Jennifer A. Batch

Bone mineral density in Australian children, adolescents and adults with cystic fibrosis: a controlled cross sectional study

Background: Low bone mineral density (BMD) is recognised in individuals with cystic fibrosis (CF) although the pathogenesis remains unclear. The aims of this study were to compare BMD over a broad continuum of Australian individuals with CF with healthy controls and to examine the relationship between BMD and clinical parameters including physical activity, nutrition, and vitamin D levels. Methods: BMD of the lumbar spine (LS), total body (TB), femoral neck (FN), cortical wrist (R33%), and distal wrist (RUD) was examined in 153 individuals with CF aged 5.3–55.8 years (84 males) and in 149 local controls aged 5.6–48.3 years (66 males) using dual energy x ray absorptiometry. Anthropometric variables, body cell mass, markers of disease severity, corticosteroid usage, measures of physical activity, dietary calcium and caloric intake and serum vitamin D were assessed and related to BMD. Results: Compared with controls, mean BMD was not significantly different in children aged 5–10 years with CF. Adolescents (females 11–18 years, males 11–20 years) had reduced TB and R33% BMD when adjusted for age, sex, and height (difference in BMD (g/cm2) adjusted means between control and CF: TB = 0.04 (95% CI 0.01 to 0.07); R33% = 0.03 (95% CI 0.01 to 0.06)). BMD was reduced at all sites except R33% in adults (difference in BMD (g/cm2) adjusted means between control and CF: TB = 0.05 (95% CI 0.02 to 0.09); LS = 0.08 (95% CI 0.03 to 0.14); FN = 0.09 (95% CI 0.03 to 0.15); RUD = 0.03 (95% CI 0.01 to 0.05)). In children/adolescents BMD was weakly associated with nutritional status and disease severity. Conclusions: BMD was normal in a well nourished group of prepubertal children with CF. A BMD deficit appears to evolve during adolescence and becomes more marked in adults. Individuals with CF should optimise nutrition, partake in physical activity, and maximise lung health in order to optimise BMD. Further longitudinal studies are required to understand the evolution of reduced BMD in young people and adults with CF.

Controlled longitudinal study of bone mass accrual in children and adolescents with cystic fibrosis

Background: A study was undertaken to observe the gains in bone mass in children and adolescents with cystic fibrosis (CF) over 24 months and to examine the relationship between areal bone mineral density (aBMD) and associated clinical parameters including physical activity, nutrition, and 25-hydroxyvitamin D (25OHD). Methods: Areal BMD of the total body (TB), lumbar spine (LS), and total femoral neck (FNt) were repeatedly measured in 85 subjects aged 5–18 years with CF and 100 age and sex matched controls over 2 years. At each visit anthropometric variables, nutritional parameters, pubertal status, disease severity, physical activity, dietary calcium, caloric intake, and serum 25OHD were assessed and related to aBMD. Results: After adjusting for age, sex, and height Z-score, gains in LS aBMD in children (5–10 years) and TB and FNt aBMD in adolescents (11–18 years) with CF were significantly less than in controls. Lean tissue mass was significantly associated with TB and LS aBMD gains in children and adolescents and explained a significant proportion of the aBMD deficit observed. Lung function parameters were significantly associated with aBMD gains in adolescents with CF. Conclusions: Inadequate bone mass accrual during childhood and adolescence contributes to the low bone mass observed in adults with CF. Accounting for the height discrepancy which is frequently observed in those with CF, in addition to age and sex, is important when assessing low bone mass in children and adolescents with CF. To optimise an individual’s potential to acquire maximal bone mass, it is necessary to maximise nutritional status and limit the progression of chronic suppurative lung disease.

