De novo variants in FRYL are associated with developmental delay, intellectual disability, and dysmorphic features.

FRY-like transcription coactivator (FRYL) belongs to a Furry protein family that is evolutionarily conserved from yeast to humans. The functions of FRYL in mammals are largely unknown, and variants in FRYL have not previously been associated with a Mendelian disease. Here, we report fourteen individuals with heterozygous variants in FRYL who present with developmental delay, intellectual disability, dysmorphic features, and other congenital anomalies in multiple systems. The variants are confirmed de novo in all individuals except one. Human genetic data suggest that FRYL is intolerant to loss of function (LoF). We find that the fly FRYL ortholog, furry (fry), is expressed in multiple tissues, including the central nervous system where it is present in neurons but not in glia. Homozygous fry LoF mutation is lethal at various developmental stages, and loss of fry in mutant clones causes defects in wings and compound eyes. We next modeled four out of the five missense variants found in affected individuals using fry knockin alleles. One variant behaves as a severe LoF variant, whereas two others behave as partial LoF variants. One variant does not cause any observable defect in flies, and the corresponding human variant is not confirmed to be de novo, suggesting that this is a variant of uncertain significance. In summary, our findings support that fry is required for proper development in flies and that the LoF variants in FRYL cause a dominant disorder with developmental and neurological symptoms due to haploinsufficiency.

Molecular Diagnosis Is Vital to the Accurate Classification and Management of Thrombotic Thrombocytopenic Purpura in Children.

Thrombotic thrombocytopenic purpura (TTP) is a rare but potentially life-threatening hematologic disease, presenting a myriad of diagnostic and management challenges in children. Here, we provide a review of this disorder and discuss 2 exemplary cases of TTP occurring in adolescents, emphasizing the need for consideration of late-onset congenital TTP (cTTP). We demonstrate the importance of early confirmation of ADAMTS13 enzyme deficiency and the presence or absence of ADAMTS13 inhibitor in order to rapidly initiate the appropriate life-saving therapies. Ultimately, molecular testing is paramount to distinguishing between congenital and acquired immune-mediated TTP.

COVID-19 vaccine (mRNA BNT162b2) and COVID-19 infection-induced thrombotic thrombocytopenic purpura in adolescents.

The mRNA COVID-19 vaccine and COVID-19 infection caused by the SARS-CoV-2 virus may be immunologic triggers for the development of thrombotic thrombocytopenic purpura (TTP). There is not yet literature that discusses TTP induced by COVID-19 vaccination or infection in pediatric or adolescent patients. We describe three adolescents presenting with TTP (both de novo and relapsed disease) following administration of the Pfizer COVID-19 vaccine or after COVID-19 infection. Our observations demonstrate that the Pfizer-BioNTech mRNA vaccine and COVID-19 infection can act as triggers for the development/relapse of both congenital and acquired TTP.

Refractory autoimmune cytopenias in pediatric Evans syndrome with underlying systemic immune dysregulation.

Evans syndrome is a rare but challenging disorder in children; and despite rapidly growing evidence for targetable systemic immune dysregulation driving these "idiopathic" autoimmune cytopenias, precision diagnosis and management remains sub-optimal among these patients. We analyzed retrospective clinical data for 60 pediatric ES patients followed at 3 large tertiary referral centers in the United States over a recent 6-year period and found that definable underlying systemic immune dysregulation was identified in only 42% of these patients throughout the course of clinical care. Median time from ES diagnosis to identification of the underlying systemic immune dysregulation disorder was 1.3 years (<1 month for rheumatologic disease, 2.3 years for CVID, 3.4 years for ALPS, and 7.4 years for monogenic disorders of immune regulation). Notably, a significantly higher percentage of patients in whom a definitive immune dysregulation disorder was ultimately identified required ≥3 cytopenia-directed therapies (92%) and also second- and third-line immunomodulatory agents (84%), vs those in whom no unifying immune dysregulation was diagnosed (65%, and 35%, respectively)-indicating that autoimmune cytopenias as a manifestation of systemic immune dysregulation are more treatment-refractory and severe. These data underline the importance of identifying the underlying systemic immune dysregulation and providing targeted therapy in pediatric ES.

Transient Pancytopenia Subsequently Diagnosed With Acute Leukemia: A Report of 4 Cases of Acute Lymphoblastic Leukemia and Acute Myeloid Leukemia.

A transient pancytopenic phase has been described in pediatric leukemia. The characteristic complete recovery of peripheral counts can obscure a clinician's suspicion for malignancy and may impact subsequent follow-up care. The authors describe 4 pediatric patients that had transient pancytopenia with an initial abnormal marrow finding. These patients were subsequently diagnosed with acute leukemia within 5 months of presentation. Awareness of this phenomenon by the provider and education of families may help with the appropriate and timely diagnosis of subsequent leukemia.

