Tebben, Peter

Abstract Hypophosphatasia (HPP) is characterized by defective bone mineralization due to reduced function of tissue-nonspecific alkaline phosphatase (TNSALP) caused by pathogenic ALPL gene variants. Hypercalcemia is more common in the perinatal and infantile forms and may be mitigated or prevented with enzyme replacement therapy asfotase alfa (AA). Here, we report a patient who developed severe hypercalcemia while receiving AA. Hypercalcemia was initially managed with intravenous fluids, dietary calcium restriction, and maximizing AA dose. Despite these measures, she required an additional hospital admission, at which time calcitonin 4 IU/kg every 12 hours was initiated. On this regimen, her calcium normalized without recurrence of severe hypercalcemia. Over the subsequent 8 months, restrictions of calcium intake were slowly lifted, and calcitonin was tapered and discontinued with maintenance of calcium within the normal range. This case underscores the significance of vigilant monitoring of calcium levels and dietary intake in infants diagnosed with HPP. While calcitonin is typically not considered as a sustained treatment for hypercalcemia, the present case illustrates the efficacy of adjunct calcitonin therapy, in conjunction with restricted calcium intake and maximum AA dosing, in managing severe hypercalcemia in an infant with perinatal HPP.

Abstract Context Tumor-induced osteomalacia (TIO), a paraneoplastic disorder characterized by renal phosphate wasting, is cured by surgical removal of the culprit tumor. Despite correct localization, some remain refractory to intervention, resulting in substantial long-term medical complications. Objective We aim to identify risk factors associated with a refractory outcome. Methods This is a retrospective cohort of 44 patients with TIO diagnosed from 1998 to 2023 who underwent targeted intervention following successfully localization. Cure was defined as maintenance of normophosphatemia without supplementation for ≥1 month, maintained at last follow-up. Results Twenty-nine patients achieved cure and 15 had a refractory outcome. On univariate Cox regression, the HR for predicting cure was 3.43 (95% CI 1.45-8.11, P = .005) for patients diagnosed after 2013 (compared to before), and that for a negative surgical tumor margin was 2.56 (95% CI 1.20-5.45, P = .015) compared to positive/unspecified margins. After adjustment for year of diagnosis, tumors originating from soft tissue (HR 2.72 vs bone, 95% CI 1.22-6.09, P = .015) or located outside the spine (HR 0.22 for spine vs nonspine, 95% CI 0.05-0.96, P = .043) had higher chances of cure. Size of tumor, age, gender, or baseline biochemistry including levels of fibroblast growth factor (FGF)23, phosphorus, 1,25-dihydroxyvitamin D, or alkaline phosphatase were not predictive of cure. Postprocedural FGF23 was the best biochemical marker of cure (area under curve 0.899, 95% CI 0.764-1.00, P < .001). Conclusion Tumors diagnosed within the past decade with clear resection margins had more favorable prognoses. With regards to tumoral factors, baseline biochemistry was uninformative in predicting cure, while bone and/or spine localizations were associated with a refractory outcome.

Abstract Objectives Plant-based milk alternatives are increasingly utilized in children with cow milk allergy, lactose intolerance, and personal preference. However, notable differences exist in mineral content between cow milk and plant-based alternatives. Almond milk, in particular, varies in mineral and caloric content across different brands. This case report highlights a toddler who developed hypercalcemia and hypophosphatemia attributed to almond milk consumption. Case presentation A fourteen-month-old girl with a history of biliary atresia underwent liver transplant at seven months of age. She was exclusively consuming almond milk for two months prior to presentation. She was admitted to the hospital for severe hypercalcemia (14.6 mg/dL) and hypophosphatemia (1.6 mg/dL). She had elevated random urine calcium to creatinine ratio (2.56 mg/g) and low urine phosphorus to creatinine ratio (<0.44 mg/g) were noted. Parathyroid hormone (PTH) level was appropriately suppressed (<6 pg/mL), while 1,25 dihydroxyvitamin D level was slightly elevated at 88 pg/mL. Initial management included intravenous fluids, followed by a switch to a formula with higher phosphorus and lower calcium concentrations. The patient was discharged after six days with normalized calcium and phosphorus levels, which remained within the normal range. Conclusions Although plant-derived milk serves as a viable alternative to cow milk, careful consideration of mineral content, particularly in infants and toddlers, is imperative. Sole reliance on almond milk for nutritional needs in this population is not recommended. Caregivers should be informed about the potential risks associated with almond milk consumption in infants and toddlers.

Abstract 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, 1,152 patients have been evaluated with an overall solve rate of 14.1% 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.

