Martine C. de Vries

PAPSS2 deficiency causes androgen excess via impaired DHEA sulfation-in vitro and in vivo studies in a family harboring two novel PAPSS2 mutations

Context: PAPSS2 (PAPS synthase 2) provides the universal sulfate donor PAPS (3′-phospho-adenosine-5′-phosphosulfate) to all human sulfotransferases, including SULT2A1, responsible for sulfation of the crucial androgen precursor dehydroepiandrosterone (DHEA). Impaired DHEA sulfation is thought to increase the conversion of DHEA toward active androgens, a proposition supported by the previous report of a girl with inactivating PAPSS2 mutations who presented with low serum DHEA sulfate and androgen excess, clinically manifesting with premature pubarche and early-onset polycystic ovary syndrome. Patients and Methods: We investigated a family harboring two novel PAPSS2 mutations, including two compound heterozygous brothers presenting with disproportionate short stature, low serum DHEA sulfate, but normal serum androgens. Patients and parents underwent a DHEA challenge test comprising frequent blood sampling and urine collection before and after 100 mg DHEA orally, with subsequent analysis of DHEA sulfation and androgen metabolism by mass spectrometry. The functional impact of the mutations was investigated in silico and in vitro. Results: We identified a novel PAPSS2 frameshift mutation, c.1371del, p.W462Cfs*3, resulting in complete disruption, and a novel missense mutation, c.809G>A, p.G270D, causing partial disruption of DHEA sulfation. Both patients and their mother, who was heterozygous for p.W462Cfs*3, showed increased 5α-reductase activity at baseline and significantly increased production of active androgens after DHEA intake. The mother had a history of oligomenorrhea and chronic anovulation that required clomiphene for ovulation induction. Conclusions: We provide direct in vivo evidence for the significant functional impact of mutant PAPSS2 on DHEA sulfation and androgen activation. Heterozygosity for PAPSS2 mutations can be associated with a phenotype resembling polycystic ovary syndrome.

Assessing children’s competence to consent in research by a standardized tool: a validity study

BackgroundCurrently over 50% of drugs prescribed to children have not been evaluated properly for use in their age group. One key reason why children have been excluded from clinical trials is that they are not considered able to exercise meaningful autonomy over the decision to participate. Dutch law states that competence to consent can be presumed present at the age of 12 and above; however, in pediatric practice children’s competence is not that clearly presented and the transition from assent to active consent is gradual. A gold standard for competence assessment in children does not exist. In this article we describe a study protocol on the development of a standardized tool for assessing competence to consent in research in children and adolescents.Methods/designIn this study we modified the MacCAT-CR, the best evaluated competence assessment tool for adults, for use in children and adolescents. We will administer the tool prospectively to a cohort of pediatric patients from 6 to18 years during the selection stages of ongoing clinical trials. The outcomes of the MacCAT-CR interviews will be compared to a reference standard, established by the judgments of clinical investigators, and an expert panel consisting of child psychiatrists, child psychologists and medical ethicists. The reliability, criterion-related validity and reproducibility of the tool will be determined. As MacCAT-CR is a multi-item scale consisting of 13 items, power was justified at 130–190 subjects, providing a minimum of 10–15 observations per item. MacCAT-CR outcomes will be correlated with age, life experience, IQ, ethnicity, socio-economic status and competence judgment of the parent(s). It is anticipated that 160 participants will be recruited over 2 years to complete enrollment.DiscussionA validity study on an assessment tool of competence to consent is strongly needed in research practice, particularly in the child and adolescent population. In this study we will establish a reference standard of children’s competence to consent, combined with validation of an assessment instrument. Results can facilitate responsible involvement of children in clinical trials by further development of guidelines, health-care policies and legal policies.

Standard 1: Consent and Recruitment

A 4-year-old boy with a serious metabolic disorder is eligible for a trial of a new enzyme replacement, the first potential option to treat this disease. His parents have little understanding of the disease or trial, even with careful explanation, but eventually they consent to entry in the trial. The treating clinician doubts whether their consent is valid. This and similar dilemmas face pediatricians in research every day. Many of the therapeutic options for children have not been tested with the rigor applied to similar treatments in adults. This highlights the need for research to improve the evidence base of childrens medicine, for more pediatricians to undertake research, and for more children and families to participate.1 … Address correspondence to Martin Offringa, MD, PhD, Senior Scientist and Program Head, Child Health Evaluative Sciences, Research Institute, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada M5G 1X8. E-mail: martin.offringa{at}sickkids.ca

Reflective Equilibrium and Empirical Data: Third Person Moral Experiences in Empirical Medical Ethics

In ethics, the use of empirical data has become more and more popular, leading to a distinct form of applied ethics, namely empirical ethics. This ‘empirical turn’ is especially visible in bioethics. There are various ways of combining empirical research and ethical reflection. In this paper we discuss the use of empirical data in a special form of Reflective Equilibrium (RE), namely the Network Model with Third Person Moral Experiences. In this model, the empirical data consist of the moral experiences of people in a practice. Although inclusion of these moral experiences in this specific model of RE can be well defended, their use in the application of the model still raises important questions. What precisely are moral experiences? How to determine relevance of experiences, in other words: should there be a selection of the moral experiences that are eventually used in the RE? How much weight should the empirical data have in the RE? And the key question: can the use of RE by empirical ethicists really produce answers to practical moral questions? In this paper we start to answer the above questions by giving examples taken from our research project on understanding the norm of informed consent in the field of pediatric oncology. We especially emphasize that incorporation of empirical data in a network model can reduce the risk of self-justification and bias and can increase the credibility of the RE reached.