The cost of a "benign" condition: Healthcare utilization and infectious outcomes in young children with primary autoimmune neutropenia.

BACKGROUND: Autoimmune neutropenia (AIN) is a common cause of chronic neutropenia in childhood. Despite an expected benign clinical course, many patients undergo extensive evaluation. Data on healthcare utilization and rates of bloodstream infections in young patients with AIN are limited. METHODS: All patients with a diagnosis code of leukopenia, neutropenia, or AIN followed within the outpatient hematology clinic of a single institution from 2014 to 2016 were identified. Patients aged ≤5 years with absolute neutrophil count (ANC) ≤500/µL persisting for ≥3 months, a clinical diagnosis of AIN, and documented resolution of neutropenia were included. Data on clinical management, including infectious outcomes and emergency center (EC) encounters, were collected. RESULTS: Forty-three patients with AIN (18 male [42%], median age at diagnosis 12 months) met eligibility criteria. Children were followed by hematology for a median duration of 18 (range, 2-85) months. Diagnostic evaluations were variable. Thirty patients (70%) had ≥ 1 EC encounters for evaluation of isolated fever with a total of 113 EC encounters for the overall cohort. Patients with ANC < 500/µL and isolated fever were admitted for observation, which resulted in 24 hospitalizations in 16 patients. Of 138 blood cultures drawn, two were positive, both later determined to be contaminants. CONCLUSION: At a large tertiary care center, no bloodstream infections were identified in a cohort of 43 children with AIN presenting to the EC for assessment of fever. A less-intensive, more cost-effective management paradigm, which continues to prioritize patient safety, among young children with AIN is needed.

Gestational Primary Hyperparathyroidism Due to Ectopic Parathyroid Adenoma: Case Report and Literature Review.

Gestational primary hyperparathyroidism (GPHPT) is a rare condition with fewer than 200 cases reported. We present the case of a 21-year-old woman who presented at 10 weeks' gestation with severe hypercalcemia. Laboratory investigation was consistent with primary hyperparathyroidism. Neck ultrasound did not reveal any parathyroid enlargement. Due to the persistence of severe hypercalcemia, she was treated with 4 weeks of cinacalcet therapy, which was poorly tolerated due to nausea and vomiting. At 14 weeks' gestation, she underwent neck exploration with right lower, left upper, and partial right upper parathyroid gland excision. Intra- and postoperative parathyroid hormone (PTH) and calcium levels remained elevated. After a thorough discussion of risks/benefits, the patient requested further treatment. A parathyroid sestamibi scan (PSS) revealed an ectopic adenoma in the left mediastinum. The adenoma was removed via video-assisted thorascopic parathyroidectomy with intraoperative PTH declining to nearly undetectable levels. She ultimately delivered a physically and developmentally normal infant at 37 weeks' gestation. Appropriate treatment of severe GPHPT may prevent the maternal and fetal complications of hypercalcemia. This case, in which cinacalcet therapy and PSS were used, adds to the body of literature regarding treatment of severe GPHPT.

Risk factors and co-morbidities in adolescent thromboembolism are different than those in younger children.

INTRODUCTION: In adolescent thromboembolism (TE), multiple risk factors (RFs) and co-morbidities (CMs) are reported, though overall prevalence has not been evaluated. We hypothesized that the spectrum of RFs/CMs in adolescent TE differs from children overall and sought to review Texas Children's Hospital's experience. PATIENTS/METHODS: Medical records of adolescents aged 12-21years, diagnosed with arterial or venous TE (AT/DVT) from 2004 to 2014, were retrospectively reviewed and analyzed with IRB approval. RESULTS: Sixty-four adolescents (median age 16, range 12-20years) met study criteria. Fifty-seven (89%) had DVT and six (9%) had AT. Associated RFs/CMs included obesity (47%), CVC (27%), infection (27%), surgery (27%), autoimmune disease (19%), immobility (22%), anatomical abnormality (20%), cancer (8%), estrogen therapy (6%), tobacco use (6%), trauma (3%), inherited thrombophilia (19%), and other medical conditions (11%). Fifty-two (81%) had ≥2 RFs/CMs. Therapy included anticoagulants, antiplatelet agents, and interventional therapy. Of those with follow-up imaging, 49 had complete or partial resolution, 5 had no change and 4 had progression. Fourteen (22%) had recurrent TE. The majority with recurrent TE (79%) had ≥2 RFs at initial diagnosis. Mean time to recurrence was 4.80years; time to recurrence was shorter for occlusive TE (p=0.026). CONCLUSION: Adolescent TE is often multi-factorial with the majority having ≥2 RFs at diagnosis, suggesting the need for detailed evaluation for RFs in this population, which may enable optimal management including thromboprophylaxis, and institution of RF-modifying strategies to prevent occurrence/recurrence.

