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Objective: Recurrent deletions involving 17q12 are associated with a variety of clinical phenotypes, including congenital abnormalities of the kidney and urinary tract (CAKUT), maturity onset diabetes of the young, type 5, and neurodevelopmental disorders. Structural and/or functional renal disease is the most common phenotypic feature, although the prenatal renal phenotypes and the postnatal correlates have not been well characterized., Method: We reviewed pre- and postnatal medical records of 26 cases with prenatally or postnatally identified 17q12/HNF1B microdeletions (by chromosomal microarray or targeted gene sequencing), obtained through a multicenter collaboration. We specifically evaluated 17 of these cases (65%) with reported prenatal renal ultrasound findings., Results: Heterogeneous prenatal renal phenotypes were noted, most commonly renal cysts (41%, n = 7/17) and echogenic kidneys (41%), although nonspecific dysplasia, enlarged kidneys, hydronephrosis, pelvic kidney with hydroureter, and lower urinary tract obstruction were also reported. Postnatally, most individuals developed renal cysts (73%, 11/15 live births), and there were no cases of end-stage renal disease during childhood or the follow-up period., Conclusion: Our findings demonstrate that copy number variant analysis to assess for 17q12 microdeletion should be considered for a variety of prenatally detected renal anomalies. It is important to distinguish 17q12 microdeletion from other etiologies of CAKUT as the prognosis for renal function and presence of associated findings are distinct and may influence pregnancy and postnatal management., (© 2023 John Wiley & Sons Ltd.)

Background: A variety of maternal risk factors for fetal alcohol spectrum disorders (FASD) have been described in the literature. Here, we conducted a multivariate analysis of a large array of potential distal influences on FASD risk., Methods: Interviews were conducted with 2515 mothers of first-grade students whose children were evaluated to assess risk for FASD. Topics included: physical/medical status, childbearing history, demographics, mental health, domestic violence, and trauma. Regression modeling utilized usual level of alcohol consumption by trimester and six selected distal variables (maternal head circumference, body mass index, age at pregnancy, gravidity, marital status, and formal years of education) to differentiate children with FASD from control children., Results: Despite individual variation in distal maternal risk factors among and within the mothers of children with each of the common diagnoses of FASD, patterns emerged that differentiated risk among mothers of children with FASD from mothers whose children were developing typically. Case-control comparisons indicate that mothers of children with FASD were significantly smaller physically, had higher gravidity and parity, and experienced more miscarriages and stillbirths, were less likely to be married, reported later pregnancy recognition, more depression, and lower formal educational achievement. They were also less engaged with a formal religion, were less happy, suffered more childhood trauma and interpersonal violence, were more likely to drink alone or with her partner, and drank to deal with anxiety, tension, and to be part of a group. Regression analysis showed that the predictor variables explain 57.5% of the variance in fetal alcohol syndrome (FAS) diagnoses, 30.1% of partial FAS (PFAS) diagnoses, and 46.4% of alcohol-related neurodevelopmental disorder (ARND) diagnoses in children with FASD compared to controls. While the proximal variables explained most of the diagnostic variance, six distal variables explained 16.7% ( 1 / 6 ) of the variance in FAS diagnoses, 13.9% ( 1 / 7 ) of PFAS, and 12.1% ( 1 / 8 ) of ARND., Conclusions: Differences in distal FASD risks were identified. Complex models to quantify risk for FASD hold promise for guiding prevention/intervention., (© 2023 Research Society on Alcohol.)

Background: Navigating the clinical literature to determine the optimal clinical management for rare diseases presents significant challenges. We introduce the Medical Action Ontology (MAxO), an ontology specifically designed to organize medical procedures, therapies, and interventions., Methods: MAxO incorporates logical structures that link MAxO terms to numerous other ontologies within the OBO Foundry. Term development involves a blend of manual and semi-automated processes. Additionally, we have generated annotations detailing diagnostic modalities for specific phenotypic abnormalities defined by the Human Phenotype Ontology (HPO). We introduce a web application, POET, that facilitates MAxO annotations for specific medical actions for diseases using the Mondo Disease Ontology., Findings: MAxO encompasses 1,757 terms spanning a wide range of biomedical domains, from human anatomy and investigations to the chemical and protein entities involved in biological processes. These terms annotate phenotypic features associated with specific disease (using HPO and Mondo). Presently, there are over 16,000 MAxO diagnostic annotations that target HPO terms. Through POET, we have created 413 MAxO annotations specifying treatments for 189 rare diseases., Conclusions: MAxO offers a computational representation of treatments and other actions taken for the clinical management of patients. Its development is closely coupled to Mondo and HPO, broadening the scope of our computational modeling of diseases and phenotypic features. We invite the community to contribute disease annotations using POET (https://poet.jax.org/). MAxO is available under the open-source CC-BY 4.0 license (https://github.com/monarch-initiative/MAxO)., Funding: NHGRI 1U24HG011449-01A1 and NHGRI 5RM1HG010860-04., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

Objective: To explore and analyze the significance of proximal influences of maternal and paternal traits associated with bearing a child with a fetal alcohol spectrum disorder (FASD)., Methods: Aggregated, maternal interview-collected data (N = 2515) concerning alcohol, tobacco, and other drug use were examined to determine risk for FASD from seven cross-sectional samples of mothers of first-grade students who were evaluated for a possible diagnosis of FASD., Results: Mothers of children with fetal alcohol syndrome (FAS) reported the highest alcohol use throughout pregnancy, proportion of binge drinking, drinks per drinking day (DDD), drinking days per week, and total drinks per week. Mothers of children with FAS also consumed significantly more alcohol than mothers of children with partial FAS (PFAS), alcohol-related neurodevelopmental disorder (ARND), or typically developing controls. Mothers of children with PFAS and ARND reported similar drinking patterns, which exposed fetuses to 3-4 times more alcohol than mothers of controls, but the PFAS group was more likely than the ARND group to abstain in latter trimesters. Fathers of all children were predominantly drinkers (70%-85%), but more fathers of children with FASD binged heavily on more days than fathers of controls. Compared to the few mothers of controls who used alcohol during pregnancy, the ARND group binge drank more (3+ DDD) throughout pregnancy and drank more DDD before pregnancy and first trimester. Regression analysis, controlling for tobacco use, indicated that mothers who reported drinking <1 DDD were significantly more likely than abstainers to bear a child with FASD (OR = 2.75) as were those reporting higher levels such as 5-5.9 DDD (OR = 32.99). Exclusive, first-trimester maternal drinking increased risk for FASD five times over that of abstinence (p < 0.001, OR = 5.05, 95% CI: 3.88-6.58), first- and second-trimester drinking by 12.4 times, and drinking all trimesters by 16 times (p < 0.001, OR = 15.69, 95% CI: 11.92-20.64). Paternal drinking during and prior to pregnancy, without adjustment, increased the likelihood of FASD significantly (OR = 1.06 and 1.11, respectively), but the significance of both relationships disappeared when maternal alcohol and tobacco use were controlled., Conclusions: Differences in FASD risk emerged from the examination of multiple proximal variables of maternal alcohol and tobacco use, reflecting increased FASD risk at greater levels of maternal alcohol consumption., (© 2023 Research Society on Alcohol.)

