No abstract

Context:PAPSS2 (PAPS synthase 2) provides the universal sulfate donor PAPS (3′-phospho-adenosine-5′-phosphosulfate) to all human sulfotransferases, including SULT2A1, responsible for sulfation of the crucial androgen precursor dehydroepiandrosterone (DHEA). Impaired DHEA sulfation is thought to increase the conversion of DHEA toward active androgens, a proposition supported by the previous report of a girl with inactivating PAPSS2 mutations who presented with low serum DHEA sulfate and androgen excess, clinically manifesting with premature pubarche and early-onset polycystic ovary syndrome.Patients and Methods:We investigated a family harboring two novel PAPSS2 mutations, including two compound heterozygous brothers presenting with disproportionate short stature, low serum DHEA sulfate, but normal serum androgens. Patients and parents underwent a DHEA challenge test comprising frequent blood sampling and urine collection before and after 100 mg DHEA orally, with subsequent analysis of DHEA sulfation and androgen metabolism by mass spectrometry. The functional impact of the mutations was investigated in silico and in vitro.Results:We identified a novel PAPSS2 frameshift mutation, c.1371del, p.W462Cfs*3, resulting in complete disruption, and a novel missense mutation, c.809G>A, p.G270D, causing partial disruption of DHEA sulfation. Both patients and their mother, who was heterozygous for p.W462Cfs*3, showed increased 5α-reductase activity at baseline and significantly increased production of active androgens after DHEA intake. The mother had a history of oligomenorrhea and chronic anovulation that required clomiphene for ovulation induction.Conclusions:We provide direct in vivo evidence for the significant functional impact of mutant PAPSS2 on DHEA sulfation and androgen activation. Heterozygosity for PAPSS2 mutations can be associated with a phenotype resembling polycystic ovary syndrome.

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Background. It can be a diagnostic challenge to identify COVID-19 patients without bacterial co-infection in whom antibiotics can be safely stopped. We sought to evaluate the validity of a guideline that recommends withholding antibiotics in patients with a low serum procalcitonin (PCT). Methods. We retrospectively collected 28-day outcome data on patients admitted to Sheffield Teaching Hospitals NHS Foundation Trust, UK, between 5 March and 15 April 2020, with a positive SARS-CoV-2 polymerase chain reaction (PCR) and PCT within 48 hours of diagnosis. PCT was considered negative if ≤0.25ng/ml and positive if >0.25ng/ml. Primary outcomes included antibiotic consumption, mortality, intensive care admission and length of hospital stay. Results. 368 patients met the inclusion criteria; 218 (59%) had a negative PCT and 150 (41%) positive. At 48 hours post-diagnosis, 73 (33%) of those with a negative PCT were receiving antimicrobials compared to 126 (84%) with a positive PCT (p<0.001), with a corresponding reduction in antimicrobial usage over 28 days (median DDD of 3.0 vs 6.8 (p<0.001); median DOT 2 vs 5 days (p<0.001) between the negative and positive PCT groups.) In the negative PCT group, there were fewer deaths (62 (28%) vs. 54 (36%), (p=0.021)) and critical care admissions (19 (9%) vs. 28 (19%), (p=0.007)) than in the positive PCT group. Median length of hospital stay was 8.7 and 9 days in the negative and positive PCT groups respectively. Conclusions. Procalcitonin is a valuable tool in the assessment of patients with SARS-CoV-2 infection, safely reducing the potential burden of unnecessary antibiotic usage.

Cellular sulfation pathways rely on the activated sulfate 3′-phosphoadenosine-5′-phosphosulfate (PAPS). In humans, PAPS is exclusively provided by the two PAPS synthases PAPSS1 and PAPSS2. Mutations found in the PAPSS2 gene result in severe disease states such as bone dysplasia, androgen excess and polycystic ovary syndrome. The APS kinase domain of PAPSS2 catalyzes the rate-limiting step in PAPS biosynthesis. In this study, we show that clinically described disease mutations located in the naturally fragile APS kinase domain are associated either with its destabilization and aggregation or its deactivation. Our findings provide novel insights into possible molecular mechanisms that could give rise to disease phenotypes associated with sulfation pathway genes.