Etienne Sochett

Heterozygous mutations in the LDL Receptor-related protein 5 (LRP5) gene are associated with primary osteoporosis in children

Three of 20 patients with juvenile osteoporosis were found to have a heterozygous mutation in the LRP5 gene. No mutations were found in the type I collagen genes. Mutations in the other family members with similar bone phenotype confirmed that LRP5 has a role in both juvenile and adult osteoporosis.

Skeletal phenotype in patients with Shwachman–Diamond syndrome and mutations in SBDS

Pancreatic exocrine and bone marrow dysfunctions are considered to be universal features of Shwachman–Diamond syndrome (SDS) whereas the associated skeletal dysplasia is variable and not consistently observed. The genetic defect in SDS has recently been identified; causative mutations have been shown in the SBDS gene. The aims of this study were to characterize the nature, frequency, and age‐related changes of radiographic skeletal abnormalities in patients with SBDS mutations and to assess genotype–phenotype correlation. Fifteen patients (mean age 9.7 years) with a clinical diagnosis of SDS and documented SBDS gene mutations were included. Review of their skeletal radiographs showed abnormalities in all patients. The skeletal changes were variable, even in patients with identical genotypes. The typical features were (1) delayed appearance of secondary ossification centers, (2) variable widening and irregularity of the metaphyses in early childhood, followed by progressive thickening and irregularity of the growth plates, and (3) generalized osteopenia. There was a tendency towards normalization of the epiphyseal maturation defect and progression of the metaphyseal changes with age. The results suggest that the characteristic skeletal changes are present in all patients with SDS and SBDS mutations, but their severity and localization varies with age. No phenotype–genotype correlation was observed.

Impact of Renin Angiotensin System Modulation on the Hyperfiltration State in Type 1 Diabetes

The initial stages of diabetic nephropathy are characterized by glomerular hyperfiltration and hypertension, processes that have been linked to initiation and progression of renal disease. Renin angiotensin system (RAS) blockade is commonly used to modify the hyperfiltration state and delay progression of renal disease. Despite this therapy, many patients progress to ESRD, suggesting heterogeneity in the response to RAS modulation. The role of the RAS in the hyperfiltration state in adolescents with uncomplicated type 1 diabetes was examined, segregated on the basis of the presence of hyperfiltration. Baseline renal hemodynamic function was characterized in 22 patients. Eleven patients exhibited glomerular hyperfiltration (GFR>or=135 ml/min), and in the remaining 11 patients, the GFR was <130 ml/min. Renal hemodynamic function was assessed in response to a graded angiotensin II (AngII) infusion during euglycemic conditions and again after 21 d of angiotensin-converting enzyme (ACE) inhibition with enalapril. AngII infusion under euglycemic conditions resulted in a significant decline in GFR and renal plasma flow in the hyperfiltration group but not in the normofiltration group. After ACE inhibition, GFR fell but did not normalize in the hyperfiltration group; the normofiltration group showed no change. These data show significant differences in renal hemodynamic function between hyperfiltering and normofiltering adolescents with type 1 diabetes at baseline, after AngII infusion and ACE inhibition. The response to ACE inhibition and AngII in hyperfiltering patients suggests that vasodilation may complement RAS activation in causing the hyperfiltration state. The interaction between glomerular vasoconstrictors and vasodilators requires examination in future studies.

Factors affecting and patterns of residual insulin secretion during the first year of type 1 (insulin-dependent) diabetes mellitus in children.

SummaryWe measured serum C-peptide, glucose, pH, islet antibodies and insulin antibody binding at diagnosis in 84 children with Type 1 (insulin-dependent) diabetes. In a subgroup of 33 children, residual insulin secretion (basal and peak C-peptide response to Sustacal), insulin antibody binding and HbA1c were measured at 10 days, 1, 3, 6 and 12 months. At presentation C-peptide correlated positively with age at onset and negatively with the blood glucose concentration. Median C-peptide concentration at diagnosis was low, rose significantly (p<0.05) at 10 days, reached a maximum at 1–3 months and declined gradually to 1 year. C-peptide concentration both at diagnosis and at 10 days correlated with that at 3 and 6 months. Of the factors investigated, only age (p<0.005) and sex (higher in females, p<0.01) were found to have a significant influence on basal/peak C-peptide levels throughout the first year. In particular there was no relationship between C-peptide, HbA1c and insulin dose during this period. A peak C-peptide response at 3–6 months>/<0.32 nmol/l was used to divide the group into two: 16 had a peak response <0.32 nmol/l (low secretors) while in 17, the peak C-peptide was >0.32 nmol/l (high secretors). While the low secretors had significantly (p<0.05) lower C-peptide levels during the first year, there were no differences between low and high secretors in HbA1c or insulin dose. These data suggest that there are two patterns of residual insulin secretion during the first 12 months after diagnosis of Type 1 diabetes. One pattern shows good amplitude and duration of residual insulin secretion, while both these features are significantly (p<0.05) reduced in the other. The C-peptide concentration both at diagnosis and at 10 days, as well as age at onset and sex are important predictors of the pattern to be followed. Our data suggest further that the magnitude of residual insulin secretion does not play a decisive role in metabolic control during this period.