The Right to an Open Future Concerning Genetic Information

primary importance placed on the child’s interests in the ACMG ES/GS scenario. Furthermore, the potential for increased knowledge relevant to parental health that arises in the WGS context is absent in conventional hypothesisdriven genetic testing. Therefore, we believe that both the ACMG ES/GS and AAP/ACMG statements are consistent with the best interests of the child and are not in ethical tension with one another.

Clinical Trial Decisions in Difficult Circumstances: Parental Consent Under Time Pressure

Treatments and interventions used to care for children in emergencies should be based on strong evidence. Well-designed clinical trials investigating these interventions for children are therefore indispensable. Parental informed consent is a key ethical requirement for the enrollment of children in such studies. However, if time is limited because of an urgent need for intervention, there are additional ethical challenges to adequately support the informed consent process. The acute situation and associated psychological impact may compromise the ability of parents to give informed consent. Little evidence exists to guide the process of consent seeking for a child’s research participation when time is limited. It is also unclear in what circumstances alternatives to prospective informed consent could be applied. This article describes possible options to manage the informed consent process in an appropriate, practical, and, we believe, ethical way when time is limited.

Medical decision-making in children and adolescents: developmental and neuroscientific aspects

BackgroundVarious international laws and guidelines stress the importance of respecting the developing autonomy of children and involving minors in decision-making regarding treatment and research participation. However, no universal agreement exists as to at what age minors should be deemed decision-making competent. Minors of the same age may show different levels of maturity. In addition, patients deemed rational conversation-partners as a child can suddenly become noncompliant as an adolescent. Age, context and development all play a role in decision-making competence. In this article we adopt a perspective on competence that specifically focuses on the impact of brain development on the child’s decision-making process.Main bodyWe believe that the discussion on decision-making competence of minors can greatly benefit from a multidisciplinary approach. We adopted such an approach in order to contribute to the understanding on how to deal with children in decision-making situations. Evidence emerging from neuroscience research concerning the developing brain structures in minors is combined with insights from various other fields, such as psychology, decision-making science and ethics. Four capacities have been described that are required for (medical) decision-making: (1) communicating a choice; (2) understanding; (3) reasoning; and (4) appreciation. Each capacity is related to a number of specific skills and abilities that need to be sufficiently developed to support the capacity. Based on this approach it can be concluded that at the age of 12 children can have the capacity to be decision-making competent. However, this age coincides with the onset of adolescence. Early development of the brain’s reward system combined with late development of the control system diminishes decision-making competence in adolescents in specific contexts. We conclude that even adolescents possessing capacities required for decision-making, may need support of facilitating environmental factors.ConclusionThis paper intends to offer insight in neuroscientific mechanisms underlying the medical decision-making capacities in minors and to stimulate practices for optimal involvement of minors. Developing minors become increasingly capable of decision-making, but the neurobiological development in adolescence affects competence in specific contexts. Adequate support should be offered in order to create a context in which minors can make competently make decisions.

Is a New Protocol for Acute Lymphoblastic Leukemia Research or Standard Therapy

In the United States, doctors generally develop new cancer chemotherapy for children by testing innovative chemotherapy protocols against existing protocols in prospective randomized trials. In the Netherlands, children with leukemia are treated by protocols that are agreed upon by the Dutch Childhood Oncology Group. Periodically, the Dutch Childhood Oncology Group revises its protocols. Sometimes, these revisions are categorized as research, sometimes as treatment. In this Ethics Rounds, we analyze whether enrollment in a new protocol ought to be considered research and, if so, we discuss the implications of that designation. Our discussion highlights the different ways different countries approach complex issues of research ethics.

Why do children decide not to participate in clinical research: a quantitative and qualitative study

Background:More pediatric drug trials are needed, but although specific pediatric regulations warrant safety, recruitment of children for these trials remains one of the main difficulties. Therefore, we investigated potential determining factors of nonparticipation in clinical research, in order to optimize research participation of children by recommending improved recruitment strategies.Methods:Between 1 January 2012 and 1 January 2014, we performed a prospective study among161 pediatric patients, aged 6 to 18 y, who were eligible for clinical research. We quantitatively analyzed the association of potential explanatory variables (e.g., age, cognitive development, experience, ethnicity) with nonparticipation and qualitatively analyzed interviews on reasons for nonparticipation.Results:Sixty percent of the children did not participate in the research project on offer (39% decided not to participate, 21% were indecisive). Lower age, less disease experience, and less complex research with lower risk were predictive for not participating. Time constraint and extra burden were expressed as decisive reasons for not participating.Conclusions:Strategies to optimize research participation should be aimed at younger children and their families, who are logistically challenged and unfamiliar with health care and research. Recommendations include informing pediatric patients and their families of the value of research; minimizing logistic burdens; and improving accessibility.

Perspectives of adolescents on decision making about participation in a biobank study: a pilot study

Objectives To be able to truly involve adolescents in decision making about clinical research participation, we need more insight in the perspective of adolescents themselves. To this end, adolescents in an ongoing biobank study were consulted to test a tentative decision assessment tool. Methods The perspectives of adolescents (n=8) concerning participation in decision making for research participation were explored in interviews with a tentative tool, which covered six topics: information material usage, understanding, disease perceptions, anxiety, decision-making process and role sharing. Results All adolescents unequivocally expressed the desire to be involved in decision making, but also wanted advice from their parents. The extent of the preferred role of adolescent versus parents varied between individuals. In decision making, adolescents relied on parents for information. More than half hardly used the information material. Conclusions Adolescents in our study preferred a shared decision-making process. The extent of sharing varied between individuals. The decision assessment tool was a fruitful starting point to discuss adolescents’ perspectives and may aid in tailoring the situation to the individual to achieve optimal participation practices. Implications Consulting adolescents about their preferences concerning decision making using the tool will facilitate tailoring of the shared decision-making process and optimising the developing autonomy of minors.