RESUMO
Fusion anomalies of the Müllerian ducts are associated with an increased risk for miscarriage and premature labor. In most cases polygenic-multifactorial inheritance can be assumed but autosomal-dominant inheritance with reduced penetrance and variable manifestation should be considered. We performed array-comparative genomic hybridization (CGH) analysis in a cohort of 103 patients with Müllerian fusion anomalies. In 8 patients we detected microdeletions and microduplications in chromosomal regions 17q12, 22q11.21, 9q33.1, 3q26.11 and 7q31.1. The rearrangement in 17q12 including LHX1 and HNF1ß as well as in 22q11.21 have already been observed in MRKHS (Mayer-Rokitansky-Küster-Hauser syndrome). In summary, we (1) detected causative micro-rearrangements in patients with Müllerian fusion anomalies, (2) show that Müllerian fusion anomalies and MRKHS may have a common etiology, and (3) identified new candidate genes for Müllerian fusion anomalies.
Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/diagnóstico , Transtornos 46, XX do Desenvolvimento Sexual/genética , Hibridização Genômica Comparativa , Anormalidades Congênitas/diagnóstico , Anormalidades Congênitas/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Ductos Paramesonéfricos/anormalidades , Hibridização Genômica Comparativa/métodos , Feminino , Estudos de Associação Genética/métodos , Marcadores Genéticos , Variação Genética , Humanos , Imageamento por Ressonância Magnética , FenótipoRESUMO
Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is a well-known malformation pattern of the Müllerian ducts (MDs) characterized by congenital absence of the uterus and vagina. To date, most cases remain unexplained at molecular level. As female Wnt9b-/- mice show a MRKHS-like phenotype, WNT9B has emerged as a promising candidate gene for this disease. We performed retrospective sequence analyses of WNT9B in 226 female patients with disorders of the MDs, including 109 patients with MRKHS, as well as in 135 controls. One nonsense mutation and five likely pathogenic missense mutations were detected in WNT9B. Five of these mutations were found in cases with MRKHS accounting for 4.6% of the patients with this phenotype. No pathogenic mutations were detected in the control group (p = 0.017). Interestingly, all of the MRKHS patients with a WNT9B mutation were classified as MRKHS type 1, representing 8.5% of the cases from this subgroup. In previous studies, two of the patients with a WNT9B mutation were found to carry either an additional deletion of LHX1 or a missense mutation in TBX6. We conclude that mutations in WNT9B were frequently associated with MRKHS in our cohort and some cases may be explained by a digenic disease model.
Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/genética , Anormalidades Congênitas/genética , Predisposição Genética para Doença/genética , Ductos Paramesonéfricos/anormalidades , Mutação , Proteínas Wnt/genética , Sequência de Bases , Códon sem Sentido , Análise Mutacional de DNA , Feminino , Frequência do Gene , Genótipo , Humanos , Mutação de Sentido Incorreto , Estudos Retrospectivos , SíndromeRESUMO
Knowledge of vulvar rhabdomyosarcoma (RMS) is based on case reports and collective reviews since the pathology is extremely rare and experience of individual institutions limited. We present a case of a 15-year-old girl with large-sized vulvar embryonal RMS. The patient was treated with wide local excision of the tumor, multiagent chemotherapy and radiotherapy, achieved complete remission but 6 months after diagnosis died of toxicity. The management is discussed. Necessity of early anticipation of malignancy in girls is pointed out as it may determine outcome of therapy.
