Cortical impairment and reduced muscle mass in children and young adults with nephropathic cystinosis.

Nephropathic cystinosis is an orphan autosomal recessive lysosomal storage disease characterized by a deficiency of cystinosin, a cystine transporter protein, leading to tissue damage, primarily in the kidney and cornea. With the introduction of cystine-depleting therapy with cysteamine and the possibility to survive to adulthood, new challenges of skeletal complications are a concern, with sparse data available regarding bone development. The aim of the current study was to gain more information on bone density and geometry in these patients. Fifty-one patients (29 males, 22 females) with genetically-proven nephropathic cystinosis were clinically evaluated with a medical history, physical examination, grip strength measurements, biochemical and imaging studies. Bone mineral density, bone geometry and muscle cross sectional area were measured, and muscle was evaluated. Results were compared with age- and gender-specific reference data. Z-scores for height (mean [M] = -1.75, standard deviation [SD] = 1.43), weight (M = -1.67, SD = 1.29), and BMI (M = -0.98, SD = 1.29) were lower than reference data. Medullary cross-sectional area (CSA) and cortical density z-scores were not compromised (M = 0.12, SD = 1.56 and M = -0.25, SD = 1.63, respectively), but cortical CSA z-scores and Strength-Strain Index (SSI) were reduced (M = -2.16, SD = 1.08, M = -2.07, SD = 1.08). Muscular deficits were reflected by reduced z-scores for muscle CSA (M = -2.43, SD = 1.27) and grip strength (M = -3.01, SD = 1.10), along with jump force (34% lower than reference value). Multiple regression analyses indicated an association of muscle mass with medullary CSA and SSI, but not with cortical CSA. While bone density parameters were normal, bone geometry was altered, resulting in a thinner cortex with possible impact on bone strength. Muscle weakness be partially responsible for altered bone geometry and could provide a potential treatment target.

Nephropathic cystinosis is a rare lysosomal storage disease affecting primarily the kidney and cornea. With new treatment options patients survive to adulthood and challenges like bone development and fracture risk become a matter of concern. In this study we investigated bone density, bone geometry and muscle mass and function using peripheral quantitative computed tomography. We included 51 patients with genetically-proven cystinosis at an age between 6.6­39.6 years. Beside height impairment and low body weight patients had a thinner bone cortex leading to a reduced stress­strain index. This index represents the resistance of bone against torsional load and, therefore, is considered to be a good marker of bone strength: with low values fracture risk might increase. Further patients had lower muscle mass and muscle function, the latter evaluated by grip strength and jump force. Looking for the interaction of muscle and bone multiple regression analyses indicated an association of muscle mass with strength strain index. The muscle weakness might be partially responsible for altered bone geometry and lower bone strength and is possibly a treatment target, which has to be investigated in the future.

Hypercalcaemia after treatment with denosumab in children: bisphosphonates as an option for therapy and prevention?

BACKGROUND: Pharmacologic options for treatment of osteolytic diseases especially in children are limited. Although not licensed for use, denosumab, a fully humanized antibody to RANKL, is used in children with good effects. Among others, one possible indication are giant cell tumors and aneurysmatic bone cysts. However, there are reports of severe hypercalcemia during weeks to months after termination of denosumab, that are rarely seen in adults. METHODS: We collected data of four patients, aged 6-17 years, who experienced severe hypercalcemia after completion of treatment with denosumab for unresectable giant cell tumors of bone or aneurysmal bone cysts and methods of their treatment. The detailed case information were described. RESULTS: One patient was treated with long-term, high-dose steroid therapy, leading to typical Cushing's syndrome. Another patient was restarted on denosumab repeatedly due to relapses of hypercalcemia after every stop. Finally, in two patients, hypercalcemia ceased definitely after treatment with bisphosphonates. However, several applications were necessary to stabilize calcium levels. CONCLUSIONS: There is a considerable risk of hypercalcemia as an adverse effect after denosumab treatment in children. Therapeutic and, preferably, preventive strategies are needed. Bisphosphonates seem to be an option for both, but effective proceedings still remain to be established.

Partial enteral nutrition has no benefit on bone health but improves growth in paediatric patients with quiescent or mild Crohn's disease.

