Variability in Swallowed Topical Corticosteroid Practice Patterns for Treatment of Pediatric Eosinophilic Esophagitis.

Given the variety of preparations and lack of standardization of swallowed topical corticosteroids (STC) for treatment of eosinophilic esophagitis (EoE), we sought to better understand STC prescribing practices of pediatric gastroenterologists. A 12-question survey was distributed to members of North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Eosinophilic Gastrointestinal Disease Special Interest Group and responses were analyzed. Forty-two of 68 physicians responded. Oral viscous budesonide (OVB) was overall first choice STC in 31 (74%) survey respondents, with OVB most frequently utilized in patients under 5 years old and fluticasone propionate in patients 13-18 years old. Nineteen types of mixing vehicles were used for OVB preparation, the 3 most frequent being sucralose, honey, and artificial maple syrup. Insurance coverage, cost, and patient compliance were most frequently cited barriers to STC use. Highly variable STC prescribing practices reported by this group highlights the need for standardization of STC treatment in EoE.

TCEAL1 loss-of-function results in an X-linked dominant neurodevelopmental syndrome and drives the neurological disease trait in Xq22.2 deletions.

An Xq22.2 region upstream of PLP1 has been proposed to underly a neurological disease trait when deleted in 46,XX females. Deletion mapping revealed that heterozygous deletions encompassing the smallest region of overlap (SRO) spanning six Xq22.2 genes (BEX3, RAB40A, TCEAL4, TCEAL3, TCEAL1, and MORF4L2) associate with an early-onset neurological disease trait (EONDT) consisting of hypotonia, intellectual disability, neurobehavioral abnormalities, and dysmorphic facial features. None of the genes within the SRO have been associated with monogenic disease in OMIM. Through local and international collaborations facilitated by GeneMatcher and Matchmaker Exchange, we have identified and herein report seven de novo variants involving TCEAL1 in seven unrelated families: three hemizygous truncating alleles; one hemizygous missense allele; one heterozygous TCEAL1 full gene deletion; one heterozygous contiguous deletion of TCEAL1, TCEAL3, and TCEAL4; and one heterozygous frameshift variant allele. Variants were identified through exome or genome sequencing with trio analysis or through chromosomal microarray. Comparison with previously reported Xq22 deletions encompassing TCEAL1 identified a more-defined syndrome consisting of hypotonia, abnormal gait, developmental delay/intellectual disability especially affecting expressive language, autistic-like behavior, and mildly dysmorphic facial features. Additional features include strabismus, refractive errors, variable nystagmus, gastroesophageal reflux, constipation, dysmotility, recurrent infections, seizures, and structural brain anomalies. An additional maternally inherited hemizygous missense allele of uncertain significance was identified in a male with hypertonia and spasticity without syndromic features. These data provide evidence that TCEAL1 loss of function causes a neurological rare disease trait involving significant neurological impairment with features overlapping the EONDT phenotype in females with the Xq22 deletion.

Update on Emerging Pharmacologic Therapies for Patients With Eosinophilic Esophagitis.

Eosinophilic esophagitis (EoE) is a chronic immune-mediated condition identified by eosinophilic infiltration of the esophageal mucosa. Historically, pharmacologic options have been limited to proton pump inhibitors and swallowed topical corticosteroids, neither of which have been approved by the US Food and Drug Administration for the treatment of EoE. The goal of therapy is ultimately to avoid irreversible stricturing disease. Despite the rising prevalence of EoE, there have been few therapeutic advancements until recently. Some newer topical corticosteroid preparations are being studied, including a budesonide suspension (TAK-721), orodispersible tablet formulations of budesonide and fluticasone (APT-1011), and mometasone and ciclesonide preparations. Also in various stages of clinical trials are potential disease-modifying biologics such as dupilumab, cendakimab, lirentelimab, benralizumab, and mepolizumab. Some of these medications have proven efficacious for other atopic conditions and show incredible promise for the treatment of eosinophilic gastrointestinal diseases. Further studies will be needed to determine long-term treatment outcomes for each of these drugs.

Robust differentiation of human enteroendocrine cells from intestinal stem cells.