Genetic Defect in CYP24A1, the Vitamin D 24-Hydroxylase Gene, in a Patient with Severe Infantile Hypercalcemia

CONTEXT Idiopathic infantile hypercalcemia (IIH) is a disorder the genetic etiology and physiological basis of which are not well understood. OBJECTIVE The objective of the study was to describe the underlying physiology and genetic cause of hypercalcemia in an infant with severe IIH and to extend these genetic findings into an additional cohort of children with IIH. DESIGN This was an inpatient study of a single patient with consanguineous parents at an academic medical center with follow-up in a specialty clinic cohort. PATIENTS The patient population was one patient with severe IIH for gene discovery and physiological testing and 27 patients with idiopathic infantile hypercalcemia in the replication cohort. INTERVENTIONS Interventions included a calcium isotopic absorption study as well as homozygosity mapping and whole-exome sequencing in a single patient followed up by gene sequencing in replication cohort. MAIN OUTCOME MEASURE Fractional absorption of calcium and genetic variants causing hypercalcemia were measured. RESULTS Intestinal calcium absorption was extremely elevated (∼90%). A rare homozygous deletion in the CYP24A1 gene was found, leading to the loss of a single highly conserved amino acid. In vivo functional studies confirmed decreased 24-hydroxylase activity because the subject had undetectable levels of 24,25-dihydroxyvitamin D. No coding variants in CYP24A1 were found in the 27 additional patients with IIH. CONCLUSIONS Our study confirms that CYP24A1 plays a causal role in some but not all cases of IIH via markedly increased intestinal absorption of calcium, suggesting that genetic diagnosis could be helpful in a subset of IIH patients. This case demonstrates the power of an unbiased, genome-wide approach accompanied by informative physiological studies to provide new insights into human biology.

Contribution of Growth Hormone and IGF-I to Early Diabetic Nephropathy in Type 1 Diabetes

In children and adolescents with type 1 diabetes, we have reported an association between duration of puberty and the prevalence of nephromegaly and microalbuminuria (MA), which are early markers of diabetic nephropathy. Growth hormone (GH), IGF-I, testosterone, and prorenin are potential mediators of this effect. This study examined the relationship of these hormonal factors to kidney volume (KV) and MA in 155 subjects (78 males, age 13.2 ± 3.5 years [mean ± SD]) with similar diabetes duration (6.83 ± 1.6 years) but varying pubertal experience (0–10 years). KV (by ultrasound), plasma IGF-I, testosterone, prorenin, and NaLi countertransport, and urinary albumin, urinary GH, and urinary IGF-I from three 24-h collections were measured. Multiple regression analysis showed that BSA (P < 0.0001) and urinary IGF-I (P = 0.001) were significantly associated with KV. MA subjects (albumin excretion rate 15–200 μg/min) had higher urinary IGF-I (P = 0.005) and urinary GH (P = 0.05) compared with normoalbuminuric subjects. Only 9% of the variance in urinary IGF-I could be attributed to plasma IGF-I (r = 0.30, P < 0.0001). Testosterone and prorenin were not associated with MA, but they were associated with KV in univariate analyses. The strong association of urinary IGF-I with KV, a marker for glomerular hypertrophy, and of both urinary IGF-I and urinary GH with MA suggests a role for these growth factors in the development of human diabetic nephropathy. Together, these data support animal studies that have shown that renal GH and IGF-I may contribute significantly to the pathogenesis of early diabetic nephropathy.

Angiotensin converting enzyme inhibitor therapy to decrease microalbuminuria in normotensive children with insulin-dependent diabetes mellitus

