Genetic Conditions of Short Stature: A Review of Three Classic Examples

Noonan, Turner, and Prader-Willi syndromes are classical genetic disorders that are marked by short stature. Each disorder has been recognized for several decades and is backed by extensive published literature describing its features, genetic origins, and optimal treatment strategies. These disorders are accompanied by a multitude of comorbidities, including cardiovascular issues, endocrinopathies, and infertility. Diagnostic delays, syndrome-associated comorbidities, and inefficient communication among the members of a patient\u27s health care team can affect a patient\u27s well-being from birth through adulthood. Insufficient information is available to help patients and their multidisciplinary team of providers transition from pediatric to adult health care systems. The aim of this review is to summarize the clinical features and genetics associated with each syndrome, describe best practices for diagnosis and treatment, and emphasize the importance of multidisciplinary teams and appropriate care plans for the pediatric to adult health care transition

Current controversies in turner syndrome: Genetic testing, assisted reproduction, and cardiovascular risks

Patients with Turner syndrome (TS) require close medical follow-up and management for cardiac abnormalities, growth and reproductive issues. This review summarizes current controversies in this condition, including: 1) the optimal genetic testing for Turner syndrome patients, particularly with respect to identification of Y chromosome material that may increase the patient's risk of gonadoblastoma and dysgerminoma, 2) which patients should be referred for bilateral gonadectomy and the recommended timing of such referral, 3) options for assisted reproduction in these patients and associated risks, 4) the increased risk of mortality associated with pregnancy in this population, and 5) how best to assess and monitor cardiovascular risks

Approach to the Patient: Safety of Growth Hormone Replacement in Children and Adolescents

The use of recombinant human growth hormone (rhGH) in children and adolescents has expanded since its initial approval to treat patients with severe GH deficiency (GHD) in 1985. rhGH is now approved to treat several conditions associated with poor growth and short stature. Recent studies have raised concerns that treatment during childhood may affect morbidity and mortality in adulthood, with specific controversies over cancer risk and cerebrovascular events. We will review 3 common referrals to a pediatric endocrinology clinic, followed by a summary of short- and long-term effects of rhGH beyond height outcomes. Methods to mitigate risk will be reviewed. Finally, this information will be applied to each clinical case, highlighting differences in counseling and clinical outcomes. rhGH therapy has been used for more than 3 decades. Data are largely reassuring, yet we still have much to learn about pharmaceutical approaches to growth in children and the lifelong effect of treatment

Cell-Free DNA Screening Positive for Monosomy X: Clinical Evaluation and Management of Suspected Maternal or Fetal Turner Syndrome

Initially provided as an alternate to evaluation of serum analytes and nuchal translucency for the evaluation of pregnancies at high-risk of Trisomy 21, cell-free DNA (cfDNA) screening for fetal aneuploidy, also referred to as non-invasive prenatal screening (NIPS), can now also screen for fetal sex chromosome anomalies (SCAs) such as monosomy X as early as 9 to 10 weeks of gestation. Early identification of Turner syndrome, a SCA resulting from the complete or partial absence of the second X chromosome, allows for medical interventions such as optimizing obstetrical outcomes, hormone replacement therapy, fertility protection and support as well improved neurocognitive outcomes. However, cfDNA screening for SCAs and monosomy X in particular is associated with high false positive rates and low positive predictive value. A cfDNA result positive for monosomy X may represent fetal TS, maternal TS, or confined placental mosaicism. A positive screen for monosomy X with discordant results of diagnostic fetal karyotype presents unique interpretation and management challenges due to potential implications for previously unrecognized maternal Turner syndrome (TS). . The current international consensus clinical practice guidelines for the care of individuals with TS throughout the lifespan do not specifically address management of individuals with a cfDNA screen positive for monosomy X. The objective of this manuscript is to provide context and expert-driven recommendations for maternal and/or fetal evaluation and management when cfDNA screening is positive for monosomy X. We highlight unique challenges of cfDNA screening that is incidentally positive for monosomy X, present recommendations for determining if the result is a true positive and discuss when diagnosis of TS is applicable to the fetus or the mother. While we defer the subsequent management of confirmed TS to the clinical practice guidelines, we highlight unique considerations for these individuals initially identified through cfDNA screening

Additional file 2: Table S2. of Peak cortisol response to corticotropin-releasing hormone is associated with age and body size in children referred for clinical testing: a retrospective review

Sub-analysis of interaction terms in multivariable models for delta cortisol. Description: Separate analysis of groups with significant interaction terms in multivariable models. This displays multivariable models of weight, BSA, and height for the group exposed to exogenous glucocorticoids only. (DOC 31 kb

Additional file 1: Table S1. of Peak cortisol response to corticotropin-releasing hormone is associated with age and body size in children referred for clinical testing: a retrospective review

Sub-analysis of interaction terms in multivariable models for peak cortisol. Description: Separate analysis of groups with significant interaction terms in multivariable models. This displays multivariable models of weight, BSA, and height for the group exposed to exogenous glucocorticoids only. (DOC 32 kb

Loss-of-function variants in endothelial lipase are a cause of elevated HDL cholesterol in humans

Elevated plasma concentrations of HDL cholesterol (HDL-C) are associated with protection from atherosclerotic cardiovascular disease. Animal models indicate that decreased expression of endothelial lipase (LIPG) is inversely associated with HDL-C levels, and genome-wide association studies have identified LIPG variants as being associated with HDL-C levels in humans. We hypothesized that loss-of-function mutations in LIPG may result in elevated HDL-C and therefore performed deep resequencing of LIPG exons in cases with elevated HDL-C levels and controls with decreased HDL-C levels. We identified a significant excess of nonsynonymous LIPG variants unique to cases with elevated HDL-C. In vitro lipase activity assays demonstrated that these variants significantly decreased endothelial lipase activity. In addition, a meta-analysis across 5 cohorts demonstrated that the low-frequency Asn396Ser variant is significantly associated with increased HDL-C, while the common Thr111Ile variant is not. Functional analysis confirmed that the Asn396Ser variant has significantly decreased lipase activity both in vitro and in vivo, while the Thr111Ile variant has normal lipase activity. Our results establish that loss-of-function mutations in LIPG lead to increased HDL-C levels and support the idea that inhibition of endothelial lipase may be an effective mechanism to raise HDL-C