Diaphanospondylodysostosis: Full Case Report with Novel Pathogenic BMPER Mutation.

Diaphanospondylodysostosis is an extremely rare, recessively inherited, perinatal lethal skeletal disorder associated with BMPER gene mutations. Clinically it is characterized by defects in costovertebral ossification, absent ribs, hypertelorism, short nose with depressed nasal bridge, low-set ears, and short neck. At the extraosseous level, the most frequent pathologic finding is nephroblastomatosis with multicystic kidneys. We present the case of a child of non-consanguineous parents who died at 2 months of age in our center. Autopsy showed a marked costovertebral ossification defect, perilobar nephrogenic rests and loss of white matter with periventricular leukomalacia. After genetic study, the diagnosis of diaphanospondylodysostosis was confirmed. A previously undescribed germinal mutation in the BMPER gene (c.576 + 2dupT) was found.

Novel germinal mutation in NF1: case report.

BACKGROUND: Neurofibromatosis 1 is a systemic pathology that predominantly affects the central and peripheral nervous system and the skin, although it can potentially affect any organ of the human body. The NF1 gene (Neurofibromatosis 1) is located on chromosome 17q11.2, a gene of great length that encodes neurofibromin, a protein with a tumor suppressor function with a functional mechanism that is not clearly known. METHODS: We reviewed the medical records, radiologic images, genetic studies, and clinical photographs of a patient with confirmed diagnosis of Neurofibromatosis 1 who was attended in our center between 2012 and 2021. The clinical course, the applied therapeutics and genetic findings were assessed. RESULTS: We present the case of a 10-year-old patient with a clinical diagnosis of neurofibromatosis type 1 (more than 6 coffee-with-milk spots, axillary ephelides, a cutaneous xanthogranuloma and hyperhidrosis) in whom a c.6255delG mutation (pMet2085IlefsTer2) in exon 42 of the NF1 gene was detected. There was no family history of diagnosed NF1. Neuroimaging studies showed myelin vacuolization in the posterior fossa, in dentate nucleus, midbrain and both globus pallidus. These findings showed stability over time. The patient is now asymptomatic and under evolutionary follow-up. CONCLUSIONS: The mutation shown here has not been previously described. Reports of previously unknown mutations are an important source of knowledge that can contribute to improved genetic diagnosis and a better understanding of the pathophysiological and genetic characteristics of diseases.

Genetic and clinical characterization of BRCA-associated hereditary breast and ovarian cancer in Navarra (Spain).

BACKGROUND: Genetic testing for BRCA1/2 genes is widely used as a strategy to reduce incidence and morbidity of hereditary breast and ovarian cancer (HBOC). The purpose of this study is to analyse the demographic and molecular characteristics of BRCA germline mutations in Navarra, Spain, and to investigate the clinical profile of hereditary and sporadic breast cancer (BC) and ovarian cancer (OC) in the Community. METHODS: The study includes 1246 individuals assessed for BRCA1/2 genetic testing in Navarra, during 2000-2016, and a cohort of BC (n = 4384) and OC (n = 561) from the population-based Navarra Cancer Registry. Distribution and molecular characteristics of BRCA1/2 mutations, as well as, comparative analysis of the clinical course, pathologic features and overall survival (OS) of patients in different risk groups were investigated. RESULTS: BRCA mutation detection rate was 16%, with higher proportion (63%) of BRCA2 families. Nineteen per cent of mutations were recurrent, one of which, BRCA2 c.6024dupG, showed high association to OC. BRCA carriers had double risk (95% CI = 1.04-4.33) of developing multiple malignancies than low risk families and were diagnosed at a much earlier age (16.6 and 11.7 years difference for BC and OC, respectively) when compared to the general population. For BC, BRCA carriers showed a more advanced histological stage, higher risk of bilateral neoplasms (OR = 4.3; 95% CI = 1.3-11.4, for BRCA2 carriers) and worse OS rate at 5-, 10- and 15- years, than women with sporadic tumors. For OC, over 70% of patients of all risk groups showed advanced stages at diagnosis, with the highest among BRCA1 carriers (91%). Furthermore, they also had higher probability of developing ovarian bilateral tumors (OR = 7.8, 95% CI = 1.7-55.7, for BRCA1 carriers) than the general population. Five-year OS rate was worse among women with sporadic OC than BRCA carriers, but it levelled out over the 15-year period. CONCLUSIONS: In addition to national similarities in the HBOC-BRCA1/2 associated mutational spectrum, we identified a recurrent BRCA2 pathogenic variant (c.6024dupG), highly associated to OC in Navarra. Carriers of BRCA1/2 mutations showed a more severe BC and OC phenotype and had a worse overall prognosis when compared to a large cohort of women with sporadic counterpart tumors.