Implementation of genomic medicine for rare disease in a tertiary healthcare system: Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD).

BACKGROUND: In the United States, rare disease (RD) is defined as a condition that affects fewer than 200,000 individuals. Collectively, RD affects an estimated 30 million Americans. A significant portion of RD has an underlying genetic cause; however, this may go undiagnosed. To better serve these patients, the Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD) was created under the auspices of the Center for Individualized Medicine (CIM) aiming to integrate genomics into subspecialty practice including targeted genetic testing, research, and education. METHODS: Patients were identified by subspecialty healthcare providers from 11 clinical divisions/departments. Targeted multi-gene panels or custom exome/genome-based panels were utilized. To support the goals of PRaUD, a new clinical service model, the Genetic Testing and Counseling (GTAC) unit, was established to improve access and increase efficiency for genetic test facilitation. The GTAC unit includes genetic counselors, genetic counseling assistants, genetic nurses, and a medical geneticist. Patients receive abbreviated point-of-care genetic counseling and testing through a partnership with subspecialty providers. RESULTS: Implementation of PRaUD began in 2018 and GTAC unit launched in 2020 to support program expansion. Currently, 29 RD clinical indications are included in 11 specialty divisions/departments with over 142 referring providers. To date, 1152 patients have been evaluated with an overall solved or likely solved rate of 17.5% and as high as 66.7% depending on the phenotype. Noteworthy, 42.7% of the solved or likely solved patients underwent changes in medical management and outcome based on genetic test results. CONCLUSION: Implementation of PRaUD and GTAC have enabled subspecialty practices advance expertise in RD where genetic counselors have not historically been embedded in practice. Democratizing access to genetic testing and counseling can broaden the reach of patients with RD and increase the diagnostic yield of such indications leading to better medical management as well as expanding research opportunities.

Evaluation of Factors Associated With Fracture and Loss of Bone Mineral Density Within 1 Year After Liver Transplantation.

OBJECTIVE: Orthotopic liver transplant recipients are at high risk of fragility fractures both in pre-liver transplant (pre-LT) and in the immediate posttransplant (post-LT) period. The aims of this study were to identify risk factors associated with post-LT fracture and identify factors that contribute to changes in bone mineral density (BMD) in post-LT as they relate to the risk of fracture in the immediate post-LT period. METHODS: We conducted a retrospective cohort study of first-time LT recipients who had BMD testing within 2-year pre-LT and 1-year post-LT. We assessed factors associated with immediate post-LT fracture using logistic regression models and linear regression models. RESULTS: New fractures occurred in 41/286 (14.3%) of LT recipients during the first year following LT. In multivariate analysis, we noted an increased odds of fracture for patients with prior history of fracture (P < .001), patients who were older (P = .03), patients with higher end-stage liver disease score (P = .03), and patients with lower BMD. After adjustment for multiple testing, only a history of prior fracture was statistically significant. CONCLUSION: Our study demonstrated that prior fracture at any site was associated with developing a new fracture in the first year post-LT.

HYPOPHOSPHATASIA: CLINICAL ASSESSMENT AND MANAGEMENT IN THE ADULT PATIENT-A NARRATIVE REVIEW.

OBJECTIVE: To review literature and present a schematic approach to hypophosphatasia (HPP) evaluation and management applicable to practicing physicians to ease its recognition and diagnosis. METHODS: Studies were obtained from online databases PubMed and MEDLINE using keyword 'hypophosphatasia.' RESULTS: HPP is a rare disease characterized by low serum alkaline phosphatase along with diverse musculoskeletal symptoms that mimic different disorders. To date, the prevalence of HPP and its impact on adults has been unrecognized. There is lack of evidence from larger and long-term studies examining the adult type of this condition. CONCLUSION: It is essential to increase awareness on the complexity of the pathophysiology and clinical features of HPP, which causes debilitating physical conditions that severely affects quality of life. A better comprehension of adult forms of HPP is essential to reduce a delay in diagnosis as well as ensure suitable management. ABBREVIATIONS: ALP = alkaline phosphatase; HPP = hypophosphatasia; PEA = phosphorethanolamine; PLP = pyridoxal-5-phosphate; PPi = inorganic pyrophosphate; TNSALP/TNAP = tissue-nonspecific alkaline phosphatase.

Review of Hypoparathyroidism.

Hypoparathyroidism is a rare endocrine disorder in which parathyroid hormone (PTH) production is abnormally low or absent, resulting in low serum calcium and increased serum phosphorus. The most common cause of hypoparathyroidism is parathyroid gland injury or inadvertent removal during thyroid surgery. Current treatments include supplementation with calcium and active vitamin D, with goal albumin-corrected serum calcium level in the low-normal range of 8-9 mg/dl. Complications of the disease include renal dysfunction, nephrocalcinosis, kidney stones, extracellular calcifications of the basal ganglia, and posterior subcapsular cataracts, as well as low bone turnover and increased bone density. Until January 2015, hypoparathyroidism was the only classic endocrine disease without an available hormone replacement. Recombinant human PTH 1-84, full-length PTH, is now available for a selected group of patients with the disease who are not well controlled on the current standard therapy of calcium and active vitamin D. In addition, the role of PTH replacement on quality of life, intracerebral calcifications, cataracts, improving bone turnover, and reduction of renal complications of the disease remains to be further investigated.

