Congenital adrenal hypoplasia and isolated gonadotropin deficiency

Congenital adrenal hypoplasia with gonadotropin deficiency is a rare X-linked recessive disorder that usually manifests with symptoms of adrenal insufficiency early in infancy. Adequate replacement therapy with glucocorticoids, mineralocorticoids, and salt has resulted in an increased survival. Slow growth and failure to undergo sexual maturation during the adolescent years usually ensues, secondary to hypogonadotropic hypogonadism. The X-linked congenital adrenal hypoplasia locus has been mapped to region Xp21.3-p21.2. Interstitial deletions of the X chromosome overlapping this region have been observed to cause complex clinical problems, with adrenal hypoplasia as a prominent component. Within a family segregating the disease, there is a 50% risk of having an affected male and a 50% risk of having a carrier female; considerations of genetic heterogeneity, possible chromosomal abnormalities, and prenatal diagnostic studies warrant medical genetic evaluations. The following case presentations illustrate the clinical spectrum of this condition.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29244/1/0000300.pd

Results of a Second Year of Therapy with the 12-Month Histrelin Implant for the Treatment of Central Precocious Puberty

Background. Gonadotropin releasing hormone analogs (GnRHas) are standard of care for central precocious puberty (CPP). The histrelin subcutaneous implant is safe and effective in the treatment of CPP for one year. Objective. The study evaluates a second year of therapy in children with CPP who received a new implant after one year of treatment. Methods. A prospective one-year study following an initial 12-month treatment period was conducted. Results. Thirty-one patients (29 girls) aged 7.7 ± 1.5 years received a second implant. Eighteen were naïve to GnRHa therapy at first implantation. Peak LH declined from 0.92 ± 0.58 mIU/mL at 12 months to 0.51 ± 0.33 mIU/mL at 24 months (P < .0001) in naïve subjects, and from 0.74 ± 0.50 mIU/mL at 12 months to 0.45 ± 0.35 mIU/mL at 24 months (P = .0081) in previously treated subjects. Predicted adult height increased by 5.1 cm at 24 months (P = .0001). Minor implant site reactions occurred in 61%, while minor difficulties with explantation occurred in 32.2% of subjects. Conclusion. The histrelin implant demonstrates profound hypothalamic-pituitary-gonadal axis suppression when a new implant is placed for a second year of treatment. Prospective follow-up of this therapeutic modality for the treatment of CPP is needed

Inherited germline TP53 mutation encodes a protein with an aberrant C-terminal motif in a case of pediatric adrenocortical tumor

Childhood adrenocortical tumor (ACT), a very rare malignancy, has an annual worldwide incidence of about 0.3 per million children younger than 15 years. The association between inherited germline mutations of the TP53 gene and an increased predisposition to ACT was described in the context of the Li-Fraumeni syndrome. In fact, about two-thirds of children with ACT have a TP53 mutation. However, less than 10% of pediatric ACT cases occur in Li-Fraumeni syndrome, suggesting that inherited low-penetrance TP53 mutations play an important role in pediatric adrenal cortex tumorigenesis. We identified a novel inherited germline TP53 mutation affecting the acceptor splice site at intron 10 in a child with an ACT and no family history of cancer. The lack of family history of cancer and previous information about the carcinogenic potential of the mutation led us to further characterize it. Bioinformatics analysis showed that the non-natural and highly hydrophobic C-terminal segment of the frame-shifted mutant p53 protein may disrupt its tumor suppressor function by causing misfolding and aggregation. Our findings highlight the clinical and genetic counseling dilemmas that arise when an inherited TP53 mutation is found in a child with ACT without relatives with Li-Fraumeni-component tumors

Community evaluation of glycoproteomics informatics solutions reveals high-performance search strategies for serum glycopeptide analysis

