Stefania Pedicelli

Genetic homogeneity but IgG subclass–dependent clinical variability of alloimmune membranous nephropathy with anti-neutral endopeptidase antibodies

Alloimmune antenatal membranous nephropathy (MN) during pregnancy results from antibodies produced by a neutral endopeptidase (NEP)-deficient mother. Here we report two recent cases that provide clues to the severity of renal disease. Mothers of the two children had circulating antibodies against NEP showing the characteristic species-dependent pattern by immunofluorescence on kidney slices. A German mother produced predominantly anti-NEP IgG4 accompanied by a low amount of IgG1. Her child recovered renal function within a few weeks. In sharp contrast, an Italian mother mainly produced complement-fixing anti-NEP IgG1, which also inhibits NEP enzymatic activity, whereas anti-NEP IgG4 has a weak inhibitory potency. Her child was dialyzed for several weeks. A kidney biopsy performed at 12 days of age showed MN, ischemic glomeruli, and arteriolar and tubular lesions. A second biopsy performed at 12 weeks of age showed aggravation with an increased number of collapsed capillary tufts. Both mothers were homozygous for the truncating deletion mutation 466delC and were thus NEP deficient. The 466delC mutation, identified in three previously described families, suggests a founder effect. Because of the potential severity of alloimmune antenatal MN, it is essential to identify families at risk by the detection of anti-NEP antibodies and NEP antigen in urine. On the basis of the five families identified to date, we propose an algorithm for the diagnosis of the disease and the prevention of complications.

Controversies in the definition and treatment of idiopathic short stature (ISS).

The term idiopathic short stature (ISS) refers to short children with no identifiable disorder of the growth hormone (GH)/insulin like growth factor (IGF) axis and no other endocrine, genetic or organ system disorder. This heterogeneous group of short children without GH deficiency (GHD) includes children with constitutional delay of growth and puberty, familial short stature, or both, as well as those with subtle cartilage and bone dysplasias. In rare cases, ISS is due to IGF molecular abnormalities. In this review we tackle the major challenges in the definition and treatment of ISS. Conflict of interest:None declared.

Clinical InvestigationGenetic homogeneity but IgG subclass–dependent clinical variability of alloimmune membranous nephropathy with anti-neutral endopeptidase antibodies

Alloimmune antenatal membranous nephropathy (MN) during pregnancy results from antibodies produced by a neutral endopeptidase (NEP)-deficient mother. Here we report two recent cases that provide clues to the severity of renal disease. Mothers of the two children had circulating antibodies against NEP showing the characteristic species-dependent pattern by immunofluorescence on kidney slices. A German mother produced predominantly anti-NEP IgG4 accompanied by a low amount of IgG1. Her child recovered renal function within a few weeks. In sharp contrast, an Italian mother mainly produced complement-fixing anti-NEP IgG1, which also inhibits NEP enzymatic activity, whereas anti-NEP IgG4 has a weak inhibitory potency. Her child was dialyzed for several weeks. A kidney biopsy performed at 12 days of age showed MN, ischemic glomeruli, and arteriolar and tubular lesions. A second biopsy performed at 12 weeks of age showed aggravation with an increased number of collapsed capillary tufts. Both mothers were homozygous for the truncating deletion mutation 466delC and were thus NEP deficient. The 466delC mutation, identified in three previously described families, suggests a founder effect. Because of the potential severity of alloimmune antenatal MN, it is essential to identify families at risk by the detection of anti-NEP antibodies and NEP antigen in urine. On the basis of the five families identified to date, we propose an algorithm for the diagnosis of the disease and the prevention of complications.

Serum insulin-like growth factor-I (IGF-I) reference ranges for chemiluminescence assay in childhood and adolescence. Data from a population of in- and out-patients

BACKGROUND Insulin-like growth factor I (IGF-I) measurement is widely used for the diagnosis of disorders of GH secretion and sensitivity, and for monitoring of both GH and IGF-I replacement therapies. However, the lack of appropriate reference values obtained from large and representative samples undermines its practical utility. OBJECTIVE To establish IGF-I reference values for a commonly used enzyme-labeled chemiluminescent immunometric assay in a large population of children aged 0 to 18 years. DESIGN Cross-sectional analysis of serum IGF-I levels from samples collected in the two major Italian Childrens Hospitals. SUBJECTS AND METHODS IGF-I was measured using a solid-phase, enzyme-labeled chemiluminescent immunometric assay in 24403 children (50.6% girls) aged 0 to 18 years. Quantile regression coupled to multivariable fractional polynomials was used to produce age- and sex-specific reference values. MAIN OUTCOME MEASURE Age- and sex-specific IGF-I reference values. RESULTS AND CONCLUSION Reference values for immunometric assay of IGF-I were produced in a large sample of children and adolescents. Prediction equations were provided to automatize their calculations.

