Copy number variants in short children born small for gestational age.

BACKGROUND/AIMS: In addition to genome-wide association studies (GWAS), height-associated genes may be uncovered by studying individuals with extreme short or tall stature. METHODS: Genome-wide analysis for copy number variants (CNVs), using single nucleotide polymorphism (SNP) arrays, was performed in 49 index cases born small for gestational age with persistent short stature. Segregation analysis was performed, and genes in CNVs were compared with information from GWAS, gene expression in rodents' growth plates, and published information. RESULTS: CNVs were detected in 13 cases. In 5 children a known cause of short stature was found: UPD7, UPD14, a duplication of the SHOX enhancer region, an IGF1R deletion, and a 22q11.21 deletion. In the remaining 8 cases, potential pathogenic CNVs were detected, either de novo (n = 1), segregating (n = 2), or not segregating with short stature (n = 5). Bioinformatic analysis of the de novo and segregating CNVs suggested that HOXD4, AGPS, PDE11A, OSBPL6, PRKRA and PLEKHA3, and possibly DGKB and TNFRSF11B are potential candidate genes. A SERPINA7 or NRK defect may be associated with an X-linked form of short stature. CONCLUSION: SNP arrays detected 5 known causes of short stature with prenatal onset and suggested several potential candidate genes.

Alu-mediated recombination defect in IGF1R: haploinsufficiency in a patient with short stature.

BACKGROUND: The insulin-like growth factor (IGF) receptor (IGF1R) is essential for normal development and growth. IGF1R mutations cause IGF-1 resistance resulting in intrauterine and postnatal growth failure. The phenotypic spectrum related to IGF1R mutations remains to be fully understood. METHODS: Auxological and endocrinological data of a patient identified previously were assessed. The patient's fibroblasts were studied to characterize the IGF1R deletion, mRNA fate, protein expression and signalling capabilities. RESULTS: The boy, who carries a heterozygous IGF1R exon 6 deletion caused by Alu element-mediated recombination and a heterozygous SHOX variant (p.Met240Ile), was born appropriate for gestational age but developed proportionate short stature postnatally. IGF-1 levels were low-normal. None of the stigmata associated with SHOX deficiency or sporadically observed in IGF1R mutation carriers were present. Nonsense-mediated mRNA decay led to a substantial decline of IGF1R dosage and IGF-1-dependent receptor autophosphorylation but not impaired downstream signalling. CONCLUSION: We present the first detailed report of an intragenic IGF1R deletion identified in a patient who, apart from short stature, deviates from all established markers that qualify a growth-retarded child for IGF1R analysis. Although such children will usually escape routine clinical mutation screenings, they can contribute to the understanding of factors and mechanisms that cooperate with the IGF1R.

IGF1, IGF1R and SHOX mutation analysis in short children born small for gestational age and short children with normal birth size (idiopathic short stature).

BACKGROUND/AIMS: Because the criteria for genetic screening of short children are unknown, we performed genetic analysis of 199 short children born small for gestational age (SGA) or with normal birth size (idiopathic short stature, ISS). METHODS: After selection with a modified scoring system for SHOX and a novel score for IGF1 and IGF1R defects, direct sequencing and multiplex ligation-dependent probe amplification (MLPA) was performed for SHOX and IGF1R in selected patients, and confirmed by SNP array analysis. RESULTS: In 6 children, gene variants were identified in SHOX, its adjacent pseudoautosomal region (PAR) and IGF1R: a SHOX mutation, terminal 15q deletion, a SHOX and IGF1R defect, a deletion of the Xp22.3 PAR region, and two patients with duplications in the Xp22.3 PAR region. In a seventh patient, steroid sulfatase deficiency was detected because a probe for STS was used as control; this syndrome has not been associated with short stature before. CONCLUSION: A selection process using clinical scores for SHOX, IGF1 and IGF1R defects followed by genetic testing with MLPA and direct sequencing led to the detection of a SHOX or IGF1R genetic variant in 6% of short children.

The use of bone age in clinical practice - part 1.

This review examines the role of skeletal maturity ('bone age', BA) assessment in clinical practice. BA is mainly used in children with the following conditions: short stature (addressed in part 1 of this review), tall stature, early or late puberty, and congenital adrenal hyperplasia (all addressed in part 2). Various manual and automatic methods of BA assessment have been developed. Healthy tall children tend to have advanced BA and healthy short children tend to have delayed BA in comparison to chronological age. Growth hormone (GH) treatment of children with GH deficiency leads to a catch-up in BA that is usually appropriate for the height of the child. Response to GH is dependent on BA delay in young children with idiopathic short stature, and GH dosage appears to affect BA acceleration. In chronic renal failure, BA is delayed until puberty but then increases due to increased sensitivity of the growth plate to sex steroids, thus further impairing adult height. The assessment of BA provides an important contribution to the diagnostic workup and management of children with short stature.

