The European Court of Justice is widely acknowledged to have played a fundamental role in developing the constitutional law of the EU, having been the first to establish such key doctrines as direct effect, supremacy and parallelism in external relations. Traditionally, EU scholarship has praised the role of the ECJ, with more critical perspectives being given little voice in mainstream EU studies. From the standpoint of legal reasoning, Gerard Conway offers the first sustained critical assessment of how the ECJ engages in its function and offers a new argument as to how it should engage in legal reasoning. He also explains how different approaches to legal reasoning can fundamentally change the outcome of case law and how the constitutional values of the EU justify a different approach to the dominant method of the ECJ.

Context: Establishing the genetic basis of early-onset primary ovarian insufficiency (EO-POI, <25 years) is important, but defining variant pathogenicity is challenging. Objective: We aimed to elucidate the genetic architecture of EO-POI in a unique, large cohort. Young women with EO-POI (n = 149; n = 31 familial, n = 118 sporadic) attending a specialist reproductive unit were included. Exome sequencing was performed. After filtering, variants were retained that were: (1) rare/novel (minor allele frequency <0.01%); (2) predicted pathogenic/likely pathogenic; and (3) enriched in the cohort. Each variant was assigned to a category: Category 1, variants in Genomics England Primary Ovarian Insufficiency PanelApp genes (n = 69); Category 2, variants in other POI-associated genes (n = 355) or Category 1 variants following unexpected inheritance patterns; and Category 3, homozygous variants in novel candidate POI genes. Results: A total of 127 Category 1 or 2 variants were identified in 74 different genes (heterozygous 30.9%; homozygous 9.4%; polygenic 21.8%). In familial EO-POI, 64.7% (11/17 kindred) had a Category 1 or 2 variant identified (homozygous: STAG3, MCM9, PSMC3IP, YTHDC2, ZSWIM7; heterozygous: POLR2C, NLRP11, IGSF10, PRKD1, PLEC; polygenic: PDE3A, POLR2H, MSH6, CLPP). In sporadic EO-POI, 63.6% (n = 75/118) women had a variant identified: 21.2% (n = 25) Category 1; 42.4% (n = 50) Category 2. Novel POI candidate genes (Category 3) included PCIF1, DND1, MEF2A, MMS22L, RXFP3, C4orf33, and ARRB1. Conclusion: The genetic basis of EO-POI is complex and affected genes span ovarian developmental processes from fetal life to adulthood. Establishing the pathogenicity of individual heterozygous variants can be challenging. However, some women have clear monogenic causes, particularly in familial POI with autosomal recessive inheritance. Others have potential polygenic causes. We describe novel candidate POI genes warranting further exploration.

A girl presenting with delayed puberty and elevated gonadotropins may have a range of conditions such as Turner syndrome (TS), primary ovarian insufficiency (POI), and 46,XY disorders of sexual development (DSD). An organized and measured approach to investigation can help reach a timely diagnosis. Management of young people often requires specialist multidisciplinary input to address the endocrine and nonendocrine features of these complex conditions, as well as the psychological challenges posed by their diagnosis. Next-generation sequencing within the research setting has revealed several genetic causes of POI and 46,XY DSD, which may further facilitate an individualized approach to care of these young people in the future. Pubertal induction is required in many and the timing of this may need to be balanced with other issues specific to the condition (eg, allowing time for information-sharing in 46,XY DSD, optimizing growth in TS). Shared decision-making and sign-posting to relevant support groups from the outset can help empower young people and their families to manage these conditions. We describe 3 clinical vignettes of girls presenting with delayed puberty and hypergonadotropic amenorrhea and discuss their clinical management in the context of current literature and guidelines.

Formal legal cooperation in matters relating to prisoners has existed at European level for over 50 years. With the development of an European Union (EU) competence in criminal law from the Treaty of Maastricht 1992 onwards, now both the Council of Europe and the EU have adopted legal instruments in this sphere. This paper analsyses the scope and rationale of transnational European cooperation relating to prisoners. It first outlines Council of Europe instruments, including the relevance of the European Convention of Human Rights, conventions specifically on prisoners, and soft law. It then examines the more recent EU instruments, following which the relevance of constitutional principles and the prospects and potential difficulties of European cooperation are analysed. It concludes that cooperation can best succeed through a specification of minimum standards and greater coordination between Council of Europe and EU action, along with greater recognition of its specifically penal context.