Glucose tolerance affects pubertal growth and final height of children with cystic fibrosis

There are few data about the impact of cystic fibrosis‐related diabetes (CFRD) on growth. We analyzed 17 children with cystic fibrosis (CF) presenting with newly diagnosed CFRD during puberty, in comparison with a matched control group of 52 CF children with normal glucose tolerance (NGT). Anthropometric evaluation showed that body mass index at CFRD diagnosis was significantly reduced in children with CFRD, in comparison with children with NGT (CFRD: −0.48 ± 1.08 vs. NGT: 0.2 ± 0.99; P = 0.01), and the same difference remained evident at the end of follow up (CFRD: −0.49 ± 0.95 vs. NGT: 0.13 ± 0.89; P = 0.04). Height standard deviation score (SDS) at baseline was slightly but not significantly lower in CFRD children (CFRD: −0.71 ± 0.83 vs. NGT: −0.25 ± 1.08; P = 0.08), while final height SDS was significantly reduced (CFRD: −1.61 ± 1.12 vs. NGT: −0.61 ± 1.15; P = 0.003). Mean final height SDS of the whole group was lower than mean target height SDS (final height SDS: −0.86 ± 1.2 vs. target height SDS: −0.3 ± 0.85; P < 0.001). Target adjusted final height was lower in CFRD children, although the difference between CFRD and NGT children did not reach statistical significance (CFRD: −0.8 ± 1.03 vs. NGT: −0.47 ± 0.9; P = 0.09). Pubertal growth and final height are negatively affected by CFRD. Intensive insulin treatment does not appear to be effective in normalizing growth, even when treatment is started early in the course of the disease, before the onset of clinical deterioration. Pediatr Pulmonol. 2015; 50:144–149.

Responses to GHRH plus arginine test are more concordant with IGF-I circulating levels than responses to arginine and clonidine provocative tests

BACKGROUND/OBJECTIVE Although pharmacological GH stimulation tests are still considered the gold standard for GH deficiency (GHD) diagnosis, they are burdened by poor specificity. The majority of children diagnosed as having GHD show normal GH responses when re-tested at the end of growth, thus questioning the initial diagnosis. We evaluated the concordance between IGF-I levels and GH responses to provocative tests. METHODS We analyzed 105 GHRH plus arginine tests, 79 arginine tests, and 124 clonidine tests performed in 192 short children. IGF-I levels ≤-2SD score (SDS) were considered suggestive for high likelihood of GHD. The percentage of positive and negative results for each test was determined and compared with IGF-I levels, clinical follow-up and response to therapy. RESULTS In children with IGF-I>-2SDS the arginine test showed a concordance rate of 6.9%, the clonidine test of 28.6%, and GHRH plus arginine test of 70%. In children with IGF-I≤-2SDS the concordance was 96.1%, 85.7%, and 46.4%, respectively. The overall concordance was 66.7% for GHRH plus arginine, 42.7% for clonidine, and 27.8% for arginine tests. CONCLUSION Our results suggest that GHRH plus arginine test provides the best concordance with the assessment of IGF-I levels thus suggesting that the combination of the two procedures may significantly reduce the need of a second provocative test.

Brain Magnetic Resonance Imaging as First-Line Investigation for Growth Hormone Deficiency Diagnosis in Early Childhood.

Background/Aims: The diagnosis of growth hormone (GH) deficiency (GHD) in infancy and early childhood is not straightforward. GH stimulation tests are unsafe and unreliable in infants, and normative data are lacking. This study aims to investigate whether brain magnetic resonance imaging (MRI) may replace GH stimulation tests in the diagnosis of GHD in children younger than 4 years. Methods: We examined a retrospective cohort, with longitudinal follow-up, of 68 children consecutively diagnosed with GHD before the age of 4 years. The prevalence of hypothalamic-pituitary (HP) alterations at MRI and the associations with age and either isolated GHD (IGHD) or multiple pituitary hormone deficiency (MPHD) were assessed. Results: The prevalences of IGHD and MPHD were 54.4 and 45.6%, respectively. In the first group, brain MRI showed abnormalities in 83.8%: isolated pituitary hypoplasia in 48.7% and complex defects in 35.1%. In patients with MPHD, MRI showed complex alterations in 100%. All children younger than 24 months showed HP MRI abnormalities, regardless of the diagnosis. Complex defects were found in 94% of patients younger than 12 months and in 75% of patients between 13 and 24 months. Conclusion: Our data suggest that brain MRI may represent the first-line investigation for diagnosing GHD in infancy and early childhood.

Water Balance and 'Salt Wasting' in the First Year of Life: The Role of Aldosterone-Signaling Defects.

In newborns and infants, dehydration and salt wasting represent a relatively common cause of admission to hospital and may result in life-threatening complications. Kidneys are responsible for electrolyte homoeostasis, but neonatal kidneys show low glomerular filtration rate and immaturity of the distal nephron, leading to reduced ability to concentrate urine. High extrarenal fluid losses often contribute to the increased occurrence of electrolyte disorders. Aldosterone is essential for sodium retention in the kidney, salivary glands, sweat glands and colon. A partial and transient aldosterone resistance is present in newborns and infants, thus reducing the capability of maintaining sodium balance in specific pathological conditions. The present review examines the mechanisms making infants more susceptible to salt wasting. Peculiar aspects of renal physiology in the first year of life and management of electrolyte disorders (i.e. sodium and potassium) are considered. Finally, inherited disorders associated with neonatal salt wasting are examined in detail.