Clustering of Genetic Anomalies of Cilia Outer Dynein Arm and Central Apparatus in Patients with Transposition of the Great Arteries.

Transposition of the great arteries (TGA) is a congenital heart defect with a complex pathogenesis that has not been fully elucidated. In this study, we performed whole-exome sequencing (WES) in isolated TGA-diagnosed patients and analyzed genes of motile and non-motile cilia ciliogenesis and ciliary trafficking, as well as genes previously associated with this heart malformation. Deleterious missense and splicing variants of genes DNAH9, DNAH11, and ODAD4 of cilia outer dynein arm and central apparatus, HYDIN, were found in our TGA patients. Remarkable, there is a clustering of deleterious genetic variants in cilia genes, suggesting it could be an oligogenic disease. Our data evidence the genetic diversity and etiological complexity of TGA and point out that population allele determination and genetic aggregation studies are required to improve genetic counseling.

Identification of genomic copy number variations in lung benign metastasizing leiomyomatosis.

OBJECTIVES: Lung metastasizing leiomyomatosis (LML) is an infrequently diagnosed pathology developed after sexual maturation, commonly preceded by uterine myomas. Symptoms can include difficulties to breathe, cough, dyspnea and pain, because of mechanical obstruction exerted by expanding local growing leiomyomas. Lung leiomyomas are normally detected by imaging studies, but nowadays the precise diagnosis demands histological characterization of biopsies obtained from the affected tissues. The purpose of the present study was to determine the presence of genomic alterations in circulating cells of LML. METHODS: Immunohistochemical characterization of a lung biopsy extracted by thoracoscopy was performed. Pathologic proliferative smooth muscle cells were observed in a major lung metastasizing nodule, with a growing pattern similar to a uterine myoma. The presence of cellular linages different to smooth muscle cells was discarded by testing the presence of a battery of molecular markers. Also, a normal karyotype was determine by GTG-banding cytogenetic study, but a high density microarray analysis revealed six submicroscopic chromosomal regions displaying genomic abnormalities: microduplications were detected on chromosomes 4, 14, 17 and 22; and microdeletions on chromosomes 8 and 10. CONCLUSION: This study remarks the relevance of submicroscopic chromosomal analysis of unusual pathologic conditions such as Benign Metastasizing Leiomyomatosis. This propitiate a better understanding of the molecular basis on the development of the pathology, in order to reckon on minimally invasive diagnostic methods, and to design appropriate treatments.

[Insights about uncertainty in genetic counseling]. / Una reflexión sobre la incertidumbre en el asesoramiento genético.

Genetic counseling is an information process to help people in the understanding and adaptation to the medical, psychological and family implications of the genetic contribution in diseases. This counseling encompasses all sorts of patients. This represents a challenge in the daily work of the medical geneticist, because giving information in a meaningful way to the patient and his family implies an emotional and psychological burden. Generally we can see two outcomes in the medical practice of genetics, which converge after a diagnosis process: 1) we can face the inability to reach a diagnostic conclusion or 2) we can establish or confirm a diagnosis with certainty, which is the main piece in the genetic counseling. However, in all the situations the uncertainty is a fact, since in the case of those individuals who come in for genetic counseling before symptoms appear or those in prenatal cases, the absence of clinical manifestations and the impossibility to change the course of events lead to the appearance of helplessness and despair. In those cases without diagnostic conclusion, this situation represents a reason for uncertainty, and even in those patients with a diagnosis, certain factors can modify the circumstances in which genetic counseling occurs, such as unpredictability or lack of control. Therefore, it is important to consider the management of uncertainty as an inherent part throughout the process of care in medical genetics. The teaching of medical genetics should also consider the inclusion of topics related to this circumstance.

El asesoramiento genético es un proceso de información para ayudar a las personas a adaptarse a las implicaciones médicas, psicológicas y familiares de la contribución genética en las enfermedades. Sus escenarios abarcan todo tipo de pacientes. Esto es un reto para el médico genetista, pues otorgar información de manera significativa al paciente y su familia conlleva una carga emotiva y psicológica. Hay dos desenlaces de la práctica médica en el área de la genética que convergen después de un proceso diagnóstico: 1) no llegar a una conclusión diagnóstica y 2) el resultado final confirma un diagnóstico de certeza alrededor del cual trata el asesoramiento genético. No obstante, en todas las situaciones la incertidumbre es un hecho patente, pues en aquellos individuos que acuden antes de la aparición de síntomas o en casos prenatales, la ausencia de manifestaciones clínicas y la imposibilidad de modificar el curso de los acontecimientos propician la aparición de impotencia y desolación. En los casos sin conclusión esto representa una razón de incertidumbre y en aquellos pacientes con un diagnóstico pueden presentarse factores que modifiquen las circunstancias en que se produce el asesoramiento genético, como la imprevisibilidad. Estos factores producen distintos grados de incertidumbre en aquellos que debieran beneficiarse con esta información; por tanto: el manejo de la incertidumbre es inherente al proceso de atención en genética médica. La enseñanza de la genética médica debe incluir tópicos relacionados a esta circunstancia durante el proceso.