BACKGROUND AND AIMS: Exclusive enteral nutrition induces remission, improves bone health and growth in paediatric Crohn's disease (CD) patients, but is highly demanding for patients. We investigated efficacy of partial enteral nutrition (PEN) on bone health, growth and course in CD patients and assessed microbial and metabolic changes induced by PEN. METHODS: We performed a two centre, non-randomized controlled intervention study in quiescent CD patients aged <19 years. Patients in intervention group received a liquid formula providing ~25% of daily energy for one year. At baseline, after 3, 6, 9 and 12 months, we collected data on bone, muscle (peripheral quantitative computertomography), anthropometry, disease activity (weighted paediatric CD activity index), metabolomic profile (liquid chromatography mass spectrometry), and faecal microbiome (16S rRNA gene sequencing). RESULTS: Of 41 CD patients, 22 received the intervention (PEN) (mean age 15.0 ± 1.9 years, 50% male), 19 served as controls (non-PEN) (12.8 ± 3.1 years, 58% male). At baseline, mean bone quality was comparable to reference population with no improvement during the intervention. Relapse rate was low (8/41, PEN 4/22 and non-PEN 4/19, ns). PEN was not associated with microbiota community changes (beta diversity) but significantly reduced species diversity. Metabolome changes with upregulation of phosphatidylcholines in PEN patients are likely related to lipid and fatty acid composition of the formula. PEN significantly improved growth in a subgroup with Tanner stage 1-3. CONCLUSION: In our cohort of paediatric CD patients, PEN did not affect bone health but improved growth in patients with a potential to grow.

A Comprehensive Cohort Analysis Comparing Growth and GH Therapy Response in IGF1R Mutation Carriers and SGA Children.

CONTEXT: IGF1 receptor mutations (IGF1RM) are rare; however, patients exhibit pronounced growth retardation without catch-up. Although several case reports exist, a comprehensive statistical analysis investigating growth profile and benefit of recombinant human growth hormone (rhGH) treatment is still missing. OBJECTIVE AND METHODS: Here, we compared IGF1RM carriers (n = 23) retrospectively regarding birth parameters, growth response to rhGH therapy, near final height, and glucose/insulin homeostasis to treated children born small for gestational age (SGA) (n = 34). Additionally, health profiles of adult IGF1RM carriers were surveyed by a questionnaire. RESULTS: IGF1RM carriers were significantly smaller at rhGH initiation and had a diminished first-year response compared to SGA children (Δ height standard deviation score: 0.29 vs. 0.65), resulting in a lower growth response under therapy. Interestingly, the number of poor therapy responders was three times higher for IGF1RM carriers than for SGA patients (53 % vs. 17 %). However, most IGF1RM good responders showed catch-up growth to the levels of SGA patients. Moreover, we observed no differences in homeostasis model assessment of insulin resistance before treatment, but during treatment insulin resistance was significantly increased in IGF1RM carriers compared to SGA children. Analyses in adult mutation carriers indicated no increased occurrence of comorbidities later in life compared to SGA controls. CONCLUSION: In summary, IGF1RM carriers showed a more pronounced growth retardation and lower response to rhGH therapy compared to non-mutation carriers, with high individual variability. Therefore, a critical reevaluation of success should be performed periodically. In adulthood, we could not observe a significant influence of IGF1RM on metabolism and health of carriers.

Evaluation of Changes in Insulin Sensitivity in Prepubertal Small for Gestational Age Children Treated with Growth Hormone.

