Two Unique Cases of X-linked SCID: A Diagnostic Challenge in the Era of Newborn Screening

In the era of newborn screening (NBS) for severe combined immunodeficiency (SCID) and the possibility of gene therapy (GT), it is important to link SCID phenotype to the underlying genetic disease. In western countries, X-linked interleukin 2 receptor gamma chain (IL2RG) and adenosine deaminase (ADA) deficiency SCID are two of the most common types of SCID and can be treated by GT. As a challenge, both IL2RG and ADA genes are highly polymorphic and a gene-based diagnosis may be difficult if the variant is of unknown significance or if it is located in non-coding areas of the genes that are not routinely evaluated with exon-based genetic testing (e.g., introns, promoters, and the 5\u27and 3\u27 untranslated regions). Therefore, it is important to extend evaluation to non-coding areas of a SCID gene if the exon-based sequencing is inconclusive and there is strong suspicion that a variant in that gene is the cause for disease. Functional studies are often required in these cases to confirm a pathogenic variant. We present here two unique examples of X-linked SCID with variable immune phenotypes, where IL2R gamma chain expression was detected and no pathogenic variant was identified on initial genetic testing. Pathogenic IL2RG variants were subsequently confirmed by functional assay of gamma chain signaling and maternal X-inactivation studies. We propose that such tests can facilitate confirmation of suspected cases of X-linked SCID in newborns when initial genetic testing is inconclusive. Early identification of pathogenic IL2RG variants is especially important to ensure eligibility for gene therapy

Two Unique Cases of X-linked SCID: A Diagnostic Challenge in the Era of Newborn Screening

In the era of newborn screening (NBS) for severe combined immunodeficiency (SCID) and the possibility of gene therapy (GT), it is important to link SCID phenotype to the underlying genetic disease. In western countries, X-linked interleukin 2 receptor gamma chain (IL2RG) and adenosine deaminase (ADA) deficiency SCID are two of the most common types of SCID and can be treated by GT. As a challenge, both IL2RG and ADA genes are highly polymorphic and a gene–based diagnosis may be difficult if the variant is of unknown significance or if it is located in non-coding areas of the genes that are not routinely evaluated with exon-based genetic testing (e.g., introns, promoters, and the 5′and 3′ untranslated regions). Therefore, it is important to extend evaluation to non-coding areas of a SCID gene if the exon-based sequencing is inconclusive and there is strong suspicion that a variant in that gene is the cause for disease. Functional studies are often required in these cases to confirm a pathogenic variant. We present here two unique examples of X-linked SCID with variable immune phenotypes, where IL2R gamma chain expression was detected and no pathogenic variant was identified on initial genetic testing. Pathogenic IL2RG variants were subsequently confirmed by functional assay of gamma chain signaling and maternal X-inactivation studies. We propose that such tests can facilitate confirmation of suspected cases of X-linked SCID in newborns when initial genetic testing is inconclusive. Early identification of pathogenic IL2RG variants is especially important to ensure eligibility for gene therapy

Association between cumulative exposure to adverse childhood experiences and childhood obesity.

BackgroundExposure to adverse childhood experiences (ACEs) is associated with many childhood diseases and poor health outcomes in adulthood. However, the association with childhood obesity is inconsistent. We investigated the association between reported cumulative ACE score and body mass index (BMI) in a large sample of patients at a single institution.MethodsThis cross-sectional study included children aged 2-20 years that were screened in a general pediatrics clinic for ACEs utilizing the Center for Youth Wellness ACEs questionnaire between July 2017 and July 2018. Overall ACE score was categorized as 'no exposure' (score = 0), 'low exposure' (score = 1), and 'high exposure' (score≥ 2). BMI was categorized as overweight/obese (BMI percentile ≥ 85) or non-obese (BMI percentile ResultsOf the 948 patients included in the study, 30% (n = 314) were overweight/obese and 53% (n = 504) had no ACE exposure, 19% (n = 179) had low ACE exposure, and 28% (n = 265) had high ACE exposure. High ACE exposure was associated with increased odds of obesity (OR = 1.47, 95%CI = 1.07-2.03, p = 0.026). However, after adjusting for age, race/ethnicity, insurance type, and birth weight, the association attenuated and was null (OR = 1.01, 95%CI = 0.70-1.46, p = 0.97).ConclusionThe study findings may suggest an association between ACE and childhood obesity. However, the association attenuated after adjusting for age, race/ethnicity, insurance type, and birth weight. Larger prospective studies are warranted to better understand the association

Additional file 1: of The role of vitamin D in pre-eclampsia: a systematic review

PRISMA Checklist. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: PRISMA. (DOC 63 kb