Hyperinsulinism and Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth syndrome first described by Beckwith in 1963.1 The incidence of BWS is about 1:13 700 births, with an equal sex distribution.2 It is a clinically and genetically heterogeneous disorder. Table 1 outlines the major clinical features. The existence of milder forms of BWS probably underestimates this incidence.1 Developmental delay in BWS has been associated with chromosomal duplication, prematurity, and hypoglycaemia.3 The long term survival in BWS is favourable1, although surveillance for tumours is required.4 The phenotype of BWS is likely to result from an imbalance of a number of critical genes at chromosome 11p15. At this location, genetic imprinting with the loss of maternally expressed tumour and/or growth suppressor genes—for example, p57KIP2and H19—or duplications and unipaternal disomy of paternally expressed growth promoter genes—for example, insulin-like growth factor II—have been implicated in BWS.2 In BWS, 85% of cases are sporadic and 15% are autosomal dominant.2 Identified causes of autosomal dominant BWS include p57KIP2 mutations and 11p15 duplications and translocations.2 About 30% of the sporadic cases result from p57KIP2 mutations, unipaternal disomy, or 11p15 duplications and translocations, while 70% have no identified cytogenetic or DNA abnormality.2 View this table: Table 1 Features of Beckwith-Wiedemann syndrome The incidence of hypoglycaemia in BWS is about 50%.3 5 In one BWS hypoglycaemia series, 80% were reported as mild and asymptomatic, requiring extra feeds or intravenous dextrose only. In 20%, the hypoglycaemia was prolonged (duration greater than one week) and difficult to control.3Hypoglycaemia has been documented into the third year of life.5 Intellectual impairment was associated with hypoglycaemia.3 Hyperinsulinism and BWS Hyperinsulinism is the cause of both transient and prolonged hypoglycaemia in BWS. A number of case reports provide data on the metabolic aspects of …

Neonatal complete generalized glucocorticoid resistance and growth hormone deficiency caused by a novel homozygous mutation in Helix 12 of the ligand binding domain of the glucocorticoid receptor gene (NR3C1).

CONTEXT Glucocorticoid resistance is a rare genetic condition characterized by reduced sensitivity to cortisol signaling and subsequent hyperactivation of the hypothalamic-pituitary-adrenal axis. OBJECTIVE The objective was to confirm the diagnosis of glucocorticoid resistance in the patient, to determine the degree of suppression of cortisol and ACTH levels in response to dexamethasone, and to determine the underlying genetic abnormality and functional consequences of the mutation. PATIENT AND METHODS The patient presented on the first day of life with profound hypoglycemia. Initial cortisol levels were appropriately elevated; however, the patient was found to have persistently elevated levels of both cortisol and ACTH. The baby developed a tanned appearance and severe hypertension and fatigued easily with feeding. Serial oral dexamethasone suppression tests were performed with doses escalating from 0.125 mg to 12 mg dexamethasone given at 2300 h. Sequencing of the glucocorticoid receptor gene was performed along with functional studies of the glucocorticoid receptor. GH secretion was assessed with an arginine glucagon stimulation test. RESULTS Cortisol and ACTH levels did not suppress with doses of up to 12 mg dexamethasone. A 2-bp deletion was found at amino acid position 773 of the glucocorticoid receptor ligand binding domain. A complete lack of dexamethasone binding and in vitro biological effect was demonstrated. GH stimulation testing was consistent with GH deficiency. CONCLUSION The homozygous mutation in the ligand-binding domain of the glucocorticoid receptor gene resulted in a functionally inactive glucocorticoid receptor and apparent complete glucocorticoid resistance with biochemical GH deficiency.

Prevalence of mutations in the short stature homeobox containing gene (SHOX) in Madelung deformity of childhood

In 1878, Madelung described a painful, disabling, and deforming abnormality of the forearm in which misalignment of the bones of the wrist and forearm resulted in a “spontaneous forward subluxation of the wrist”.1 A familial form of a bilateral wrist deformity resulting from dorsal dislocation of the ulnar head, accompanied by mesomelic short stature was first reported in 1929 and later termed Leri-Weill dyschondrosteosis (LWD).2–4 In LWD, the Madelung deformity results from dysplasia located at the medial aspect of the distal radial growth plate, where narrowing and premature fusion of the physis occurs.5 This dysplasia leads to differential growth rates between the lesion and the distal lateral radial physis impeding growth and pulling the lateral radial epiphysis off line as the remaining physis advances.6 In its fully developed form, Madelung deformity leads to shortening and bowing (sometimes marked) of the radius and the involvement of other epiphyses in this disorder results in mesomelia.7 Typically, Madelung deformity does not appear until mid-childhood but is usually preceded by radiological signs.8 Other localised lesions in the ulnar-palmar zone of the distal radius can result in differential growth rates leading to Madelung deformity including Turner, Olliers, and multiple exostoses syndromes and environmental causes.3,4,9 ### Key points

