The importance of gonadal mosaicism in families with apparently de novo mutations is being increasingly recognized. We report on two affected brothers initially suggestive of X-linked or autosomal recessive inheritance. Malan syndrome due to shared NFIX variants was diagnosed in the brothers using exome sequencing. The boys shared the same paternal but not maternal haplotype around NFIX, and deep amplicon sequencing showed ~7% of the variant in paternal sperm but not in paternal blood and saliva. We performed review of previous cases of gonadal mosaicism, which suggests that the phenomenon is not uncommon. Gonadal mosaicism is often not accompanied by somatic mosaicism in tissues routinely used for testing, and if both types of mosaicism are present, the frequency of the variant in sperm is often higher than in somatic cells. In families with shared apparently de novo variants without evidence of parental somatic mosaicism, the transmitting parent may be determined through haplotyping of exome variants. Gonadal mosaicism has important consequences for recurrence risks and should be considered in genetic counseling in families with de novo variants.

• MeSH
• dítě MeSH
• gonády patologie   MeSH
• lidé MeSH
• mladý dospělý MeSH
• mnohočetné abnormality genetika   MeSH
• mozaicismus * MeSH
• mutace genetika   MeSH
• předškolní dítě MeSH
• rodokmen MeSH
• sekvence aminokyselin MeSH
• sekvence nukleotidů MeSH
• sourozenci * MeSH
• syndrom MeSH
• těhotenství MeSH
• transkripční faktory NFI chemie   genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH

Secretory carcinoma of the skin is a rare adnexal carcinoma, which is morphologically and immunohistochemically identical to secretory carcinoma of the breast and is associated with the presence of t (12;15) translocation, resulting in the ETV6-NTRK3 gene fusion. Nineteen cases of primary cutaneous secretory carcinoma have been previously published in the literature. In this study, we describe 6 new cases of secretory carcinoma of the skin. The study group consisted of 5 female patients and 1 male patient, ranging in age from 57 to 98 years (mean: 74.2, median: 74). Locations included the axilla (2), neck, eyelid, thigh, and nipple base, each one. Microscopically, all but 1 tumor were well circumscribed and nonencapsulated and exhibited characteristic abundant secretions within the microcystic and tubular spaces comprised by bland oval, round to cuboidal neoplastic cells. In addition, solid areas and focal pseudopapillae were seen, and, in 1 case, a focal mucinous component with small lakes of mucin containing small tumor nests or tubules of the neoplastic cells was present. The remaining neoplasm was mostly solid and papillary, with only few characteristic lumina containing secretions. Immunohistochemically, all cases expressed S-100 protein, mammaglobin, STAT5, GATA3, and NTRK. ETV6-NTRK3 gene fusion was detected in 5 cases, whereas, in the remaining tumor, a novel NFIX-PKN1 gene fusion was found.

• MeSH
• databáze faktografické MeSH
• fenotyp MeSH
• fúze genů * MeSH
• genetická predispozice k nemoci MeSH
• hybridizace in situ fluorescenční MeSH
• imunohistochemie MeSH
• karcinom chemie   genetika   patologie   chirurgie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové biomarkery analýza   genetika   MeSH
• nádory kůže chemie   genetika   patologie   chirurgie   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• prospektivní studie MeSH
• proteinkinasa C genetika   MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• transkripční faktory NFI genetika   MeSH
• translokace genetická * MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Adenoid cystic carcinoma (ACC) of the skin is a rare malignant neoplasm histologically identical to homonymous tumors in other organs. Cutaneous ACC has been found to harbor MYB gene activations, either through MYB chromosomal abnormalities or by generation of the MYB-NFIB fusion. In salivary gland ACC, in addition to the MYB gene, alterations in MYBL1, the gene closely related to MYB, have been reported. We studied 10 cases of cutaneous ACC (6 women, 4 men; and age range 51-83 years) for alterations in the MYB, NFIB, and MYBL1 genes, using FISH and PCR. MYB break-apart and NFIB break-apart tests were positive in 4 and 5 cases, respectively. MYB-NFIB fusions were found in 4 cases. The break of MYBL1 was found in 2 cases, and in one of them, the NFIB break-apart probe was positive, strongly indicating a MYBL1-NFIB fusion. In 2 cases, the MYB break-apart test was positive, whereas no MYB-NFIB was detected, strongly suggesting another fusion partner. It is concluded that MYBL1 alterations are detected in primary cutaneous ACC but are apparently less common compared with MYB and NFIB alterations.

