Objective Ovarian pregnancy is a rare but well-known pathology. However, pathophysiology, diagnosis and treatment are not clearly established. Data sources. All case reports published in Pubmed from Nov 2011 till Nov 2022. Study eligibility criteria. A systematic review and 2 case reports of ovarian pregnancy Study appraisal and synthesis methods. Not applicable Results Ovarian pregnancies occur in 8% of women without or blocked oviducts and in 23% on the other side than the corpus luteum and the symptoms of ovarian pregnancies are not specific. Therefore ovarian pregnancy has to be suspected in all women with abdominal bleeding. As for extrauterine pregnancies, the presence of an intrauterine pregnancy does not rule out an ovarian pregnancy. Surgical excision is the preferred treatment. Important is that in women with both an intra-uterine and an ovarian pregnancy, care should be taken not to damage the corpus luteum. Conclusions Ovarian pregnancies can occur in women with blocked tubes, on the other side of the corpus luteum, in the presence of an intrauterine pregnancy, and even when pregnancy tests or tranvaginal ultrasonography are negative. The diagnosis being difficult to exclude, a laparoscopy is indicated in all women with intra-abdominal bleeding, keeping in mind that an intra-uterine pregnancy cannot be exluded and that a corpus luteum need to be respected.

Fibrodysplasia Ossificans Progressiva (FOP) is an enigmatic, ultra-rare genetic disorder characterized by progressive heterotopic ossification, wherein soft connective tissues undergo pathological transformation into bone structures. This incapacitating process severely limits patient mobility and poses formidable challenges for therapeutic intervention. Predominantly caused by missense mutations in the ACVR1 gene, the disorder has hitherto defied comprehensive mechanistic understanding and effective treatment paradigms. This write-up offers a comprehensive overview of the contemporary understanding of FOP's complex pathobiology, underscored by advances in molecular genetics and proteomic studies. We shed light on targeted therapy, spanning genetic therapeutics, enzymatic and transcriptional modulation, stem cell therapies, and innovative immunotherapies. We also focused on the intricate complexities surrounding clinical trial design for ultra-rare disorders like FOP, addressing fundamental statistical limitations, ethical conundrums, and methodological advancements essential for the success of interventional studies. We advocate for the adoption of a multi-disciplinary approach that converges bench-to-bedside research, clinical expertise, and ethical considerations to tackle the challenges of ultra-rare diseases like FOP and comparable ultra-rare diseases. Overall, this article serves a dual role: as a definitive scientific resource for ongoing and future FOP research and as a call to action for innovative solutions to address methodological and ethical challenges that impede progress in the broader field of medical research for ultra-rare conditions.

Heterotopic ossification (HO) is most dramatically manifested in the rare and severely debilitating disease, fibrodysplasia ossificans progressiva (FOP), in which heterotopic bone progressively accumulates in skeletal muscles and associated soft tissues. The great majority of FOP cases are caused by a single amino acid substitution in the type 1 bone morphogenetic protein (BMP) receptor ACVR1, a mutation that imparts responsiveness to activin A. Although it is well-established that biological sex is a critical variable in a range of physiological and disease processes, the impact of sex on HO in animal models of FOP has not been explored. We show that female FOP mice exhibit both significantly greater and more variable HO responses after muscle injury. Additionally, the incidence of spontaneous HO was significantly greater in female mice. This sex dimorphism is not dependent on gonadally-derived sex hormones, and reciprocal cell transplantations indicate that apparent differences in osteogenic activity are intrinsic to the sex of the transplanted cells. By circumventing the absolute requirement for activin A using an agonist of mutant ACVR1, we show that the female-specific response to muscle injury or BMP2 implantation is dependent on activin A. These data identify sex as a critical variable in basic and preclinical studies of FOP.