Effect of Clothing on Measurement of Bone Mineral Density.

It is unknown whether allowing patients to have BMD (bone mineral density) studies acquired while wearing radiolucent clothing adlib contributes appreciably to the measurement error seen. To examine this question, a spine phantom was scanned 30 times without any clothing, while draped with a gown, and while draped with heavy winter clothing. The effect on mean BMD and on SD (standard deviation) was assessed. The effect of clothing on mean or SD of the area was not significant. The effect of clothing on mean and SD for BMD was small but significant and was around 1.6% for the mean. However, the effect on BMD precision was much more clinically important. Without clothing the spine phantom had an least significant change of 0.0077 gm/cm(2), while when introducing variability of clothing the least significant change rose as high as 0.0305 gm/cm(2). We conclude that, adding clothing to the spine phantom had a small but statistically significant effect on the mean BMD and on variance of the measurement. It is unlikely that the effect on mean BMD has any clinical significance, but the effect on the reproducibility (precision) of the result is likely clinically significant.

Utility of Reviewing Radiology Studies in Electronic Medical Records When Preparing Bone Mineral Density Reports.

We quantitated how often review of recent radiology studies provides information useful to the densitometrist. While preparing bone mineral density (BMD) reports on 1012 consecutive patients, radiology reports in electronic medical records (EMRs) for the previous 5 years at potentially relevant sites (lumbar spine X-rays, abdominal computed tomography (CT) scans, and so forth) were reviewed. When a study was found, it received a grade according to how relevant findings were to the BMD report: "1" for studies that were irrelevant, "2" for those that confirmed the impression formed from review of the BMD images, "3" for those that clarified the impression that was unclear after reviewing the BMD images, and "4" for those that revealed new relevant data when no abnormality was noted on review of the BMD images. A total of 562 patients (55.5%) had a radiologic study at a site of potential interest within the past 5 years. Fifty-three patients (5.2% of all patients) had a grade 4 study, 88 patients (8.7% of all patients) had a grade 3 study, and 185 patients (18.3% of all patients) had a grade 2 study. Two hundred sixty-four patients (25.8%) had a grade 2 or 3 study, and 299 (29.5%) had a grade 2-4 study. The radiographic study that was most likely to be found in patients' EMR was chest X-ray (34.7% of all patients), but it was also the one that was least likely to have any relevance to the reader; only 10.5% of the total chest X-rays were graded 2-4. The next most likely studies to be found in patients' EMR were abdominal CT scans (18.0% of all patients) and lumbar spine X-rays (14.4% of all patients), but these studies were much more likely to be useful to the reader, as 62.6% of abdominal CT scans and 78.1% of lumbar spine X-rays were graded 2-4. The likelihood of a patient having radiologic examinations in the EMR at sites potentially relevant to the BMD reader is high, but the likelihood that these clarify abnormalities noted on BMD is only moderate. Review of the EMR is unlikely to be relevant when the dual-energy X-ray absorptiometry images are normal.

Tumor induced osteomalacia secondary to anaplastic thyroid carcinoma: A case report and review of the literature.

CONTEXT: Tumor induced osteomalacia related to anaplastic thyroid cancer has never been reported. OBJECTIVE: We describe a case of tumor induced osteomalacia (TIO) in a patient with a fibroblast growth factor 23 (FGF-23) secreting anaplastic thyroid carcinoma. The current imaging modalities are reviewed. DESIGN AND INTERVENTION: Clinical, biochemical, and radiological assessments were done, including computer tomography (CT) of the neck and skull to thigh positron emission tomography (PET)/CT. The patient underwent surgical tumor debulking three days after presentation due to airway compromise. Molecular studies of the resected tissue were performed using reverse transcriptase-polymerase chain reaction (RT-PCR) and gel electrophoresis for the phosphaturic mesenchymal tumor FGF-23. RESULTS: Resected tissue demonstrated features of anaplastic thyroid cancer with positive markers for FGF-23 protein, consistent with a FGF-23 secreting paraneoplastic tumor. The patient's metastatic burden rapidly progressed as demonstrated by a dramatic rise in serum FGF-23 levels and worsening hypophosphatemia in concert with progression of the metastatic lesions on PET/CT. CONCLUSION: We believe that our patient's rapidly progressive anaplastic thyroid cancer was responsible for persistent hypophosphatemia and osteomalacia, substantiated by the finding of FGF-23 protein within the thyroid tumor cells. Our case indicates that anaplastic thyroid cancer can cause TIO.

Managing anaplastic thyroid carcinoma.

Anaplastic thyroid cancer is one of the most lethal malignancies, with dismal prognosis, resistance to multimodal treatments and a median survival of only 5-6 months. Advances in the discovery of genetic pathway aberrations involved in this aggressive disease have been made, and multiple novel therapies targeting these pathways are undergoing clinical trials. So far, there is no single effective treatment for this disease; however, multimodal therapies with a combination of surgery, radiation and chemotherapy hold some promise. We conducted a PubMed search using the words thyroid neoplasm, anaplastic thyroid carcinoma, anaplastic thyroid cancer and anaplastic thyroid neoplasm, revealing 1673 publications. We review the pathophysiology, current treatments and advances made in identifying the alterations in genetic pathways, as well as novel therapies targeting these pathways.