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Open access

Letícia Ribeiro Oliveira, Carlos Alberto Longui, Guilherme Guaragna-Filho, José Luiz Costa, Rafael Lanaro, David Antônio Silva, Maria Izabel Chiamolera, Maricilda Palandi de Mello, André Moreno Morcillo, Andrea Trevas Maciel-Guerra, and Gil Guerra-Junior

Objective

Steroid measurement is a challenge in pediatric endocrinology. Currently, liquid chromatography with tandem mass spectrometry (LC-MS/MS) is considered a gold standard for this purpose. The aim of this study was to compare both LC-MS/MS and immunoassay (IA) for androgens before and after human recombinant chorionic gonadotropin (rhCG) stimulus in children with 46,XY disorders of sex development (DSD).

Methods

Nineteen patients with 46,XY DSD were evaluated; all of them were prepubertal and non-gonadectomized. Testosterone, dihydrotestosterone (DHT), DHEA and androstenedione were measured by IA and LC-MS/MS before and 7 days after rhCG injection. The correlation between IA and LC-MS/MS was analyzed by the intraclass correlation coefficient (ICC) and Spearman’s rank correlation coefficient (SCC). For concordance analysis the Passing and Bablok (PB) regression and the Bland and Altman (BA) method were used.

Results

Testosterone showed excellent correlation (ICC = 0.960 and SCC = 0.964); DHT showed insignificant and moderate correlations as indicated by ICC (0.222) and SCC (0.631), respectively; DHEA showed moderate correlation (ICC = 0.585 and SCC = 0.716); and androstenedione had poor and moderate correlations in ICC (0.363) and SCC (0.735), respectively. Using the PB method, all hormones showed a linear correlation, but proportional and systematic concordance errors were detected for androstenedione, systematic errors for testosterone and no errors for DHEA and DHT. By the BA method, there was a trend of IA to overestimate testosterone and androstenedione and underestimate DHEA and DHT when compared to LC-MS/MS.

Conclusion

Traditional IA should be replaced by LC-MS/MS for the androgens measurement in prepubertal children whenever is possible.

Open access

Nathalia Liberatoscioli Menezes Andrade, Mariana Ferreira de Assis Funari, Alexsandra Christianne Malaquias, Paulo Ferrez Collett-Solberg, Nathalia L R A Gomes, Renata Scalco, Naiara Castelo Branco Dantas, Raissa C Rezende, Angelica M F P Tiburcio, Micheline A R Souza, Bruna L Freire, Ana C V Krepischi, Carlos Alberto Longui, Antonio Marcondes Lerario, Ivo J P Arnhold, Alexander A L Jorge, and Gabriela Andrade Vasques

Objective

Most children with short stature remain without an etiologic diagnosis after extensive clinical and laboratory evaluation and are classified as idiopathic short stature (ISS). This study aimed to determine the diagnostic yield of a multigene analysis in children classified as ISS.

Design and methods

We selected 102 children with ISS and performed the genetic analysis as part of the initial investigation. We developed customized targeted panel sequencing, including all genes already implicated in the isolated short-stature phenotype. Rare and deleterious single nucleotide or copy number variants were assessed by bioinformatic tools.

Results

We identified 20 heterozygous pathogenic (P) or likely pathogenic (LP) genetic variants in 17 of 102 patients (diagnostic yield = 16.7%). Three patients had more than one P/LP genetic alteration. Most of the findings were in genes associated with the growth plate differentiation: IHH (n  = 4), SHOX (n  = 3), FGFR3 (n  = 2), NPR2 (n  = 2), ACAN (n  = 2), and COL2A1 (n  = 1) or involved in the RAS/MAPK pathway: NF1 (n  = 2), PTPN11 (n  = 1), CBL (n  = 1), and BRAF (n  = 1). None of these patients had clinical findings to guide a candidate gene approach. The diagnostic yield was higher among children with severe short stature (35% vs 12.2% for height SDS ≤ or > −3; P = 0.034). The genetic diagnosis had an impact on clinical management for four children.

Conclusion

A multigene sequencing approach can determine the genetic etiology of short stature in up to one in six children with ISS, removing the term idiopathic from their clinical classification.