BACKGROUND: Although growth hormone (GH) therapy for children born small for gestational age (SGA) has been approved for many years, there are still concerns about increasing their risk for insulin resistance and diabetes mellitus type 2. Monitoring of glucose homeostasis is therefore generally recommended, but there is no consensus on either the methods or consequences. METHODS AND AIMS: The aim of our study was to analyze the oral Glucose Tolerance Tests (oGTTs) which were performed yearly from baseline to 4 years of GH therapy in a collective of 93 SGA children, who were prepubertal during the whole follow-up. We looked for correlations with auxological and laboratory data as well as predictive baseline results for glucose homeostasis during further treatment. RESULTS: While glucose levels remained constant, insulin secretion increased from baseline to the first year of GH therapy. Insulin sensitivity index (ISI) showed no significant change afterwards; HOMA1, HOMA2, and QUICKI stabilized after the second year. For all indices mean values never reached pathological levels and no cases of diabetes mellitus were induced. Higher gestational age, lower birth length, and older age at start of GH therapy were associated with lower insulin sensitivity. No predictive factors for later insulin resistance could be found. CONCLUSION: As expected, in GH-treated prepubertal SGA children insulin resistance was induced, but not to pathological levels. No special risk factors for disturbed glucose homeostasis could be identified. Based on our opinion, performing oGTTs in GH-treated SGA children at baseline and in puberty should remain mandatory, but the current study recommendations regarding further surveillance of glucose homeostasis are questionable.

Height-obesity relationship in school children in Sub-Saharan Africa: results of a cross-sectional study in Cameroon.

BACKGROUND: In developed nations, taller children exhibit a greater propensity to overweight/obesity. This study investigates whether this height-adiposity relationship holds true for Cameroon children using two parameters of adiposity including body mass index (BMI) and waist circumference (WC). METHODS: In 557 children (287 boys and 270 girls, mean age 9.0 ± 1.8 years) from the North West Region of Cameroon height, weight and WC were measured and BMI calculated. Variables were converted to standard deviation scores (SDS). Participants were divided into quartiles of height SDS, then mean of age and sex-standardized body fat parameters compared across quartiles. The frequency of excess adiposity was calculated within each quartile. Correlation and regression analysis were used to assess height-adiposity relationships. RESULTS: Multiple comparisons indicated a significant increase in mean BMI (-0.08 to 0.65) and WC (-0.11 to 0.87) SDSs with increasing quartiles of height SDS. Frequency of overweight/obesity and abdominal overweight/obesity was highest among children with highest height SDS (30.2 - 33.1%) and lowest in their shortest peers (0.7 - 5.0%). There was a linear relationship between height SDS and BMI SDS (R(2) = 0.087, p < 0.001); height SDS and WC SDS (R(2) = 0.356, p < 0.001) among both boys and girls. CONCLUSIONS: This study shows that in Cameroon just as in developed economies a higher height SDS is associated with a higher frequency of overweight/obesity. This is independent of the parameter used to evaluate overweight/obesity (BMI SDS or WC SDS).

Long-term development of bone geometry and muscle in pediatric inflammatory bowel disease.

OBJECTIVES: The muscle-bone unit is crucial for normal bone development. As muscle mass is frequently reduced in pediatric patients with inflammatory bowel disease (pIBD), we investigated the impact of muscles on the bone development over time. METHODS: Bone and muscle parameters were measured repeatedly in 102 pIBD patients (67 boys; 82 Crohn's disease; 30 newly diagnosed) by peripheral quantitative computed tomography (pQCT) at the forearm. The first and last measurements were included in the evaluation. Results were expressed as sex- and age-specific and partly height-corrected Z-scores for a healthy reference population. RESULTS: At baseline, patients showed reduced Z-scores for height (median -0.7; range -3.7 to 1.6), trabecular bone mineral density (TrbBMD; -0.6; 3.0-2.8), and for height-corrected cortical cross-sectional area (CSA(height); -0.4; -3.0 to 2.2), cortical thickness (CrtTh(height); -0.7; -3.0 to 1.2), and MuscleCSA(height) (-1.0; -4.9 to 2.0; all P<0.01). Cortical bone mineral density (CrtBMD) and height-corrected TotalCSA(height) Z-scores were elevated (0.57; -4.55 to 2.8, both P<0.01). Over time, TotalCSA(height) (+0.36; -1.5 to 4.5) further increased, CorticalCSA(height) (+0.21; -2.1 to 3.0) and MuscleCSA(height) (+0.64; -2.0 to 3.9, all P<0.01) improved, whereas CrtBMD decreased toward normalization (-0.36; -5.1 to 3.6, P<0.05). The change in MuscleCSA(height) significantly correlated with the changes in TrbBMD (r=0.42), TotalCSA(height) (r=0.35), CorticalCSA(height) (r=0.38), and CrtTh(height) (r=0.24; all P<0.02). The relations became even stronger after adjustment for several confounders. CONCLUSIONS: Bone metabolism and geometry are altered in pIBD patients expressed by low trabecular mineral density, low cortical thickness, and high cortical mineral density. The increased height-corrected cortical CSA might reflect a compensatory effect. In our cohort, treatment increased height-corrected muscle CSA and its changes were closely associated with bone parameters. Therefore, physical activity to enhance muscle mass and bone health should be promoted in pIBD patients.