Heterozygous pathogenic variants in POLR1A, which encodes the largest subunit of RNA Polymerase I, were previously identified as the cause of acrofacial dysostosis, Cincinnati-type. The predominant phenotypes observed in the cohort of 3 individuals were craniofacial anomalies reminiscent of Treacher Collins syndrome. We subsequently identified 17 additional individuals with 12 unique heterozygous variants in POLR1A and observed numerous additional phenotypes including neurodevelopmental abnormalities and structural cardiac defects, in combination with highly prevalent craniofacial anomalies and variable limb defects. To understand the pathogenesis of this pleiotropy, we modeled an allelic series of POLR1A variants in vitro and in vivo. In vitro assessments demonstrate variable effects of individual pathogenic variants on ribosomal RNA synthesis and nucleolar morphology, which supports the possibility of variant-specific phenotypic effects in affected individuals. To further explore variant-specific effects in vivo, we used CRISPR-Cas9 gene editing to recapitulate two human variants in mice. Additionally, spatiotemporal requirements for Polr1a in developmental lineages contributing to congenital anomalies in affected individuals were examined via conditional mutagenesis in neural crest cells (face and heart), the second heart field (cardiac outflow tract and right ventricle), and forebrain precursors in mice. Consistent with its ubiquitous role in the essential function of ribosome biogenesis, we observed that loss of Polr1a in any of these lineages causes cell-autonomous apoptosis resulting in embryonic malformations. Altogether, our work greatly expands the phenotype of human POLR1A-related disorders and demonstrates variant-specific effects that provide insights into the underlying pathogenesis of ribosomopathies., Competing Interests: Declaration of interests A.B., M.J.G.S., K. McWalters, R.P., and R.S. are employees of GeneDx., (Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Introduction: Digital photography can be securely stored in the medical record and enhance documentation of physical exam findings and monitor wound healing. A standardized protocol that respects the dignity of the patient and maintains the fidelity of objective documentation is needed for patients with differences in sexual development (DSD) and congenital adrenal hyperplasia (CAH)., Objective: The purpose of this study was to evaluate the feasibility, acceptability, and applications of a HIPAA-compliant digital photography protocol in the care of female patients with CAH., Study Design: A protocol for standardized digital imaging including consent, permission, data capture, and storage in the electronic medical record (EMR) was implemented. Patients undergoing physical examination during multidisciplinary CAH clinic visits, preoperative evaluation, and postoperative follow-up from October 2020 through May 2021 were included. Male patients with CAH, patients with clitoromegaly or urogenital sinus not from CAH, and patients seen through telehealth were excluded. Consent was obtained from caregivers and permission from patients. Images of the exam were taken during clinic visits or at the time of surgery with no identifying features included. Images were directly uploaded into the patient's chart in the HIPAA-protected EMR separate from other clinical documentation and not stored on personal devices., Results: There were 17 patients with CAH seen with median age 6 years (range 2 weeks-18 years). There was a median of 3 photos per patient during the study period with cooperation from both the patient and their caregiver. Amongst the patients seen, 6 patients underwent reconstruction with a median of 10 photos per patient. Images were available and used for preoperative planning and counseling. Patients with previous images did not require repeat examinations and were subjected to fewer genital examinations. Fewer providers were present during exams. Images taken by providers and caregivers during the postoperative period were used to monitor wound healing and surgical outcomes., Discussion: Protocol implementation improved patient care by reducing the number of exams and number of providers present, enhancing clinical documentation, and providing a means of tracking the physical exam over time. This was in concordance with guidelines for limiting exams for patients with DSD and CAH. Implementation of best practices for medical photography was important in respecting patient dignity and confidentiality., Conclusion: Implementation of standardized digital photography was feasible and acceptable to patients and caregivers. Digital images reduced the need for repeat physical examination and provided a visual means of enhancing clinical documentation., Competing Interests: Conflicts of interest The authors have no disclosures or conflicts of interest to report., (Copyright © 2022 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

An international group of clinicians working in the field of dysmorphology has initiated the standardization of terms used to describe human morphology. The goals are to standardize these terms and reach consensus regarding their definitions. In this way, we will increase the utility of descriptions of the human phenotype and facilitate reliable comparisons of findings among patients. Additional discussions with other workers in dysmorphology and related fields, such as developmental biology and molecular genetics, will become more precise. Here we introduce the anatomy of the trunk and limbs and define and illustrate the terms that describe the major characteristics of these body regions., (© 2022 Wiley Periodicals LLC.)

Au-Kline syndrome (AKS) is a neurodevelopmental disorder associated with multiple malformations and a characteristic facial gestalt. The first individuals ascertained carried de novo loss-of-function (LoF) variants in HNRNPK. Here, we report 32 individuals with AKS (26 previously unpublished), including 13 with de novo missense variants. We propose new clinical diagnostic criteria for AKS that differentiate it from the clinically overlapping Kabuki syndrome and describe a significant phenotypic expansion to include individuals with missense variants who present with subtle facial features and few or no malformations. Many gene-specific DNA methylation (DNAm) signatures have been identified for neurodevelopmental syndromes. Because HNRNPK has roles in chromatin and epigenetic regulation, we hypothesized that pathogenic variants in HNRNPK may be associated with a specific DNAm signature. Here, we report a unique DNAm signature for AKS due to LoF HNRNPK variants, distinct from controls and Kabuki syndrome. This DNAm signature is also identified in some individuals with de novo HNRNPK missense variants, confirming their pathogenicity and the phenotypic expansion of AKS to include more subtle phenotypes. Furthermore, we report that some individuals with missense variants have an "intermediate" DNAm signature that parallels their milder clinical presentation, suggesting the presence of an epi-genotype phenotype correlation. In summary, the AKS DNAm signature may help elucidate the underlying pathophysiology of AKS. This DNAm signature also effectively supported clinical syndrome delineation and is a valuable aid for variant interpretation in individuals where a clinical diagnosis of AKS is unclear, particularly for mild presentations., Competing Interests: Declaration of interests H.T.B. is a consultant for Mahzi therapeutics., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Multiple studies have demonstrated the benefit of incorporating certified child life specialist (CCLS) services in various aspects of pediatric care. Although the significance of psychosocial support of patients with Disorders of Sexual Development (DSD) and Congenital Adrenal Hyperplasia (CAH) is increasingly recognized, the involvement of CCLS services into the DSD and CAH multidisciplinary care model has yet to be described., Objective: To evaluate the feasibility, acceptability, and patient and family experience of routinely incorporating CCLS services into the multidisciplinary DSD and CAH care model., Study Design: As part of a quality improvement initiative, CCLS services were routinely incorporated in the multidisciplinary DSD and CAH clinics at our institution. Encounters for patients seen in clinic between July 2018 through October 2019 were reviewed for demographic information, DSD diagnosis classification, CCLS documentation, and whether an exam under anesthesia (EUA) was required due to an incomplete clinical exam. CCLS documentation was reviewed for assessments, interventions, whether patients tolerated their physical exams, time of CCLS services, and additional CCLS support beyond the physical exam. All patients were limited to one physical exam per clinic visit., Results: Out of the 45 encounters with CCLS involvement, 42 (93.3%) exams were well-tolerated. CCLS assessments considered patient development, communication considerations, temperament, medical stressors, coping preferences, and patient preferences for activities and distractions. Interventions included preparing patients for their physical exams, encouragement before and during exams, addressing patient stressors, distractions and coping mechanisms, and advocating for the patient. No patients required an EUA., Discussion: The CCLS aimed to provide families with a sense of control during clinic visits and teach them to advocate for themselves. The CCLS helped prepare and distract patients for their clinic visit and addressed the sensitive nature of the physical exam by focusing on the emotional and development needs of patients. CCLS contributions to a positive patient experience are consistent with multiple studies demonstrating the benefit of CCLS services for pediatric care. This quality improvement initiative ultimately helped to create a positive experience for patients and families., Conclusion: This study demonstrates the feasibility, acceptability, and positive impact of CCLS services in the delivery of patient and family-centered care for patients with DSD and CAH as part of the multidisciplinary team model., (Copyright © 2022 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Kabuki syndrome (KS) is a rare neuro-developmental disorder caused by variants in genes of histone modification, including KMT2D and KDM6A . This review assesses our current understanding of KS, which was originally named Niikawa-Kuroki syndrome, and aims to guide surveillance and medical care of affected individuals as well as identify gaps in knowledge and unmet patient needs. Ovid MEDLINE and EMBASE databases were searched from 1981 to 2021 to identify reports related to genotype and systems-based phenotype characterization of KS. A total of 2418 articles were retrieved, and 152 were included in this review, representing a total of 1369 individuals with KS. Genotype, phenotype, and the developmental and behavioral profile of KS are reviewed. There is a continuous clinical phenotype spectrum associated with KS with notable variability between affected individuals and an emerging genotype-phenotype correlation. The observed clinical variability may be attributable to differences in genotypes and/or unknown genetic and epigenetic factors. Clinical management is symptom oriented, fragmented, and lacks established clinical care standards. Additional research should focus on enhancing understanding of the burden of illness, the impact on quality of life, the adult phenotype, life expectancy and development of standard-of-care guidelines.

