Newborn Screening for the Detection of the TP53 R337H Variant and Surveillance for Early Diagnosis of Pediatric Adrenocortical Tumors: Lessons Learned and Way Forward

The incidence of pediatric adrenocortical tumors (ACT) is high in southern Brazil due to the founder TP53 R337H variant. Neonatal screening/surveillance (NSS) for this variant resulted in early ACT detection and improved outcomes. The medical records of children with ACT who did not participate in newborn screening (non-NSS) were reviewed (2012–2018). We compared known prognostic factors between the NSS and non-NSS cohorts and estimated surveillance and treatment costs. Of the 16 non-NSS children with ACT carrying the R337H variant, the disease stages I, II, III, and IV were observed in five, five, one, and five children, respectively. The tumor weight ranged from 22 to 608 g. The 11 NSS children with ACT all had disease stage I and were alive. The median tumor weight, age of diagnosis, and interval between symptoms and diagnosis were 21 g, 1.9 years, and two weeks, respectively, for the NSS cohort and 210 g, 5.2 years, and 15 weeks, respectively, for the non-NSS cohort. The estimated surveillance/screening cost per year of life saved is US$623/patient. NSS is critical for improving the outcome of pediatric ACT in this region. Hence, we strongly advocate for the inclusion of R337H in the state-mandated universal screening and surveillance.

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Identification of Clinical and Biologic Correlates Associated With Outcome in Children With Adrenocortical Tumors Without Germline TP53 Mutations: A St Jude Adrenocortical Tumor Registry and Children’s Oncology Group Study

Journal of Clinical Oncology ◽

10.1200/jco.2017.74.2460 ◽

2017 ◽

Vol 35 (35) ◽

pp. 3956-3963 ◽

Cited By ~ 17

Author(s):

Emilia Modolo Pinto ◽

Carlos Rodriguez-Galindo ◽

Stanley B. Pounds ◽

Lei Wang ◽

Michael R. Clay ◽

...

Keyword(s):

Overall Survival ◽

Cox Regression ◽

Prognostic Indicator ◽

Disease Stage ◽

Ki 67 ◽

Chromosome 11P15 ◽

Cox Regression Analysis ◽

Tumor Weight ◽

Tp53 Mutations ◽

Adrenocortical Tumors

Purpose The clinical features, pathogenesis, and outcomes in children with adrenocortical tumors (ACTs) without germline TP53 mutations have not been systematically studied. Herein, we describe these correlates and analyze their association with outcome. Patients and Methods Genomic DNA was analyzed for TP53, CTNNB1, CDKN1C, ATRX, and chromosome 11p15 abnormalities. β-catenin expression and Ki-67 labeling index (LI) were evaluated by immunostaining. Primary end points were progression-free (PFS) and overall survival. Results Median age of 42 girls and 18 boys was 3.3 years (range, 0.25 to 21.7 years). Complete resection (stages I and II) was achieved in 32 patients, and 28 patients had stage III or IV disease. Constitutional abnormalities of chromosome 11p15 occurred in nine of 40 patients, with six patients not showing phenotype of Beckwith-Wiedemann syndrome. Three-year PFS and overall survival for all patients were 71.4% and 80.5%, respectively. In single-predictor Cox regression analysis, age, disease stage, tumor weight, somatic TP53 mutations, and Ki-67 LI were associated with prognosis. Ki-67 LI and age remained significantly associated with PFS after adjusting for stage and tumor weight. Three-year PFS for 27 patients with Ki-67 LI ≥ 15% was 48.5% compared with 96.2% for 29 patients with Ki-67 LI < 15% (log-rank P = .002), and the rate of relapse increased by 24% with each 1-year increase in age at diagnosis (hazard ratio, 1.24; P = .0057). Conclusion Clinicopathologic features and outcomes of children with ACTs without germline TP53 mutations overlapped those reported for children with germline TP53 mutations. Our findings highlight the central role of genetic or epigenetic alterations on chromosome 11p15 in pediatric ACTs. Ki-67 LI is a strong prognostic indicator and should be investigated to improve the histologic classification of pediatric ACTs.

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From the Basis of Epimorphic Regeneration to Enhanced Regenerative Therapies

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.605120 ◽

2021 ◽

Vol 8 ◽

Author(s):

Béryl Laplace-Builhé ◽

Sarah Bahraoui ◽

Christian Jorgensen ◽

Farida Djouad

Keyword(s):