Abstract Context Pseudohypoparathyroidism type Ib (PHP1B) is characterized by hypocalcemia and hyperphosphatemia due to parathyroid hormone resistance in the proximal renal tubules. Maternal pathogenic STX16/GNAS variants leading to maternal epigenetic GNAS changes impair expression of the stimulatory G protein alpha-subunit (Gsα) thereby causing autosomal dominant PHP1B. In contrast, genetic defects responsible for sporadic PHP1B (sporPHP1B) remain mostly unknown. Objective Determine whether PHP1B encountered after in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) causes GNAS remethylation defects similar to those in sporPHP1B. Design Retrospective analysis. Results Nine among 36 sporPHP1B patients investigated since 2000, all with loss of methylation (LOM) at the 3 maternal GNAS differentially methylated regions (DMRs) and gain of methylation at the paternal NESP DMR, had been conceived through IVF or ICSI. Besides abnormal GNAS methylation, IVF/ICSI PHP1B cases revealed no additional imprinting defects. Three of these PHP1B patients have dizygotic twins, and 4 have IVF/ICSI-conceived siblings, all with normal GNAS methylation; 2 unaffected younger siblings were conceived naturally. Conclusion Sporadic and IVF/ICSI-conceived PHP1B patients revealed indistinguishable epigenetic changes at all 4 GNAS DMRs, thus suggesting a similar underlying disease mechanism. Given that remethylation at the 3 maternal DMRs occurs during oogenesis, male factors are unlikely to cause LOM postfertilization. Instead, at least some of the sporPHP1B variants could be caused by a defect or defects in an oocyte-expressed gene that is required for fertility and for re-establishing maternal GNAS methylation imprints. It remains uncertain, however, whether the lack of GNAS remethylation alone and the resulting reduction in Gsα expression is sufficient to impair oocyte maturation.

Abstract Context Maternally inherited STX16 deletions that cause loss of methylation at GNAS exon A/B and thereby reduce Gsα expression are the most frequent cause of autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP1B). Early identification of these disease-causing variants in the children of affected and unaffected female carriers would prompt treatment with calcium and calcitriol once parathyroid hormone (PTH) levels increase, thereby preventing hypocalcemia and associated complications. Objective This study aimed to determine when PTH and calcium abnormalities develop after birth if a STX16 deletion is inherited maternally. Methods Forty-four children of affected (n = 7) or unaffected (n = 7) females with a STX16 deletion were investigated for the presence of these variants. If a deletion was identified, measurement of PTH, calcium, phosphate, and thyrotropin (TSH) was advised. Results The STX16 deletion that causes AD-PHP1B was identified in 25 children. Pretreatment laboratory results were available for 19 of those cases. Elevated PTH levels were detected by 2 years of age, and these were progressively higher if laboratory testing was first performed after establishing the genetic defect later in life. Total serum calcium levels remained within normal limits until about 5 years of age. TSH levels showed no consistent rise over time. Conclusion Establishing whether a STX16 deletion is inherited from a female carrier of a disease-causing variant rapidly establishes the diagnosis of AD-PHP1B. Several years before overt hypocalcemia developed, PTH levels increased, thereby establishing the onset of PTH resistance. Our findings provide diagnostic guidance and when treatment with calcium and calcitriol should be considered in order to prevent hypocalcemia and associated sequelae.

AbstractCongenital nephrotic syndrome (CNS) is a complex condition that requires multidisciplinary care. Hyperlipidemia is a characteristic feature with elevation of serum cholesterol and triglycerides. Little evidence is available to guide treatment of dyslipidemia in infants with CNS. We describe successful treatment of severe hypertriglyceridemia through dietary changes in a boy with CNS. A 9‐day‐old boy presented to the emergency department with lower extremity edema caused by deep venous thrombosis. Laboratory evaluation identified hypoalbuminemia, nephrotic‐range proteinuria, and a pathogenic variant of the NPHS1 gene. The initial triglyceride concentration of 369 mg/dl increased to 3096 mg/dl by 5 weeks of age, when his diet consisted of breast milk. Refrigerated breast milk was skimmed by removing the top layer after allowing it to separate for 24 h. This process was repeated prior to use. Skimmed breast milk was supplemented with medium‐chain triglyceride oil and an infant protein powder. After 2 days, the triglyceride concentration declined to 481 mg/dl and, by day 10, to 148 mg/dl. When breast milk supply decreased, a 1:1 ratio of skimmed maternal breast milk to an elemental, very low‐fat formula was utilized. The triglyceride concentration remained below 400 mg/dl for the first year of life, except when skimmed breast milk was not available during hospitalization. Severe hypertriglyceridemia caused by CNS can present in the neonatal period and be difficult to manage. In our patient, skimmed maternal breast milk was successful in reducing the triglyceride concentration and should be considered a therapeutic option for children with hyperlipidemia caused by CNS.

