High frequency of pathogenic ACAN variants including an intragenic deletion in selected individuals with short stature.

CONTEXT: Defining the underlying etiology of idiopathic short stature (ISS) improves the overall management of an individual. OBJECTIVE: To assess the frequency of pathogenic ACAN variants in selected individuals. DESIGN: The single-center cohort study was conducted at a tertiary university children's hospital. From 51 unrelated patients with ISS, the 16 probands aged between 3 and 18 years (12 females) with advanced bone age and/or autosomal dominant inheritance pattern of short stature were selected for the study. Fifteen family members of ACAN-positive probands were included. Exome sequencing was performed in all probands, and additional copy number variation (CNV) detection was applied in selected probands with a distinct ACAN-associated phenotype. RESULTS: Systematic phenotyping of the study cohort yielded 37.5% (6/16) ACAN-positive probands, with all novel pathogenic variants, including a 6.082 kb large intragenic deletion, detected by array comparative genomic hybridization (array CGH) and exome data analysis. All variants were co-segregated with short stature phenotype, except in one family member with the intragenic deletion who had an unexpected growth pattern within the normal range (-0.5 SDS). One patient presented with otosclerosis, a sign not previously associated with aggrecanopathy. CONCLUSIONS: ACAN pathogenic variants presented a common cause of familial ISS. The selection criteria used in our study were suggested for a personalized approach to genetic testing of the ACAN gene in clinical practice. Our results expanded the number of pathogenic ACAN variants, including the first intragenic deletion, and suggested CNV evaluation in patients with typical clinical features of aggrecanopathy as reasonable. Intra-familial phenotypic variability in growth patterns should be considered.

New Mutations Associated with Rasopathies in a Central European Population and Genotype-Phenotype Correlations.

We performed the genetic analysis of Rasopathy syndromes in patients from Central European by direct sequencing followed by next generation sequencing of genes associated with Rasopathies. All 51 patients harboured the typical features of Rasopathy syndromes. Thirty-five mutations were identified in the examined patients (22 in PTPN11, two in SOS1, one in RIT1, one in SHOC2, two in HRAS, three in BRAF, two in MAP2K1 and two in the NF1 gene). Two of them (p.Gly392Glu in the BRAF gene and p.Gln164Lys in the MAP2K1 gene) were novel with a potentially pathogenic effect on the structure of these proteins. Statistically significant differences in the presence of pulmonary stenosis (63.64% vs. 23.81%, P = 0.013897) and cryptorchidism (76.47% vs. 30%, P = 0.040224) were identified as the result of comparison of the prevalence of phenotypic features in patients with the phenotype of Noonan syndrome and mutation in the PTPN11 gene, with the prevalence of the same features in patients without PTPN11 mutation. Cryptorchidism as a statistically significant feature in our patients with PTPN11 mutation was not reported as significant in other European countries (Germany, Italy and Greece). The majority of mutations were clustered in exons 3 (45.45%), 8 (22.73%), and 13 (22.73%) of the PTPN11 gene.

[The hemodiafiltration with infusion of acetate-free dialysis fluid can modify the inflammatory response in patients "high responders" to inflammatory stimuli?]. / Il trattamento in emodiafiltrazione con infusione di liquido di dialisi (PHF acetate free) può modificare la risposta infiammatoria in pazienti già identificati come "high responders" a stimoli infiammatori?

PURPOSE: This study aimed to verify the effects of paired hemodiafiltration on-line (PHF-AF) on inflammation in patients who were "high responders" to inflammatory stimuli: elevated C-reactive protein (CRP), genetic polymorphisms influencing a low transcription for interleukin-10 (IL-10) and a high transcription for IFN-gamma. METHODS: Ten patients selected as high responders for IFN-gamma and low responders for IL-10 were included in a crossover study to compare PHF-AF and standard bicarbonate hemodialysis (BHD). At study entry and before the start of each dialysis session the following examinations were performed: CRP, albumin, fibrinogen, ferritin, transferrin, prealbumin and serum levels of IL-6, IL-10, IFN-gamma, tumor necrosis factor-alpha (TNF-alpha). After the 1st and 3rd week of the study, the blood samples were also collected after the dialysis session. RESULTS: . There was a significant reduction in albumin and prealbumin in PHF-AF patients during the study; none of the other parameters were changed in both patient groups. CRP tended to be elevated after dialysis in both PHF-AF and BHD. While IL-6, IL-10 and IFN-gamma were unchanged during the dialysis session, there was a significant variation in TNF-alpha levels, which were increased in BHD (from 10.9 +/- 3.1 to 14.7 +/- 4.1 pg/mL; p=0.004) and reduced in PHF-AF (from 11.9 +/-2.8 to 6.3 +/- 2.2 pg/mL; p=0.0004). CONCLUSION: Although the cytokine levels were unchanged during the study in both BHD and PHF-AF, the modification of TNF-alpha during the dialysis session was considered as inflammatory significance.