Prenatal diagnosis of Hartsfield syndrome with a novel genetic variant.

A G2P0, 24-year-old woman presented at 17 weeks 3 days gestation for a fetal anatomy scan. Ultrasound identified bilateral upper and lower extremity ectrodactyly, semilobar holoprosencephaly, midface hypoplasia, and cleft lip and palate. Amniocentesis for a chromosome microarray demonstrated no significant copy number changes. Whole exome sequencing was subsequently completed, which revealed a de novo, likely pathogenic variant in FGFR1, c.2044G>A (D682N), consistent with FGFR1-related Hartsfield syndrome. This case highlights the first presumed molecularly confirmed prenatal diagnosis of Hartsfield syndrome and identifies a new pathogenic variant.

The broader phenotypic spectrum of congenital caudal abnormalities associated with mutations in the caudal type homeobox 2 gene.

The caudal type homeobox 2 (CDX2) gene encodes a developmental regulator involved in caudal body patterning. Only three pathogenic variants in human CDX2 have been described, in patients with persistent cloaca, sirenomelia and/or renal and anogenital malformations. We identified five patients with de novo or inherited pathogenic variants in CDX2 with clinical phenotypes that partially overlap with previous cases, that is, imperforate anus and renal, urogenital and limb abnormalities. However, additional clinical features were seen including vertebral agenesis and we describe considerable phenotypic variability, even in unrelated patients with the same recurrent p.(Arg237His) variant. We propose CDX2 variants as rare genetic cause for a multiple congenital anomaly syndrome that can include features of caudal regression syndrome and VACTERL. A causative role is further substantiated by the relationship between CDX2 and other proteins encoded by genes that were previously linked to caudal abnormalities in humans, for example, TBXT (sacral agenesis and other vertebral segmentation defects) and CDX1 (anorectal malformations). Our findings confirm the essential role of CDX2 in caudal morphogenesis and formation of cloacal derivatives in humans, which to date has only been well characterized in animals.

EEG endophenotypes in autism spectrum disorder.

OBJECTIVES: The association between autism spectrum disorder (ASD) and epilepsy is well-known. Abnormalities on electroencephalography (EEG) results have been reported in patients with ASD without a history of seizures. However, little is known about the relationship between abnormalities on EEG results and the core features of ASD. The purpose of the study was to determine the relationship between the presence of epilepsy and/or abnormalities on EEG results and disease-associated impairments in young children with ASD. METHODS: Data were collected from medical records at Cincinnati Children's Hospital Medical Center (CCHMC) of patients with well-characterized ASD. Patients were subdivided into three groups: ASD without epilepsy but with abnormal EEG results, ASD without epilepsy and normal EEG results, and ASD with epilepsy. Developmental (Mullen Scales of Early Learning (MSEL)), adaptive (Vineland Adaptive Behavior Scales (VABS)), behavioral (Child Behavior Checklist), and language (Preschool Language Scales (PLS)) assessments, along with birth and developmental histories, medications, and medical comorbidities were collected. Electroencephalography data were abstracted from reports and included presence, characterization, and location of abnormalities. RESULTS: Analysis was performed on 443 patients with ASD. Seventy patients (15.8%) had epilepsy at the time of ASD diagnosis. Out of 372 patients with ASD and no epilepsy, 95 (25.5%) had an abnormal EEG result (67.4% epileptiform, 36.8% other abnormalities). Majority of epileptiform discharges were focal (83%) and most commonly seen in the left temporal region. The group with abnormal EEG results exhibited more impaired adaptive functioning when compared with the group with normal EEG results (p < 0.05). The group with abnormal EEG results was more similar to the group with epilepsy, differing only in expressive language (p < 0.01) and fine motor (p < 0.05) skills on the Mullen Scales. The group with epilepsy exhibited lower scores in all areas of developmental and adaptive functioning compared with the group with normal EEG results (p < 0.05). At the time of analysis, 13 patients (8 in the group with abnormal EEG results, 5 in the group with normal EEG results) developed epilepsy at a mean age of 10.5 years ±â€¯3.3 years. CONCLUSIONS: The presence of an abnormal EEG result or epilepsy in the setting of ASD suggests worse developmental and adaptive functioning. Further analysis will help to clarify associations and offer insight into treatment for this subpopulation without epilepsy but with abnormal EEG results.