We compared growth, physical features, and minor anomalies in 131 first-grade children with fetal alcohol spectrum disorders (FASD) to those of a representative comparison group of typically developing children from the same populations (n = 1212). The data were collected from three regional sites in the NIAAA-funded Collaboration on FASD Prevalence (CoFASP). Dysmorphology examinations were performed by a team of expert clinical geneticists, and FASD diagnoses were assigned according to the Revised Institute of Medicine Guidelines, which include assessments of growth, dysmorphology, neurobehavior, and maternal risk interviews. We present detailed data on 32 physical traits, minor anomalies, and a summary dysmorphology score for children within each of the four diagnostic categories in the continuum of FASD. There were few differences in the frequency of FASD diagnoses by race or Hispanic ethnicity. Children with FASD were born to mothers who reported using alcohol, tobacco (28.3%), and other drugs (14.2%) during pregnancy. Controlling for tobacco and other drug use, risk analysis indicated that women with a drinking pattern of 3 drinks per drinking day prior to pregnancy were 10 times more likely (p < 0.001, OR = 9.92, 95% CI: 4.6-21.5) to bear a child with FASD than those who reported abstinence prior to pregnancy., (© 2022 Wiley Periodicals LLC.)

Objective: Findings from previous small studies have been reassuring regarding the safety of treatment with hydroxychloroquine (HCQ) during pregnancy. In one recent study, it was demonstrated that the frequency of major birth defects was increased in women who had received HCQ at a dose of ≥400 mg/day during pregnancy. This study was undertaken to examine pregnancy outcomes among women following the use of HCQ., Methods: The study cohort comprised pregnant women who were prospectively enrolled in the MotherToBaby/Organization of Teratology Information Specialists Autoimmune Diseases in Pregnancy Study and were receiving treatment with HCQ. For the control groups, disease-matched women without HCQ exposure and healthy women were randomly selected from the same source, with subject matching using a 1:1 ratio. Data were collected through interviews, medical records, and dysmorphology examinations. Pregnancy outcome measures included the presence or absence of major and minor birth defects, rates of spontaneous abortion, rates of preterm delivery, and infant growth measures., Results: Between 2004 and 2018, 837 pregnant women met the criteria for study inclusion, including 279 women exposed to HCQ during pregnancy and 279 women in each unexposed control group. Sixty pregnant women (7.2%) were lost to follow-up. Among the women with live births, major birth defects occurred as a pregnancy outcome in 20 (8.6%) of 232 women with HCQ exposure in the first trimester, compared to 19 (7.4%) of 256 disease-matched unexposed controls (odds ratio [OR] 1.18, 95% confidence interval [95% CI] 0.61-2.26) and 13 (5.4%) of 239 healthy controls (adjusted OR 0.76, 95% CI 0.28-2.05). Risks did not differ in women who were receiving an HCQ dose of ≥400 mg/day. No pattern of birth defects was identified. There were no differences in the rates of spontaneous abortion or preterm delivery between groups. Occurrence of infant growth deficiencies did not differ in the HCQ-exposed group compared to the disease-matched unexposed control group, except in the infant's head circumference at birth (adjusted OR 1.85, 95% CI 1.07-3.20)., Conclusion: In this study, there was no evidence of an increased risk of structural birth defects or other adverse outcomes among women receiving HCQ during pregnancy, with the exception of infant head circumference at birth. For pregnant women being treated with HCQ, these findings are reassuring., (© 2021 American College of Rheumatology.)

Objective: Utilize a random sample to estimate the prevalence, child traits, and maternal risk for fetal alcohol spectrum disorders (FASD) in a Southeastern United States county., Methods: From all first-grade students (n = 1073) a simple random sample was drawn, and 32 % (n = 231) were consented. All 231 children were examined for dysmorphology and growth, 84 were tested and rated on neurobehavior, and 72 mothers were interviewed for maternal risk., Results: Significant differences (α = .05) between the physical traits of children diagnosed with FASD and the entire sample were height, weight, head circumference, body mass index, and total dysmorphology scores, and all three cardinal features of fetal alcohol syndrome: palpebral fissure length, smooth philtrum, and narrow vermilion. Intellectual function and inhibition were not significantly different between FASD and typically-functioning children, but two executive function measures and one visual/spatial measure approached significance (α = .10). Three behavioral measures were significantly worse for the FASD group: parent-rated problems of communication, daily living, and socialization. Significant maternal risk factors reported were postpartum depression, frequency of drinking, and recovery from problem drinking. The prevalence of FASD was 71.4 per 1,000 or 7.1 %. This rate falls clearly within the prevalence range identified in eight larger samples of other communities in the Collaboration on FASD Prevalence (CoFASP) study in four regions of the United States., Conclusion: Careful and detailed clinical evaluation of children from small random samples can be useful for estimating the prevalence and traits of FASD in a community., (Copyright © 2021 Elsevier B.V. All rights reserved.)

In this review, we explore evidence that hypoxia in the developing human fetus can lead not only to the more commonly accepted disruptive-type defects, but also patterns of anomalies that suggest that hypoxia can exert a more classic teratogenic effect, using the brain as one example. We review neuropathology in the context of intrauterine hypoxia, particularly as it relates to carbon monoxide poisoning, in utero strokes, and homozygous alpha-thalassemia. In general, the associated brain injuries resemble those seen with other causes of hypoxic-ischemic injury. Fetal strokes during development usually lead to loss of brain tissue in areas that do not follow a typical embryologic pattern, and therefore are considered disruptions. However, there is also evidence that fetal brain ischemia can cause more classically recognized patterns of abnormal embryonic neuronal migration and organization such as polymicrogyria, cortical dysplasia, or dysgenesis, including select types of focal cortical dysplasia. This study summarizes available literature and evidence to raise clinicians' awareness regarding the association between hypoxia and congenital anomalies, including brain malformations., (© 2021 Wiley Periodicals LLC.)