Association between head circumference and body size.

BACKGROUND/AIMS: Studies on the association between head circumference (HC) and height or weight have shown variable results. METHODS: Using data from the Dutch nationwide survey performed in 1997 (n = 14,500), we calculated correlations for different ages, and fitted a regression model for the estimation of HC. HC versus height charts were created for different age groups. Data from children from other ethnic groups and children with various growth disorders were plotted on the charts and compared with reference data. RESULTS: Correlations between HC and height or weight showed similar patterns: highest at birth, followed by a rapid decline to a stable level and a peak in adolescence. On charts containing the regression line ±2 standard deviations for subjects aged 0-2 months and 2 months to 21 years, Turkish and Moroccan children, as well as children with idiopathic short stature and small for gestational age, had a normal HC for height, whereas children with an insulin-like growth factor 1 receptor defect or Sotos syndrome showed trends towards a smaller or larger HC for height, respectively. CONCLUSION: HC correlates strongly with height and weight. The charts of HC for height may serve as an additional tool to interpret HC in short or tall children.

The Auxological and Biochemical Continuum of Short Children Born Small for Gestational Age (SGA) or with Normal Birth Size (Idiopathic Short Stature).

Objective. Retrospective single-centre analysis of growth characteristics in 182 healthy short children born small for gestational age (SGA) or appropriate for gestational age (idiopathic short stature, ISS). Methods. Birth size references from the USA and Sweden were compared, and for the classification as SGA or ISS the Swedish reference was chosen. Height, target height (TH), bone age (BA), predicted adult height (PAH), IGF-I and IGFBP-3 values were compared between SGA and ISS. Results. In the combined group, birth weight and length showed a symmetric Gaussian distribution. The American reference overestimates the percentage of short birth length and underestimates that of low birth weight. In childhood, SGA children were shorter than ISS (-3.1 versus -2.6 SDS, P < .001), also in comparison to TH (-2.6 versus -1.9 SDS, P < .001). TH, height SDS change over time, BA delay, and PAH were similar. IGF-I and IGFBP-3 were lower in ISS (P = .03 and .09). Conclusions. SGA children represent the left tail of the Gaussian distribution of birth size in short children. The distinction between SGA and ISS depends on birth size reference. Childhood height of SGA is lower than of ISS, but the other auxological features are similar.

Network of European studies of genes in growth (NESTEGG).

The network of European studies of genes in growth (NESTEGG) is an international growth genomics project, focusing on the birth size phenotypes of small for gestational age (SGA) and idiopathic short stature. Seven hundred controls and 1,275 cases with their parents have been recruited. Detailed clinical histories and auxological measurements are recorded in a clinical database. Candidate gene studies are being undertaken with the study DNA samples. These genetic data will be used to explore associations with the clinical phenotypes of short stature and SGA birth size, and, in a subset, response to growth hormone (GH) therapy. This article describes the study methodology and reviews the association of the exon 3-deleted genotype of the GH receptor with GH responsiveness in GH-treated children born SGA.

Material-dependent levels of heat-shock protein 70 (hsp70) in human plasma following contact of blood with artificial surfaces.

Recently, it has been shown that heat-shock protein 70 (hsp70) functions in a dual role as a chaperone and a cytokine. However, no information is available on the occurrence of hsp70 in the extracellular milieu or on its ability to modulate cellular immune response. This study shows a material-dependent increase of hsp70 levels in plasma following contact of fresh heparinized whole human blood with three different biomaterials (PVC, heparin-coated PVC, Silicone). We report a previously unknown behavior of hsp70 to act as a plasma-adsorption protein. Further, high binding capacities for hsp70 to artificial surfaces (measured by Western blotting) and elevated hsp70 levels in plasma (measured by EIA) following contact with blood correspond with a reduced hemocompatibility. The degree of surface-induced activation of blood was determined by analysis of markers for coagulation, inflammation and complement activation. These findings indicate that the selective adsorption of hsp70 on artificial surfaces and the increased hsp70 levels in plasma may be important in directing host inflammatory and immune responses. We suggest that the levels of hsp70 in human plasma may represent a new prognostic factor or a diagnostic biomarker in hemostasis research.