• MeSH
• adenoidně cystický karcinom genetika   patologie   MeSH
• fenotyp MeSH
• fúze genů MeSH
• fúzní onkogenní proteiny genetika   MeSH
• genetická predispozice k nemoci MeSH
• genová přestavba MeSH
• hybridizace in situ fluorescenční MeSH
• imunohistochemie MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové biomarkery genetika   MeSH
• nádory kůže genetika   patologie   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• protoonkogenní proteiny genetika   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• trans-aktivátory genetika   MeSH
• transkripční faktory NFI genetika   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH

Adenoid cystic carcinoma (AdCC) of the salivary glands is characterized by MYB-NFIB or MYBL1-NFIB fusion, prolonged but relentlessly progressive clinical course with frequent recurrences, and development of distant metastasis resulting in high long-term mortality. Currently, no effective therapy is available for patients with advanced non-resectable and/or metastatic disease. Complicating the clinical management of this patient group is the lack of prognostic markers. The purpose of this study is to investigate the prognostic value of 1p36 loss in patients with AdCC. The presence of 1p36 deletion and gene fusions involving the MYB, NFIB, and MYBL1 genes in a cohort of 93 salivary gland AdCCs was studied using fluorescence in situ hybridization. These results were statistically correlated with clinical data and outcome. Deletion of 1p36 in AdCC was identified in 13 of 85 analyzable cases (15.29%). MYB-NFIB fusion was detected in 57/85 (67.1%), MYBL1-NFIB fusion in 12/85 (14.1%), MYB-X fusion in 4/85 (4.7%), MYBL1-X in 4/85 (4.7%), and NFIB-X in 2/85 (2.4%) of AdCC cases. None of the 1p36-deleted samples showed MYBL1 rearrangement. Statistical analysis demonstrated a significant correlation between 1p36 deletion and advanced tumor stage and solid histology (p = 0.0061 and 0.0007, respectively). Kaplan-Meier survival curves showed statistically significant correlations between 1p36 deletion and decreased overall survival, disease-specific survival, recurrence-free interval, and recurrence-free survival, all of which were maintained in multivariate analysis. We demonstrate that 1p36 deletion can serve as an indicator of unfavorable outcome of patients with salivary gland AdCC.

• MeSH
• adenoidně cystický karcinom genetika   mortalita   sekundární   terapie   MeSH
• časové faktory MeSH
• chromozomální delece * MeSH
• dospělí MeSH
• fenotyp MeSH
• fúze genů MeSH
• fúzní onkogenní proteiny genetika   MeSH
• genetická predispozice k nemoci MeSH
• hybridizace in situ fluorescenční MeSH
• imunohistochemie MeSH
• Kaplanův-Meierův odhad MeSH
• lidé středního věku MeSH
• lidé MeSH
• lidské chromozomy, pár 1 * MeSH
• lokální recidiva nádoru MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádorové biomarkery genetika   MeSH
• nádory slinných žláz genetika   mortalita   patologie   terapie   MeSH
• přežití po terapii bez příznaků nemoci MeSH
• progrese nemoci MeSH
• proporcionální rizikové modely MeSH
• protoonkogenní proteiny genetika   MeSH
• rizikové faktory MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• staging nádorů MeSH
• stupeň nádoru MeSH
• trans-aktivátory genetika   MeSH
• transkripční faktory NFI genetika   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND AND AIM: Sotos syndrome 2 (MIM #614753), known also as Malan syndrome, is caused by heterozygous mutations/deletions of the NFIX gene located on chromosome 19p13.2. It manifests in developmental delay, intellectual impairment, macrocephaly, central nervous system anomalies, postnatal overgrowth, and craniofacial dysmorphism. Unusual behavior with/without autistic traits, ophthalmologic, gastrointestinal, musculo-skeletal, and hand/foot abnormalities are also frequent. Due to the limited number of such cases, no definitive conclusions about genotype-phenotype correlations have been possible. In the following paper, we discuss physical features consistent with Sotos syndrome 2 based on literature review and two new cases [a patient with de novo 19p13.2 deletion encompassing a part of the NFIX gene and a patient with de novo (not described so far) heterozygous missense mutation c.367C>T (p.Arg123Trp) in the NFIX gene]. RESULTS: Apart from overgrowth and psychomotor developmental delay, the most consistent physical features of our two patients are dysmorphism including high forehead, downslanting palpebral fissures, pointed chin, and abnormalities of the pinna. Both show abnormal behavior and present with long, tapered fingers and toenail defect. No severe congenital malformations were noted. CONCLUSIONS: We hope these data will serve as a material for further studies and provide an opportunity to make more reliable genotype-phenotype correlations.

• MeSH
• chromozomální delece * MeSH
• dítě MeSH
• fenotyp MeSH
• heterozygot MeSH
• kraniofaciální abnormality genetika   MeSH
• lidé MeSH
• lidské chromozomy, pár 19 genetika   MeSH
• missense mutace genetika   MeSH
• Sotosův syndrom genetika   MeSH
• transkripční faktory NFI genetika   MeSH
• vývojové poruchy u dětí genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• přehledy MeSH