Despite widespread clinical genetic testing, many individuals with suspected genetic conditions lack a precise diagnosis, limiting their opportunity to take advantage of state-of-the-art treatments. In some cases, testing reveals difficult-to-evaluate structural differences, candidate variants that do not fully explain the phenotype, single pathogenic variants in recessive disorders, or no variants in genes of interest. Thus, there is a need for better tools to identify a precise genetic diagnosis in individuals when conventional testing approaches have been exhausted. We performed targeted long-read sequencing (T-LRS) using adaptive sampling on the Oxford Nanopore platform on 40 individuals, 10 of whom lacked a complete molecular diagnosis. We computationally targeted up to 151 Mbp of sequence per individual and searched for pathogenic substitutions, structural variants, and methylation differences using a single data source. We detected all genomic aberrations-including single-nucleotide variants, copy number changes, repeat expansions, and methylation differences-identified by prior clinical testing. In 8/8 individuals with complex structural rearrangements, T-LRS enabled more precise resolution of the mutation, leading to changes in clinical management in one case. In ten individuals with suspected Mendelian conditions lacking a precise genetic diagnosis, T-LRS identified pathogenic or likely pathogenic variants in six and variants of uncertain significance in two others. T-LRS accurately identifies pathogenic structural variants, resolves complex rearrangements, and identifies Mendelian variants not detected by other technologies. T-LRS represents an efficient and cost-effective strategy to evaluate high-priority genes and regions or complex clinical testing results., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

The 41st Annual David W. Smith Workshop on Malformation and Morphogenesis was scheduled to take place in Skamania, Washington, on September 11-16, 2020. Due to the COVID-19 pandemic and the associated recommendations to avoid travel and congregation in large groups, this meeting took place differently from its original plan. Rather than bringing trainees, clinicians and researchers with an interest in congenital malformations and their underlying morphogenesis together for several days in a workshop with submitted presentations and research lectures, this meeting took place virtually. A 1 day online meeting was organized in order to allow trainees to present their work. This Conference Report includes the highest scoring abstracts submitted by trainees and presented at the 2020 virtual David W. Smith Workshop., (© 2021 Wiley Periodicals LLC.)

The delineation of disease entities is complex, yet recent advances in the molecular characterization of diseases provide opportunities to designate diseases in a biologically valid manner. Here, we have formalized an approach to the delineation of Mendelian genetic disorders that encompasses two distinct but inter-related concepts: (1) the gene that is mutated and (2) the phenotypic descriptor, preferably a recognizably distinct phenotype. We assert that only by a combinatorial or dyadic approach taking both of these attributes into account can a unitary, distinct genetic disorder be designated. We propose that all Mendelian disorders should be designated as "GENE-related phenotype descriptor" (e.g., "CFTR-related cystic fibrosis"). This approach to delineating and naming disorders reconciles the complexity of gene-to-phenotype relationships in a simple and clear manner yet communicates the complexity and nuance of these relationships., (Copyright © 2020 American Society of Human Genetics. All rights reserved.)

Objectives: To evaluate the clinical usefulness of rapid exome sequencing (rES) in critically ill children with likely genetic disease using a standardized process at a single institution. To provide evidence that rES with should become standard of care for this patient population., Study Design: We implemented a process to provide clinical-grade rES to eligible children at a single institution. Eligibility included (a) recommendation of rES by a consulting geneticist, (b) monogenic disorder suspected, (c) rapid diagnosis predicted to affect inpatient management, (d) pretest counseling provided by an appropriate provider, and (e) unanimous approval by a committee of 4 geneticists. Trio exome sequencing was sent to a reference laboratory that provided verbal report within 7-10 days. Clinical outcomes related to rES were prospectively collected. Input from geneticists, genetic counselors, pathologists, neonatologists, and critical care pediatricians was collected to identify changes in management related to rES., Results: There were 54 patients who were eligible for rES over a 34-month study period. Of these patients, 46 underwent rES, 24 of whom (52%) had at least 1 change in management related to rES. In 20 patients (43%), a molecular diagnosis was achieved, demonstrating that nondiagnostic exomes could change medical management in some cases. Overall, 84% of patients were under 1 month old at rES request and the mean turnaround time was 9 days., Conclusions: rES testing has a significant impact on the management of critically ill children with suspected monogenic disease and should be considered standard of care for tertiary institutions who can provide coordinated genetics expertise., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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. We recorded the type of twinning, any overlapping features of another RCEM, maternal characteristics, and the use of ART. Statistically significant associations included an excess of monozygotic twins and 80% discordance rate for the phenotype across all twins. There was an 18.5% rate of ART and no consistently reported maternal adverse events during pregnancy. We found 24 instances of co-occurrence of two RCEM, suggesting a shared pathogenesis across all RCEM phenotypes. We hypothesize the following timing for RCEM phenotypes from the earliest perturbation in development to the latest: LBWC, POC, OEIS, VACTERL, OAVS, then MURCS. The RCEM group of conditions should be considered a spectrum that could be studied as a group., (© 2020 Wiley Periodicals LLC.)

Fetal alcohol spectrum disorders (FASD) describe a range of physical, behavioral, and neurologic deficits in individuals exposed to alcohol prenatally. Reduced palpebral fissure length is one of the cardinal facial features of FASD. However, other ocular measurements have not been studied extensively in FASD. Using the Fetal Alcohol Syndrome Epidemiologic Research (FASER) database, we investigated how inner canthal distance (ICD), interpupillary distance (IPD), and outer canthal distance (OCD) centiles differed between FASD and non-FASD individuals. We compared ocular measurement centiles in children with FASD to non-FASD individuals and observed reductions in all three centiles for ICD, IPD, and OCD. However, when our non-FASD children who had various forms of growth deficiency (microcephaly, short-stature, or underweight) were compared to controls, we did not observe a similar reduction in ocular measurements. This suggests that reductions in ocular measurements are a direct effect of alcohol on ocular development independent of its effect on growth parameters, which is consistent with animal models showing a negative effect of alcohol on developing neural crest cells. Interpupillary distance centile appeared to be the most significantly reduced ocular measure we evaluated, suggesting it may be a useful measure to be considered in the diagnosis of FASD., (© 2020 Wiley Periodicals LLC.)

Purpose: We aim to report outcomes and safety with hormonal suppression to facilitate gonadal preservation in a select group of patients with 46,XY differences in sex development (DSD) who are raised and identify as female yet have diagnoses with potential for androgenization at puberty., Methods: We performed a retrospective review of the past 10 years of DSD patients treated by a multidisciplinary program. Inclusion criteria were 46,XY DSD, female sex of rearing, risk of androgenization at puberty, and plan for hormonal suppression at puberty. Patients on hormonal suppression had at least 6 months of follow-up from initiation. We excluded those with complete gonadal dysgenesis or complete androgen insensitivity., Results: Four patients met inclusion criteria. Initial evaluation by DSD team was at a mean age of 6.6 years (3 weeks-16 years). All patients were evaluated in a coordinated multidisciplinary clinic. The diagnoses are listed in Table 1. Mean follow-up was 5.7 years (1.2-10.9 years). One patient presented as an infant, and is being monitored until Tanner stage 2 and/or serum hormonal evidence to initiate hormonal suppression. Three patients have been receiving hormonal suppression for 1.4 years (1.1-1.9 years) without side effects or complication. Three patients were initiated with estrogen replacement to promote desired breast development. At last follow-up, all patients had retained their gonads, all have female gender identity with no reported gender dysphoria, and no progression of androgenization., Conclusions: In our initial experience, gonadal preservation with hormonal suppression is a tool in multidisciplinary management of select DSD patients with female gender identity with conditions associated with androgenization at puberty. Patients' growth, bone health, and overall psychosocial well-being will need to be monitored closely.