Crystal structure of a hypothetical protein from Giardia lamblia. Corrigendum.

The name of one of the authors in Beard et al. [(2022), Acta Cryst. F78, 59-65] is corrected.

Crystal structure of a hypothetical protein from Giardia lamblia.

Giardiasis is the most prevalent diarrheal disease globally and affects humans and animals. It is a significant problem in developing countries, the number one cause of travelers' diarrhea and affects children and immunocompromised individuals, especially HIV-infected individuals. Giardiasis is treated with antibiotics (tinidazole and metronidazole) that are also used for other infections such as trichomoniasis. The ongoing search for new therapeutics for giardiasis includes characterizing the structure and function of proteins from the causative protozoan Giardia lamblia. These proteins include hypothetical proteins that share 30% sequence identity or less with proteins of known structure. Here, the atomic resolution structure of a 15.6 kDa protein was determined by molecular replacement. The structure has the two-layer αß-sandwich topology observed in the prototypical endoribonucleases L-PSPs (liver perchloric acid-soluble proteins) with conserved allosteric active sites containing small molecules from the crystallization solution. This article is an educational collaboration between Hampton University and the Seattle Structural Genomics Center for Infectious Disease.

Peptidomic profiling of human milk with LC-MS/MS reveals pH-specific proteolysis of milk proteins.

Human milk is a dynamic protein-protease system that delivers bioactive peptides to infants. The pH of milk changes from the mother's mammary gland to the infant's digestive tract. Although the release of human milk peptides has been studied during in vivo or in vitro digestion, these models did not explicitly vary nor observe the effect of pH. The objective of this research was to determine the effect of pH on the proteolysis of human milk. Using high-resolution accurate-mass Orbitrap mass spectrometry, profiles of endogenous human milk peptides before and after incubation at various pH levels have been mapped. Over 5000 peptides were identified. Comparative analyses classified 74 peptides that were consistently found independent of pH alterations, and 8 peptides that were released only at pH 4 or 5 (typical infant gastric pH). Results documented that the proteolysis of milk proteins, particularly ß-casein, polymeric immunoglobulin receptor, and α-lactalbumin, is pH-dependent.

Improving Access to Diagnostic Assessments for Autism Spectrum Disorder Using an Arena Model.

OBJECTIVE: To improve access to diagnostic evaluations for children younger than 3 years with concerns for possible autism spectrum disorder. METHODS: A multidisciplinary "arena model" for children younger than 3 years was developed, tested, and implemented over an approximately 2-year period. Arena assessment teams comprised a developmental behavioral pediatrician (DBP), psychologist, and speech language pathologist (SLP). Quality improvement methods were used during the design phase, conducting Plan-Do-Study-Act (PDSA) cycles and collecting feedback from key stakeholders, and during implementation, plotting data on run charts to measure outcomes of the time to initial visit and time to diagnosis. RESULTS: Over the 9-month implementation period, 6 arena assessment teams were formed to provide 60 evaluation slots per month for children younger than 3 years. The time to first visit was reduced from a median of 122 days to 19 days, and the time to final diagnosis was reduced from 139 days to 14 days, maintaining these outcomes at <35 and <18 days, respectively, over a 2-year period. Total visits required decreased from 4 to 5 visits to just 2 visits, and the average assessment cost was reduced by $992 per patient. Feedback from both providers and families participating in this model was overwhelmingly positive. CONCLUSION: Access for young children referred for developmental assessments can be improved through an understanding of supply and demand and the development of creative and flexible care delivery models.

Reduced bone cortical thickness in boys with autism or autism spectrum disorder.

Bone development, casein-free diet use, supplements, and medications were assessed for 75 boys with autism or autism spectrum disorder, ages 4-8 years. Second metacarpal bone cortical thickness (BCT), measured on hand-wrist radiographs, and % deviations in BCT from reference medians were derived. BCT increased with age, but % deviations evidenced a progressive fall-off (p = .02): +3.1 +/- 4.7%, -6.5 +/- 4.0%, -16.6 +/- 3.4%, -19.4 +/- 3.7%,-24.1 +/- 4.4%, at ages 4-8, respectively, adjusting for height. The 12% of the boys on casein-free diets had an overall % deviation of -18.9 +/- 3.7%, nearly twice that of boys on minimally restricted or unrestricted diets (-10.5 +/- 1.3%, p < .04), although even for boys on minimally restricted or unrestricted diets the % deviation was highly significant (p < .001). Our data suggest that the bone development of autistic boys should be monitored as part of routine care, especially if they are on casein-free diets.