Glycoproteomics is a powerful yet analytically challenging research tool. Software packages aiding the interpretation of complex glycopeptide tandem mass spectra have appeared, but their relative performance remains untested. Conducted through the HUPO Human Glycoproteomics Initiative, this community study, comprising both developers and users of glycoproteomics software, evaluates solutions for system-wide glycopeptide analysis. The same mass spectrometrybased glycoproteomics datasets from human serum were shared with participants and the relative team performance for N- and O-glycopeptide data analysis was comprehensively established by orthogonal performance tests. Although the results were variable, several high-performance glycoproteomics informatics strategies were identified. Deep analysis of the data revealed key performance-associated search parameters and led to recommendations for improved 'high-coverage' and 'high-accuracy' glycoproteomics search solutions. This study concludes that diverse software packages for comprehensive glycopeptide data analysis exist, points to several high-performance search strategies and specifies key variables that will guide future software developments and assist informatics decision-making in glycoproteomics

A randomised controlled trial of compression therapies for the treatment of venous leg ulcers (VenUS 6) : study protocol for a pragmatic, multicentre, parallel group, three arm randomised controlled trial

Background Venous leg ulcer(s), are common, recurring, open wounds on the lower leg, resulting from diseased or damaged leg veins impairing blood flow. Wound healing is the primary treatment aim for venous leg ulceration, alongside management of pain, wound exudate and infection. Full (high) compression therapy delivering 40mmHg of pressure at the ankle is the recommended first line treatment for venous leg ulcers. There are several different forms of compression therapy available including wraps, two-layer hosiery, and two-layer or four-layer bandages. There is good evidence for the clinical and cost effectiveness of four-layer bandage and two-layer hosiery but more limited evidence for other treatments (two-layer bandage and compression wraps). Robust evidence is required to compare clinical and cost effectiveness of these and to investigate which is the best compression treatment for reducing time to healing of venous leg ulcers whilst offering value for money. VenUS 6 will therefore investigate the clinical and cost effectiveness of evidence-based compression, two-layer bandage and compression wraps for time to healing of venous leg ulcers. Methods VenUS 6 is a pragmatic, multi-centre, three arm, parallel group, randomised controlled trial. Adult patients with a venous leg ulcer will be randomised to receive 1) compression wraps, 2) two-layer bandage or 3) evidence-based compression (two-layer hosiery or four-layer bandage). Participants will followed up for between 4 and 12 months. The primary outcome will be time to healing (full epithelial cover in absence of a scab) in days since randomisation. Secondary outcomes will include key clinical events (e.g., healing of the reference leg; ulcer recurrence; ulcer/skin deterioration, amputation, admission/discharge, surgery to close/remove incompetent superficial veins, infection, or death), treatment changes, adherence and ease of use, ulcer related pain, health-related quality of life and resource use. Discussion VenUS 6 will provide robust evidence on the clinical and cost-effectiveness of the different forms of compression therapies for venous leg ulceration. VenUS 6 opened to recruitment in January 2021 and is currently recruiting across 30 participating centres. Clinical Trial Registry: ISRCTN 67321719 (https://doi.org/10.1186/ISRCTN67321719). Prospectively Registered: 14.09.202

Definitive characterization of CA 19-9 in resectable pancreatic cancer using a reference set of serum and plasma specimens

The validation of candidate biomarkers often is hampered by the lack of a reliable means of assessing and comparing performance. We present here a reference set of serum and plasma samples to facilitate the validation of biomarkers for resectable pancreatic cancer. The reference set includes a large cohort of stage I-II pancreatic cancer patients, recruited from 5 different institutions, and relevant control groups. We characterized the performance of the current best serological biomarker for pancreatic cancer, CA 19-9, using plasma samples from the reference set to provide a benchmark for future biomarker studies and to further our knowledge of CA 19-9 in early-stage pancreatic cancer and the control groups. CA 19-9 distinguished pancreatic cancers from the healthy and chronic pancreatitis groups with an average sensitivity and specificity of 70-74%, similar to previous studies using all stages of pancreatic cancer. Chronic pancreatitis patients did not show CA 19-9 elevations, but patients with benign biliary obstruction had elevations nearly as high as the cancer patients. We gained additional information about the biomarker by comparing two distinct assays. The two CA 9-9 assays agreed well in overall performance but diverged in measurements of individual samples, potentially due to subtle differences in antibody specificity as revealed by glycan array analysis. Thus, the reference set promises be a valuable resource for biomarker validation and comparison, and the CA 19-9 data presented here will be useful for benchmarking and for exploring relationships to CA 19-9