More than 50 individuals with activating variants in the receptor tyrosine kinase PDGFRB have been reported, separated based on clinical features into solitary myofibromas, infantile myofibromatosis, Penttinen syndrome with premature aging and osteopenia, Kosaki overgrowth syndrome, and fusiform aneurysms. Despite their descriptions as distinct clinical entities, review of previous reports demonstrates substantial phenotypic overlap. We present a case series of 12 patients with activating variants in PDGFRB and review of the literature. We describe five patients with PDGFRB activating variants whose clinical features overlap multiple diagnostic entities. Seven additional patients from a large family had variable expressivity and late-onset disease, including adult onset features and two individuals with sudden death. Three patients were treated with imatinib and had robust and rapid response, including the first two reported infants with multicentric myofibromas treated with imatinib monotherapy and one with a recurrent p.Val665Ala (Penttinen) variant. Along with previously reported individuals, our cohort suggests infants and young children had few abnormal features, while older individuals had multiple additional features, several of which appeared to worsen with advancing age. Our analysis supports a diagnostic entity of a spectrum disorders due to activating variants in PDGFRB. Differences in reported phenotypes can be dramatic and correlate with advancing age, genotype, and to mosaicism in some individuals., (© 2020 Wiley Periodicals, LLC.)

Background: Mowat-Wilson syndrome (MWS; OMIM #235730) is a genetic condition caused by heterozygous mutations or deletions of the ZEB2 gene. It is characterized by moderate-severe intellectual disability, epilepsy, Hirschsprung disease and multiple organ malformations of which congenital heart defects and urogenital anomalies are the most frequent ones. To date, a clear description of the physical development of MWS patients does not exist. The aim of this study is to provide up-to-date growth charts specific for infants and children with MWS. Charts for males and females aged from 0 to 16 years were generated using a total of 2865 measurements from 99 MWS patients of different ancestries. All data were collected through extensive collaborations with the Italian MWS association (AIMW) and the MWS Foundation. The GAMLSS package for the R statistical computing software was used to model the growth charts. Height, weight, body mass index (BMI) and head circumference were compared to those from standard international growth charts for healthy children., Results: In newborns, weight and length were distributed as in the general population, while head circumference was slightly smaller, with an average below the 30th centile. Up to the age of 7 years, weight and height distribution was shifted to slightly lower values than in the general population; after that, the difference increased further, with 50% of the affected children below the 5th centile of the general population. BMI distribution was similar to that of non-affected children until the age of 7 years, at which point values in MWS children increased with a less steep slope, particularly in males. Microcephaly was sometimes present at birth, but in most cases it developed gradually during infancy; many children had a small head circumference, between the 3rd and the 10th centile, rather than being truly microcephalic (at least 2 SD below the mean). Most patients were of slender build., Conclusions: These charts contribute to the understanding of the natural history of MWS and should assist pediatricians and other caregivers in providing optimal care to MWS individuals who show problems related to physical growth. This is the first study on growth in patients with MWS.

Objective: To detail the characteristic traits of children with fetal alcohol spectrum disorders (FASDs) and maternal risk factors in a southeastern U.S. County., Methods: Independent samples were drawn from 2 different cohorts of first-grade students. All consented children (49.8%) were measured for height, weight, and head circumference, and those ≤ 25th centile entered the study along with a random sample drawn from all enrolled students. Study children were examined for physical growth, dysmorphology, and neurobehavior, and their mothers were interviewed., Results: Total dysmorphology scores discriminated well the physical traits of children across the FASD continuum: fetal alcohol syndrome (FAS) = 15.8, partial FAS (PFAS) = 10.8, alcohol-related neurobehavioral disorder (ARND) = 5.2, and typically developing controls = 4.4. Additionally, a neurobehavioral battery distinguished children with each FASD diagnosis from controls. Behavioral problems qualified more children for FASD diagnoses than cognitive traits. Significant proximal maternal risk variables were as follows: reports of prepregnancy drinking, drinking in any trimester, and comorbid use of other drugs in lifetime and during pregnancy, especially alcohol and marijuana (14.9% among mothers of children with FASD vs. 0.4% for controls). Distal maternal risks included reports of other health problems (e.g., depression), living unmarried with a partner during pregnancy, and a lower level of spirituality. Controlling for other drug use during pregnancy, having a child diagnosed with a FASD was 17.5 times greater for women who reported usual consumption of 3 drinks per drinking day prior to pregnancy than for nondrinking mothers (p < 0.001, 95% CI = 5.1 to 59.9). There was no significant difference in the prevalence of FASD by race, Hispanic ethnicity, or socioeconomic status. The prevalence of FASD was not lower than 17.3 per 1,000, and weighted estimated prevalence was 49.0 per 1,000 or 4.9%., Conclusion: This site had the second lowest rate in the CoFASP study, yet children with FASD are prevalent., (© 2020 by the Research Society on Alcoholism.)

Objective: To determine the characteristics of children with fetal alcohol spectrum disorders (FASD) and their mothers in a Midwestern city., Methods: Case-control samples were drawn from 2 separate first-grade cohorts (combined N = 4,047) in every city school using different methods. In Cohort Sample 1, all consented small children (≤25th centile on height, weight, and/or head circumference) entered the study along with a random sample from all enrolled students. Cohort Sample 2 was drawn totally at random. Child growth, dysmorphology, and neurobehavior were assessed using the Collaboration on FASD Prevalence (CoFASP) criteria, and mothers were interviewed., Results: For the samples combined, 891 children received dysmorphology examinations, and 692 were case-conferenced for final diagnosis. Forty-four children met criteria for FASD. Total dysmorphology scores differentiated diagnostic groups: fetal alcohol syndrome (FAS), 16.7; partial FAS, 11.8; alcohol-related neurodevelopmental disorder (ARND), 6.1; and typically developing controls, 4.2. Neurobehavioral tests distinguished children with FASD from controls, more for behavioral problems than cognitive delay. Children with ARND demonstrated the poorest neurobehavioral indicators. An adjusted regression model of usual prepregnancy drinking indicated that maternal reports of 3 drinks per drinking day (DDD) were significantly associated with a FASD diagnosis (p = 0.020, OR = 10.1, 95% CI = 1.44 to 70.54), as were 5 or more DDD (p < 0.001, OR = 26.47, 95% CI = 4.65 to 150.62). Other significant maternal risk factors included the following: self-reported drinking in any trimester; smoking and cocaine use during pregnancy; later pregnancy recognition and later and less prenatal care; lower maternal weight, body mass index (BMI), and head circumference; and unmarried status. There was no significant difference in FASD prevalence by race, Hispanic ethnicity, or socioeconomic status at this site, where the prevalence of FASD was 14.4 to 41.2 per 1,000 (1.4 to 4.1%)., Conclusion: This city displayed the lowest prevalence of FASD of the 4 CoFASP sites. Nevertheless, FASD were common, and affected children demonstrated a common, recognizable, and measurable array of traits., (© 2020 by the Research Society on Alcoholism.)