[The role of the medical geneticist in the pediatric consultation]. / La participación del médico genetista en la consulta pediátrica.

The work of the medical geneticist is, from the clinical point of view, scarcely known. His healthcare-related activity requires close collaboration with specialists in different fields; hence, it is vital for the physician directly in charge of the patient to have at hand some useful recommendations in order to make care provided by the multidisciplinary team efficient and timely. The purpose of this paper is to outline some of the professional features of medical genetics specialists and to describe, in general terms, the work in clinical genetics, as well as to inform first contact clinicians - especially pediatricians - about the clinical and imaging studies they should order for patients with the most common congenital conditions before referring them for diagnostic or genetic counseling. It is important to point out that the communication process between the treating clinician and his/her patients (which in pediatric patients is with the family) is essential not only with regard to the reason for referral to the medical genetics department, but also for the family to be able to obtain information prior to the appointment, so that time and quality of care are improved once the genetics consultation takes place. Finally, this manuscript outlines the requirements for the communication between specialists, in order for them to promote and provide knowledge on medical genetics at all levels of care, for the benefit of patients.

El trabajo del médico genetista desde el punto de vista clínico es poco conocido. Su labor asistencial requiere la colaboración estrecha entre especialistas de diferentes ramas, por ello es vital que el médico directamente encargado del paciente tenga a la mano algunas recomendaciones para hacer eficiente y oportuna la atención del equipo multidisciplinario. La presente comunicación tiene como objetivo dar a conocer algunas características profesionales del médico genetista y describir a grandes rasgos su trabajo en el área clínica, además de informar a los médicos de primer contacto ­en especial a los pediatras­ de los estudios clínicos y de gabinete que deben solicitarse en los pacientes con los padecimientos congénitos más comunes, antes de enviarlos a diagnóstico o asesoramiento genético. Es importante destacar que el proceso de comunicación entre el médico tratante y la familia (en el caso de los pacientes pediátricos) es imprescindible no solo respecto al motivo del envío al servicio de genética médica, sino también para que la familia obtenga información previa a la cita y se mejore el tiempo y la calidad de la atención una vez en la consulta de genética. Por último, en este documento se plantean las necesidades de comunicación entre los especialistas, para que promuevan y aporten conocimientos en genética médica en todos los niveles de atención, en beneficio de los pacientes.

[Li-Fraumeni familial cancer syndrome: case report and review of the literature]. / Síndrome de Li Fraumeni. Cáncer familiar comunicación de un caso y revisión de la literatura.

INTRODUCTION: Multiple familial cancer is a rare entity as is also Li-Fraumeni Syndrome (LFS), which involves a mutation in the germ cell line of Tp53 suppresor gene that is expressed in chromosome 17p13.1 and occurs as an autosomal dominant condition. OBJECTIVE: Presentation of one case of LFS. CLINICAL CASE: Family history: maternal grandfather had melanoma and maternal aunt had osteoblastic osteosarcoma of the left distal femur. Eight-and-a-half year-old child with a history of a CNS tumor (choroid plexus carcinoma) and two years later, a melanoma (Spitz nevus). SYMPTOMS: impaired motor function of the left half of the body and pain upon ipsilateral gait. The physical exam showed swelling of the left iliac crest. The X-rays showed osteoblastic osteosarcoma and the fine needle aspiration biopsy (FNAB) was positive. The diagnosis was made according to the clinical criteria for LFS. DISCUSSION: We report a case of LFS diagnosed based on clinical criteria. We suggest that the questioning of patients with cancer be aimed at finding out the family history of neoplasias. The case presented herein shows an evident association between both choroid plexus carcinoma and osteoblastic osteosarcoma and the patient's family history. We think that any physician treating children with cancer should consider these multiple familial cancer syndromes.