AbstractContextCYP24A1 encodes 24-hydroxylase, which converts 25(OH)D3 and 1,25(OH)2D3 to inactive metabolites. Loss-of-function variants in CYP24A1 are associated with 24-hydroxylase deficiency (24HD), characterized by hypercalcemia, nephrolithiasis, and nephrocalcinosis. We retrospectively reviewed laboratory, imaging, and clinical characteristics of patients with suspected or confirmed 24HD and patients with other vitamin D−mediated hypercalcemia disorders: sarcoidosis, lymphoma, and exogenous vitamin D toxicity (EVT).ObjectiveTo identify features that differentiate 24HD from other vitamin D-mediated hypercalcemia disorders.MethodsPatients seen at the Mayo Clinic (Rochester, MN) from January 1, 2008, to 31 December, 2016, with the following criteria were retrospectively identified: serum calcium ≥9.6 mg/dL, parathyroid hormone &lt;30 pg/mL, and 1,25(OH)2D3 &gt;40 pg/mL. Patients were considered to have 24HD if they had (1) confirmed CYP24A1 gene variant or (2) 25(OH)D3:24,25(OH)2D ratio ≥50. Patients with sarcoidosis, lymphoma, and EVT were also identified. Groups were compared using the Fisher exact test (categorical variables) or the Wilcoxon rank sum test (continuous variables).ResultsWe identified 9 patients with 24HD and 28 with other vitamin D−mediated disorders. Patients with 24HD were younger at symptom onset (median 14 vs 63 years; P = .001) and had positive family history (88.9% vs 20.8%; P &lt; .001), nephrocalcinosis (88.9% vs 6.3%; P &lt; .001), lower lumbar spine Z-scores (median −0.50 vs 1.20; P = .01), higher peak serum phosphorus (% of peak reference range, median 107 vs 84; P = .01), and higher urinary calcium:creatinine ratios (median 0.24 vs 0.17; P = .047).ConclusionPatients with 24HD had clinical and laboratory findings that differed from other vitamin D−mediated hypercalcemia disorders. 24HD should be suspected in patients with hypercalcemia who present at younger age, have positive family history, and have nephrocalcinosis.

AbstractBackgroundWe sought to evaluate the association between vitamin D deficiency and the severity of coronavirus disease 2019 (COVID‐19) infection.MethodsMultiple databases from 1 January 2019 to 3 December 2020 were searched for observational studies evaluating the association between vitamin D deficiency and severity of COVID‐19 infection. Independent reviewers selected studies and extracted data for the review. The main outcomes of interest were mortality, hospital admission, length of hospital stay and intensive care unit admission.ResultsSeventeen observational studies with 2756 patients were included in the analyses. Vitamin D deficiency was associated with significantly higher mortality (odds ratio [OR]: 2.47, 95% confidence interval [CI]: 1.50–4.05; 12 studies; hazard ratio [HR]: 4.11, 95% CI: 2.40–7.04; 3 studies), higher rates of hospital admissions (OR: 2.18, 95% CI: 1.48–3.21; 3 studies) and longer hospital stays (0.52 days; 95% CI: 0.25–0.80; 2 studies) as compared to nonvitamin D deficient status. Subgroup analyses based on different cut‐offs for defining vitamin D deficiency, study geographic locations and latitude also showed similar trends.ConclusionsVitamin D deficiency is associated with greater severity of COVID‐19 infection. Further studies are warranted to determine if vitamin D supplementation can decrease the severity of COVID‐19.

Abstract Context Hypoparathyroidism is characterized by low serum calcium, increased serum phosphorus, and inappropriately low or decreased serum parathyroid hormone, which may be associated with soft tissue calcification in the basal ganglia of the brain. Objective To assess the prevalence and factors involved in the pathophysiology of basal ganglia calcification (BGC) in the brain in chronic hypoparathyroidism and to evaluate proposed pathophysiologic mechanisms. Design Case-control study with retrospective review of medical records over 20 years. Setting Single academic medical center. Patients 142 patients with chronic hypoparathyroidism and computed tomography (CT) head scans followed between January 1, 2000 and July 9, 2020, and 426 age- and sex-matched controls with CT head scans over the same interval. Interventions None. Main Outcome Measures Demographic, biochemical, and CT head imaging findings, with semiquantitative assessment of volumetric BGC. Results The study found that 25.4% of 142 patients followed for a median of 17 years after diagnosis of chronic hypoparathyroidism had BGC, which developed at a younger age than in controls. BGC was 5.1-fold more common in nonsurgical patients and less common in postsurgical patients. Low serum calcium and low calcium/phosphate ratio correlated with BGC. Neither serum phosphorus nor calcium × phosphate product predicted BGC. Lower serum calcium was associated with greater volume of BGC. The extent of BGC varied widely, with nonsurgical patients generally having a greater volume and distribution of calcification. Conclusions BGC is associated with low serum calcium and low serum calcium/phosphate ratio, which may be related to severity of the disease, its etiology, or duration of treatment.