Enteroendocrine (EE) cells are the most abundant hormone-producing cells in humans and are critical regulators of energy homeostasis and gastrointestinal function. Challenges in converting human intestinal stem cells (ISCs) into functional EE cells, ex vivo, have limited progress in elucidating their role in disease pathogenesis and in harnessing their therapeutic potential. To address this, we employed small molecule targeting of the endocannabinoid receptor signaling pathway, JNK, and FOXO1, known to mediate endodermal development and/or hormone production, together with directed differentiation of human ISCs from the duodenum and rectum. We observed marked induction of EE cell differentiation and gut-derived expression and secretion of SST, 5HT, GIP, CCK, GLP-1 and PYY upon treatment with various combinations of three small molecules: rimonabant, SP600125 and AS1842856. Robust differentiation strategies capable of driving human EE cell differentiation is a critical step towards understanding these essential cells and the development of cell-based therapeutics.

Real World Experience With Dupilumab in Eosinophilic Esophagitis in Children and Young Adults at a Tertiary Care Pediatric Medical Center.

Dupilumab is one of a number of biologics currently under investigation for the treatment of eosinophilic esophagitis (EoE). We report on a group of 7 pediatric and young adult patients with EoE who were treated with dupilumab for a primary indication of asthma or atopic dermatitis, all of whom previously failed swallowed topical corticosteroid therapy dietary for management of their EoE. All 7 patients demonstrated histologic improvement in their EoE while on dupilumab, with a drop in median peak esophageal eosinophil count from 50 eosinophils per high-powered field (eos/hpf) (IQR 48-95 eos/hpf) to 2 eos/hpf (IQR 0-5 eos/hpf) off swallowed topical corticosteroid. Additionally, improvements in EoE symptoms and endoscopic findings were noted. This report highlights the effectiveness of dupilumab in a group of multiply atopic pediatric and young adult patients with difficult-to-treat EoE in real world practice.

Genetic counseling for congenital heart disease - Practice resource of the National Society of Genetic Counselors.

Congenital heart disease (CHD) is an indication which spans multiple specialties across various genetic counseling practices. This practice resource aims to provide guidance on key considerations when approaching counseling for this particular indication while recognizing the rapidly changing landscape of knowledge within this domain. This resource was developed with consensus from a diverse group of certified genetic counselors utilizing literature relevant for CHD genetic counseling practice and is aimed at supporting genetic counselors who encounter this indication in their practice both pre- and postnatally.

Treatment for eosinophilic esophagitis.

PURPOSE OF REVIEW: To summarize current dietary and pharmacologic approaches in the treatment of eosinophilic esophagitis (EoE). RECENT FINDINGS: Studies comparing dietary approaches in EoE treatment support empiric elimination diets as the preferred approach to dietary EoE treatment, with no data to support use of currently available allergy tests to guide specific food elimination diets. Swallowed topical corticosteroid therapy is the current standard of care in pharmacologic EoE treatment, with similar effectiveness of fluticasone and budesonide, but their discontinuation results in return of both EoE symptoms and disease. A number of nonsteroid-based therapies are currently under investigation for the treatment of EoE, which are focused on targeting disease at a cellular level. SUMMARY: EoE can be treated with diet or medications. Empiric elimination is presently the preferred dietary approach. Swallowed steroids is the standard of care to treat EoE with medication; however, there are several promising drugs currently undergoing clinical trials.

Does Supply Equal Demand? The Workforce of Direct Patient Care Genetic Counselors in Wisconsin.

BACKGROUND: Recent studies documented a shortage of direct patient care (DPC) genetic counselors in the United States. We aimed to survey genetic counselor members of the Wisconsin Genetic Counselors Association (WIGCA) to determine if the supply and demand was met within the state and where access to services can improve. METHODS: An email invitation was sent to all genetic counselor members of the WIGCA with a link to a confidential online survey. Survey questions addressed the workforce composition, elements that impact services, and professional satisfaction of practicing genetic counselors. RESULTS: The Wisconsin workforce currently has half of the projected need for full-time DPC genetic counselors. One-third of genetic counselors reported changing from direct to non-direct patient care positions. In-person services are concentrated within Milwaukee and Madison. Appointment wait times are decreased when patients meet with a genetic counselor only, and half of the genetic counselors reported moderate to high stress levels. DISCUSSION/CONCLUSION: A shortage of DPC genetic counselors in Wisconsin is confirmed due to the total full-time effort in direct patient care. Data provided here can be used to identify targets for increasing the number of DPC genetic counselors, maximizing time spent on patient care, and improving access.

