ANDRESA DE SANTI RODRIGUES

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Instituto Central, Hospital das Clínicas, Faculdade de Medicina
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina

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  • article 2 Citação(ões) na Scopus
    High frequency of non-classical congenital adrenal hyperplasia form among children with persistently elevated levels of 17-hydroxyprogesterone after newborn screening
    (2019) CASTRO, Patricia S.; RASSI, Tatiana O.; ARAUJO, Raquel F.; PEZZUTI, Isabela L.; RODRIGUES, Andresa S.; BACHEGA, Tania A. S. S.; SILVA, Ivani N.
    Background: Early diagnosis after newborn screening (NBS) for congenital adrenal hyperplasia (CAH) allows proper treatment, reducing mortality rates and preventing development of hyperandrogenic manifestations and incorrect sex assignment at birth. Despite the high NBS sensitivity to detect CAH classical forms, one of the main issues is identifying asymptomatic children who remained with increased 17-hydroxyprogesterone (17-OHP) levels. In this study, we aimed to contribute to understanding the diagnosis of these children. Methods: Children with increased serum 17-OHP levels, and without disease-related clinical features during follow-up, underwent the entire CYP21A2 gene sequencing and multiplex ligation-dependent probe amplification (MLPA) analysis (SALSA MLPA P050B CAH). Patients' genotypes were subsequently sorted as compatible with CAH disease, and children were evaluated to determine the clinical status. Results: During the study period, 106,476 newborns underwent CAH NBS. During follow-up, 328 children (0.3%) were identified as having false-positive tests and 295 were discharged after presenting with 17-OHP levels within reference values. Thirty-three remained asymptomatic and with increased serum 17-OHP levels after a mean follow-up of 3.4 years, and were subjected to molecular analysis. Seventeen out of the 33 children carried mutations: seven in the heterozygous state, nine carried non-classical genotypes and the remaining child carried a classical genotype. Conclusions: We found a high frequency of non-classical CAH (NCCAH) diagnosis among children with persistent elevation of 17-OHP levels. Our findings support molecular study as decisive for elucidating diagnosis in these asymptomatic children. Molecular analysis as a confirmatory test is relevant to guide their follow-up, allows genetic counseling and avoids over treating NCCAH form.
  • article 12 Citação(ões) na Scopus
    Mobile DNA in Endocrinology: LINE-1 Retrotransposon Causing Partial Androgen Insensitivity Syndrome
    (2019) BATISTA, Rafael Loch; YAMAGUCHI, Katsumi; RODRIGUES, Andresa di Santi; NISHI, Mirian Yumie; GOODIER, John L.; CARVALHO, Luciani Renata; DOMENICE, Sorahia; COSTA, Elaine M. F.; KAZAZIAN JR., Haig H.; MENDONCA, Berenice Bilharinho
    Context: Androgen insensitivity syndrome (AIS) is the most common cause of disorders of sex development in 46,XY individuals. It is an X-linked condition usually caused by pathogenic allelic variants in the androgen receptor (AR) gene. The phenotype depends on the AR variant, ranging from severe undervirilization (complete AIS) to several degrees of external genitalia undervirilization. Although 90% of those with complete AIS will have AR mutations, this will only be true for 40% of those with partial AIS (PAIS). Objective: To identify the genetic etiology of AIS in a large multigenerational family with the PAIS phenotype. Participants: Nine affected individuals with clinical and laboratory findings consistent with PAIS and a normal exonic AR sequencing Settings: Endocrine clinic and genetic institute from two academic referral centers Design: Analysis of whole exons of the AR gene, including splicing regions, was performed, followed by sequencing of the 5'untranslated region (UTR) of the AR gene. Detailed phenotyping was performed at the initial diagnosis and long-term follow-up, and circulating levels of steroid gonadal hormones were measured in all affected individuals. AR expression was measured using RT-PCR and cultured fibroblasts. Results: All 46,XY family members with PAIS had inherited, in hemizygosity, a complex defect (similar to 1100 bp) in the 5'UTR region of the AR surrounded by a duplicated 18-bp sequence (target site duplication). This sequence is 99.7% similar to an active, long, interspersed element present on the X chromosome (AC002980; Xq22.2), which was inserted in the 5' UTR of the AR gene, severely reducing AR expression and leading to PAIS. Conclusion: The molecular diagnosis of PAIS remains challenging. The genomic effect of retrotransposon mobilization should be considered a possible molecular cause of AIS and other AR diseases.