Expansions and contractions of the FMR1 CGG repeat in 5,508 transmissions of normal,intermediate, and premutation alleles

Instability of the FMR1 repeat, commonly observed in transmissions of premutation alleles (55–200 repeats), is influenced by the size of the repeat, its internal structure and the sex of the transmitting parent. We assessed these three factors in unstable transmissions of 14/3,335 normal (~5 to 44 repeats), 54/293 intermediate (45–54 repeats), and 1561/1,880 premutation alleles. While most unstable transmissions led to expansions, contractions to smaller repeats were observed in all size classes. For normal alleles, instability was more frequent in paternal transmissions and in alleles with long 3′ uninterrupted repeat lengths. For premutation alleles, contractions also occurred more often in paternal than maternal transmissions and the frequency of paternal contractions increased linearly with repeat size. All paternal premutation allele contractions were transmitted as premutation alleles, but maternal premutation allele contractions were transmitted as premutation, intermediate, or normal alleles. The eight losses of AGG interruptions in the FMR1 repeat occurred exclusively in contractions of maternal premutation alleles. We propose a refined model of FMR1 repeat progression from normal to premutation size and suggest that most normal alleles without AGG interruptions are derived from contractions of maternal premutation alleles.     

The changing face of reoperative parathyroidectomy: a single-centre comparison of 147 parathyroid reoperations

IntroductionReoperative parathyroidectomy for persistent and recurrent primary hyperparathyroidism is dependent on radiology. This study aimed to compare outcomes in reoperative parathyroidectomy at a single centre using a combination of traditional and newer imaging studies.Materials and methodsRetrospective case note review of all reoperative parathyroidectomies for persistent and recurrent primary hyperparathyroidism over five years (June 2014 to June 2019; group A). Imaging modalities used and their positive predictive value, complications and cure rates were compared with a published dataset spanning the preceding nine years (group B).ResultsFrom over 2000 parathyroidectomies, 147 were reoperations (101 in group A and 46 in group B). Age and sex ratios were similar (56 vs 62 years; 77% vs 72% female). Ultrasound use remains high and shows better positive predictive value (76% vs 57 %). 99mTc-sestamibi use has declined (79% vs 91%) but the positive predictive value has improved (74% vs 53%). 4DCT use has almost doubled (61% vs 37%) with better positive predictive value (88% vs 75%). 18F-fluorocholine positron emission tomography-computed tomography and ultrasound-guided fine-needle aspiration for parathyroid hormone are novel modalities only available for group A. Both carried a positive predictive value of 100%. Venous sampling with or without angiography use has decreased (35% vs 39%) but maintains a high positive predictive value (86% vs 91%). Cure rates were similar (96% vs 100%). Group A had 5% permanent hypoparathyroidism, 1% permanent vocal cord palsy and 1% haematoma requiring reoperation. No complications for group B.ConclusionOptimal imaging is key to good cure rates in reoperative parathyroidectomy. High-quality, non-interventional imaging techniques have produced a shift in the preoperative algorithm without compromising outcomes.     

Lung bullae and pulmonary fibrosis associated with marijuana smoking

A 26‐year‐old man with a history of heavy marijuana and minimal tobacco use was found to have extensive bilateral lung bullae and interstitial fibrosis, heavily infiltrated by pigmented macrophages. These features can be associated with marijuana smoking. The differential diagnoses in this patient are also discussed.     

Decreased Conversion of 25-hydroxyvitamin D3 to 24,25-dihydroxyvitamin D3 Following Cholecalciferol Therapy in Patients with CKD

Background and objectives

Elevated concentrations of fibroblast growth factor 23 (FGF23) are postulated to promote 25-hydroxyvitamin D (25[OH]D) insufficiency in CKD by stimulating 24-hydroxylation of this metabolite, leading to its subsequent degradation; however, prospective human studies testing this relationship are lacking.

Design, setting, participants, & measurements

An open-label prospective study was conducted from October 2010 through July 2012 to compare the effect of 8 weeks of oral cholecalciferol therapy (50,000 IU twice weekly) on the production of 24,25(OH)₂D₃ in vitamin D–insufficient patients with CKD (n=15) and controls with normal kidney function (n=15). Vitamin D metabolites were comprehensively profiled at baseline and after treatment, along with FGF23 and other mineral metabolism parameters.

Results

Vitamin D₃ and 25(OH)D₃ concentrations increased equivalently in the CKD and control groups following cholecalciferol treatment (median D₃ change, 8.6 ng/ml [interquartile range, 3.9–25.6 ng/ml] for controls versus 12.6 ng/ml [6.9–41.2 ng/ml] for CKD [P=0.15]; 25(OH)D₃ change, 39.2 ng/ml [30.9–47.2 ng/ml] for controls versus 39.9 ng/ml [31.5–44.1 ng/ml] for CKD [P=0.58]). Likewise, the absolute increase in 1α,25(OH)₂D₃ was similar between CKD participants and controls (change, 111.2 pg/ml [64.3–141.6 pg/ml] for controls versus 101.1 pg/ml [74.2–123.1 pg/ml] for CKD; P=0.38). Baseline and post-treatment 24,25(OH)₂D₃ concentrations were lower in the CKD group; moreover, the absolute increase in 24,25(OH)₂D₃ after therapy was markedly smaller in patients with CKD (change, 2.8 ng/ml [2.3–3.5 ng/ml] for controls versus 1.2 ng/ml [0.6–1.9 ng/ml] for patients with CKD; P<0.001). Furthermore, higher baseline FGF23 concentrations were associated with smaller increments in 24,25(OH)₂D₃ for individuals with CKD; this association was negated after adjustment for eGFR by multivariate analysis.

Conclusions

Patients with CKD exhibit an altered ability to increase serum 24,25(OH)₂D₃ after cholecalciferol therapy, suggesting decreased 24-hydroxylase activity in CKD. The observed relationship between baseline FGF23 and increments in 24,25(OH)₂D₃ further refutes the idea that FGF23 directly contributes to 25(OH)D insufficiency in CKD through stimulation of 24-hydroxylase activity.