The clinical and laboratory spectrum of Hb C [ß6(A3)Glu→Lys, GAG>AAG] disease.

Newborn screening (NBS) provides early diagnosis of sickle hemoglobinopathies. After Hb S [ß6(A3)Glu→Val, GAG>GTG], Hb C [ß6(A3)Glu→Lys, GAG>AAG] is the most common hemoglobin (Hb) abnormality identified in the United States (1,2). Published data regarding children with Hb C disease are limited. This study was conducted to summarize a single institution's clinical and laboratory data for patients with Hb C disease, specifically homozygous Hb CC and its variants over a 10-year period. Forty-seven patients, whose mean age at diagnosis was 2.9 years (range 0.04 to 23 years), were identified. Twenty-nine had Hb CC and the remainder had compound heterozygous variants [10 Hb C/ß(+)-thalassemia (ß(+)-thal), four Hb C/ß(0)-thal, and one each with Hb C/Hb Hope or ß136(H14)Gly→Asp (GGT>GAT), Hb C/Hb Lepore (a hybrid δß-globin gene), Hb C/HPFH (hereditary persistence of fetal Hb) [probably a (G)γ HPFH-2 (the Ghanaian type)], and Hb C/Osu-Christiansborg or ß52(D3)Asp→Asn (GAT>AAT)]. All patients had mild microcytic anemia with reticulocytosis and frequent target cells on peripheral smear. Splenomegaly or cholelithiasis occurred in 2.6% of patients <8 years of age, however, these symptoms were more common (71.0%) in patients >8 years of age. No patient had serious infections or painful events resembling vasoocclusion. Accurate diagnosis and understanding of Hb C-related disorders helped to avoid confusion with sickle hemoglobinopathies and aided in proper clinical management.

Pilot Study of iPad Incorporation Into Graduate Medical Education.

BACKGROUND: Increased documentation and charting requirements are challenging for residents, given duty hour limits. Use of mobile electronic devices may help residents complete these tasks efficiently. OBJECTIVE: To collect initial data on usage rates, information technology (IT) support requirements, and resident use of iPads during training. METHODS: In this pilot study, we provided 12 residents/fellows from various specialties at the University of Virginia with an iPad with IT support. The system used a virtual private network with access to the institution's electronic health record. Participants were allowed to develop their own methods and systems for personalized iPad use, and after 9 months they provided data on the utility of the iPad. Feedback from the IT team also was obtained. RESULTS: Average iPad use was 2.1 h/d (range, 0.5-6 h/d). The average self-reported reduction in administrative work due to the iPad was 2.7 h/wk (range, 0-9 h/wk). A total of 75% (9 of 12) of the users would recommend universal adoption among residents and fellows. More than 90% (11 of 12) of users reported the iPad would improve communication for coordination of care. A total of 68% (8 of 12) of users reported that an iPad facilitated their activities as educators of medical students and junior residents. Residents cited slow data entry into the electronic health record and hospital areas lacking Wi-Fi connectivity as potential drawbacks to iPad use. The IT team reported minimal support time for device setup, maintenance, and upgrades, and limited security risks. CONCLUSIONS: The iPad may contribute to increased clinical efficiency, reduced hours spent on administrative tasks, and enhanced educational opportunities for residents, with minimal IT support.

Practice-based learning and improvement for institutions: a case report.

BACKGROUND: In 2006, the University of Virginia became one of the first academic medical institutions to be placed on probation, after the Accreditation Council for Graduate Medical Education (ACGME) Institutional Review Committee implemented a new classification system for institutional reviews. INTERVENTION: After University of Virginia reviewed its practices and implemented needed changes, the institution was able to have probation removed and full accreditation restored. Whereas graduate medical education committees and designated institutional officials are required to conduct internal reviews of each ACGME-accredited program midway through its accreditation cycle, no similar requirement exists for institutions. LEARNING: As we designed corrective measures at the University of Virginia, we realized that regularly scheduled audits of the entire institution would have prevented the accumulation of deficiencies. We suggest that institutional internal reviews be implemented to ensure that the ACGME institutional requirements for graduate medical education are met. This process represents practice-based learning and improvement at the institutional level and may prevent other institutions from receiving unfavorable accreditation decisions.

Hypoglycemia in athletes with diabetes.

For many years, one of the mainstays of therapy for patients with either type 1 or type 2 diabetes has been exercise, balanced with medical nutrition therapy and medications. A key limitation to achieving this balance has been the increased risk of hypoglycemia, including that induced by increased glucose use brought about by exercise or athletic activity. This review focuses primarily on type 1 diabetes and athletic activity; however, many of the principles discussed below apply to type 2 diabetes as well.