The Mirena intrauterine device (IUD) is a hormone-secreting contraceptive device. Pregnancy with the Mirena is rare and effects to the fetus are unknown. Here we present four females with genital virilization after pregnancy with persistent Mirena IUD. All patients had a 46, XX karyotype and normal hormone evaluation. All underwent exam under anesthesia, demonstrating posterior labial fusion and short urogenital sinus with normal bladder, urethra, vagina, and cervix. Three of four patients underwent flap vaginoplasty without complications and good cosmetic outcomes. This series suggests that persistent levonorgestrel-secreting IUD during pregnancy is associated with genital virilization in female fetuses., (Copyright © 2020 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Objective: To document prevalence and traits of children with fetal alcohol spectrum disorders (FASD) and maternal risk factors in a Rocky Mountain city., Methods: Variations on active case ascertainment methods were used in 2 first-grade cohorts in all city schools. The consent rate was 59.2%. Children were assessed for physical growth, dysmorphology, and neurobehavior and their mothers interviewed., Results: Thirty-eight children were diagnosed with FASD and compared with 278 typically developing controls. Total dysmorphology scores summarized well the key physical indicators of FASD and defined specific diagnostic groups. On average, children with FASD performed significantly poorer than controls on intellectual, adaptive, learning, attention, and behavioral tasks. More mothers of children with FASD reported drinking prior to pregnancy and in the first and second trimesters, and had partners with drinking problems than mothers of controls; however, reports of comorbid alcohol use and 6 other drugs were similar for mothers of children with FASD and mothers of controls. Mothers of children with FASD were significantly younger at pregnancy, had lower average weight before pregnancy and less education, initiated prenatal clinic visits later, and reported more health problems (e.g., stomach ulcers and accidents). Children with FASD had significantly lower birth weight and more problems at birth, and were less likely to be living with biological mother and father. Controlling for other drug and tobacco use, a FASD diagnosis is 6.7 times (OR = 6.720, 95% CI = 1.6 to 28.0) more likely among children of women reporting prepregnancy drinking of 3 drinks per drinking day (DDD) and 7.6 times (OR = 7.590, 95% CI = 2.0 to 31.5) more likely at 5 DDD. Prevalence of FAS was 2.9-5.8 per 1,000 children, and total FASD was 34.9 to 82.5 per 1,000 children or 3.5 to 8.3% at this site., Conclusion: This site had the second highest prevalence of FASD of the 4 Collaboration on FASD Prevalence sites and clearly identifiable child and maternal risk traits., (© 2020 by the Research Society on Alcoholism.)

Background and Objectives: Fetal alcohol spectrum disorders (FASD) comprise the continuum of disabilities associated with prenatal alcohol exposure. Although infancy remains the most effective time for initiation of intervention services, current diagnostic schemes demonstrate the greatest confidence, accuracy, and reliability in school-aged children. Our aims for the current study were to identify growth, dysmorphology, and neurodevelopmental features in infants that were most predictive of FASD at age 5, thereby improving the timeliness of diagnoses., Methods: A cohort of pregnant South African women attending primary health care clinics or giving birth in provincial hospitals was enrolled in the project. Children were followed longitudinally from birth to 60 months to determine their physical and developmental trajectories ( N = 155). Standardized protocols were used to assess growth, dysmorphology, and development at 6 weeks and at 9, 18, 42, and 60 months. A structured maternal interview, including estimation of prenatal alcohol intake, was administered at 42 or 60 months., Results: Growth restriction and total dysmorphology scores differentiated among children with and without FASD as early as 9 months (area under the receiver operating characteristic curve = 0.777; P < .001; 95% confidence interval: 0.705-0.849), although children who were severely affected could be identified earlier. Assessment of developmental milestones revealed significant developmental differences emerging among children with and without FASD between 18 and 42 months. Mothers of children with FASD were significantly smaller, with lower BMIs and higher alcohol intake during pregnancy, than mothers of children without FASD., Conclusions: Assessment of a combination of growth, dysmorphology, and neurobehavioral characteristics allows for accurate identification of most children with FASD as early as 9 to 18 months., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2019 by the American Academy of Pediatrics.)

Background: There are limited data on the characteristics of children with fetal alcohol spectrum disorders (FASD) and their mothers from the general population in the United States., Methods: During the 2012 and 2013 academic years, first-grade children in a large urban Pacific Southwest city were invited to participate in a study to estimate the prevalence of FASD. Children who screened positive on weight, height, or head circumference ≤25th centile or on parental report of developmental concerns were selected for evaluation, along with a random sample of those who screened negative. These children were examined for dysmorphology and neurobehavior and their mothers or collateral sources were interviewed. Children were classified as fetal alcohol syndrome (FAS), partial fetal alcohol syndrome (pFAS), alcohol-related neurodevelopmental disorder (ARND), or No FASD., Results: A total of 854 children were evaluated; 5 FAS, 44 pFAS, 44 ARND, and 761 No FASD. Children with FAS or pFAS were more likely to have dysmorphic features, and 32/49 (65.3%) of those met criteria for neurobehavioral impairment on cognitive measures with or without behavioral deficits. In contrast, 28/44 (63.6%) of children with ARND met criteria on behavioral measures alone. Mothers of FASD children were more likely to recognize pregnancy later, be unmarried, and report other substance use or psychiatric disorders, but did not differ on age, socioeconomic status, education, or parity. Mothers of FASD children reported more drinks/drinking day each trimester. The risk of FASD was elevated with increasing number of drinks/drinking day prior to pregnancy recognition, even at the level of 1 drink per day (adjusted odds ratio 3.802, 95% confidence interval 1.634, 8.374)., Conclusions: Data from this general population sample in a large urban region in the United States demonstrate the variability of expression of FASD and point to risk and protective factors for mothers in this setting., (© 2019 by the Research Society on Alcoholism.)

Background: Information is needed on the safety of adalimumab when used in pregnancy for the treatment of certain autoimmune diseases., Methods and Findings: Between 2004 and 2016, the Organization of Teratology Information Specialists Research Center at the University of California San Diego conducted a prospective controlled observational cohort study in 602 pregnant women who had or had not taken adalimumab. Women in the adalimumab-exposed cohort had received at least one dose of the drug in the first trimester for the treatment of rheumatoid arthritis or Crohn's Disease (N = 257). Women in the disease comparison cohort had not used adalimumab in pregnancy (N = 120). Women in the healthy comparison cohort had no rheumatic or inflammatory bowel diseases (N = 225). Women and their infants were followed to one year postpartum with maternal interviews, medical records abstraction, and physical examinations. Study outcomes were major structural birth defects, minor defects, spontaneous abortion, preterm delivery, pre and post-natal growth deficiency, serious or opportunistic infections and malignancies. 42/602 (7.0%) of pregnancies were lost-to-follow-up. 22/221 (10.0%) in the adalimumab-exposed cohort had a live born infant with a major birth defect compared to 8/106 (7.5%) in the diseased unexposed cohort (adjusted odds ratio 1.10, 95% confidence interval [CI] 0.45 to 2.73). Women in the adalimumab-exposed cohort were more likely to deliver preterm compared to the healthy cohort (adjusted hazard ratio [aHR] 2.59, 95% CI 1.22 to 5.50), but not compared to the diseased unexposed cohort (aHR 0.82, 95% CI 0.66 to 7.20). No significant increased risks were noted with adalimumab exposure for any other study outcomes., Conclusions: Adalimumab exposure in pregnancy compared to diseased unexposed pregnancies was not associated with an increased risk for any of the adverse outcomes examined. Women with rheumatoid arthritis or Crohn's Disease were at increased risk of preterm delivery, irrespective of adalimumab exposure., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: Drs. Chambers, Jones and Xu received research funding from AbbVie, Amgen, Astra Zeneca, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Pfizer, Regeneron, Roche Genentech, Sanofi Genzyme, Seqirus, Takeda, Teva, and UCB during the conduct of the study.