Anthropometry, metabolic control, and follow-up in children and adolescents with type 1 diabetes mellitus and biopsy-proven celiac disease.

OBJECTIVE: To evaluate the influence of biopsy-proven celiac disease (BPCD) on somatic development and metabolic parameters in children with type 1 diabetes mellitus (T1DM) in a multicenter survey. STUDY DESIGN: Within the Diabetes Patienten Verlaufsdokumentationssystem-Wiss project, data of 41 951 patients with T1DM, aged <20 years (52% males, mean age 13.9 years; mean duration of diabetes 5.5 years) were collected in 297 centers in Germany and Austria from 1995 to 2009. RESULTS: The number of BPCD (0.6% in 1995; 1.3% in 2008) has increased over time. Patients with BPCD were significantly younger at diabetes onset (5.9 vs 8.3 years), had a significantly lower weight standard deviation score (SDS); (0.20 vs 0.43) and height SDS (-0.28 vs -0.03) (P < .001, each) compared with patients without celiac disease. No differences were found in hemoglobin A1c or numbers of severe hypoglycemia. In a subgroup of 9805 patients (183 with BPCD) significantly lower height and weight SDS (P < .001) were still found after a 5-year follow-up. CONCLUSIONS: Screening for celiac disease is important in children with T1DM to prevent persistent growth failure.

Hydrocortisone dosing during puberty in patients with classical congenital adrenal hyperplasia: an evidence-based recommendation.

CONTEXT: Patients with congenital adrenal hyperplasia (CAH) are at risk for early pubertal development and diminished pubertal growth. Liberal treatment with glucocorticoids will prevent early puberty but may inhibit growth outright. OBJECTIVE: The aim of the study was to determine an optimal range for hydrocortisone dosing during puberty in children with classical CAH who were exclusively treated with hydrocortisone. METHODS: The effects of glucocorticoid treatment for classical CAH were retrospectively analyzed in 92 patients (57 females). Growth pattern, final height (FH), and mean daily hydrocortisone dose were recorded. RESULTS: Pubertal growth was significantly reduced in all patients: salt-wasting (SW) females, 13.8 +/- 7.4 cm; simple virilizing (SV) females, 13.1 +/- 6.2 cm; vs. reference, 20.3 +/- 6.8 cm (P < 0.05); and SW males, 17.7 +/- 6.7 cm; SV males, 16.2 +/- 5.7 cm; vs. reference, 28.2 +/- 8.2 cm (P < 0.05). Decreased pubertal growth resulted in FH at the lower limit of genetic potential (corrected FH in SW females, -0.6 +/- 0.9; SV females, -0.3 +/- 0.9; SW males, -0.8 +/- 0.8; and SV males, -1.0 +/- 1.0). During puberty, mean daily hydrocortisone dose was 17.2 +/- 3.4 mg/m(2) in females (SW, 17.0 +/- 3.3; SV, 17.4 +/- 3.5) and 17.9 +/- 2.5 mg/m(2) in males (SW, 17.4 +/- 2.0; SV, 18.7 +/- 3.1). In a logistic regression model, a significant correlation between hydrocortisone dose and FH was found (P < 0.01), and the positive predictive value for short stature rose from below 30% to above 60% when hydrocortisone dose exceeded 17 mg/m(2). CONCLUSION: With conventional hydrocortisone treatment, pubertal growth is significantly reduced in both sexes, resulting in a FH at the lower limit of genetic potential. These deleterious effects on pubertal growth can be reduced if hydrocortisone does not exceed 17 mg/m(2).