Insight Into the Ontogeny of GnRH Neurons From Patients Born Without a Nose.

CONTEXT: The reproductive axis is controlled by a network of gonadotropin-releasing hormone (GnRH) neurons born in the primitive nose that migrate to the hypothalamus alongside axons of the olfactory system. The observation that congenital anosmia (inability to smell) is often associated with GnRH deficiency in humans led to the prevailing view that GnRH neurons depend on olfactory structures to reach the brain, but this hypothesis has not been confirmed. OBJECTIVE: The objective of this work is to determine the potential for normal reproductive function in the setting of completely absent internal and external olfactory structures. METHODS: We conducted comprehensive phenotyping studies in 11 patients with congenital arhinia. These studies were augmented by review of medical records and study questionnaires in another 40 international patients. RESULTS: All male patients demonstrated clinical and/or biochemical signs of GnRH deficiency, and the 5 men studied in person had no luteinizing hormone (LH) pulses, suggesting absent GnRH activity. The 6 women studied in person also had apulsatile LH profiles, yet 3 had spontaneous breast development and 2 women (studied from afar) had normal breast development and menstrual cycles, suggesting a fully intact reproductive axis. Administration of pulsatile GnRH to 2 GnRH-deficient patients revealed normal pituitary responsiveness but gonadal failure in the male patient. CONCLUSIONS: Patients with arhinia teach us that the GnRH neuron, a key gatekeeper of the reproductive axis, is associated with but may not depend on olfactory structures for normal migration and function, and more broadly, illustrate the power of extreme human phenotypes in answering fundamental questions about human embryology.

Molecular analysis of exons 8, 9 and 10 of the fibroblast growth factor receptor 2 (FGFR2) gene in two families with index cases of Apert Syndrome.

INTRODUCTION: Apert syndrome (AS) is a craniosynostosis condition caused by mutations in the Fibroblast Growth Factor Receptor 2 (FGFR2) gene. Clinical features include cutaneous and osseous symmetric syndactily in hands and feet, with variable presentations in bones, brain, skin and other internal organs. METHODS: Members of two families with an index case of Apert Syndrome were assessed to describe relevant clinical features and molecular analysis (sequencing and amplification) of exons 8, 9 and 10 of FGFR2 gen. RESULTS: Family 1 consists of the mother, the index case and half -brother who has a cleft lip and palate. In this family we found a single FGFR2 mutation, S252W, in the sequence of exon 8. Although mutations were not found in the study of the patient affected with cleft lip and palate, it is known that these diseases share signaling pathways, allowing suspected alterations in shared genes. In the patient of family 2, we found a sequence variant T78.501A located near the splicing site, which could interfere in this process, and consequently with the protein function.

INTRODUCCIÓN: El síndrome Apert (SA) es un síndrome que cursa con craneosinostosis el cual es ocasionado por mutaciones en el gen del Receptor 2 del Factor de Crecimiento de Fibroblastos (FGFR2). Se caracteriza clínicamente por presentar sindactilias cutáneas y óseas en manos y pies de forma simétrica, cursa además con manifestaciones variables esqueléticas, cerebrales, en piel y otros órganos internos. MÉTODOS: Miembros de dos familias con caso índice de Síndrome Apert fueron evaluados con el objetivo de describir las características clínicas relevantes y el análisis molecular (secuenciación y amplificación) de los exones 8, 9 y 10 del gen FGFR2. RESULTADOS: La familia 1 está constituida por la madre, el caso índice y un medio hermano que presenta labio y paladar hendido. En esta familia solo se encontró la mutación S252W en la secuencia del exón 8 del gen FGFR2 del caso índice. A pesar no encontrarse mutaciones dentro del estudio realizado al paciente afectado con labio y paladar hendido, se conoce que estas patologías comparten vías de señalización, lo que permite sospechar alteraciones en genes compartidos. En la familia 2, el resultado molecular del caso índice reportó la variante T78.501A en la secuencia del intrón 8, la cual se sitúa cercana al sitio de splicing, pudiendo alterar este proceso con una consecuente alteración de la función de la proteína.

Molecular analysis of exons 8, 9 and 10 of the fibroblast growth factor receptor 2 (FGFR2) gene in two families with index cases of Apert Syndrome / Análisis molecular de los exones 8, 9 y 10 del gen del factor de crecimiento de fibroblastos (FGFR2) en dos familias con casos índice de síndrome de Apert

Introduction: Apert syndrome (AS) is a craniosynostosis condition caused by mutations in the Fibroblast Growth Factor Receptor 2 (FGFR2) gene. Clinical features include cutaneous and osseous symmetric syndactily in hands and feet, with variable presentations in bones, brain, skin and other internal organs. Methods: Members of two families with an index case of Apert Syndrome were assessed to describe relevant clinical features and molecular analysis (sequencing and amplification) of exons 8, 9 and 10 of FGFR2 gen. Results: Family 1 consists of the mother, the index case and half -brother who has a cleft lip and palate. In this family we found a single FGFR2 mutation, S252W, in the sequence of exon 8. Although mutations were not found in the study of the patient affected with cleft lip and palate, it is known that these diseases share signaling pathways, allowing suspected alterations in shared genes. In the patient of family 2, we found a sequence variant T78.501A located near the splicing site, which could interfere in this process, and consequently with the protein function.

Introducción: El síndrome Apert (SA) es un síndrome que cursa con craneosinostosis el cual es ocasionado por mutaciones en el gen del Receptor 2 del Factor de Crecimiento de Fibroblastos (FGFR2). Se caracteriza clínicamente por presentar sindactilias cutáneas y óseas en manos y pies de forma simétrica, cursa además con manifestaciones variables esqueléticas, cerebrales, en piel y otros órganos internos. Métodos: Miembros de dos familias con caso índice de Síndrome Apert fueron evaluados con el objetivo de describir las características clínicas relevantes y el análisis molecular (secuenciación y amplificación) de los exones 8, 9 y 10 del gen FGFR2. Resultados: La familia 1 está constituida por la madre, el caso índice y un medio hermano que presenta labio y paladar hendido. En esta familia solo se encontró la mutación S252W en la secuencia del exón 8 del gen FGFR2 del caso índice. A pesar no encontrarse mutaciones dentro del estudio realizado al paciente afectado con labio y paladar hendido, se conoce que estas patologías comparten vías de señalización, lo que permite sospechar alteraciones en genes compartidos. En la familia 2, el resultado molecular del caso índice reportó la variante T78.501A en la secuencia del intrón 8, la cual se sitúa cercana al sitio de splicing, pudiendo alterar este proceso con una consecuente alteración de la función de la proteína.