It has been proposed that lowering glomerular pressure in children with insulin-dependent diabetes mellitus will reduce microalbuminuria and that this reduction may preserve renal function. We therefore conducted a double-blind, placebo-controlled, crossover trial to compare 3 months of treatment with the angiotensin converting enzyme inhibitor captopril (0.9 mg/kg/day), and 3 months of placebo administration to 12 normotensive adolescents with insulin-dependent diabetes mellitus, 11 with microalbuminuria (albumin excretion rate of 15 to 200 micrograms/min) and one with early overt nephropathy. Mean age (+/- SD) was 14.4 +/- 1.7 years, and disease duration was 5.1 +/- 2.5 years. Albumin excretion rate decreased significantly during captopril therapy (baseline 78 +/- 114 micrograms/min; mean of monthly measurements 38 +/- 55 micrograms/min vs placebo 78 +/- 140 micrograms/min; p less than 0.001). During captopril therapy, albumin excretion was reduced by 41 +/- 44% and decreased in 10 of 12 subjects, but was unchanged in two, one with a borderline albumin excretion rate (16.3 micrograms/min) and one with diabetes of short duration (2.9 years). Plasma renin activity rose significantly during captopril therapy, and mean arterial pressure decreased slightly (placebo 81 +/- 7 mm Hg; captopril 76 +/- 5 mm Hg; p = 0.004). After 3 months of captopril treatment, glomerular filtration rate and renal plasma flow did not change significantly. Hemoglobin Alc values remained stable during the study. The only side effect of captopril was diarrhea in one patient. We conclude that, in the short term, captopril is effective in decreasing albumin excretion rate in normotensive children with insulin-dependent diabetes mellitus and microalbuminuria, without significant side effects. Longer trials are indicated in an attempt to delay or prevent overt nephropathy.

The Effect of Cyclooxygenase-2 Inhibition on Renal Hemodynamic Function in Humans With Type 1 Diabetes

OBJECTIVE—Studies in animal models suggest that cyclooxygenase-2 (COX2) plays a role in the regulation of the renal microcirculation in diabetes. Accordingly, we examined the role of COX2 in the control of renal hemodynamic function and in the renal response to hyperglycemia in humans with uncomplicated type 1 diabetes. We hypothesized that COX2 inhibition would alleviate the hyperfiltration state and would abrogate the hyperglycemia-mediated rise in glomerular filtration rate (GFR). RESEARCH DESIGN AND METHODS—Renal function was assessed during clamped euglycemia and hyperglycemia on 2 consecutive days before and then again after 14 days of COX2 inhibition using 200 mg celecoxib once daily by mouth. For analysis, the cohort was then divided into two groups based on the baseline GFR: 9 subjects exhibited hyperfiltration (GFR ≥135 ml/min per 1.73 m2), and 12 subjects exhibited normofiltration (GFR <135 ml/min per 1.73 m2). RESULTS—Under euglycemic conditions, COX2 inhibition resulted in a significant decline in GFR in the hyperfiltration group (150 ± 5 to 139 ± 5 ml/min per 1.73 m2) but increased GFR in the normofiltration group (118 ± 5 to 138 ± 5 ml/min per 1.73 m2). COX2 inhibition did not blunt the hyperglycemia-associated rise in GFR in the normofiltration group and was instead associated with an augmented rise in GFR. CONCLUSIONS—In summary, our results support the hypothesis that COX2 is an important determinant of renal hemodynamic function in subjects with type 1 diabetes. The renal response to COX2 inhibition emphasizes that hyperfiltration and normofiltration are distinct physiological states.

The natural history of microalbuminuria in adolescents with type 1 diabetes.

OBJECTIVE To describe the natural history of urinary albumin excretion measured initially during the first decade of type 1 diabetes in adolescents and to identify predictors of the onset and progression of microalbuminuria (MA) in this population. STUDY DESIGN A retrospective cohort follow-up study was done on 76 adolescents whose albumin excretion rate (AER) had been determined in the first decade of their diabetes. Subjects were monitored for a mean of 6 years after initial AER testing. Those with MA were compared with a group with similar age, sex, and diabetes duration who initially had normoalbuminuria (NA). RESULTS Of the 28 with initial MA, 9 (32%) regressed (8 to within the NA range), whereas MA was persistent in 10 (36%) and progressed in 9 (32%), 5 to overt proteinuria. Of the 47 who had initial NA, MA developed in 14 (30%) and overt proteinuria in 3 (6%). With MA status at follow-up as the dependent variable, multiple regression analysis showed that initial AER (P =.0002) and hemoglobin A1c (P =.02) measured at the same time were significant independent variables. CONCLUSIONS These data suggest that in adolescents: (1) MA detected in the first decade of disease will persist or progress in the second decade in approximately two thirds of patients, and new MA will develop in a third of those initially normoalbuminuric; and (2) the appearance, persistence, or progression of MA is influenced in large part by metabolic control assessed by hemoglobin A1c both at initial MA screening and throughout the course of diabetes. This underlines the need for MA screening starting early in the course of type 1 diabetes in adolescents and for maintenance of good metabolic control.

Informing evidence‐based clinical practice guidelines for children with cerebral palsy at risk of osteoporosis: a systematic review

Aim  The aim of this systematic review was to inform evidence‐based clinical practice guidelines for children with cerebral palsy (CP) and low bone mineral density (BMD).