Two boys with 47, XXY and autism.

Two children with autism and Klinefelter syndrome (KS) (47, XXY) are presented. Both qualify for the diagnosis of autism based on DSM-IV with severely delayed and disordered language, difficulties with social interaction, and a restricted range of interests and activities. Both also have abnormal EEGs, and one patient has had what appear to be clinical seizures. Trials of antiepileptic medications have not been beneficial in either patient. We report the clinical and EEG findings of each patient, and discuss the implications of this combination of disorders.

Parenting African American Children With Autism: The Influence of Respect and Faith in Mother, Father, Single-, and Two-Parent Care.

PURPOSE: Parents are the most significant contributor to care of children with autism spectrum disorder (ASD), and as such research on African American parenting in ASD is conspicuously absent. Findings relevant to parenting are discussed from a study with urban African American families caring for children with ASD. DESIGN: An ethnonursing study was conducted with 24 African American family members of children with ASD and 28 professionals. Data were analyzed and reported as themes. FINDINGS: Two universal themes of were found of respect and faith in God and family that influenced parental care. Two diverse themes of mother's watchful care and father's protective care, along with differences in feelings of isolation and dependence on supports were found among single- and two-parent families. Discussion and Practice Implications: When health care professionals increase their knowledge and understanding of cultural practices in the parental care of children with ASD, they provide health care that is culturally congruent.

Elevated cytokine levels in children with autism spectrum disorder.

UNLABELLED: This study compared production of IL-2, IFN-gamma, IL-4, IL-13, IL-5 and IL-10 in peripheral blood mononuclear cells from 20 children with autism spectrum disorder to those from matched controls. Levels of all Th2 cytokines were significantly higher in cases after incubation in media alone, but the IFN-gamma/IL-13 ratio was not significantly different between cases and controls. Cases had significantly higher IL-13/IL-10 and IFN-gamma/IL-10 than controls. CONCLUSION: Children with ASD had increased activation of both Th2 and Th1 arms of the adaptive immune response, with a Th2 predominance, and without the compensatory increase in the regulatory cytokine IL-10.

Improving Access to Care at Autism Treatment Centers: A System Analysis Approach.

OBJECTIVE: The prevalence of autism spectrum disorder is steadily increasing and placing more demands on already overburdened diagnostic and treatment systems. A thoughtful, systematic reorganization of autism service delivery may reduce delays and better meet the growing need. METHODS: Two clinical centers in the Autism Intervention Research Network on Physical Health, Cincinnati Children's Hospital Medical Center (CCHMC) and Nationwide Children's Hospital (NCH), undertook a year-long access improvement project to reduce delays to care by using system analysis to identify sources of delay and to target changes by using a set of defined access principles. Although both sites addressed access, they focused on slightly different targets (reducing number of patients with autism spectrum disorders waiting for follow-up appointments at NCH and reducing delay to new diagnosis at CCHMC). RESULTS: Both sites achieved dramatic improvements in their complex, multidisciplinary systems. A 94% reduction in number of patients on the waitlist from 99 to 6 patients and a 22% reduction in median delay for a new ongoing care appointment were realized at NCH. A 94% reduction in third next available appointment for new physician visits for children 3 to 5 years old was realized at CCHMC. CONCLUSIONS: This article demonstrates that 2 different clinical systems improved access to care for autism diagnosis and follow-up care by identifying sources of delay and using targeted changes based on a set of access change principles. With appropriate guidance and data analysis, improvements in access can be made.

Electronic Health Record Based Algorithm to Identify Patients with Autism Spectrum Disorder.