Lessons Learned ◽

Therapeutic Effects ◽

Degenerative Diseases ◽

Beneficial Effects ◽

Knee Oa ◽

Cellular Events ◽

Current Cell ◽

Improved Outcomes ◽

Progenitor Cell Proliferation ◽

Regenerative Therapies

Current cell-based therapies to treat degenerative diseases such as osteoarthritis (OA) fail to offer long-term beneficial effects. The therapeutic effects provided by mesenchymal stem cell (MSC) injection, characterized by reduced pain and an improved functional activity in patients with knee OA, are reported at short-term follow-up since the improved outcomes plateau or, even worse, decline several months after MSC administration. This review tackles the limitations of MSC-based therapy for degenerative diseases and highlights the lessons learned from regenerative species to comprehend the coordination of molecular and cellular events critical for complex regeneration processes. We discuss how MSC injection generates a positive cascade of events resulting in a long-lasting systemic immune regulation with limited beneficial effects on tissue regeneration while in regenerative species fine-tuned inflammation is required for progenitor cell proliferation, differentiation, and regeneration. Finally, we stress the direct or indirect involvement of neural crest derived cells (NCC) in most if not all adult regenerative models studied so far. This review underlines the regenerative potential of NCC and the limitations of MSC-based therapy to open new avenues for the treatment of degenerative diseases such as OA.

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The Use of Whole Genome and Exome Sequencing for Newborn Screening: Challenges and Opportunities for Population Health

Frontiers in Pediatrics ◽

10.3389/fped.2021.663752 ◽

2021 ◽

Vol 9 ◽

Author(s):

Audrey C. Woerner ◽

Renata C. Gallagher ◽

Jerry Vockley ◽

Aashish N. Adhikari

Keyword(s):

Newborn Screening ◽

Exome Sequencing ◽

Genetic Disorders ◽

Population Based ◽

Lessons Learned ◽

Screening Tests ◽

Whole Genome ◽

Whole Exome ◽

Challenges And Opportunities ◽

History Of

Newborn screening (NBS) is a population-based program with a goal of reducing the burden of disease for conditions with significant clinical impact on neonates. Screening tests were originally developed and implemented one at a time, but newer methods have allowed the use of multiplex technologies to expand additions more rapidly to standard panels. Recent improvements in next-generation sequencing are also evolving rapidly from first focusing on individual genes, then panels, and finally all genes as encompassed by whole exome and genome sequencing. The intersection of these two technologies brings the revolutionary possibility of identifying all genetic disorders in newborns, allowing implementation of therapies at the optimum time regardless of symptoms. This article reviews the history of newborn screening and early studies examining the use of whole genome and exome sequencing as a screening tool. Lessons learned from these studies are discussed, along with technical, ethical, and societal challenges to broad implementation.

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Lessons Learned from Pompe Disease Newborn Screening and Follow-up

International Journal of Neonatal Screening ◽

10.3390/ijns6010011 ◽

2020 ◽

Vol 6 (1) ◽

pp. 11

Author(s):

Tracy L. Klug ◽

Lori B. Swartz ◽

Jon Washburn ◽

Candice Brannen ◽

Jami L. Kiesling

Keyword(s):

Newborn Screening ◽

Pompe Disease ◽

Human Services ◽

Lessons Learned ◽

Lysosomal Storage ◽

Health And Human Services ◽

Disease Phenotypes ◽

Department Of Health ◽

The World

In 2015, Pompe disease became the first lysosomal storage disorder to be recommended for universal newborn screening by the Secretary of the U.S. Department of Health and Human Services. Newborn screening for Pompe has been implemented in 20 states and several countries across the world. The rates of later-onset disease phenotypes for Pompe and pseudodeficiency alleles are higher than initially anticipated, and these factors must be considered during Pompe disease newborn screening. This report presents an overview of six years of data from the Missouri State Public Health Laboratory for Pompe disease newborn screening and follow-up.

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Early Identification of Fragile X Syndrome through Expanded Newborn Screening

Brain Sciences ◽

10.3390/brainsci9010004 ◽

2019 ◽

Vol 9 (1) ◽

pp. 4 ◽

Cited By ~ 5

Author(s):

Katherine C. Okoniewski ◽

Anne C. Wheeler ◽

Stacey Lee ◽

Beth Boyea ◽

Melissa Raspa ◽

...

Keyword(s):

North Carolina ◽

Newborn Screening ◽

Fragile X Syndrome ◽

Fragile X ◽

Pilot Studies ◽

The Past ◽

Innovative Program ◽

Expanded Newborn Screening ◽

Age Of Diagnosis

Over the past 20 years, research on fragile X syndrome (FXS) has provided foundational understanding of the complex experiences of affected individuals and their families. Despite this intensive focus, there has been little progress on earlier identification, with the average age of diagnosis being 3 years. For intervention and treatment approaches to have the greatest impact, they need to begin shortly after birth. To access this critical timespan, differential methods of earlier identification need to be considered, with an emerging focus on newborn screening practices. Currently, barriers exist that prevent the inclusion of FXS on standard newborn screening panels. To address these barriers, an innovative program is being implemented in North Carolina to offer voluntary screening for FXS under a research protocol, called Early Check. This program addresses the difficulties observed in prior pilot studies, such as recruitment, enrollment, lab testing, and follow-up. Early Check provides an opportunity for stakeholders and the research community to continue to gain valuable information about the feasibility and greater impact of newborn screening on the FXS population.

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