Introduction and Background: Although the pediatric urologic community has embraced a multidisciplinary genetic and endocrine evaluation for newborns with ambiguous genitalia, this approach has been reserved for the most severe cases of undervirilized 46,XY individuals despite growing evidence that genetic differences are found even in patients whose only genitourinary anomaly appears to be proximal hypospadias. Identifying these genetic differences is vital for counseling patients as they move through puberty to parenthood as well as parents on future pregnancies., Objective: The primary objective was to evaluate genetic diagnosis in patients with proximal hypospadias. The authors hypothesized the more sensitive genetic evaluation available in the modern era will reveal a high rate of patients with proximal hypospadias and descended testicles who are found to have a genetic difference, supporting a thorough genetic evaluation in these patients., Study Design: A retrospective review was performed of all patients who underwent surgical correction for proximal hypospadias at a single institution from January 1, 2010, to December 31, 2016. Those with midshaft hypospadias were excluded as were patients whose primary surgery was performed at an outside institution. Patient characteristics, including demographics, clinical presentation, genetic evaluation, and referral to a multidisciplinary difference of sex development (DSD) clinic, were collected. The chi-squared test and t-test were used for analysis., Results: There were 112 patients with proximal hypospadias who met the inclusion criteria. Of these, 91 had bilaterally descended testicles, whereas 21 had one or more undescended testicles. Thirty-three percent of patients with isolated proximal hypospadias received genetic testing of some kind, with 24% seen in the multidisciplinary DSD clinic. Four patients had an associated genetic syndrome identified, and 5 had a genetic difference of unknown clinical significance. Overall, 10% of patients with proximal hypospadias and descended testicles had an identifiable genetic difference vs 33% with associated cryptorchidism. Of these, one patient with proximal hypospadias and descended testicles had a genetic difference of known clinical significance that was likely to have been missed in the absence of an evaluation by a geneticist., Discussion and Conclusion: There was a high rate of identifiable genetic differences in patients whose only genitourinary abnormality was proximal hypospadias, especially with the 1% risk of a likely missed diagnosis. These findings support the discussion of a genetic evaluation for all patients with proximal hypospadias, regardless of the testicular location., (Copyright © 2019 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

1p36 deletion syndrome is a well-described condition with a recognizable phenotype, including cognitive impairment, seizures, and structural brain anomalies such as periventricular leukomalacia (PVL). In a large series of these individuals by Battaglia et al., "birth history was notable in 50% of the cases for varying degrees of perinatal distress." Given the potential for perinatal distress, seizures and PVL, we questioned if this disorder has clinical overlap with hypoxic ischemic encephalopathy (HIE). We reviewed the medical records of 69 individuals with 1p36 deletion to clarify the perinatal phenotype of this disorder and determine if there is evidence of perinatal distress and/or hypoxic injury. Our data provides evidence that these babies have signs of perinatal distress. The majority (59% term; 75% preterm) needed resuscitation and approximately 18% had cardiac arrest. Most had abnormal brain imaging (84% term; 73% preterm) with abnormal white matter findings in over half of patients. PVL or suggestion of "hypoxic insult" was present in 18% of term and 45% of preterm patients. In conclusion, individuals with 1p36 deletion have evidence of perinatal distress, white matter changes, and seizures, which can mimic HIE but are likely related to their underlying chromosome disorder., (© 2019 Wiley Periodicals, Inc.)

Purpose: Defects in the cohesin pathway are associated with cohesinopathies, notably Cornelia de Lange syndrome (CdLS). We aimed to delineate pathogenic variants in known and candidate cohesinopathy genes from a clinical exome perspective., Methods: We retrospectively studied patients referred for clinical exome sequencing (CES, N = 10,698). Patients with causative variants in novel or recently described cohesinopathy genes were enrolled for phenotypic characterization., Results: Pathogenic or likely pathogenic single-nucleotide and insertion/deletion variants (SNVs/indels) were identified in established disease genes including NIPBL (N = 5), SMC1A (N = 14), SMC3 (N = 4), RAD21 (N = 2), and HDAC8 (N = 8). The phenotypes in this genetically defined cohort skew towards the mild end of CdLS spectrum as compared with phenotype-driven cohorts. Candidate or recently reported cohesinopathy genes were supported by de novo SNVs/indels in STAG1 (N = 3), STAG2 (N = 5), PDS5A (N = 1), and WAPL (N = 1), and one inherited SNV in PDS5A. We also identified copy-number deletions affecting STAG1 (two de novo, one of unknown inheritance) and STAG2 (one of unknown inheritance). Patients with STAG1 and STAG2 variants presented with overlapping features yet without characteristic facial features of CdLS., Conclusion: CES effectively identified disease-causing alleles at the mild end of the cohensinopathy spectrum and enabled characterization of candidate disease genes.

Background: Kabuki syndrome (KS) is a clinically recognisable syndrome in which 70% of patients have a pathogenic variant in KMT2D or KDM6A . Understanding the function of these genes opens the door to targeted therapies. The purpose of this report is to propose diagnostic criteria for KS, particularly when molecular genetic testing is equivocal., Methods: An international group of experts created consensus diagnostic criteria for KS. Systematic PubMed searches returned 70 peer-reviewed publications in which at least one individual with molecularly confirmed KS was reported. The clinical features of individuals with known mutations were reviewed., Results: The authors propose that a definitive diagnosis can be made in an individual of any age with a history of infantile hypotonia, developmental delay and/or intellectual disability, and one or both of the following major criteria: (1) a pathogenic or likely pathogenic variant in KMT2D or KDM6A ; and (2) typical dysmorphic features (defined below) at some point of life. Typical dysmorphic features include long palpebral fissures with eversion of the lateral third of the lower eyelid and two or more of the following: (1) arched and broad eyebrows with the lateral third displaying notching or sparseness; (2) short columella with depressed nasal tip; (3) large, prominent or cupped ears; and (4) persistent fingertip pads. Further criteria for a probable and possible diagnosis, including a table of suggestive clinical features, are presented., Conclusion: As targeted therapies for KS are being developed, it is important to be able to make the correct diagnosis, either with or without molecular genetic confirmation., Competing Interests: Competing interests: The clinical and molecular genetic experts on Kabuki syndrome who collaborated on this manuscript were all participants of the Kabuki Syndrome Medical Advisory Board organised and sponsored by Takeda in January 2018. Although the meeting was facilitated and organised by Takeda, Takeda did not have any influence on the content of this report., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Baratela-Scott syndrome (BSS) is a rare, autosomal-recessive disorder characterized by short stature, facial dysmorphisms, developmental delay, and skeletal dysplasia caused by pathogenic variants in XYLT1. We report clinical and molecular investigation of 10 families (12 individuals) with BSS. Standard sequencing methods identified biallelic pathogenic variants in XYLT1 in only two families. Of the remaining cohort, two probands had no variants and six probands had only a single variant, including four with a heterozygous 3.1 Mb 16p13 deletion encompassing XYLT1 and two with a heterozygous truncating variant. Bisulfite sequencing revealed aberrant hypermethylation in exon 1 of XYLT1, always in trans with the sequence variant or deletion when present; both alleles were methylated in those with no identified variant. Expression of the methylated XYLT1 allele was severely reduced in fibroblasts from two probands. Southern blot studies combined with repeat expansion analysis of genome sequence data showed that the hypermethylation is associated with expansion of a GGC repeat in the XYLT1 promoter region that is not present in the reference genome, confirming that BSS is a trinucleotide repeat expansion disorder. The hypermethylated allele accounts for 50% of disease alleles in our cohort and is not present in 130 control subjects. Our study highlights the importance of investigating non-sequence-based alterations, including epigenetic changes, to identify the missing heritability in genetic disorders., (Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Objective: Non-invasive prenatal screening (NIPS) utilizes circulating cell-free DNA (cfDNA) to screen for fetal genetic abnormalities. NIPS is the first widely-available prenatal screen to assess genotypic sex. Most pediatricians have limited familiarity with NIPS technology and potential etiologies of discordant results. Increased familiarity may provide diagnostic insight and improve clinical care., Study Design: We reviewed all patients with discordant genotypic fetal sex assessed by cfDNA and neonatal phenotypic sex referred to our medical center., Result: Four infants with discordant cfDNA result and phenotypic sex were identified. Etiologies include vanishing twin syndrome, difference of sexual development, sex chromosome aneuploidy and maternal chimerism., Conclusions: We present four cases illustrating potential etiologies of discordant cfDNA result and postnatal phenotypic sex. Unanticipated cfDNA results offer the perinatologist a unique opportunity for early diagnosis and targeted treatment of various conditions, many of which may not have otherwise been detected in the perinatal period.