OBJECTIVE: Cohort selection is challenging for large-scale electronic health record (EHR) analyses, as International Classification of Diseases 9th edition (ICD-9) diagnostic codes are notoriously unreliable disease predictors. Our objective was to develop, evaluate, and validate an automated algorithm for determining an Autism Spectrum Disorder (ASD) patient cohort from EHR. We demonstrate its utility via the largest investigation to date of the co-occurrence patterns of medical comorbidities in ASD. METHODS: We extracted ICD-9 codes and concepts derived from the clinical notes. A gold standard patient set was labeled by clinicians at Boston Children's Hospital (BCH) (N = 150) and Cincinnati Children's Hospital and Medical Center (CCHMC) (N = 152). Two algorithms were created: (1) rule-based implementing the ASD criteria from Diagnostic and Statistical Manual of Mental Diseases 4th edition, (2) predictive classifier. The positive predictive values (PPV) achieved by these algorithms were compared to an ICD-9 code baseline. We clustered the patients based on grouped ICD-9 codes and evaluated subgroups. RESULTS: The rule-based algorithm produced the best PPV: (a) BCH: 0.885 vs. 0.273 (baseline); (b) CCHMC: 0.840 vs. 0.645 (baseline); (c) combined: 0.864 vs. 0.460 (baseline). A validation at Children's Hospital of Philadelphia yielded 0.848 (PPV). Clustering analyses of comorbidities on the three-site large cohort (N = 20,658 ASD patients) identified psychiatric, developmental, and seizure disorder clusters. CONCLUSIONS: In a large cross-institutional cohort, co-occurrence patterns of comorbidities in ASDs provide further hypothetical evidence for distinct courses in ASD. The proposed automated algorithms for cohort selection open avenues for other large-scale EHR studies and individualized treatment of ASD.

Electroencephalogram abnormalities in children with autism spectrum disorders.

Children with an autism spectrum disorder (ASD) often are evaluated with electroencephalogram (EEG) studies to assess their risk for seizures or other underlying abnormalities. Their risk is estimated at 7% - 42%. EEG studies were conducted on a subgroup of children while following established practice parameters for evaluating children for ASD. Abnormal EEG results were obtained in 85 (27%) of the 316 children evaluatedfor ASD. Within the subset of abnormal results, 64 children had autism, 10 had an ASD or milder presentation, 6 had another developmental disorder, 3 had Rett syndrome, had Down syndrome, and 1 had Wolf-Hirshhorn syndrome. The abnormal EEG findings included epileptiform abnormalities in 55 patients (65%), and slowing in only 13 patients (15%). The focality of the epileptiformfindings included 26 (30%) in the temporal areas, 24 (28%) in the central area, 20 (23%) in the frontal area, and 7 (8%) in the occipital area. These findings confirm the importance of ongoing medicalfollow-up for children with ASDs, especially for those with abnormal EEG results.

Can Screening with the Ages and Stages Questionnaire Detect Autism?

OBJECTIVE: Parents rely on pediatricians to monitor their child's development. The American Academy of Pediatrics recommends routine developmental screening with both broadband and autism-specific instruments at specified ages. If broadband screeners can detect autism risk, this might minimize the burden of administering autism-specific screens to all children. The current study examines the ability of the Ages and Stages Questionnaire-Third Edition (ASQ-3) to identify children at risk for autism. We looked at ASQ-3 scores of children who screen positive on the Modified Checklist for Autism in Toddlers-Revised (M-CHAT-R), children who continue to screen positive on the M-CHAT-R Follow-up Interview, and children diagnosed with autism spectrum disorder (ASD). METHODS: A total of 2848 toddlers, aged 16 to 30 months, were screened with the ASQ-3 and M-CHAT-R across 20 pediatric sites. Children who screened positive on the M-CHAT-R and its follow-up interview were offered a diagnostic evaluation. RESULTS: Using the "monitor and/or fail" cutoff on any domain, the ASQ-3 identified 87% of the children who screened positive on the M-CHAT-R with follow-up and 95% (20/21) of those diagnosed with an ASD. Monitor and/or fail on the Communication domain alone also identified 95% of the diagnosed children. CONCLUSIONS: Scores below the "monitor" cutoff on the Communication domain of the ASQ-3 can indicate initial concern requiring autism-specific follow-up. If these results are confirmed with a sample large enough to separately examine toddlers of different ages and different cultural backgrounds, it may be feasible to implement a 2-stage screening strategy, with autism-specific screening reserved for those who are positive on a broadband screen.

Late diagnosis of autism spectrum disorder after initial negative assessment by a multidisciplinary team.