Serum vitamin D levels are lower in Australian children and adolescents with type 1 diabetes than in children without diabetes

Vitamin D is synthesised in the skin through the action of UVB radiation (sunlight), and 25‐hydroxy vitamin D (25OHD) measured in serum as a marker of vitamin D status. Several studies, mostly conducted in high latitudes, have shown an association between type 1 diabetes mellitus (T1DM) and low serum 25OHD. We conducted a case–control study to determine whether, in a sub‐tropical environment with abundant sunlight (latitude 27.5°S), children with T1DM have lower serum vitamin D than children without diabetes. Fifty‐six children with T1DM (14 newly diagnosed) and 46 unrelated control children participated in the study. Serum 25OHD, 1,25‐dihydroxy vitamin D (1,25(OH)2D) and selected biochemical indices were measured. Vitamin D receptor (VDR) polymorphisms Taq1, Fok1, and Apa1 were genotyped. Fitzpatrick skin classification, self‐reported daily hours of outdoor exposure, and mean UV index over the 35 d prior to blood collection were recorded. Serum 25OHD was lower in children with T1DM (n = 56) than in controls (n = 46) [mean (95%CI) = 78.7 (71.8–85.6) nmol/L vs. 91.4 (83.5–98.7) nmol/L, p = 0.02]. T1DM children had lower self‐reported outdoor exposure and mean UV exposure, but no significant difference in distribution of VDR polymorphisms. 25OHD remained lower in children with T1DM after covariate adjustment. Children newly diagnosed with T1DM had lower 1,25(OH)2D [median (IQR) = 89 (68–122) pmol/L] than controls [121 (108–159) pmol/L, p = 0.03], or children with established diabetes [137 (113–153) pmol/L, p = 0.01]. Children with T1DM have lower 25OHD than controls, even in an environment of abundant sunlight. Whether low vitamin D is a risk factor or consequence of T1DM is unknown.

Physical Activity of Young Children

Occupational therapists concerned with the long-term health and welfare of children need to be aware of the decline in physical activity of children in most Western societies. The current study examined the extent of physical activity in the lives of 50 Australian children with a mean age of 7.74 years through questionnaires completed by the childrens parents and pedometer (step) data collected from the children during 4 days. The current data show that higher self-perception of physical competence, childs levels of physical skill, and low parental perception of peer teasing were the best predictors of physical activity. Higher family socioeconomic status was found to be a significant predictor of more steps being taken on weekends, and partners (usually a fathers) level of exercise was an important predictor of the number of weekend steps. Children who were perceived to experience more peer teasing completed fewer steps on the weekend. The findings from this study indicate that childrens physical activity levels may depend on the availability of family resources, and that children in their early school years may already experience negative effects from teasing that, combined with reduced self-confidence, may lay the foundation for their withdrawing from physical activity as they get older.

Vascular endothelial growth factor-B and retinal vascular development in the mouse

Purpose: Vascular endothelial growth factor‐A (VEGF‐A) is crucial to retinal vascular growth, both normal and pathological. VEGF‐B, recently characterized, is reported to be expressed in retinal tissues, but the importance of VEGF‐B to retinal vascular development remained unknown. The aim of this study was to analyse retinal vascular growth in the Vegfb−/− knockout mouse.

How well are we doing? – Metabolic control in patients with diabetes

Objective: To compare the present level of metabolic control in children and adolescents with insulin‐dependent diabetes mellitus (IDDM) attending Brisbane paediatric diabetes clinics with published overseas data.

The child of uncertain sex: 17 years of experience

Objective: To review the common clinical presentations, investigations and final diagnosis of children presenting with genital ambiguity.