| 11. |
- Vakkilainen, S, et al.
(författare)
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'Metaphyseal dysplasia without hypotrichosis' can present with late-onset extraskeletal manifestations
- 2020
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Ingår i: Journal of medical genetics. - : BMJ. - 1468-6244 .- 0022-2593. ; 57:1, s. 18-22
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Tidskriftsartikel (refereegranskat)abstract
- Metaphyseal dysplasia without hypotrichosis (MDWH) is a rare form of chondrodysplasia with no extraskeletal manifestations. MDWH is caused by RMRP mutations, but it is differentiated from the allelic condition cartilage-hair hypoplasia (CHH), which in addition to chondrodysplasia is characterised by thin hair, immunodeficiency and increased risk of malignancy. The long-term outcome of MDWH remains unknown.ObjectiveWe diagnosed severe agranulocytosis in a subject with RMRP mutations and normal hair. Based on this observation, we hypothesised that MDWH may, similar to CHH, associate with immune deficiency and malignancy.MethodsWe collected clinical and laboratory data for a cohort of 80 patients with RMRP mutations followed for over 30 years and analysed outcome data for those with features consistent with MDWH.ResultsIn our cohort, we identified 10 patients with skeletal but no extraskeletal features during preschool age. Eight of these patients developed malignancy or clinically significant immunodeficiency during follow-up. Two of them died during chemotherapy for malignancy. At the time of the first extraskeletal manifestation, patients were school aged, 20, 43 and 50 years old. Laboratory signs of immunodeficiency (impaired lymphocyte proliferative responses) were demonstrated in four patients before the onset of symptoms. The patient outside this cohort, who had RMRP mutations, skeletal dysplasia, normal hair and severe agranulocytosis at 18 years of age, underwent haematopoietic stem cell transplantation.ConclusionsMDWH can present with severe late-onset extraskeletal manifestations and thus should be reclassified and managed as CHH.
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| 12. |
- Yang, X, et al.
(författare)
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Prospective validation of the BOADICEA multifactorial breast cancer risk prediction model in a large prospective cohort study
- 2022
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Ingår i: Journal of medical genetics. - : BMJ. - 1468-6244 .- 0022-2593. ; 59:12, s. 1196-1205
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Tidskriftsartikel (refereegranskat)abstract
- The multifactorial Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) breast cancer risk prediction model has been recently extended to consider all established breast cancer risk factors. We assessed the clinical validity of the model in a large independent prospective cohort.MethodsWe validated BOADICEA (V.6) in the Swedish KARolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA) cohort including 66 415 women of European ancestry (median age 54 years, IQR 45–63; 816 incident breast cancers) without previous cancer diagnosis. We calculated 5-year risks on the basis of questionnaire-based risk factors, pedigree-structured first-degree family history, mammographic density (BI-RADS), a validated breast cancer polygenic risk score (PRS) based on 313-SNPs, and pathogenic variant status in 8 breast cancer susceptibility genes:BRCA1,BRCA2,PALB2,CHEK2,ATM,RAD51C,RAD51DandBARD1. Calibration was assessed by comparing observed and expected risks in deciles of predicted risk and the calibration slope. The discriminatory ability was assessed using the area under the curve (AUC).ResultsAmong the individual model components, the PRS contributed most to breast cancer risk stratification. BOADICEA was well calibrated in predicting the risks for low-risk and high-risk women when all, or subsets of risk factors are included in the risk prediction. Discrimination was maximised when all risk factors are considered (AUC=0.70, 95% CI: 0.66 to 0.73; expected-to-observed ratio=0.88, 95% CI: 0.75 to 1.04; calibration slope=0.97, 95% CI: 0.95 to 0.99). The full multifactorial model classified 3.6% women as high risk (5-year risk ≥3%) and 11.1% as very low risk (5-year risk <0.33%).ConclusionThe multifactorial BOADICEA model provides valid breast cancer risk predictions and a basis for personalised decision-making on disease prevention and screening.
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