OBJECTIVE: Describe a cohort of children who received a diagnosis of autism spectrum disorder (ASD) after age 6 and after having undergone a comprehensive multidisciplinary assessment before the age of 6, through which they were not diagnosed with ASD. METHODS: Extensive chart review of patients' electronic medical records comprised a representative population-based registry of patients seen during 2004 to 2011. The study focused only on the cohort of children who were diagnosed with ASD after the age of 6 but were not diagnosed with ASD at an earlier age. The charts were reviewed for the number of developmental assessments completed and the clinician's diagnostic impressions. The charts were also examined for documentation of ASD-suggestive features pulled directly from the text of the evaluators' reports. RESULTS: A total of 221 patients (189 males) were diagnosed with ASD after age 6 although their initial comprehensive developmental evaluations before the age of 6 were negative for ASD. The study cohort underwent a total of 1028 developmental evaluations before the age of 6, with initial diagnostic impressions that included language deficits (70%), motor difficulties (67%), attention problems (46%), and cognitive difficulties (42%). Less than half of the cohort had ASD-suggesting features documented in their initial assessment. CONCLUSIONS: Subsequent late diagnosis of ASD after an initial ASD-negative comprehensive assessment is a common clinical experience. Reasons for this scenario may include evolving diagnosis as well as missed and overdiagnosed cases of ASD.

African American families on autism diagnosis and treatment: the influence of culture.

Cultural factors such as health care access and autism spectrum disorder (ASD) symptom interpretations have been proposed as impacting delayed diagnosis and treatment for African American children with ASD. A qualitative study of urban African American families caring for their child with autism was conducted with 24 family members and 28 ASD professionals. Cultural caring meant families protected their child from harm including potential or actual distrustful encounters, and took action for their child and community to optimize their child's health and address the knowledge deficits of ASD within their community. Families and professionals believed cultural influences delayed families' receiving and seeking appropriate health care for the African American child with ASD affecting timely autism diagnosis and treatment.

Dietary Supplementation in Children with Autism Spectrum Disorders: Common, Insufficient, and Excessive.

BACKGROUND: Little is known about the effect on dietary adequacy of supplements given to children with autism spectrum disorder (ASD). OBJECTIVE: This cross-sectional study examines dietary supplement use and micronutrient intake in children with ASD. DESIGN: Three-day diet/supplement records and use of a gluten/casein-free diet (GFCF) were documented. Estimates of usual intake of micronutrients from food and supplements were compared with the Dietary Reference Intakes. PARTICIPANTS: Children aged 2 to 11 years (N=288) with ASD from five Autism Treatment Network sites from 2009-2011. MAIN OUTCOME MEASURES: Percentage of children meeting or exceeding upper limits of micronutrient intake with or without supplements and relative to GFCF diet status. STATISTICAL ANALYSIS: Micronutrient intake from food and supplements was compared by Spearman rank correlation. Usual intake was estimated by the National Cancer Institute method adjusted for age, sex, supplement use, and GFCF diet. Adequacy of intake was compared between supplement use status and between food and total intake in supplement users relative to Dietary Reference Intakes limits. RESULTS: Dietary supplements, especially multivitamin/minerals, were used by 56% of children with ASD. The most common micronutrient deficits were not corrected (vitamin D, calcium, potassium, pantothenic acid, and choline) by supplements. Almost one-third of children remained deficient for vitamin D and up to 54% for calcium. Children receiving GFCF diets had similar micronutrient intake but were more likely to use supplements (78% vs 56%; P=0.01). Supplementation led to excess vitamin A, folate, and zinc intake across the sample, vitamin C, and copper among children aged 2 to 3 years, and manganese and copper for children aged 4 to 8 years. CONCLUSIONS: Few children with ASD need most of the micronutrients they are commonly given as supplements, which often leads to excess intake. Even when supplements are used, careful attention should be given to adequacy of vitamin D and calcium intake.

Lack of benefit of intravenous synthetic human secretin in the treatment of autism.

The objective of this study was to determine if an intravenous infusion of synthetic human secretin improves language and behavioral symptoms in children with autism. Forty-two children with the diagnosis of autism were randomized to one of two groups in this double-blind cross-over trial. One group received 2 IU/kg of intravenous synthetic human secretin at the first visit, followed by an equal volume of intravenous saline placebo at week 6. The other group received treatments in the reverse order. All children were evaluated at weeks 1, 3, 6, 9, and 12 with standardized assessments of language, behavior, and autism symptomatology. There were no significant differences in the mean scores on any measure of language, behavior, or autism symptom severity after treatment with secretin compared to treatment with placebo. The results of this study do not support secretin as a treatment for autism.