Four infants who were exposed to sodium valproate or valproic acid during pregnancy are described. Common facial features in the three surviving infants include epicanthic folds, a flat nasal bridge, a broad nasal base, anteverted nostrils, a shallow philtrum, and a thin upper lip with a thick lower lip. Ridging of the metopic suture, congenital heart defect, postaxial polydactyly, and hypospadias were additional features in individual cases. In agreement with previous authors, we feel that there is a distinctive 'fetal valproate' phenotype.

Fetal valproate syndrome: isthere arecognisable phenotype?

Neonates of different species are born with a set of predispositions that influence their early orienting responses toward the first stimuli encountered in their life. Human neonates and domestic chicks exhibit several similarities in the predisposition for attending to objects that move with speed changes, face-like stimuli and biological motion. Although early predispositions are connected to physiological development, little is known on the temporal course of early predispositions (whether they are stable or change in time) and on the associated genetic variability. To address these issues, we tested the preference for objects that change in speed vs. linear motion in three chicken breeds (Padovana, Polverara and Robusta maculata) within one day after hatching and three days after hatching. We found that the predisposition to preferentially attend to changes in speed is shared by different breeds on the first day of life and that it disappears by day three. These results indicate the existence of a short and transient time window of early predispositions that does not depend on visual experience.

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A transient time window for early predispositions in newborn chicks.

The zebrafish is an appealing model organism for investigating the genetic (G) and environmental (E) factors, as well as their interactions (GxE), which contribute to craniofacial malformations. Here, we review zebrafish studies on environmental factors involved in the etiology of craniofacial malformations in humans including maternal smoking, alcohol consumption, nutrition and drug use. As an example, we focus on the (cleft) palate, for which the zebrafish ethmoid plate is a good model. This review highlights the importance of investigating ExE interactions and discusses the variable effects of exposure to environmental factors on craniofacial development depending on dosage, exposure time and developmental stage. Zebrafish also promise to be a good tool to study novel craniofacial teratogens and toxin mixtures. Lastly, we discuss the handful of studies on gene-alcohol interactions using mutant sensitivity screens and reverse genetic techniques. We expect that studies addressing complex interactions (ExE and GxE) in craniofacial malformations will increase in the coming years. These are likely to uncover currently unknown mechanisms with implications for the prevention of craniofacial malformations. The zebrafish appears to be an excellent complementary model with high translational value to study these complex interactions.

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Zebrafish Models of Craniofacial Malformations: Interactions of Environmental Factors.

Raskausajan lääkkeiden käyttö ja syntyneiden lasten terveys 1996-2016

Assessing the impacts on fetal dosimetry of the modelling of the placental transfers of xenobiotics in a pregnancy physiologically based pharmacokinetic model

A pattern of major and minor congenital anomalies, facial dysmorphic features, and neurodevelopmental difficulties, including cognitive and social impairments has been reported in some children exposed to sodium valproate (VPA) during pregnancy. Recognition of the increased risks of in utero exposure to VPA for congenital malformations, and for the neurodevelopmental effects in particular, has taken many years but these are now acknowledged following the publication of the outcomes of several prospective studies and registries. As with other teratogens, exposure to VPA can have variable effects, ranging from a characteristic pattern of major malformations and significant intellectual disability to the other end of the continuum, characterised by facial dysmorphism which is often difficult to discern and a more moderate effect on neurodevelopment and general health. It has become clear that some individuals with FVSD have complex needs requiring multidisciplinary care but information regarding management is currently lacking in the medical literature. An expert group was convened by ERN-ITHACA, the European Reference Network for Congenital Malformations and Intellectual Disability comprised of professionals involved in the care of individuals with FVSD and with patient representation. Review of published and unpublished literature concerning management of FVSD was undertaken and the level of evidence from these sources graded. Management recommendations were made based on strength of evidence and consensus expert opinion, in the setting of an expert consensus meeting. These were then refined using an iterative process and wider consultation. Whilst there was strong evidence regarding the increase in risk for major congenital malformations and neurodevelopmental difficulties there was a lack of high level evidence in other areas and in particular in terms of optimal clinical management.. The expert consensus approach facilitated the formulation of management recommendations, based on literature evidence and best practice. The outcome of the review and group discussions leads us to propose the term Fetal Valproate Spectrum Disorder (FVSD) as we feel this better encompasses the broad range of effects seen following VPA exposure in utero. The expert consensus approach can be used to define the best available clinical guidance for the diagnosis and management of rare disorders such as FVSD. FVSD can have medical, developmental and neuropsychological impacts with life-long consequences and affected individuals benefit from the input of a number of different health professionals.

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Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability

Abstract Introduction/Background This case has many important discussions and demonstrates the role of psychological therapy in treatment. The young person presented with chronic pain and was unable to walk (in a wheelchair). There had been a missed ASD diagnosis due to atypical presentation. There were accusations of fabricated illness which had led to mistrust of professionals and had impacted on family. The patient’s selective mutism was a challenge to therapeutic approach and required increased creativity and flexibility. This case highlights the impact of Sensory processing difference and the relationship to chronic pain. The patient’s significant anxiety led to treatment limitations. Description/Method This young person was referred to us after they had been seen by several teams over a significant period. There were multiple presenting issues without a systemic understanding of the problems. It was important to review previous assessments and information thoroughly and have transparent discussions with the family. The two most difficult tasks were gaining the families trust and to engage a young person who did not speak. The previous MDT had raised safeguarding concerns, in particular the possibility of fabricated illness; this was based on the conclusion that mothers account of social communication difficulties differed from that of school. There had also been concerns raised about the young person’s engagement with professionals and difficultly developing relationships. Discussion/Results We approached the case with an open mind. We reassessed and made a diagnosis of ASD. The MDT approach to care is very important and has many positives however it can also lead to “groupthink” and make it difficult to challenge the group view. This helped us and the family to understand the evolution of presenting symptoms and for them to begin to feel believed. Common disorders can present in unusual ways, and this is particularly true for developmental disorders such as ASD. Sensory processing differences are part of ASD and impacted significantly on the symptoms of pain, loss of function and the ability to engage the young person in physical therapy. The patients difficulty with change and rigidity of thought needed care consideration when supporting engagement with new aspects of care. It also prompted us to think about sensory processing differences and how they may be linked to the presentation of chronic pain and use this understanding to promote engagement with treatment. This young person was selectively mute and we used novel strategies to engage them in psychotherapy – raising the issue of engaging someone who doesn’t talk in talking therapies. We utilised activities and their interests to develop a therapeutic relationship and motivate engagement in recovery. Given the levels of mistrust and anxiety this took a significant amount of time. It was an essential task to repair the relationships with key agencies and educate them about this child’s needs. In complex cases this systemic working is essential to ensure progress is made and maintained. Key learning points/Conclusion Listen to families Look at the evidence critically and question your clinical hypothesis. Don’t be afraid to question and challenge the MDT – this should be a part of a functional MDT. Case management is an important part of care and recovery. Continued MDT communication and supervision maintains hope and manages the psychological burden of care. Work with the patient’s interests and strengths and utilise this to motivate recovery. Building trust can take time – be patient and consistent.

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Neelo Aslam

Papers

Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability

P07 Finding recovery, trust and hope in silence. Psychological treatment in chronic pain