Mathilde Lefebvre1,2,3, Fabienne Dufernez4, Ange-Line Bruel2, Marie Gonzales5, Bernard Aral6, Judith Saint-Onge6, Nadège Gigot6, Julie Desir7, Caroline Daelemans8, Frédérique Jossic9, Sébastien Schmitt10, Raphaele Mangione11, Fanny Pelluard12, Catherine Vincent-Delorme13, Jean-Marc Labaune14, Nicole Bigi15, Dominique D'Olne16, Anne-Lise Delezoide17, Annick Toutain18, Sophie Blesson18, Valérie Cormier-Daire19, Julien Thevenon2, Salima El Chehadeh1,2, Alice Masurel-Paulet1, Nicole Joyé5, Claude Vibert-Guigue20, Luc Rigonnot21, Thierry Rousseau22, Pierre Vabres2,23, Philippe Hervé24, Antonin Lamazière25, Jean-Baptiste Rivière2,6, Laurence Faivre1,2, Nicole Laurent3, Christel Thauvin-Robinet1,2. 1. Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Est, FHU-TRANSLAD, CHU Dijon, France. 2. GAD: EA4271 « Génétique des Anomalies du Développement » (GAD), FHU-TRANSLAD, Université de Bourgogne, Dijon, France. 3. Service d'Anatomo-Pathologie, Faculté de Médecine de Dijon, Dijon, France. 4. APHP, Hôpital Saint-Antoine, Biochimie B, Laboratoire de Référence pour le Diagnostic Génétique des Maladies Rares, Paris, France. 5. Service de Génétique et d'Embryologie Médicales, Université Paris VI, Hôpital Trousseau, Paris, France. 6. Laboratoire de Génétique Moléculaire, CHU Dijon, France. 7. Center for Medical Genetics, Hospital Erasme, ULB, Brussels, Belgium. 8. Institut de Recherches Interdisciplinaires en Biologie Humaine et Moléculaire, Hôpital Erasme, Université Libre de Bruxelles, Brussel, Belgium. 9. CHU Nantes, Laboratoire d'anatomopathologie A, Nantes, France. 10. CHU Nantes, Service de Génétique Médicale, Nantes, France. 11. Department of Gynecology, Hôpital Pellegrin, Bordeaux, France. 12. Service de pathologie, CHU de Bordeaux, Bordeaux, France. 13. Service de Génétique Médicale, Hôpital Jeanne de Flandre, CHRU de Lille, Lille, France. 14. Hôpital de la Croix Rousse, CHU Lyon, France. 15. Génétique médicale, CHRU Arnaud de Villeneuve, Montpellier, France. 16. Pathological Anatomy and Cytology Centre, Brussels, Belgium. 17. Department of Developmental Biology, Hôpital Robert Debré, Paris, France. 18. Service de Génétique, Centre Hospitalo-Universitaire Tours, Tours, France. 19. Institut Imagine, Hôpital Necker Enfants Malades (AP-HP), Paris, France. 20. Service de Gynécologie-Obstétrique, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France. 21. Service de Gynécologie-Obstétrique, Centre Hospitalier Sud Francilien (CHSF), Corbeil-Essonnes, France. 22. Service de Gynécologie, Hôpital Le Bocage, Dijon, France. 23. Service de dermatologie, Hôpital Le Bocage, Dijon, France. 24. Service de Gynécologie, Centre Hospitalo-Universitaire Tours, Tours, France. 25. Laboratory of Mass Spectrometry-APLIPID, Faculté de Médecine Pierre et Marie Curie, ER7-UPMC, Paris, France.
Abstract
OBJECTIVES: Conradi-Hünermann-Happle [X-linked dominant chondrodysplasia punctata 2 (CDPX2)] syndrome is a rare X-linked dominant skeletal dysplasia usually lethal in men while affected women show wide clinical heterogeneity. Different EBP mutations have been reported. Severe female cases have rarely been reported, with only six antenatal presentations. METHODS: To better characterize the phenotype in female fetuses, we included nine antenatally diagnosed cases of women with EBP mutations. All cases were de novo except for two fetuses with an affected mother and one case of germinal mosaicism. RESULTS: The mean age at diagnosis was 22 weeks of gestation. The ultrasound features mainly included bone abnormalities: shortening (8/9 cases) and bowing of the long bones (5/9), punctuate epiphysis (7/9) and an irregular aspect of the spine (5/9). Postnatal X-rays and examination showed ichthyosis (8/9) and epiphyseal stippling (9/9), with frequent asymmetric short and bowed long bones. The X-inactivation pattern of the familial case revealed skewed X-inactivation in the mildly symptomatic mother and random X-inactivation in the severe fetal case. Differently affected skin samples of the same fetus revealed different patterns of X-inactivation. CONCLUSION: Prenatal detection of asymmetric shortening and bowing of the long bones and cartilage stippling should raise the possibility of CPDX2 in female fetuses, especially because the majority of such cases involve de novo mutations.
OBJECTIVES: Conradi-Hünermann-Happle [X-linked dominant chondrodysplasia punctata 2 (CDPX2)] syndrome is a rare X-linked dominant skeletal dysplasia usually lethal in men while affected women show wide clinical heterogeneity. Different EBP mutations have been reported. Severe female cases have rarely been reported, with only six antenatal presentations. METHODS: To better characterize the phenotype in female fetuses, we included nine antenatally diagnosed cases of women with EBP mutations. All cases were de novo except for two fetuses with an affected mother and one case of germinal mosaicism. RESULTS: The mean age at diagnosis was 22 weeks of gestation. The ultrasound features mainly included bone abnormalities: shortening (8/9 cases) and bowing of the long bones (5/9), punctuate epiphysis (7/9) and an irregular aspect of the spine (5/9). Postnatal X-rays and examination showed ichthyosis (8/9) and epiphyseal stippling (9/9), with frequent asymmetric short and bowed long bones. The X-inactivation pattern of the familial case revealed skewed X-inactivation in the mildly symptomatic mother and random X-inactivation in the severe fetal case. Differently affected skin samples of the same fetus revealed different patterns of X-inactivation. CONCLUSION: Prenatal detection of asymmetric shortening and bowing of the long bones and cartilage stippling should raise the possibility of CPDX2 in female fetuses, especially because the majority of such cases involve de novo mutations.
Authors: Nadirah Damseh; Karen Chong; Christian Marshall; Lisa Kratz; Ronni Teitelbaum; Patrick Shannon; Peter Kannu Journal: Clin Case Rep Date: 2017-07-20