Purpose: Mowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS., Methods: In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations., Results: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations., Conclusion: Knowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.

Importance: Fetal alcohol spectrum disorders are costly, life-long disabilities. Older data suggested the prevalence of the disorder in the United States was 10 per 1000 children; however, there are few current estimates based on larger, diverse US population samples., Objective: To estimate the prevalence of fetal alcohol spectrum disorders, including fetal alcohol syndrome, partial fetal alcohol syndrome, and alcohol-related neurodevelopmental disorder, in 4 regions of the United States., Design, Setting, and Participants: Active case ascertainment methods using a cross-sectional design were used to assess children for fetal alcohol spectrum disorders between 2010 and 2016. Children were systematically assessed in the 4 domains that contribute to the fetal alcohol spectrum disorder continuum: dysmorphic features, physical growth, neurobehavioral development, and prenatal alcohol exposure. The settings were 4 communities in the Rocky Mountain, Midwestern, Southeastern, and Pacific Southwestern regions of the United States. First-grade children and their parents or guardians were enrolled., Exposures: Alcohol consumption during pregnancy., Main Outcomes and Measures: Prevalence of fetal alcohol spectrum disorders in the 4 communities was the main outcome. Conservative estimates for the prevalence of the disorder and 95% CIs were calculated using the eligible first-grade population as the denominator. Weighted prevalences and 95% CIs were also estimated, accounting for the sampling schemes and using data restricted to children who received a full evaluation., Results: A total of 6639 children were selected for participation from a population of 13 146 first-graders (boys, 51.9%; mean age, 6.7 years [SD, 0.41] and white maternal race, 79.3%). A total of 222 cases of fetal alcohol spectrum disorders were identified. The conservative prevalence estimates for fetal alcohol spectrum disorders ranged from 11.3 (95% CI, 7.8-15.8) to 50.0 (95% CI, 39.9-61.7) per 1000 children. The weighted prevalence estimates for fetal alcohol spectrum disorders ranged from 31.1 (95% CI, 16.1-54.0) to 98.5 (95% CI, 57.5-139.5) per 1000 children., Conclusions and Relevance: Estimated prevalence of fetal alcohol spectrum disorders among first-graders in 4 US communities ranged from 1.1% to 5.0% using a conservative approach. These findings may represent more accurate US prevalence estimates than previous studies but may not be generalizable to all communities.

Although perfectly transparent specimens are imaged faster with light-sheet microscopy, less transparent samples are often imaged with two-photon microscopy leveraging its robustness to scattering; however, at the price of increased acquisition times. Clearing methods that are capable of rendering strongly scattering samples such as brain tissue perfectly transparent specimens are often complex, costly, and time intensive, even though for many applications a slightly lower level of tissue transparency is sufficient and easily achieved with simpler and faster methods. Here, we present a microscope type that has been geared toward the imaging of semicleared tissue by combining multispot two-photon excitation with rolling shutter wide-field detection to image deep and fast inside semicleared mouse brain. We present a theoretical and experimental evaluation of the point spread function and contrast as a function of shutter size. Finally, we demonstrate microscope performance in fixed brain slices by imaging dendritic spines up to 400-μm deep., ((2018) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE).)

Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome (OMIM# 601338) is a rare autosomal dominant disorder characterized by episodic, fever-induced ataxic encephalopathy in childhood with residual symptoms. All identified patients have the same heterozygous missense variant c.2452G>A (p.Glu818Lys) in the ATP1A3 gene, encoding Na + /K + ATPase α3. We describe a large CAPOS pedigree with three generations of affected members, the first ascertained in the United States. Deafness, optic atrophy, and pes cavus were present in all three members of the family evaluated. In addition, one of the affected individuals experienced markedly worsening features during her three pregnancies and in the immediate postpartum period, a potential element of the natural history of CAPOS previously unreported. We conclude that the triggering factors and clinical spectrum of pathogenic ATP1A3 variants may be broader than previously described. Targeted sequencing of ATP1A3 should be considered in any patient presenting with cerebellar ataxia triggered by febrile illness, or pregnancy and delivery, especially in the presence of sensorineural hearing loss, optic atrophy, pes cavus, or early childhood history of acute encephalopathic ataxia. Prophylactic administration of acetazolamide or flunarizine may prevent acute episodes of ataxia or mitigate neurologic symptoms, although their efficacies have not been well studied., (© 2017 Wiley Periodicals, Inc.)

Purpose: Mowat-Wilson syndrome (MWS) is a genetic disease characterized by distinctive facial features, moderate to severe intellectual disability, and congenital malformations, including Hirschsprung disease, genital and eye anomalies, and congenital heart defects, caused by haploinsufficiency of the ZEB2 gene. To date, no characteristic pattern of brain dysmorphology in MWS has been defined., Methods: Through brain magnetic resonance imaging (MRI) analysis, we delineated a neuroimaging phenotype in 54 MWS patients with a proven ZEB2 defect, compared it with the features identified in a thorough review of published cases, and evaluated genotype-phenotype correlations., Results: Ninety-six percent of patients had abnormal MRI results. The most common features were anomalies of corpus callosum (79.6% of cases), hippocampal abnormalities (77.8%), enlargement of cerebral ventricles (68.5%), and white matter abnormalities (reduction of thickness 40.7%, localized signal alterations 22.2%). Other consistent findings were large basal ganglia, cortical, and cerebellar malformations. Most features were underrepresented in the literature. We also found ZEB2 variations leading to synthesis of a defective protein to be favorable for psychomotor development and some epilepsy features but also associated with corpus callosum agenesis., Conclusion: This study delineated the spectrum of brain anomalies in MWS and provided new insights into the role of ZEB2 in neurodevelopment.Genet Med advance online publication 10 November 2016.