectively). Reduced exercise capacity may account in part for the excess adiposity observed in long term survivors of ALL.

Childhood diabetes: parents’ experience of home management and the first year following diagnosis

Aims  To explore parents’ experience of having a child diagnosed with Type 1 diabetes, managed at home, and their first year following diagnosis.