Three year experience of a clinical cardiovascular genetics program for infants with congenital heart disease.

OBJECTIVE: To describe the first 3 years of experience of having an inpatient "cardiogenetics" program which involves medical geneticist assessment of infants with major congenital heart disease (CHD) requiring surgical intervention in the first year of life. PATIENTS: Patients less than a year of age admitted to Children's Hospital of Wisconsin's Herma Heart Institute for surgical intervention for CHD seen by the cardiogenetics program. Patients with major trisomies (13, 18, and 21) were excluded. OUTCOME MEASURES: Utilization and yield of genetic testing, and diagnostic rate were assessed as outcome measures and compared to a baseline time period and a genetic testing protocol time period. RESULTS: There were 201 infants with CHD evaluated by the cardiogenetics program over 3 years. A total of patients 46 patients of the 196 who underwent genetic testing had multiple tests completed. This is a significant decrease from the baseline (247/329, P < .0001) and from the genetic testing protocol (29/81, P < .0387) time periods. The diagnostic rate was 33% which is significantly increased compared to the baseline rate of 15% (80/524, P < .0001) and trends toward a significant increase during the testing protocol rate (25/113, P = .0520). The number of dual diagnosis increased to 9 of 201 compared to the baseline (2/524) and the genetic testing protocol (1/113) time periods. The rate of incidental diagnoses altering care increased to 6 of 201 from the baseline (1/524) and the genetic testing protocol (1/113) time periods. CONCLUSION: An inpatient cardiogenetics program significantly increases the diagnostic rate, the detection of complex phenotypes with dual diagnoses, the identification of incidental genetic diagnoses associated with changes in care, and significantly decreases the likelihood of multiple tests being completed on an individual patient. Increased medical geneticist involvement in programs that care for infants with CHD should be encouraged to improve patient care and genetic testing utilization.

DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency.

During genome replication, polymerase epsilon (Pol ε) acts as the major leading-strand DNA polymerase. Here we report the identification of biallelic mutations in POLE, encoding the Pol ε catalytic subunit POLE1, in 15 individuals from 12 families. Phenotypically, these individuals had clinical features closely resembling IMAGe syndrome (intrauterine growth restriction [IUGR], metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary anomalies in males), a disorder previously associated with gain-of-function mutations in CDKN1C. POLE1-deficient individuals also exhibited distinctive facial features and variable immune dysfunction with evidence of lymphocyte deficiency. All subjects shared the same intronic variant (c.1686+32C>G) as part of a common haplotype, in combination with different loss-of-function variants in trans. The intronic variant alters splicing, and together the biallelic mutations lead to cellular deficiency of Pol ε and delayed S-phase progression. In summary, we establish POLE as a second gene in which mutations cause IMAGe syndrome. These findings add to a growing list of disorders due to mutations in DNA replication genes that manifest growth restriction alongside adrenal dysfunction and/or immunodeficiency, consolidating these as replisome phenotypes and highlighting a need for future studies to understand the tissue-specific development roles of the encoded proteins.

Adolescents' Perceptions of Transition Importance, Readiness, and Likelihood of Future Success: The Role of Anticipatory Guidance.

Expert consensus supports anticipatory guidance around health care transition (HCT), but little is known about its impact on adolescents' perceptions of HCT. This study aimed to evaluate the frequency of HCT anticipatory guidance delivery and the effect it had on participants' perceptions of HCT. Adolescents (n = 209) with special health care needs were administered National Survey for Children with Special Health Care Needs transition assessment questions, then reported perceptions of transition importance, readiness, and likely future success. Over half of the participants reported no history of discussion about transition to an adult provider (64%) or insurance needs (67%); just under half (43%) had not discussed their changing health care needs. In participants reporting receipt of anticipatory guidance, ratings of transition readiness and future success were significantly higher than those who received no anticipatory guidance, supporting that HCT anticipatory guidance has a significantly positive impact on adolescents' perceptions of the HCT process.