Kabuki syndrome (KS) is a dominantly inherited disorder mainly due to de novo pathogenic variation in KMT2D or KDM6A genes. Initially, a representative cohort of 14 Czech cases with clinical features suggestive of KS was analyzed by experienced clinical geneticists in collaboration with other specialties, and observed disease features were evaluated according to the 'MLL2-Kabuki score' defined by Makrythanasis et al. Subsequently, the aforementioned genes were Sanger sequenced and copy number variation analysis was performed by MLPA, followed by genome-wide array CGH testing. Pathogenic variants in KMT2D resulting in protein truncation in 43% (6/14; of which 3 are novel) of all cases were detected, while analysis of KDM6A was negative. MLPA analysis was negative in all instances. One female patient bears a 6.6 Mb duplication of the Xp21.2-Xp21.3 region that is probably disease causing. Subjective KS phenotyping identified predictive clinical features associated with the presence of a pathogenic variant in KMT2D. We provide additional evidence that this scoring approach fosters prioritization of patients prior to KMT2D sequencing. We conclude that KMT2D sequencing followed by array CGH is a diagnostic strategy with the highest diagnostic yield.
BackgroundCowden syndrome (CS) is a cancer predisposition syndrome associated with increased risk of breast, thyroid, and endometrial cancers, and is characterized by development of benign mucocutaneous lesions.Case presentationHere we report on a 58-year-old woman with multiple primary malignancies and subtle mucocutaneous lesions such as small polyps and wart-like papulas. Over a period of 23 years, she developed various malignant neoplasms including thyroid, ovarian, stomach, and colon carcinomas, and a benign meningioma. Direct sequencing analysis of the PTEN gene revealed a novel germline mutation (c.438delT, p.Leu146X).ConclusionThis case demonstrates that Cowden syndrome is a multi-system disease that can result in the development of multiple malignant and benign tumors.
Although there are no standard guidelines for management of FA carriers with malignancies and reports about chemo- or radiosensitivity in this population are scarce; patients with FA-A heterozygosity may have a high rate of complications from chemo/radiotherapy. Up to now, an optimum method for the prediction of radiosensitivity and the best parameter has not been found. Clinical radioresponsiveness is unpredictable in FA carriers and there is a pressing need of new rapid and predictive in vitro assays of radiation responses. Until then, the treatment of FA carriers with malignancies should be individualized, with respect to potential hypersensitivity to ionizing radiation or cross-linking agents.
Small cell carcinoma of hypercalcemic type (SCCOHT) is a rare gynaecological neoplasm, originating mostly in the ovaries. Cervical origin of this very aggressive malignancy with unknown histogenesis is an extremely rare condition, without published management recommendations. Alterations in SMARCA4 gene are supposed to play the major role in SCCOHT oncogenesis and their identification is crucial for the diagnosis. Adequate genetic counselling of the patients and their families seems to be of great importance. Optimal management and treatment approaches are not known yet but may extremely influence the prognosis of young female patients that suffer from this very resistant disease. Nowadays, a translational research seems to be the key for the further diagnostic and treatment strategies of SCCOHT. The purpose of the case report is to provide practical information and useful recommendations on the diagnosis, management, and treatment of SMARCA4-deficient carcinoma of the uterine cervix resembling SCCOHT.
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