Perspectives on the future of dysmorphology.

The field of clinical genetics and genomics continues to evolve. In the past few decades, milestones like the initial sequencing of the human genome, dramatic changes in sequencing technologies, and the introduction of artificial intelligence, have upended the field and offered fascinating new insights. Though difficult to predict the precise paths the field will follow, rapid change may continue to be inevitable.

Lethal respiratory course and additional features expand the phenotypic spectrum of PIEZO2-related distal arthrogryposis type 5.

Distal arthrogryposes (DA) are a group of conditions presenting with multiple congenital contractures in the distal joints. The 10 types of DA are distinguished by different extra-articular manifestations. Heterozygous gain-of-function variants in PIEZO2 are known to cause a spectrum of DA conditions including DA type 3, DA type 5, and possibly Marden Walker syndrome, which are usually distinguished by the presence of cleft palate (DA3), ptosis and restriction in eye movements (DA5), and specific facial abnormalities and central nervous system involvement, respectively.

Examining the Vanishing Twin Hypothesis of Neural Tube Defects: Application of an Epigenetic Predictor for Monozygotic Twinning.

Strong associations between neural tube defects (NTDs) and monozygotic (MZ) twinning have long been noted, and it has been suggested that NTD cases who do not present as MZ twins may be the survivors of MZ twinning events. We have recently shown that MZ twins carry a strong, distinctive DNA methylation signature and have developed an algorithm based on genomewide DNA methylation array data that distinguishes MZ twins from dizygotic twins and other relatives at well above chance level. We have applied this algorithm to published methylation data from five fetal tissues (placental chorionic villi, kidney, spinal cord, brain and muscle) collected from spina bifida cases (n = 22), anencephalic cases (n = 15) and controls (n = 19).

The contributions of careful clinical observations: A legacy.

Clinical Medicine is an Art which is learned, together with hard work, as an apprentice-observing how a master works, and improving with experience and exposure. Clinicians are performing multiple things at the same time-trying to make a diagnosis, providing best therapies and preventative strategies, and looking for the underlying mechanism(s). Families want to know what to expect over time-the natural history of their disorder.

Northwest Indigenous Art and the Inspiring Spirits.

Indigenous Art often expresses the complex culture of their creators and provides insight into the origins, histories, and values of that culture. Two examples of Northwest Indigenous Art suggest deeper meanings and the "power" of congenital anomalies.

The mystery of monozygotic twinning II: What can monozygotic twinning tell us about Amyoplasia from a review of the various mechanisms and types of monozygotic twinning?

Monozygotic (MZ) twins ("identical twins") are essentially unique to human beings. Why and how they arise is not known. This article reviews the possible different types of MZ twinning recognized in the previous article on twins and arthrogryposis.

The mystery of monozygotic twinning I: What can Amyoplasia tell us about monozygotic twinning and the possible role of twin-twin transfusion?

Amyoplasia is a very specific, nongenetic clinically recognizable form of arthrogryposis, representing about one-third of individuals with arthrogryposis surviving the newborn period. There is a markedly increased number of individuals with Amyoplasia who are one of monozygotic (MZ) twins, with the other twin being normal. Thus, it would appear that Amyoplasia is definitely associated with and may be caused by an MZ twinning event.

Deformations associated with arthrogryposis.

Fetal movement is essential to normal human development. If the fetus does not move for whatever reason, then multiple organs and organ systems develop secondary and tertiary effects not normally present. Most of these are deformations with secondary structural damage.

The spectrum of brain malformations and disruptions in twins.

Twins have an increased risk for congenital malformations and disruptions, including defects in brain morphogenesis. We analyzed data on brain imaging, zygosity, sex, and fetal demise in 56 proband twins and 7 less affected co-twins with abnormal brain imaging and compared them to population-based data and to a literature series. We separated our series into malformations of cortical development (MCD, N = 39), cerebellar malformations without MCD (N = 13), and brain disruptions (N = 11).

Continuing contributions of older academics.

Academics go through many stages. Perhaps the most challenging is retirement. This article summarizes some of the challenges and opportunities that await.

Recurrent constellations of embryonic malformations re-conceptualized as an overlapping group of disorders with shared pathogenesis.

Several recurrent malformation associations affecting the development of the embryo have been described in which a genetic etiology has not been found, including LBWC, MURCS, OAVS, OEIS, POC, VACTERL, referred to here as "recurrent constellations of embryonic malformations" (RCEM). All are characterized by an excess of reported monozygotic discordant twins and lack of familial recurrence. We performed a comprehensive review of published twin data across all six phenotypes to allow a more robust assessment of the association with twinning and potential embryologic timing of a disruptive event.

Collaborating to advance interdisciplinary care for individuals with arthrogryposis.

This Special Issue on Interdisciplinary Care in Arthrogryposis highlights a collection of articles spanning topics in interdisciplinary care, genetic discoveries, and clinical research. An international group of clinicians and researchers from various backgrounds who attended the "3rd International Symposium on Arthrogryposis", held in Philadelphia, September 24-26, 2018, were invited to contribute to this issue. The goal of the 2018 Symposium and of this Special Issue is to provide momentum to advancing evidence-based practice and research in arthrogryposis, by working collaboratively with adults and families of children with arthrogryposis, clinicians, and researchers.

Central nervous system involvement in arthrogryposis multiplex congenita: Overview of causes, diagnosis, and care.

Arthrogryposis or AMC, arthrogryposis multiplex congenita, is defined as multiple congenital joint contractures in more than two joints and in different body areas. The common cause of all AMC is lack of movement in utero, which in turn can have different causes, one of which is CNS involvement. Intellectual disability/CNS involvement is found in approximately 25% of all AMC.

A standardized autopsy protocol for arthrogryposis (multiple congenital contractures).

Arthrogryposis multiplex congenita (AMC) describes disorders with multiple joint contractures that arise from neurological, neuromuscular, or mechanical origin. Although impaired fetal movement is the typical clinical presentation, the etiology underlying this phenotype for a number of conditions remains unknown. In an effort to better characterize and define the etiologies underlying these disorders, we recommend a standardized autopsy protocol that will allow for appropriate diagnosis and a methodical approach for examination that will facilitate subsequent study by investigators across disciplines.

Gene ontology analysis of arthrogryposis (multiple congenital contractures).

In 2016, we published an article applying Gene Ontology Analysis to the genes that had been reported to be associated with arthrogryposis (multiple congenital contractures) (Hall & Kiefer, 2016). At that time, 320 genes had been reported to have mutations associated with arthrogryposis. All were associated with decreased fetal movement.

Research platform for children with arthrogryposis multiplex congenita: Findings from the pilot registry.

A pediatric registry for arthrogryposis multiplex congenita (AMC) proposes to advance research by providing the platform to inform the distribution, etiology, and natural history of AMC. The registry was piloted on 40 families of children (mean = 8.25 years, 48% males) presenting with AMC across two hospitals in North America.